Anatomical Substrates of Hypothalamic Integration

C H A P T E R

14 Anatomical Substrates of Hypothalamic Integration RICHARD B. SIMERLY Division of Neuroscience, Oregon National Primate Research Center Oregon Health & Sciences University, Beaverton, Oregon, USA

The primary biological imperatives imposed on an organism are to first ensure its survival and second to propagate its species. To satisfy these imperatives an animal must coordinate complex physiological processes with diverse environmental conditions and elaborate appropriate adaptive responses to specific sensory cues. Thus, the maintenance of homeostasis represents a key component of biological adaptation and depends upon the successful integration of endocrine, visceral, and somatomotor control mechanisms. An extensive body of literature supports an important role for the hypothalamus in mediating this integration and the hypothalamus is generally viewed as an essential interface between the endocrine, autonomic, and somatomotor systems. In mammals the hypothalamus has been shown to regulate the cardiovascular system, the thermoregulatory responses, and the abdominal viscera, as well as defensive–aggressive behavior and ingestive behaviors that provide nutrients and water. In addition, the hypothalamus plays an essential role in assuring the survival of the species by controlling the expression of sexual and maternal behaviors. Of fundamental importance to the function of the hypothalamus is its intimate relationship with the pituitary gland and the now clearly established pathways for neural control of endocrine secretion patterns (Harris, 1948; Sawyer, 1978; Swanson, 1986). In addition, the hypothalamus has extensive connections with the major ascending and descending fiber systems that allow it to sample and influence activity in all major parts of the brain and spinal cord. Thus,

The Rat Nervous System, Third Edition

the unique relationship between the hypothalamus and the pituitary gland, together with its position in the neuraxis, make the hypothalamus the logical neurological substrate for the integration of diverse and dynamic environmental cues with the biological requirements of the individual. Although several interesting and insightful hypotheses have been advanced to explain hypothalamic function (Stellar, 1954; Szentágothai et al., 1962; Valenstein et al., 1969; Morgane, 1979), only recently has the relationship between form and function begun to be elucidated. This is due, at least in part, to the fact that cell groups in the hypothalamus are not clearly differentiated and the region is traversed by diffuse fiber systems that rank among the most complex fiber systems of the nervous system. Nevertheless, work carried out with modern neuroanatomical methods has yielded new insight into the organization of the hypothalamus and suggests that functionally distinct neural systems can be identified and studied in great detail (Swanson, 1999). This chapter presents an overview of hypothalamic anatomy and attempts to illustrate some of the ways in which functional integration is accomplished. Space does not allow for a complete description of the connections and neurochemistry of the hypothalamus, but interested readers may consult excellent reviews of these subjects by Nauta and Haymaker (1969), Palkovits and Zaborszky (1979), Zaborszky (1982), Hoffman et al. (1986), Silverman and Pickard (1983), Swanson (1986, 1987), Markakis and Swanson (1997).

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MORPHOLOGICAL ORGANIZATION OF THE HYPOTHALAMUS The hypothalamus occupies the ventral half of the diencephalon on both sides of the third ventricle and lies immediately above the pituitary gland. Dorsally, the hypothalamus is bounded along most of its length by the zona incerta, and the medial edge of the cerebral peduncle corresponds to its lateral border. Caudally, the hypothalamus merges with the periaqueductal gray and ventral tegmental area of the midbrain. The preoptic region represents the rostral-most part of the hypothalamus and is bordered dorsally by the anterior commissure and anteroventrally by the nucleus of the diagonal band of Broca. The medial preoptic area does not extend beyond the lamina terminalis, but the lateral preoptic area (see below) appears to extend medially, where it replaces the medial preoptic area at rostral levels (Simerly and Swanson, 1988). The hypothalamic parcellation scheme adopted for the third edition of The Rat Nervous System is that described in detail by Swanson (1987, 1998) and is based on the work of Gurdjian (1927) and Krieg (1932). This nomenclature and organizational scheme is the most commonly used and in general is supported by neurochemical and hodological studies. Reference to other interpretations of hypothalamic anatomy and nomenclature can be found in the work of Diepen (1962) and Bleier et al. (1979, 1985). Crosby and Woodburne (1940) recognized that the hypothalamus is best regarded as three distinct longitudinal zones (periventricular, medial, and lateral) and this perspective is supported by physiological and behavioral analyses (Swanson, 1987). The periventricular zone contains most of the neurons that project to the pituitary and is therefore primarily involved in regulating secretion of hormones from this gland. The medial zone of the hypothalamus consists of a rostrocaudally organized series of distinct cell groups that receive their major inputs from various parts of the limbic region of the telencephalon such as the septum and the amygdala. Neurons located in the lateral zone of the hypothalamus are scattered among the fibers of the medial forebrain bundle and can be viewed as a bed nucleus for this complex fiber system. Based on the organization of cell groups in the medial zone, Le Gros Clark (1938) divided the hypothalamus into four rostrocaudal levels designated the preoptic, supraoptic (replaced here by the more common term anterior), tuberal, and mammillary regions. The superposition of LeGros Clark’s regions onto Crosby and Woodburne’s zones divides the hypothalamus into 12 compartments that contain all of the recognized hypothalamic nuclei (Fig. 1). Although this

general organizational plan remains a useful framework for understanding the functional organization of the hypothalamus, certain exceptions and modifications are suggested by recent anatomical data (Swanson, 2000).

Periventricular Zone The hypothalamus represents the final common pathway for the neural control of the anterior, intermediate, and posterior lobes of the pituitary gland and most of the neurons that contain hormone-releasing hormones reside in the periventricular zone (Swanson, 1986; Markakis and Swanson, 1997). Two notable exceptions to this organizational plan are the supraoptic and accessory supraoptic nuclei, which consist of magnocellular cells that during development migrate away from the periventricular zone, and gonadotropinreleasing hormone neurons, which are derived from the olfactory epithelium and migrate to the septal and preoptic regions of the forebrain. By analogy with the motor neurons in the spinal cord, these neuroendocrine neurons have been referred to as “the motoneurons of the neuroendocrine system,” since these cells are the effector units of the neuroendocrine hypothalamus in a way similar (to the way that the) motor neurons are the effector units of neuromuscular pathways (Swanson, 1986; Swanson et al., 1987). In addition, the periventricular zone contains other cell groups that are intimately connected to the neuroendocrine cells and thereby play important roles in controlling neuroendocrine secretion. Cytoarchitectonically the periventricular zone is characterized by small, vertically oriented fusiform neurons and is traversed by a complex array of ascending and descending fibers that are part of the periventricular system connecting the periventricular zone of the hypothalamus with the midline thalamus and the midbrain periaqueductal gray (Sutin, 1966; Nauta and Haymaker, 1969). The periventricular zone is composed of the four periventricular nuclei (preoptic, anterior, intermediate (or tuberal), and posterior) and six other distinct cell groups that represent differentiated parts of this zone. Swanson (2000) has recently proposed that a hypothalamic periventricular region should also be recognized that consists of neurons in the periventricular zone that do not project to the median eminence (are not neuroendocrine) and the diffusely organized parts of the medial zone (those neurons not included in the large nuclei). Although such a region is hard to conceptualize in purely anatomical terms, the proposal that neurons in this region constitute a visceromotor pattern generator network represents a potentially important functional notion that deserves experimental attention.

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Regions Preoptic

Anterior

Tuberal

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Mammillary MCLH

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Lateral

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PD

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DMH AH

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TU PHA PMV

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Areas and Nuclei Periventricular zone Preoptic periventricular n. (PePO) Vascular organ of the lamina terminalis (vo) Median preoptic n. (MnPO) Anteroventral periventricular n. (AVPV) Suprachiasmatic preoptic n. (PSCh)

Medial zone Medial preoptic a. (MPA) Medial preoptic n. (MPO) Anterodorsal preoptic n. (AD) Anteroventral preoptic n. (AV) Parastrial n. (PS) Posterodorsal preoptic n. (PD)

Lateral zone Lateral preoptic a. (LPO) Magnocellular preoptic n. (MCPO)

Periventricular zone Anterior periventricular n. (PeA) Suprachiasmatic n. (SCh) Paraventricular n. (Pa)

Medial zone Anterior hypothalamic a. (AHA) Anterior hypothalamic n. (AH) Retrochiasmatic area (RCh) Nucleus circularis (NC)*

Lateral zone Lateral Hypothalamic a. (LH) Supraoptic n. (SO)*

Periventricular zone Tuberal periventricular n. (PeI) Arcuate n. (Arc)

Medial zone Tuberal a. (TA) Ventromedial n. (VMH) Dorsomedial n. (DMH)

Lateral zone Lateral hypothalamic a. (LH) Tuberal n. (TU)

Periventricular zone Posterior periventricular n. (PeP) Dorsal tuberomammillary n. (TMD)**

Medial zone Dorsal premammillary n. (PMD) Ventral premammillary n. (PMV) Mammillary complex medial mammillary n. (MM) lateral mammillary n. (LM) supramammillary n. (SuM) Posterior hypothalamic area

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MPO AD AV MnPO PSCh PeriPePO ventricular vo AVPV

SO AHA NC

Lateral zone Lateral hypothalamic area (LH) Magnocellular n. of LHA Ventral tuberomammillary n. (TMV)

FIGURE 1 Organization of the hypothalamus. A highly schematic representation of the morphological organization of the hypothalamus to show a simplified view of its zones, regions, areas, and nuclei. Abbreviations used: a, area; n, nucleus. Notes: *The supraoptic n. and n. circularis are best considered a displaced part of the periventricular zone. **Despite the location of the TMD in the periventricular zone, the connections and presumed function of both parts of the tuberomammillary n. are more closely related to the lateral zone.

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Preoptic Region In addition to the periventricular preoptic nucleus (PePO) the preoptic part of the periventricular zone contains three identifiable cell groups. The median preoptic nucleus (MnPO) is a dense cluster of small cells in the lamina terminalis that extends along the anterior border of the third ventricle from the tip of the preoptic recess of the third ventricle dorsocaudally to a small triangular area between the descending columns of the fornix (Atlas plates 18–20). The MnPO plays a critical role in neural circuits controlling cardiovascular responses and fluid homeostasis (Saper and Levisohn, 1983; Saper, 2003). Consistent with this role it receives strong inputs from the subfornical organ and the parabrachial nucleus (Lind et al., 1982; Saper and Levisohn, 1983; Fulwiler and Saper, 1984; Lind, 1987; Bester et al., 1997) and sends projections to the paraventricular nucleus and magnocellular cell groups, as well as to the dorsomedial hypothalamic nucleus (Gu and Simerly, 1997; Thompson and Swanson, 1998). The anteroventral periventricular nucleus (AVPV) occupies a ventral position in the periventricular zone of the preoptic region and is located immediately caudal to the vascular organ of the lamina terminalis. This oval cluster of densely packed, darkly stained neurons is readily distinguishable from the periventricular preoptic nucleus, which lies immediately caudal and dorsal to the AVPV, and is limited laterally by a cell-sparse region that separates the AVPV from the anteroventral preoptic nucleus (Atlas plates 19 and 20). Ventrally the AVPV is separated from the optic chiasm by the suprachiasmatic preoptic nucleus (PSCh), which consists of obliquely oriented fusiform cells also known as the ventromedial preoptic nucleus (Paxinos and Watson, 1998). The morphology of the AVPV and PSCh were first defined by Bleier et al. (1979, 1985) who referred to them as dorsal and ventral subdivisions of the “medial preoptic nucleus,” a term that is generally used to describe the major preoptic nucleus of the medial zone (Gurdjian, 1927; Christ, 1969; Simerly et al., 1984b). This discrepancy in nomenclature derives from different interpretations of Gurdjian’s description of preoptic nuclei (Gurdjian, 1927; see Simerly, 1995a, for review). However, on the basis of cytoarchitectonic (Simerly et al., 1984b), neurochemical (Simerly et al., 1985; Simerly and Swanson, 1987; Simerly, 1989; Herbison, 1992), connectional (Simerly and Swanson, 1988; Gu and Simerly, 1997; Simerly, 1998), and functional grounds (Wiegand and Terasawa, 1982; Herbison, 1998; Le et al., 1999), the AVPV and PSCh are clearly part of the periventricular zone of the hypothalamus. The AVPV has also been included in a region called the “nucleus preopticus,

pars suprachiasmatica” (König and Klippel, 1963), and in a region termed the “AV3V” region, which is defined functionally on the basis of its involvement in the regulation of fluid and electrolyte metabolism (Saper and Levisohn, 1983; Lind and Ganten, 1990; Saper, 2003). The afferents of the AVPV have not been mapped in detail, but results of retrograde (Wiegand and Price, 1980; Wiegand, 1984; Simerly, 1998) and anterograde tracing studies (Simerly and Swanson, 1988; Gu and Simerly, 1997) support its proposed functional role as a nodal point in neural circuitry controlling gonadotropin secretion (Wiegand and Terasawa, 1982). Of primary importance are the strong inputs from the posterior and medial nuclei of the amygdala and from the principal nucleus of the bed nuclei of the stria terminalis (Simerly et al., 1989; Canteras et al., 1992a; Hutton et al., 1998), which presumably convey olfactory information (Halpern, 1987; Segovia and Guillamön, 1993; Guillamon and Segovia, 1996). The AVPV also receives a strong input from the ventral part of the lateral septal nucleus, which relays multimodal information from the hippocampal formation to periventricular and medial parts of the hypothalamus (Risold and Swanson, 1996, 1997b; Risold, 2003). The AVPV is heavily innervated by all parts of the periventricular zone of the hypothalamus, the medial preoptic nucleus, and the dorsomedial hypothalamic nucleus and receives a particularly dense input from the ventral premammillary nucleus as well (Wiegand, 1984; Ter Horst and Luiten, 1986; Simerly and Swanson, 1988; Canteras et al., 1992b; Thompson et al., 1996). Circadian regulation of AVPV activity may be conveyed by direct inputs from the suprachiasmatic nucleus, which appear stronger in females (Watts et al., 1987; Van der Beek et al., 1997). The AVPV also receives afferents from many of the same brain stem nuclei that provide inputs to the medial part of the medial preoptic nucleus (Simerly and Swanson, 1986), such as the nucleus of the solitary tract, ventrolateral tegmentum, and periaqueductal gray. Consistent with its proposed functional role, neurons in the AVPV appear to provide direct inputs to gonadotropin-releasing hormone containing neurons in the region adjacent to the vascular organ of the lamina terminalis, as well as to tuberoinfundibular dopaminergic neurons in the arcuate nucleus (Gu and Simerly, 1997). A broader role in neuroendocrine regulation is suggested by the observation that the heaviest projections from the AVPV are to nuclei within the periventricular zone of the hypothalamus, including the paraventricular nucleus, and these regions also regulate autonomic function (Westerhaus and Loewy, 1999). In addition, strong connections between the AVPV and the subfornical organ, the median preoptic nucleus, and the

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parastrial nucleus (see below) suggest a possible role for these neurons in the regulation of fluid homeostasis (Lind and Ganten, 1990; Simerly, 1995a; Saper, 2003). Although the AVPV has not been implicated in the neural control of behavior, and does not generally provide major inputs to medial zone nuclei, it does send strong projections to the medial part of the medial preoptic nucleus and dorsomedial hypothalamic nucleus. The only major telencephalic projection of the AVPV is to the ventral part of the lateral septal nucleus (Gu and Simerly, 1997) and it sends more diffuse projections to the bed nuclei of the stria terminalis (BST). Anterior Region The anterior periventricular nucleus (PeA) is a caudal extension of the PePO and has a similar morphological appearance, although the width of the PeA is somewhat greater. Two of the most recognizable and clearly differentiated of all hypothalamic nuclei reside in the anterior part of the periventricular zone. The first of these, the suprachiasmatic nucleus (SCh), consists of small, closely packed, darkly staining neurons. It is bordered anteroventrally by the optic chiasm and posteroventrally by the supraoptic commissure. The SCh is generally divided into dorsomedial and ventrolateral parts that can be seen readily in Nissl or histochemically stained frontal sections (Fig. 2) (van den Pol, 1980). The SCh receives a direct input from the retina and many studies have established its critical role in the control of rodent circadian and diurnal rhythms (Moore and Lenn, 1972; Rusak and Zucker, 1979; Moore, 1983). Because biological rhythmicity appears to be relatively free of feedback modulation (Zucker, 1983) it is not surprising that the SCh receives few other inputs, although the ventral part of the nucleus receives a strong serotonergic input from the midbrain raphe nuclei (Conrad et al., 1974; Moore et al., 1978; Moga and Moore, 1997) and a projection from the ventral

A

B

lateral geniculate nucleus that contains neuropepitede (NPY) (Swanson et al., 1974; Moore et al., 1984; Watts and Swanson, 1987). The projections of the SCh have been analyzed in detail with the surprising finding that the strongest terminal field lies in a region designated the “subparaventricular zone,” which is bordered by the periventricular nucleus, the paraventricular hypothalamic nucleus, and the anterior hypothalamic nucleus (Swanson and Cowan, 1975a; Watts et al., 1987). Moreover, recent observations with retrograde tracers indicate that the subdivisions of the SCh have distinct projections (Leak and Moore, 2001). Another well-differentiated nucleus in the anterior part of the periventricular zone is the paraventricular nucleus, which perhaps best typifies the functional importance of the periventricular zone in that it contains neurons that express hypothalamic-releasing hormones (such as corticotropin-releasing hormone) and project to the median eminence. It also contains neurons that provide direct projections to regions containing preganglionic autonomic neurons, as well as to neurons that send projections to the posterior pituitary (Sawchenko and Swanson, 1983a, 1983b; Swanson and Sawchenko, 1983; Armstrong, 2003). Accordingly, the paraventricular nucleus is thought to play a central role in mediating hypothalamic responses to stress, feeding, and drinking behavior and participates in a variety of autonomic responses (Swanson and Mogenson, 1981; Loewy, 1991; Sawchenko, 1991, 1998; Sawchenko et al., 1996; Elmquist et al., 1999). The nucleus is composed of parvicellular and magnocellular divisions, and each division is composed of distinct subdivisions that have characteristic connections and distributions of neurotransmitter–specific populations of neurons (Armstrong et al., 1980; Swanson and Kuypers, 1980b). As a whole, the parvicellular parts of the paraventricular nucleus share strong bidirectional connections with other nuclei in the periventricular zone such as the AVPV and the

C

SCh

VAS

5HT

FIGURE 2 The suprachiasmatic nucleus (SCh). (A,B) Fluorescence photomicrographs of the same field, taken with two different filter systems, to show the localization of vasopressin-immunoreactive neurons (A) to the dorsal part of the SCh. (C) Fluorescence photomicrograph of an adjacent section to show a dense plexus of serotonin (5-HT)-immunoreactive fibers and terminals in the ventral part of the SCh (original magnification, ×60).

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arcuate nucleus (Levin et al., 1987; Gu and Simerly, 1997; Li et al., 2000) as well as with the medial part of the medial preoptic nucleus, dorsomedial nucleus, and ventral premammillary nucleus (Sawchenko and Swanson, 1983b; Simerly and Swanson, 1986, 1988; Canteras et al., 1992b; Thompson et al., 1996). The paraventricular nucleus is considered in detail in Chapter 15 by Armstrong. The magnocellular neurons of the supraoptic nucleus have much in common with magnocellular neurons of the paraventricular nucleus and, as such, may be considered to be a part of the periventricular zone that was displaced by the optic chiasm (Cunningham and Sawchenko, 1988; Cunningham et al., 1990). Tuberal Region The majority of the tuberal part of the periventricular zone is occupied by the intermediate periventricular nucleus, which is continuous with the PeA and extends caudal to the arcuate hypothalamic nucleus (Arc) (van den Pol and Cassidy, 1982) along the walls of the mammillary recess. The Arc begins just rostral to the infundibular recess and lies along the walls of this recess throughout its length. Two distinct cytoarchitectonic subdivisions of the Arc are generally recognized: a small-celled dorsomedial part and a larger ventrolateral part that contains medium-sized neurons. These two subdivisions of the Arc are apparent in histochemically stained material (Meister and Hauokfelt, 1988; Simerly and Young, 1991) and many Arc neurons contain hypophysiotropic hormones that are released from the terminals located in the neurohemal zone of the median eminence into the hypophysial portal system which carries them to the anterior pituitary (Harris, 1948; Sawyer, 1975, 1978). The strongest inputs to the Arc are from other parts of the periventricular zone, including the paraventricular hypothalamic nucleus and the anteroventral periventricular nucleus, as well as from medial parts of the medial zone, such as the medial subdivision of the medial preoptic nucleus, the dorsomedial nucleus (Thompson and Swanson, 1998) and the ventral premammillary nucleus (Zaborzsky, 1982; Sawchenko and Swanson, 1983b; Simerly and Swanson, 1988; Canteras et al., 1992b). Similarly, the projections of the Arc are largely confined to the periventricular zone, but notably avoid the suprachiasmatic nucleus, with the densest terminal fields found in many of the regions that supply strong afferents to the Arc (Fig. 3), Extrahypothalamic connections are sparse, but the Arc receives strong inputs from the principal nucleus of the BST and the posterodorsal part of the medial nucleus of the amygdala (Simerly et al., 1989; Canteras et al., 1992a; Gu et al., 2003), as well as from the ventral part of the

lateral septal nucleus (Risold and Swanson, 1997b). It also receives substantial inputs from several brain stem sites thought to convey ascending visceral sensory information to the Arc (Jones and Moore, 1977; Azmitia and Segal, 1978; Ricardo and Koh, 1978; Swanson, 1987). Mammillary Region The mammillary part of the periventricular zone is occupied solely by the caudal part of the posterior periventricular nucleus (PeP) which surrounds the posterior end of the third ventricle. This diffuse cell mass is continuous dorsally with the dorsomedial hypothalamic nucleus and ventrally with the Arc. Because its cells resemble those of the Arc it is often included as part of this nucleus, but on neurochemical and connectional grounds it appears to more closely resemble the other periventricular nuclei (Everitt et al., 1986; Swanson, 1987) and contains few neurons that project to the median eminence (Wiegand and Price, 1980).

Medial Zone The medial zone of the hypothalamus contains a series of large nuclei that collectively play key roles in the initiation of motivated behaviors such as copulatory, aggressive, and appetitive behaviors (see Swanson, 1987, 2000). Accordingly, the connections of these nuclei are exceedingly complex with each nucleus possessing strong connections with widely distributed parts of the telencephalon, diencephalon, and brain stem that are thought to mediate the somatomotor integration necessary for the elaboration of appropriate adaptive responses to specific exteroceptive cues. In addition, many of the nuclei of the medial zone are in a position to be influenced by every major sensory modality. Much of this sensory information is relayed by nuclei in the limbic region of the telencephalon (Swanson, 1983a) and these limbic afferents may represent the key to understanding the functional anatomy of the medial zone of the hypothalamus (Risold and Swanson, 1996; Swanson and Petrovich, 1998; Swanson, 2000; Petrovich et al., 2001; Fig. 4). Superimposed on the limbic inputs are afferents from a well-defined set of brain stem nuclei, some of which relay visceral sensory information (see Saper, 2003). A notable feature of nuclei in the medial zone is that they share strong bidirectional connections with most limbic and brain stem regions that supply medial zone afferents. In addition, nuclei in the medial zone of the hypothalamus share strong intrahypothalamic connections with each other, and all project to cell groups in the periventricular zone, thereby providing a route for limbic modulation of neuroendocrine function. Medial nuclei also have connections with the lateral zone of the hypothalamus, which may be involved in

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A

341

B

AVPV

3V Arc

3V

C

D

C

PaMP

MPOM

FIGURE 3 Projections of the arcuate nucleus (Arc). (A) Bright-field photomicrograph to illustrate the appearance and location of a Phaseolus vulgaris leucoagglutinin (PHA-L) injection site centered in the Arc. (B–D) Dark-field photomicrographs that illustrate projection axons and terminals, emanating from the injection site shown in panel A, observed in the anteroventral periventricular nucleus (AVPV), the medial part of the medial preoptic nucleus (MPOm; c, central part of the MPO), and the medial parvocellular part of the paraventricular nucleus (PaMP; original magnification, ×50). This largely periventricular projection pattern was typical of nuclei located in the periventricular zone.

mediating generalized aspects of behavioral state and arousal (Wayner et al., 1981), and contain subpopulations of neurons that appear to participate in a variety of complex behaviors (Pfaff et al., 1994; Canteras et al., 1997; Siegel, 1999; Watts, 2000; Willie et al., 2001; Blaustein and Erskine, 2002; Hull et al., 2002; Schneider and Watts, 2002; Thompson and Swanson, 2002).

Like the periventricular zone, the medial zone of the hypothalamus can be divided into preoptic, anterior, tuberal, and mammillary levels. Thus, the medial zone is divided into discrete areas designated (from rostral to caudal) the medial preoptic, the anterior, the tuberal, and the posterior hypothalamic areas and the mammillary region. Each of these areas consists of a

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A

B sm

BST

fx V3 MPO

AVPV

C

D

PMV

MPO

FIGURE 4 Limbic inputs to the hypthalamus Photomicrographs to illustrate the appearance of an injection of PHA-L centered in the nucleus of the BST (BSTp) of a male rat and the inputs to the AVPV, ventral premammillary nucleus (PMV), and medial preoptic nucleus (MPO). (Data from Hutton et al., 1998; Gu et al., 2003) (See Ju and Swanson, 1989, for nomenclature, but see also Alheid et al., 2003)

somewhat undifferentiated hypothalamic gray in which several cellular condensations, or nuclei, are embedded. As described in detail by Swanson (1987), axonal transport studies have revealed fundamental organizational principals regarding the functional role of medial zone nuclei. Briefly, the mammillary region appears to be primarily involved in the modulation of cortical information processing, whereas the other nuclei of the medial zone are more directly involved in the production of behavioral responses to visceral, gustatory, and olfactory stimuli. These generalizations are supported by a large body of evidence that defines critical roles for the major nuclei of the medial preoptic, anterior, and tuberal regions of the hypothalamus in the expression of homeostatic and reproductive behaviors,

and the anatomical relationships of the mammillary region suggest that it may indirectly participate in the modulation of auditory and visual influences on these essential behaviors. Preoptic Region The preoptic region is the most complex and differentiated part of the medial zone of the hypothalamus and, not surprisingly, causes the most confusion in the literature regarding its morphological limits, cytoarchitecture, and nomenclature. Because of this, the normal morphology of the medial preoptic area is addressed here in some detail. At least five distinct cell groups are embedded in the undifferentiated gray that makes up the medial preoptic area (MPA). The large oval-shaped

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medial preoptic nucleus (MPO) extends nearly the entire length of the preoptic region and is composed of three distinct subdivisions: a cell-sparse lateral part (MPOl), a cell-dense medial part (MPOm), and a compact, very cell-dense central part (MPOc) that is embedded in the medial subdivision (Simerly et al., 1984b). The MPO as described here corresponds to Gurdjian’s “medial preoptic nucleus” as depicted in Fig. 12, p. 23, of Gurdjian (1927), and to his “nucleus b” of the medial preoptic area (p. 79). Bleier et al. (1979, 1985) designate this nucleus as the “anterior hypothalamic nucleus,” and the term “medial preoptic nucleus” has also been

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used to refer to the medial preoptic area as a whole (Le Gros Clark, 1938; König and Klippel, 1963; Nauta and Haymaker, 1969; Palkovits and Zaborszky, 1979). The connections of the MPO are among the most complex of any cell group of the hypothalamus (Simerly, 1995b, 1998). In addition to extensive intrahypothalamic connections, the MPO receives strong inputs from the posterior and medial nuclei of the amygdala, the principal nucleus of the BST (Fig. 5), caudal and ventral parts of the lateral septal nucleus (Canteras et al., 1992a, 1995; Risold and Swanson, 1997b; Hutton et al., 1998; Risold, 2003), and distinct brain stem regions including the

A mt

cp

DMH opt f

LHA MePD

VMH

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C PaV

f

DMH

3V AHC VMH

Arc opt

FIGURE 5 Projections of medial zone nuclei Dark-field photomicrographs that illustrate marked differences in the patterns of projections from the medial preoptic nucleus (MPO) and central part of the anterior nucleus (AHC; B) to the tuberal region of hypothalamus. Note the dense projections from the MPO to the arcuate nucleus and ventrolateral part of the VMH (A; original magnification, ×40). In contrast, projections from the AHC avoid nuclei in the periventricular zone such as the paraventricular nucleus (PaV; B; original magnification, ×50) and do not innervate the ventrolateral part of the VMH (C; original magnification, ×50).

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ventral tegmental area, nucleus of the solitary tract, and parabrachial nucleus (Berk and Finkelstein, 1981; Simerly and Swanson, 1986; Murphy et al., 1999). Each of the inputs to the MPO are distributed topographically within its three subdivisions, with projections from hypothalamic nuclei of the periventricular zone terminating primarily in the MPOm, and projections from the ventral subiculum, caudal part of the lateral septum, and brain stem serotonergic neurons ending in the MPOl (Simerly et al., 1984a; Simerly and Swanson, 1986; Canteras and Swanson, 1992b; Kishi et al., 2000). The projections of the MPO are equally extensive (Swanson, 1976; Conrad and Pfaff, 1977; Simerly and Swanson, 1988) and include regions thought to mediate the neuroendocrine, autonomic, and somatomotor responses that are important components of the many functions associated with this nucleus such as reproductive and maternal behavior (Numan, 1992; Meisel and Sachs, 1994; Pfaff et al., 1994). Like its inputs, the projections of each subdivision of the MPO are unique. The MPOc is the most sexually dimorphic part of the MPO and sends its strongest projections to other sexually dimorphic parts of the forebrain such as the ventral lateral septal nucleus, the ventrolateral part of the ventromedial nucleus of the hypothalamus, the ventral premammillary nucleus, the principal nucleus of the BST, and the posterodorsal part of the medial nucleus of the amygdala. The MPOm sends its strongest projections to the parts of the hypothalamus involved in the regulation of hormone secretion from the anterior pituitary such as the AVPV, the arcuate nucleus, and the paraventricular nucleus. The cellsparse lateral part of the MPO has the most diffuse projections with a projection to the lateral septum and perifornical region of the hypothalamus, as well as projections to several brain stem nuclei. In addition to the MPO, four smaller nuclei can be distinguished in the medial preoptic area, although little is known regarding the functional role of these nuclei. The first of these smaller cell groups is the anteroventral preoptic nucleus, which lies at the base of the medial preoptic area between the AVPV and the nucleus of the diagonal band of Broca and is separated from each nucleus by clearly demarcated cell-sparse zones. Cells located in this intermediate zone have been termed the ventrolateral preoptic nucleus (VLPO) by Saper and colleagues, and contain GABAergic and galanin containing neurons that provide direct projections to the tuberomammillary nucleus (Sherin et al., 1996, 1998). In addition, the VLPO appear to play an important role in production of sleep, whereas the anteroventral preoptic nucleus seems to participate in neural pathways related to temperature control (Lu et al., 2000). The anterodorsal preoptic nucleus (ADPO)

lies in the dorsal part of the medial preoptic area and appears roughly round in frontal sections through rostral levels of the preoptic region, but caudally it merges imperceptibly with undifferentiated parts of the medial preoptic area. In the nomenclature of Bleier et al. (1979, 1985) the ADPO together with the ventral part of the lateral septal nucleus make up the “septohypothalamic nucleus.” However, the ADPO and the lateral septum are quite different in terms of their cytoarchitecture (Swanson and Cowan, 1979; Simerly et al., 1984b), neurochemistry (Simerly et al., 1988), and connections (Swanson and Cowan, 1979; Simerly and Swanson, 1988). Immediately lateral to the ADPO is a triangular region of low cell density that contains the precommissural component of the stria terminalis. This region was studied in detail by Raisman and Field (1973), who referred to it as the “strial part of the preoptic area.” Raisman and Field also identified a distinct “round nucleus” just lateral to the strial area (StA). This round cluster of cells is replaced caudally by a lens-shaped group of fusiform cells and these two cell groups here are referred to collectively as the parastrial nucleus (PS) (Simerly et al., 1984b; Ju and Swanson, 1989). The PS receives a strong input from the AVPV (Gu and Simerly, 1997) and is notable for its direct projections to magnocellular neurons in the paraventricular nucleus (Simerly and Swanson, 1988). The posterodorsal preoptic nucleus (PDPO) is a small cluster of large, darkly staining neurons that lie at caudal levels of the preoptic region near the posterior tip of the PS, just ventrolateral to the anterior magnocellular part of the paraventricular nucleus (Swanson and Kuypers, 1980b) along the medial border of the BST. Although the PS and PDPO are often considered to be part of the BST, neither nucleus receives inputs from the amygdala and each appears to be more closely related to hypothalamic circuits. Due to its direct projections to magnocellular neurons the parastrial nucleus is likely involved in regulation of fluid homeostasis, whereas the posterodorsal nucleus has been implicated in the neural control of male sexual behavior (Coolen et al., 1998). Because the caudal border of the medial preoptic area is difficult to identify in Nissl-stained sections, it is often included erroneously within the anterior hypothalamic area. Axonal transport studies clearly indicate that the projections of the MPO and medial preoptic area are quite different from those of the cell groups in the anterior hypothalamic region (Fig. 5) (Saper et al., 1978; Simerly and Swanson, 1988; Risold et al., 1994) and therefore support the interpretation of Saper et al. (1978) regarding the caudal limits of the preoptic area. The caudal part of the medial preoptic area, including much of the caudal MPO and BST, has also been

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referred to as the “preoptic–anterior hypothalamic junctional area” (de Olmos and Ingram, 1972). In addition, the term “striohypothalamic nucleus” (Paxinos and Watson, 1998) has been used to define a region between the BST and the dorsolateral aspect of the MPO. However, the results of anterograde tract-tracing studies indicate that the area designated “striohypothalamic nucleus” is part of the terminal field formed by projections of neurons in the medial amygdala to the principal nucleus of the BST and to the MPO (Simerly et al., 1989) and that this region (see Ju and Swanson, 1989) contains numerous fibers en route to the MPO. Anterior Region Compared with the medial preoptic area, the anatomical organization of the anterior hypothalamic area (AHA) is rather simple. The bulk of the AHA is occupied by the oval-shaped anterior hypothalamic nucleus (AH), which is first recognizable near the rostral end of the suprachiasmatic nucleus and lies ventrolateral to the caudal pole of the medial preoptic nucleus. As it increases in size it replaces the medial preoptic area, and caudally the AH is displaced dorsally by the ventromedial hypothalamic nucleus before merging with the rostral end of the dorsomedial hypothalamic nucleus. On cytoarchitectural grounds the AH can be divided into anterior, central, and posterior components (Saper et al., 1978). In addition, a small discrete cluster of neurons (AHd; Atlas plates 26 and 27) in the dorsal aspect of the caudal part of the AH can be recognized and has been designated elsewhere as the stigmoid nucleus (Paxinos and Watson, 1998) or dorsal tuberal nucleus (Bleier et al., 1979; Bleier and Byne, 1985). In general, the connections of the AH appear to be a subset of the connections of the medial preoptic nucleus: complex connections with other parts of the medial zone, sparse inputs from the lateral zone, and only limited inputs from telencephalic regions such as the ventral subiculum, BST, and ventral part of the lateral septal nucleus (Swanson, 1987). The overall pattern of projections from each subdivision of the AH is similar, but there are distinct differences in the relative densities of inputs to specific regions. The major efferents of the AH are to those parts of the medial zone that provide AH afferents and to widespread areas of the lateral zone with a particularly dense terminal field in the perifornical region, as well as to the paraventricular nucleus of the thalamus (Conrad and Pfaff, 1976; Saper et al., 1978; Risold et al., 1994). Significant projections are also directed toward the anterior periventricular and paraventricular nuclei of the hypothalamus and a strong descending projection ends in the periaqueductal gray. The rest of the anterior hypothalamic area is occupied by an undifferentiated

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hypothalamic gray. Ventral to the third ventricle, and between the optic chiasm and the arcuate hypothalamic nucleus, lies a region designated the retrochiasmatic area (RCh) which contains fibers of the supraoptic commissure and neurons that project to the brain stem and spinal cord (Swanson and Kuypers, 1980a). Tuberal Region The tuberal area (TA) of the hypothalamus contains two large and well-differentiated nuclei: the ventromedial (VMH) and dorsomedial (DM) hypothalamic nuclei. The VMH is the largest cell group in the tuberal region and is composed of two distinct cell condensations designated the dorsomedial (VMHDM) and ventromedial (VMHVL) subdivisions (Gurdjian, 1927), which are separated from each other by a cell-sparse zone (VMHc). A fourth subdivision is apparent at anterior levels and is designated the anterior part (VMHA) (Canteras et al., 1993). The VMH is surrounded by a thick fiber capsule or “shell” (Millhouse, 1973) that separates it from the surrounding hypothalamic gray. The major telencephalic afferents to the VMH are from the amygdala and ventral subiculum, with inputs from the posterior nucleus of the amygdala (Canteras et al., 1992a) and ventral subiculum (Canteras and Swanson, 1992b; Kishi et al., 2000) innervating the ventrolateral part of the shell of the VMH. In contrast, the medial and basolateral nuclei of the amygdala send fibers to the cellular core of the nucleus (Krettek and Price, 1977, 1978). The VMH also receives inputs from all parts of the medial zone of the hypothalamus (except the medial and lateral mammillary nuclei) with the input from the DM being especially strong to the VMHDM (Ter Horst and Luiten, 1986). In addition, the VMH receives inputs from the lateral zone, the posterior hypothalamic area, and the suprachiasmatic nucleus (Saper et al., 1979; Watts et al., 1987; Fahrbach et al., 1989). Among the brain stem inputs to the VMH, afferents from the parabrachial nucleus have received the most attention due to the possible importance of this pathway in feeding behavior (Fulwiler and Saper, 1984, 1985; Bester et al., 1997). The VMH sends massive projections to other parts of the medial zone of the hypothalamus and tends to avoid periventricular regions and the lateral zone. The VMH also sends widespread projections to the amygdala and the septum, with the strongest projection to the bed nuclei of the stria terminalis, as well as providing descending projections to brain stem regions such as the periaqueductal gray (Saper et al., 1976b; Canteras and Simerly, 1994) that are known to project either to the spinal cord or to the basal ganglia. These descending projections are consistent with the proposed role of the VMH in mediating somatomotor aspects of

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complex motivated behaviors (Pfaff et al., 1994). The subdivisions of the VMH appear to have quantitatively different projections, but the overall pattern of projections is qualitatively similar. In general, the VMHVL shares connections with regions of the forebrain and brain stem that also contain high densities of neurons that express sex steroid receptors (Fig. 6) and are involved in mediating reproductive behavior, such as the medial amygdala and the medial preoptic area, while the VMHDM shares strong connections with regions involved with appetitive behaviors, such as the paraventricular nucleus and dorsomedial hypothalamic nuclei (Saper et al., 1976b; Canteras and Simerly, 1994; see Keay and Bandler, 2003, for review of PAG anatomy). In addition, the central, lateral, and medial nuclei of the amygdala receive substantial inputs from the VMH; other forebrain regions that receive inputs from the VMH include the BST, the nucleus accumbens, and the infralimbic cortex. Each part of the VMH sends a massive projection to the periaqueductal gray (PAG) that is topographically organized with the VMHDL preferentially innervating rostral and dorsal parts, and the VMHVL providing more widespread inputs to caudal parts of the PAG (Canteras and Simerly, 1994).

A

Immediately lateral to the VMHVL lies the tuberal nucleus (TU), which consists of an oval cluster of smallto medium-sized neurons embedded in the tuberal part of the lateral hypothalamic area. The TU was originally described by Malone (1910) and is also known as the lateral tuberal nucleus (Diepen, 1962; Nauta and Haymaker, 1969). Bleier and colleagues (1979, 1985) named this cell group the medial tuberal nucleus and referred to what is described here as the magnocellular nucleus of the lateral hypothalamus (see below) as the lateral tuberal nucleus. Paxinos and Watson (1998) utilized the term medial tuberal nucleus and recognized a lateral condensation of neurons that is demarcated in Timm’s and acetylcholinesterase stained preparations, which they termed the nucleus terete (Te; “Atlas” plates 31 and 32). Many neurons in the TU express estrogen receptor mRNA (Simerly et al., 1990) and the connections of the TU appear to represent a subset of those described for the VMHVL. Thus, the TU provides dense inputs to other hypothalamic nuclei that contain high densities of neurons that express sex steroid receptors, including the medial preoptic nucleus, the VMHVL, and the ventral premammillary nucleus. However, the TU appears to provide stronger inputs

B 3V

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FIGURE 6 Hormone–sensitive neurons in the hypothalamus Dark-field photomicrographs to show the distribution and density of neurons in the arcuate nucleus (Arc) and ventrolateral part of the ventromedial (VMHVL) nucleus that express estrogen receptor (ER) mRNA (A). Panel B illustrates the density of androgen receptor (AR) mRNA containing neurons in the ventral premammillary nucleus (PMV; X40). Note the relative absence of neurons that express ER or AR mRNA in adjacent cell groups. (C) Cluster of neurons in paraventricular nucleus (PaV) that express ERβ mRNA. (D) Expression of PR mRNA in the AVPV of a female rat (original magnification, ×50).

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than the VMHVL to regions that participate in regulating neurosecretion, such as the arcuate, anterior periventricular, and paraventricular nuclei of the hypothalamus, and its projections to the amygdala, midbrain, and caudal brain stem are weaker than those of the VMHVL (Canteras and Simerly, 1994). The DM occupies the dorsal half of the tuberal area between the anterior hypothalamic nucleus, rostrally, and the posterior hypothalamic area, caudally. It is generally considered to be composed of three parts which are best appreciated at mid levels through the nucleus where the cell-dense posterior part of the DM (which corresponds to the compact part of the DM of Paxinos and Watson (1998) separates the dorsally positioned anterior subdivision from the ventral part of the nucleus (Atlas plate 31). The DM receives afferents from the BST and the ventral part of the lateral septal nucleus, and all parts of the brain stem that provide inputs to the MPO except for the nuclei of the raphe (Thompson and Swanson, 1998). In addition, the DM receives inputs from most parts of the hypothalamus including the AVPV, MPO, AH, VMH, and SCh. Although descending fibers from the DM provide inputs to the periaqueductal gray and appear to innervate Barrington’s nucleus, the parabrachial nucleus, and the nucleus of the solitary tract, the projections of the DM are mostly intrahypothalamic (Ter Horst and Luiten, 1986; Thompson et al., 1992). Thus, the most densely innervated areas are the anterodorsal and suprachiasmatic preoptic nuclei, the parastrial nucleus, the preoptic and anterior periventricular nuclei, and the parvicellular parts of the paraventricular nucleus. The functional role of the DM remains a matter of discussion, but it has been implicated in the regulation of ingestive behavior, stress, reproduction, circadian rhythms, and thermogenesis (Bernardis and Bellinger, 1998; Sawchenko, 1998), (Gunnet and Freeman, 1983; Rothwell, 1994; Polston and Erskine, 1995; Coolen et al., 1996; Thompson and Swanson, 1998, 2002). Mammillary Region The mammillary part of the medial zone of the hypothalamus is occupied by the mammillary complex— which consists of the medial and lateral mammillary (mammillary body) and supramammillary nuclei— together with the premammillary nuclei (dorsal and ventral) and the posterior hypothalamic area. Although we also consider the tuberomammillary nucleus here, it should be considered as part of the lateral zone of the hypothalamus because of its widespread telencephalic projections and postulated role in modulating behavioral state (Köhler et al., 1985). The mammillary body is divided into a medial mammillary nucleus (MM) that occupies the majority of the mammillary

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body and a lateral mammillary nucleus (LM) that is easily distinguished by its large, darkly stained neurons. The MM is further subdivided into three parts: a small medial part (MMm) located at the midline, the lateral part (MMl) which is by far the largest, and the posterior part (MMp). Perhaps the most important input to the mammillary body is that from the subicular region of the hippocampal formation that travels along the postcommissural fornix (Swanson and Cowan, 1975b; Canteras and Swanson, 1992b; Kishi et al., 2000; Witter and Amaral, 2003). Other limbic inputs include afferents from the lateral septal nucleus and BST, which appear to preferentially terminate in the LM, while the medial septal–diagonal band complex preferentially innervates the medial nucleus (Swanson and Cowan, 1979). In contrast to the other nuclei of the medial zone, the mammillary body receives only modest inputs from the brain stem, although the dorsal tegmental nucleus of Gudden sends a projection to the LM and the ventral tegmental nucleus appears to preferentially innervate the MM. The projections of the mammillary body are equally unique among medial zone nuclei. Projection axons form two major fiber tracts: a descending mammillotegmental tract containing fibers from both the MM and the LM that terminate in the tegmental nuclei of Gudden, and the ascending mammillothalamic tract that terminates in the anterior complex of the thalamus. The anterior thalamic nuclei in turn send projections to a continuous strip of limbic cortex that includes the anterior limbic area, retrosplenial area, presubiculum, and parasubiculum and receives inputs from visual and auditory areas of the isocortex. The connections of the mammillary body serve to distinguish it from the other nuclei of the medial zone and separate this zone into distinct rostral and caudal (mammillary) components. In contrast to the strong olfactory, gustatory, and visceral sensory information that regulates the MPO, AH, DM, and VMH, the mammillary body appears to be most strongly influenced by visual and auditory information. In addition, the mammillary body lacks the extensive intrahypothalamic connections typical of the other medial zone cell groups. Finally, the MPO, AH, DM, and VMH all send projections to regions of the brain stem and spinal cord that control somatomotor and autonomic responses, whereas the mammillary body appears to lack such projections, although at least some intrahypothalamic connections have been reported (Gonzalo-Ruiz et al., 1992), and its cortical connections may provide an indirect pathway for inputs to the striatum (Swanson, 1987). The premammillary nuclei lie at the level of the mammillary recess of the third ventricle immediately caudal to the ventromedial hypothalamic nucleus and rostral to the mammillary body. The dorsal

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premammillary nucleus (PMD) appears as a trapezoidalor rectangular-shaped cluster of pale neurons in Nisslstained frontal sections and is bordered laterally by the fornix column and medially by a cell-poor zone that separates the two nuclei. The ventral premammillary nucleus (PMV) is somewhat easier to distinguish and was first recognized by Gurdjian (1927) as a compact cluster of darkly staining neurons. It is most clearly delimited by retrograde labeling, for example, after injections of tracers into the medial preoptic nucleus (Simerly and Swanson, 1986), or by labeling neurons in the PMV that express sex steroid receptors (Fig. 8) (Pfaff and Keiner, 1973; Simerly et al., 1990). The major inputs to the PMV arise in sexually dimorphic forebrain regions that compose a distinct circuit (see Simerly and Swanson, 1986; Simerly and Swanson, 1988; Canteras et al., 1992b) that includes the posterior nucleus of the amygdala, the medial preoptic nucleus, the principal nucleus of the BST (a.k.a. BSTMP) (Paxinos and Watson, 1998), and the posterodorsal part of the medial nucleus of the amygdala (see Simerly, 1995b, for review). Thus, olfactory information relayed by these nuclei appears to provide the major sensory input to the PMV. The PMV contributes strong inputs to most parts of the periventricular zone, including the anteroventral periventricular and arcuate nuclei, as well as sends projections to other sexually dimorphic regions that innervate it, which may represent feedback connections (Canteras et al., 1992b). The connections of the PMV are consistent with functional data that suggest a possible role in mediating certain aspects of reproductive behavior and physiology (Beltramino and Taleisnik, 1978, 1980; Akesson and Micevych, 1995), and perhaps aggressive behavior as well (Van den Berg et al., 1983). In contrast, the PMD has quite a different pattern of connections and Canteras and Swanson (1992a) have suggested that it may be viewed as a rostral component of the mammillary body that serves as an interface between the anterior nuclei of the medial zone and the mammillary body. Unlike the mammillary body, which lacks strong inputs from the hypothalamus, the PMD receives its major input from the anterior hypothalamic nucleus (Saper et al., 1978; Risold et al., 1994), which in turn receives inputs from the prefrontal cortex, the amygdala, and the hippocampus. The PMD is also innervated by the interfascicular nucleus of the BST and receives substantial input from the infralimbic and prelimbic areas, as well as from the lateral septal nucleus (Comoli et al., 2000). In addition to inputs from the anterior hypothalamus, the PMD is innervated by the perifornical region and the anterior and dorsomedial parts of the ventromedial hypothalamic nucleus. The projections of the PMD more closely resemble those of the mammillary body than those of the PMV. Like the

mammillary body the PMD sends a branched projection that ends in the anterior thalamus and brain stem, but it also provides afferents to the anterior hypothalamic nucleus and a descending projection to the periaqueductal gray, superior colliculus, and adjacent parts of the reticular formation (Canteras and Swanson, 1992a). Thus, the PMD represents an interface between medial zone nuclei of the rostral hypothalamus and mammillary nuclei. By virtue of its projections to the hippocampus (by way of the anteromedial nucleus of the thalamus and its projections) and to motor-related brain stem regions, it provides a means for communication between medial zone nuclei and brain regions involved in spatial memory and diverse behavioral responses including expression of fear and defensive responses to environmental stimuli (Canteras et al., 1997; Comoli et al., 2000). The supramammillary nucleus (SuM) lies between the mammillary body and the posterior hypothalamic area and is bordered dorsolaterally by the ventral tegmental area (VTA). It can be divided into a largecelled lateral part and small-celled medial part that contains many dopaminergic neurons (Swanson, 1982). Although its inputs have not been examined systematically, it appears to receive a massive input from the ventral part of the septal nucleus, the BST, the medial preoptic nucleus, and the lateral zone of the hypothalamus (Saper et al., 1979; Swanson and Cowan, 1979; Simerly and Swanson, 1988; Risold and Swanson, 1997b; Dong et al., 2000). The SuM projects to most major telencephalic regions, including the entire cortical mantle, including a prominent projection to the dentate gyrus and the entorhinal cortex. It provides weaker inputs to other parts of the hippoccampal formation and avoids the corpus striatum (Haglund et al., 1984; Vertes, 1992). The SuM also sends a projection to the central nucleus of the amygdala (Swanson, 1982). Descending projections of the SuM appear to be relatively minor, but a few fibers appear to end in the periaqueductal gray (Vertes, 1992). The posterior hypothalamic area (PHA), the most caudal and dorsal hypothalamic region, is limited laterally by the mammillothalamic tract and merges in the midline at the level of the mammillary recess. It begins just dorsal to the DM—a region often referred to as the dorsal hypothalamic area–which it replaces caudally until it merges with the periaqueductal gray of the midbrain. The connections of the PHA appear to have much in common with those of the periaqueductal gray. The PHA receives inputs from the amygdala, the septum, and the hippocampal formation, as well as from much of the hypothalamus, and many of these connections appear to be bidirectional (Abrahamson and Moore, 2001; Cavdar et al., 2001). The PHA sends the

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majority of its ascending projections via the medial forebrain bundle (mfb) and provides significant inputs to cortical regions related to limbic structures such as perirhinal, insular, limbic, and prelimbic regions of the cerebral cortex (Vertes et al., 1995). In addition, the PHA innervates subcortical regions in the hypothalamus, thalamus, amygdala, septum, and basal forebrain. Because of the close association between the PHA and the forebrain regions connected to the hippocampus it has been suggested that the PHA may play a role in various aspects of emotional behavior (Vertes et al., 1995). The majority of the tuberomammillary nucleus (TM) lies along the base of the caudal diencephalon and is best considered as a nuclear complex that forms a shell around ventral parts of the mammillary body. It can be divided into two magnocellular parts with scattered cells in between. Thus, the complex consists of a dorsomedial TM that appears as a dense cluster of large neurons along the dorsal aspect of the mammillary recess, just dorsal to the rostral part of the posterior periventricular nucleus (Atlas plate 34); a ventral nucleus (TMV) that is considerably larger than the TMD and lies along the base of the hypothalamus ventral and lateral to the PMV (Atlas plates 34 and 35); and a diffuse component (TMdif) that consists of scattered, darkly staining neurons between the TMD and the TMV within the posterior periventricular nucleus (Köhler et al., 1985). Various parcellation schemes have been used to classify these cell groups (for review see Ericson et al., 1987), but it was the advent of immunohistochemical methods that distinguished the TM from the more rostral supraoptic magnocellular neurons and clarified the organization of the complex. Most, if not all, neurons in the TM stain with antisera to histidine decarboxylase and amino decarboxylase, and all parts of the TM receive catecholaminergic afferents from the C1–C3 and A1–A2 cell groups in the brain stem, as well as serotonergic inputs from the B5–B9 cell groups (Ericson et al., 1989). The TM also receives afferents from the lateral septal nucleus and the bed nuclei of the stria terminalis, the medial preoptic nucleus, the lateral preoptic and hypothalamic areas, and the ventromedial nucleus (Ericson et al., 1991). The projections of the TM resemble those of the locus coeruleus and dorsal raphe in that they are distributed to widespread parts of the brain, including the entire cortical mantle, the basal ganglia, the septum and amygdala, parts of the thalamus, the cerebellum, and several brain stem nuclei. The extensive pattern of projections has led to the suggestion that the TM plays a role in the modulation of arousal and behavioral state and, therefore, conceptually belongs to the lateral zone of the hypothalamus. However, the strongest projections of TM neurons are to the hypothalamus, with particularly

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dense terminal fields in the paraventricular and supraoptic nuclei (Ericson et al., 1987), suggesting an important role for the TM in regulating neuroendocrine function as well.

Lateral Zone Although the functional importance of the lateral zone of the hypothalamus has been appreciated for several decades (Stevenson, 1969; Hitt et al., 1970; Siegel and Edinger, 1981), it is safe to say that no aspect of hypothalamic circuitry is less clear. Few distinct regions can be distinguished on cytoarchitectural or neurochemical grounds and attempts to functionally dissect this complex region have largely been impeded by technical limitations. The primary reason for this is that the lateral zone is traversed by the mfb, undoubtedly the most complex fiber system in the mammalian brain (Veening et al., 1982). The mfb contains ascending and descending fibers that arise from more than 50 different cell groups which extend from the prefrontal cortex, through the hypothalamus and ventral brain stem reticular formation, to sacral levels of the spinal cord, and many of these projections appear to contribute inputs to cells in the lateral zone. Thus, it has proven difficult to interpret experimental findings based on methods that fail to distinguish between specific manipulations of neurons and perturbations of fibers passing through the lateral zone. Nevertheless, the lateral zone of the hypothalamus has been implicated in the processing of sensory information and the expression of behaviors associated with hunger and thirst (Swanson and Mogenson, 1981; Swanson, 1987; Elmquist et al., 1999; Siegel, 1999; Watts, 2000), aggression (Kruk, 1991; Siegel et al., 1999), and reproduction (Pfaff et al., 1994). In more general terms, the functional evidence suggests that the lateral zone is involved in mediating general arousal and sensory sensitization associated with motivated behavior and may modulate spinal pathways and so affect the likelihood that specific behavioral patterns will be expressed (Swanson, 1987). However, by virtue of its strong connections with telencephalic regions such as the cerebral cortex, the amygdala, and the septum, and its connections with parts of the periventricular zone, it is in a good position to coordinate motivational aspects of behavior with visceromotor responses. Like the other zones of the hypothalamus the lateral zone can be divided into preoptic, anterior, tuberal, and mammillary regions. However, because clear criteria for subdivision have not emerged it is generally considered to have only two major divisions, the lateral preoptic area (preoptic level) and the lateral hypothalamic area (anterior, tuberal, and mammillary levels).

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Lateral Preoptic Area (LPA)

forebrain bundle, a definition that is supported by the results of anterograde tract-tracing studies (Fig. 7) (Swanson, 1976; Simerly and Swanson, 1988). The only distinct nucleus in the preoptic part of the lateral zone is the magnocellular preoptic nucleus (MCPO), which is differentiated from the dorsally adjacent LPA and substantia innominata by its large darkly staining neurons. This cell group has been called the “nucleus interstitialis septo-hypothalamicus” by Gurdjian (1927)

The LPA is characterized by lightly stained (thionin) medium-sized neurons scattered amongst the fibers of the dorsomedial division of the medial forebrain bundle. It is bordered dorsally by the BST and the substantia innominata, and caudally it merges imperceptibly with the lateral hypothalamic area. The medial border of the LPA (designated Lpo in Fig 7) corresponds rather precisely with the medial border of the medial

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FIGURE 7 Lateral zone projections. (A) Bright-field photomicrograph to illustrate the appearance and location of a PHA-L injection site centered in the lateral preoptic area (LPO). (B, C) Dark-field photomicrographs that illustrate projection axons and terminals, emanating from the injection site shown in panel A, observed in the lateral hypothalamic area (LH) and lateral habenula (LHb; B and C) and in the posterior hypothalamic area (C; original magnification, ×50). Note the relative absence of labeled fibers in the periventricular and medial zones of the hypothalamus. See Fig. 1 for other abbreviations.

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and the “nucleus of the horizontal limb of the diagonal band” by Price and Powell (1970). However, the MCPO is clearly separated from the ventrolateral tip of the nucleus of the diagonal band which forms the medial border of the MCPO. Because the MCPO consists mostly of large cholinergic neurons that project to the olfactory bulb and isocortex (Swanson, 1976; Woolf et al., 1984), it may be considered a differentiated component of the substantia innominata in the rat that corresponds in part to the basal nucleus of Meynert of primates (Saper, 1984, 2000; Saper and Chelimsky, 1984). The projections of the LPA travel almost exclusively in the medial forebrain bundle. In contrast to the projections of the medial preoptic nuclei, the LPO provides widespread inputs to the cerebral cortex and hippocampus, as well as inputs to the mediodorsal and reticular nuclei of the thalamus (Swanson, 1976; Simerly and Swanson, 1988). In addition, the dorsomedial hypothalamic nucleus, supramammillary nucleus, and ventral tegmental area receive significant inputs from the LPO. Descending projections extend into the medulla with particularly dense terminal fields in the parabrachial and pedunculopontine nuclei. Lateral Hypothalamic Area (LHA) The LHA may be further divided into three rostrocaudal subregions that correspond to the anterior (LHAa), tuberal (LHAt), and mammillary (posterior) (LHAp) levels of the hypothalamus. Despite containing several cell condensations the LHA has not been further subdivided, although each major subdivision appears to have a unique set of connections (Saper et al., 1979). The LHAa is continuous with the LPA and is bounded medially by the anterior hypothalamic area and the descending columns of the fornix. Laterally it merges with the substantia innominata and the amygdala. The LHAt replaces the LHAa at tuberal levels and is bordered laterally by the optic tract and the internal capsule and, more caudally, by the subthalamic nucleus. The TU is embedded in the LHAt and consists of an oval cluster of neurons lying lateral to the VMH. Many TU neurons express estrogen receptors (Simerly et al., 1990) and have connections that are similar to those of the VMH (Canteras and Simerly, 1994). At the level of the mammillary complex, the LHAt is replaced by the LHAp which merges caudally with the ventral tegmental area. Medially the LHAp is limited by the fornix, the mammillothalamic tract, and the posterior hypothalamic area and is separated dorsally from the thalamus by the zona incerta and the fields of Forel. The connections of the LHA are extremely complex and, although it is clear that fibers in the medial forebrain bundle innervate neurons in the lateral zone

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(Millhouse, 1979; Veening et al., 1982), for the most part the region-specific pattern of lateral zone afferents has not been established. The results of retrograde tracttracing studies have proven difficult to interpret because of the possibility of retrograde labeling produced by uptake of tracers by fibers of passage. This problem is severe in the lateral zone because all regions that contribute fibers to the medial forebrain bundle also project to one or more nuclei in the medial zone (see Swanson, 1987, for references). Information derived from anterograde tract-tracing studies suggests that restricted parts of the amygdala, septum, and hippocampal formation supply strong inputs to the LHA, as do the substantia innominata and lateral preoptic areas. In general, cell groups in the periventricular zone do not send many projections to the LHA, but the arcuate nucleus is an exception and sends direct inputs to peptidergic neurons in the LHA that are thought to play an important role in feeding (Elias et al., 1999). Other parts of the periventricular zone, such as the anteroventral periventricular nucleus, have relatively weak descending projections to the lateral zone that appear to end primarily in the perifornical region and in the ventrolateral part of the LHAt (Gu and Simerly, 1997). Although brain stem regions also appear to provide inputs to the LHA, the detailed organization of these pathways is yet to be defined. Evidence from systematic anterograde tract-tracing studies indicates that the outputs of the lateral zone of the hypothalamus closely resemble those of the medial zone as a whole. Thus, widespread projections have been demonstrated that include inputs to the entire cerebral cortical mantle (including the hippocampal formation), parts of the amygdala and septum, the substantia innominata, parts of the thalamus, nearly every part of the periventricular and medial zones of the hypothalamus, numerous brain stem cell groups, and the spinal cord. As a whole the hypothalamus provides the largest nonthalamic input to the cerebral cortex. This input is derived primarily from neurons in the lateral zone of the hypothalamus (Saper, 1985, 2000), in addition to the cortical inputs supplied by the tuberomammillary and supramammillary nuclei alluded to above. The lateral zone also projects to many parts of the septum and amygdala, but this projection is much more diffuse than the massive input it receives from these telencephalic regions, suggesting that it represents a possible feedback pathway. With respect to projections from the lateral zone to the thalamic nuclei, both the LPA and the LHA appear to provide inputs to the lateral habenula, the paraventricular nucleus of the thalamus, the nucleus reunions, and the zona incerta, as well as to the intralaminar nuclei (Swanson, 1976; Saper et al., 1979; Berk and Finkelstein,

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1982; Simerly and Swanson, 1988). These thalamic cell groups, in turn, may relay afferent information from the lateral zone to the hippocampal formation, amygdala, septum, prefrontal cortex, and nucleus accumbens. Neurons in the lateral zone send projections to widespread regions in the brain stem and most of these connections are bidirectional. These regions include nuclei that relay visceral sensory information to the forebrain, such as the nucleus of the solitary tract and the parabrachial nucleus (Saper and Loewy, 1980; Ter Horst et al., 1989; Bester et al., 1997), and nuclei involved in mediating somatomotor control mechanisms, such as the ventral tegmental area and substantia nigra, the posterior hypothalamus, and periaqueductal gray, as well as the locus coeruleus and various nuclei of the raphe (Swanson, 1976; Saper et al., 1979). Finally, there are direct projections from the LHA to the spinal cord that are distributed such that it may directly influence sensory, somatomotor, and autonomic spinal mechanisms (Saper et al., 1976a; Hosoya and Matsushita, 1983).

HYPOTHALAMIC INTEGRATION At the outset of this review the hypothalamus was described as providing a suitable neurological substrate for coordinating the needs of the individual animal with dynamic changes in its environment. The appropriate display of adaptive responses to specific cues from the environment involve complex endocrine, autonomic, and somatomotor mechanisms that must be integrated for these responses to be of optimal benefit to the animal. Moreover, because the simultaneous expression of multiple behaviors is not adaptive, these responses must be coordinated and be subject to a hierarchy of homeostatic priorities, a process termed “motivational time-sharing” by McFarland (1974). For example, animals do not generally feed while copulating or simultaneously display defensive and courtship behaviors. These functional requirements, therefore, imply not only integration of endocrine, autonomic, and somatomotor aspects of each adaptive response but also coordination and communication between neural systems mediating different functional responses. Behaviors are generally considered to consist of three phases: initiation, procurement, and consummation (see Beach, 1967; Swanson and Mogenson, 1981, for reviews). The initiation phase involves the perception of a stimulus, while the procurement phase consists of behaviors that are directed toward a specific goal. The consummatory phase is characterized by preprogrammed motor responses thought to be established by central pattern generators. By analogy, endocrine responses can also be divided into three distinct phases.

Hormone secretion from the anterior lobe of the pituitary gland (functional output or consummation) is controlled by neuroendocrine neurons in the hypothalamus whose intrinsic activity is controlled by neural circuits that regulate the pattern of hormone secretion into the portal circulation (pattern generation). These neural circuits are in turn activated, or modulated, by both neural and humoral afferent information (initiation). Thus, a prerequisite to understanding the neurobiology of hypothalamic integration is the characterization of not only the neural pathways that convey specific signals to the hypothalamus but also of circuits that mediate the procurement and consummatory aspects of goal-directed behaviors or, alternatively, the secretion patterns of hypothalamic hormones. Superimposed on the organization of these neural pathways are patterns of neural activity that are regulated by changes in physiological state (e.g., estrous cycle, availability of metabolic fuels, circulating hormones, etc.) that alter the transmission of information through hypothalamic circuits. Although hypothalamic circuits are considerably more complex than the three neuron reflex arcs studied by Sherrington (1906), hypothalamic circuits can be viewed as essentially consisting of sensory and motor components, with intrahypothalamic integrative circuits interposed between the sensory and motor parts of the circuit. As outlined above, the hypothalamus receives sensory activation from visceral sensory regions such as the nucleus of the solitary tract and subfornical organ, as well as olfactory and other sensory information from limbic regions such as the amygdala and hippocampal formation. Superimposed on hypothalamic regions receiving these sensory pathways are projections from the brain stem reticular formation that may effect a more generalized arousal. With respect to motor pathways, the hypothalamus sends direct and massive projections to preganglionic autonomic neurons and all parts of the pituitary gland, as well as projections to regions that mediate somatomotor responses. Thus, the hypothalamus represents an interface between sensory and motor pathways that has intimate connections with the pituitary gland, thereby providing an effective means of coordinating stimulus-specific behaviors with appropriate autonomic and endocrine responses. The integrative mechanisms underlying this process occur at the level of intact neural systems, individual hypothalamic nuclei, and single cells and at the molecular level. Integration at the Neural Systems Level A great deal remains to be learned regarding the organization of the neural systems that mediate homeostatic responses, but certain patterns are emerging that

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suggest ways in which essential behaviors and endocrine responses are coordinated (Risold et al., 1997; Swanson, 2000). One such mechanism is for separate sensory pathways to converge onto functionally distinct parts of the hypothalamus. For example, pheromonal information is relayed to the hypothalamus from the vomeronasal organ by the medial amygdala and principal nucleus of the BST (Fig. 8). Each of these limbic regions provide strong inputs to both the anteroventral periventricular nucleus and the parvicellular division of the paraventricular nucleus. The anteroventral periventricular and paraventricular nuclei also receive strong inputs from the ventral part of the lateral septal nucleus, which is innervated topographically by the ventral subiculum and hippocampal field CA1. Thus, these two periventricular zone nuclei receive convergent sensory information: olfactory cues conveyed to the hypothalamus by the medial amygdala and BST, and information related to exploratory behavior conveyed to the hypothalamus by the ventral lateral septum. In a similar way, parallel limbic inputs to sexually dimorphic nuclei in the hypothalamus from the hippocampal formation and accessory olfactory pathway converge onto subcircuitries that regulate reproductive behavior and neuroendocrine responses (Simerly, 2002). In this way sexually relevant sensory cues can coordinate display of reproductive behavior with accompanying changes in reproductive physiology. Analysis of hypothalamic connections suggests that there are functionally distinct sets of pathways that mediate different homeostatic functions. Reproductive behavior is mostly dependent on the activities of the medial preoptic nucleus and ventrolateral part of the ventromedial hypothalamic nucleus, which play decisive roles in male and female copulatory behavior, respectively (Meisel and Sachs, 1994; Pfaff et al., 1994). Agonistic behavior is primarily controlled by a circuit between the anterior hypothalamic nucleus, the dorsomedial part of the ventromedial nucleus, and the dorsal premammillary nucleus (Canteras and Swanson, 1992a; Canteras et al., 1997). In contrast to the predominate role of these medial zone nuclei in social behaviors, nuclei of the periventricular zone are chiefly involved in neuroendocrine regulation and visceromotor responses (Markakis and Swanson, 1997). The major components of this system are the anteroventral periventricular nucleus, the periventricular and paraventricular hypothalamic nuclei, and the arcuate nucleus. Strong intrahypothalamic connections link these cell groups and they receive similar sensory inputs, either directly by regions such as the ventral lateral septal nucleus and the principal BST or via relays from medial zone nuclei such as the medial part of the medial preoptic nucleus and dorsomedial hypothalamic nucleus. These same

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FIGURE 8 Integration at the neural systems level. Pheromonal information from the accessory olfactory bulb (AOB) is relayed to the hypothalamus by cell groups in the amygdala and the BST. This information differentially impacts subsystems in the hypothalamus involved in defensive and reproductive behaviors. The reproductive subsystem has strong connections with periventricular nuclei that control endocrine and autonomic responses, whereas the defensive subsystem projects to several nuclei in the rostral thalamus thought to participate in attention and learning (modified from Fig. 2 of Risold et al., 1997, with permission ).

major sensory routes provide input to the medial preoptic nucleus and the ventrolateral part of the ventromedial nucleus. Therefore, a potential mechanism for functional integration is for a single sensory modality to affect multiple functional neural systems. For example, olfactory influences emanating from the vomeronasal organ play an important role in modulating gonadotropin secretion and the display of copulatory behavior (Wysocki, 1979; Johns, 1986). This olfactory information is relayed to the hypothalamus primarily by the medial nucleus of the amygdala and the principal nucleus of the BST (see Simerly, 1990), both of which provide strong inputs to the medial preoptic nucleus and ventromedial nucleus (Fig. 6) (Swanson and Cowan, 1979). The medial nucleus of the amygdala and the principal nucleus of the BST also provide strong inputs to the anteroventral periventricular and ventral premammillary nuclei, which in turn project to regions

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such as the paraventricular and arcuate hypothalamic nuclei, which contain high densities of neurons that secrete hypothalamic-releasing factors. Thus, the distribution of a distinct sensory input to neural systems modulating different functions provides a direct means of coordinating behavioral and endocrine responses to a single stimulus. Similarly, regions involved in mediating motor aspects of behavior can receive inputs from hypothalamic cell groups involved in initiating different behaviors, as illustrated by the strong projections from the medial preoptic nucleus (male copulatory behavior) and the ventromedial nucleus (female copulatory behavior) to the periaqueductal gray. Although the same major regions that supply telencephalic sensory inputs to the subsystem of hypothalamic nuclei involved in reproduction also send inputs to the subsystem that mediates agonistic behavior, these inputs are topographically organized such that each subsystem is differentially regulated by the telencephalon (Fig. 8) (see Risold et al., 1997). Connections between various parts of functionally distinct neural systems, such as those that exist between the medial preoptic and ventromedial nuclei, or between dorsomedial hypothalamic and anteroventral periventricular nuclei, may serve to coordinate the activity of these systems and provide for the display of appropriate responses. An important illustration of this principle relates to how animals integrate intrinsic physiologic stressors with those that require interpretation by the animal. The paraventricular nucleus acts as the final common pathway for the regulation of glucocorticoid secretion and receives convergent inputs that transmit visceral sensory information, via brain stem afferents, and telencephalic afferents from the limbic region of the forebrain that convey information from the external environment requiring interpretation before elaborating the appropriate adaptive response (Herman and Cullinan, 1997). Integration at the Level of Hypothalamic Nuclei Insight into the function of a hypothalamic nucleus can be gained by considering the functions of the structures it innervates, the types of information it receives from regions that supply afferents to it, and the amount of information processing that occurs within the nucleus. Most hypothalamic nuclei can be divided into components that share a distinct pattern of connections or cytoarchitectural and neurochemical characteristics. The spatial segregation of functionally distinct cell types in the periventricular zone is best illustrated by the paraventricular nucleus of the hypothalamus (PaV) (Swanson and Kuypers, 1980b; see Fig. 9). The projections of essentially separate populations of neurons in the PaV to the posterior pituitary, to the anterior pituitary,

and to autonomic preganglionic neurons divide the PaV into three distinct components. However, on homological, cytoarchitectonic, and neurochemical grounds these components can be subdivided further to form eight distinct subdivisions which represent an unusual degree of anatomical complexity and suggest that each subdivision may play a unique role in mediating visceral responses (Swanson and Sawchenko, 1983). This compartmentalization also suggests several possible mechanisms whereby disparate visceral responses are integrated. For example, different cell types in the PaV may receive a common input, such as the brain stem afferents from the nucleus of the solitary tract, which convey visceral sensory information to both the oxytocin neurons in the magnocellular division of the PaV and the corticotropin-releasing hormone neurons in the parvicellular division of the nucleus (Sawchenko et al., 1996). Additional integrative mechanisms operating at the level of the PaV are for different cells to have outputs that converge onto the same motor effector circuit or to be coupled by recurrent collaterals or connections with interneurons (Rho and Swanson, 1987). The organizational principals identified for the PaV may also apply to medial zone nuclei. As reviewed above, a variety of anatomical criteria indicate that the MPO is composed of three distinct sexually dimorphic subdivisions: a cell-sparse lateral subdivision and celldense medial and central subdivisions that are larger in males (Simerly et al., 1984b). As is the case for the PaV, sensory inputs are not uniformly distributed throughout the subdivisions of the MPO. Olfactory information relayed to the MPO by the medial amygdala and principal nucleus of the BST is primarily distributed to the medial and central parts of the MPO. Other classes of cortical information reach the MPO via the infralimbic cortex, subiculum, and rostral septal nucleus and end primarily in the lateral part of the MPO (Simerly and Swanson, 1986; Swanson, 2000), although projections from the ventral lateral septal nucleus are mostly distributed in the medial part of the MPO (Risold and Swanson, 1997a). Ascending noradrenergic inputs from the brain stem, which probably carry visceral sensory information, are distributed primarily to the central and medial parts of the MPO, whereas serotonergic afferents are largely localized to the lateral part of the nucleus. Thus, each compartment of the MPO receives a unique complement of inputs and may therefore respond differently to specific sensory modalities. However, because dendritic fields of one compartment may extend into an adjacent compartment, there may be some degree of overlap in sensory responsiveness. Nevertheless, afferents that terminate on distal dendrites have a functional impact distinctly different than that of inputs that terminate

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FIGURE 9 Integration at the level of hypothalamic nuclei. Schematic drawing of a midsagittal section through the rat brain to illustrate possible convergence of major sensory pathways onto CRH neurons in the paraventricular nucleus. Abbreviations used: C1, adrenergic cell groups; CG, central gray; HYP, hypothalamus; IGL, intergeniculate leaflet; LIMBIC, limbic region; LDT, laterodorsal tegmental nucleus; MePO, median preoptic nucleus; NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PIN, posterior intralaminar nucleus; PP, peripeduncular nucleus; PPN, pedunculopontine nucleus; PVT, paraventricular nucleus of the thalamus; SFO, subfornical organ. (Reproduced from Sawchenko, P. E., Imaki, T., Potter, E., Kovacs, K., Imaki, J., and Vale, W. (1993) The functional neuroanatomy of corticotropin-releasing factor. Ciba Foundation Sympasium 172, 5–29, 1998, with permission).

directly onto the cell soma. Because each component of the MPO also displays a unique pattern of projections (Simerly and Swanson, 1988), the functional impact of information conveyed by these outputs depends at least in part on the distribution and intensity of afferents to each part of the MPO. Convergent inputs to a region that arise from multiple parts of a nucleus, such as those from the central and medial parts of the MPO to the arcuate nucleus, may provide for the integration of processed sensory cues. Each compartment of a nucleus may also display a unique neurochemical organization with the majority of neurons that display a particular transmitter phenotype localized to one compartment. This is especially true for the magnocellular neurons of the PaV, although under certain hormonal conditions vasopressin is induced in parvicellular neurons (Sawchenko et al., 1984). In a similar way, each neurotransmitter-specific cell type found in the MPO is largely localized to one of its three subdivisions (Simerly et al., 1986). For instance, cholecystokinin- and thyrotropin-releasing hormoneimmunoreactive neurons are nearly entirely localized to the central part of the MPO, whereas neurotensin and corticotropin-releasing factor-immunoreactive cells are localized to the lateral part of the nucleus. Similarly, neurotransmitter-specific terminals appear to be distributed in accordance with the three subdivisions of the MPO as illustrated by substance P- and enkephalin-immunoreactive fibers, which are localized primarily to the medial and lateral parts of the MPO, respectively. In addition, each compartment of a nucleus may contain unique patterns of neurotransmitter

receptors adding additional complexity to the complete response profile of hypothalamic nuclei. The hypothalamus is particularly responsive to the regulatory effects of circulating factors. Steroid and thyroid hormones have free access to hypothalamic neurons, and many aspects of hormone responsiveness depend on the expression of specific nuclear receptors by discrete subpopulations of cells in the hypothalamus. Autoradiographic, immunocytochemical, and in situ hybridization methods have been used to demonstrate the distribution of neurons that express steroid and thyroid hormone receptors including androgen, estrogen, progesterone, corticosteroids, and thyroid hormone receptors (see Simerly, 1993, for review). That hormone-sensitive neurons are often distributed in accordance with cytoarchitectonic subdivisions of hypothalamic nuclei (Simerly et al., 1990) suggests that functions mediated by such nuclear compartments may be differentially modulated by changes in levels of circulating hormones. Conversely, expression of hormone receptors by otherwise separate populations of neurons may serve to coordinate the activity of these hormone-sensitive neurons. Strong projections from telencephalic regions that contain high densities of neurons that express steroid hormone receptors to hypothalamic nuclei that also receive hormonesensitive intrahypothalamic inputs indicate that the regulatory effects of hormones can be amplified by convergent inputs from hormone-sensitive regions. For example, the medial part of the medial preoptic nucleus receives strong inputs from the posterodorsal part of the medial amygdaloid nucleus and principal

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nucleus of the BST, as well as from the anterior periventricular, arcuate, ventral premammillary, and ventromedial nuclei of the hypothalamus, all of which have numerous cells that express high levels of receptors for sex steroid hormones. Taken together with the fact that most neurons in the medial part of the MPO express high levels of sex steroid receptors it is clear that the influence of sex steroids acting locally can be complemented by that of the same hormones acting on afferent populations of neurons, thereby bringing together disparate hormonally regulated sensory influences at the level of the MPO. In addition to steroid and thyroid hormones other factors secreted in the periphery travel in the blood to regulate the activity of hypothalamic circuits. The adipocyte-derived leptin hormone acts to inhibit food intake and stimulates catabolic autonomic and neuroendocrine responses that tend to direct nutrient stores away from the fat compartment (Woods et al., 1998).

The effectiveness of leptin in regulating energy stores is due to its direct access to hypothalamic neurons that control feeding behavior and other aspects of energy metabolism (Fig. 10) (see Sawchenko, 1998; Elmquist et al., 1999; Watts, 2000; Woods et al., 2000). Distinct subsets of hypothalamic neurons may respond to humoral factors such as leptin by virtue of their location in a region where the blood–brain barrier is compromised or through connections with circumventricular organs. The arcuate nucleus of the hypothalamus meets both of these features since it resides above the median eminence and shares connections with regions such as the subfornical organ and ovlt. The arcuate nucleus has long been associated with obesity (Olney, 1969), expresses high levels of leptin receptor (Fei et al., 1997; Elmquist et al., 1998a; Hakansson et al., 1998), and has high densities of neurons that express fos protein following intravenous injection of leptin (Woods and Stock, 1996; Elmquist et al., 1998b). Moreover, the

FIGURE 10 Neurohumoral integration in feeding pathways. Schematic representation of the organization and chemical specificity of projections from leptin–sensitive neurons in the arcuate nucleus to the dorsomedial nucleus of the hypothalamus (DM), the paraventricular nucleus (PVH), and the lateral hypothalamic area (LHA). Neurons in the arcuate nucleus that express neuropeptide Y (NPY) and agouti-related protein (AgRP; black circles), or that express proopiomelanocortin (POMC) products (gray circles), project directly to discrete populations of LHA neurons that express melanin-concentrating hormone (MCH; black circles) or hypocretin/orexin (H/O; gray circles), which have been implicated in the control of feeding behavior. MCH and H/O neurons are thought to send widespread projections to regions involved in generalized arousal and sensorimotor integration. Abbreviations used: CRF, corticotropin-releasing factor; IML, intermediolateral cell column; PAG, periaqueductal gray; TRH, thyrotropin-releasing hormone; VMH, ventromedial nucleus; ZI, zona incerta. (Reproduced from Sawchenko, 1998, with permission)

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projections of the arcuate nucleus to other sites implicated in the control of feeding such as the paraventricular and dorsomedial nuclei that also show leptin-induced increases in fos expression suggest that the arcuate nucleus is a principal monitor of leptin signaling in the brain. Integration of leptin signals with other systems mediating a variety of homeostatic mechanisms, such as reproduction (Mantzoros, 2000; Schneider et al., 2000), may take place at the level of the arcuate nucleus by virtue of common populations of peptidergic neurons with divergent connections. For example, injections of leptin activate both NPY and POMC neurons in the arcuate nucleus, which project to regions such as the paraventricular and dorsomedial nuclei and appear to convey leptin-based signals (Elias et al., 2000), but arcuate neurons also project to gonadotropin-releasing hormone cells in the preoptic region (Chen et al., 1989; Li et al., 1999). Thus, different physiological functions may be coordinated by interactions between neurons located in the arcuate nucleus through common activation by leptin, or possibly through intercellular communication. Similarly, projections to the anterior and ventral parts of the dorsomedial hypothalamic nucleus from the anteroventral periventricular nucleus, presumably carrying information sensitive to sex steroid regulation, overlap with those from the arcuate nucleus that may be influenced by leptin. Thus, convergent humor signals may regulate the activity of neurons in the dorsomedial nucleus via these convergent neural pathways (Gu and Simerly, 1997; Thompson and Swanson, 1998; Qiu et al., 2001). However, since the leptin-induced foscontaining neurons are in the posterior part of the dorsomedial nucleus, coupling of these different hormonally regulated sets of signals must take place at the level of the dorsomedial nucleus, perhaps through local connections between nuclear subdivisions. Therefore, it is important to bear in mind that some of the distinct classes of neurons defined by the criteria outlined above may be coupled within a nucleus by gap junctions, recurrent collaterals, or connections with interneurons, thereby providing for an additional level of information processing and integration. Integration at the Cellular Level Despite the organization of hypothalamic nuclei into compartments with distinct connections, rarely are such compartments homogeneous with respect to the neurochemical phenotype of individual cells. For instance, neurons in the medial parvicellular part of the PaV that contain corticotropin-releasing hormone (CRH) can coexpress at least seven other neuropeptides (enkephalin, vasopressin, neurotensin, angiotensin II, vasoactive intestinal polypeptide, PHI, and cholecystokinin). Technical limitations have prevented deter-

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mining if single CRH neurons are capable of expressing all of these molecules, but triple-labeling studies have shown that at least some CRH neurons coexpress two other peptides (Swanson et al., 1987; Sawchenko, 1991). Little is currently known, however, regarding the cellular mechanisms responsible for patterns of coexpression within subpopulations of CRH neurons. Moreover, these patterns of coexpression are often dynamic with fluctuations in the expression of some, but not other, coexpressed peptides within individual neurons (Sawchenko et al., 1992; Kovács and Sawchenko, 1996). Such differential regulation of coexpressed neuropeptides may represent a cellular mechanism for “chemical switching” of information through hypothalamic circuits (Swanson, 1983b, 1991). For example, neurons in the medial nucleus of the amygdala that project to the hypothalamus coexpress cholecystokinin (CCK) and substance P, yet changes in levels of circulating sex steroid hormones affect only levels of cholecystokinin (Simerly et al., 1989). Thus, when circulating levels of estrogen are high, as they are during proestrus, cellular levels of cholecystokinin are induced and decrease in response to lowered levels of circulating hormone. In contrast, cellular expression of substance P in these cells remains unchanged during the estrous cycle, or in response to acute changes in circulating estrogen. Taken together with similar finding in other pathways (Swanson, 1991), these observations suggest a possible cellular mechanism for gating sensory information through hormone-sensitive circuits. If we assume that release of coexpressed peptides at individual synapses is proportional to cellular content, then the functional impact of this release might preferentially promote activation of postsynaptic neurons that express cholecystokinin receptors, relative to those that express only receptors for substance P. If similar events occur in the vomeronasal pathway, activation of neurons in the medial amygdala by olfactory stimuli during periods when cholecystokinin levels are increased will lead to a preferential activation of postsynaptic cells that express high levels of CCK receptors, thereby effecting a hormone- dependent “switching” of sensory information to discrete subpopulations of hypothalamic neurons (Simerly, 1990). Similarly, endocrine changes bring about alterations in the expression of neuropeptides contained in neurons that express CRH (Swanson et al., 1987; Sawchenko, 1991) and gonadotropinreleasing hormone (Marks et al., 1992), which may alter the impact of these releasing factors on hormone secretion from the anterior pituitary. The distribution of neurotransmitter receptors in the hypothalamus has been studied extensively with autoradiographic methods. This approach has contributed greatly to clarifying which hypothalamic cell

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groups are responsive to various neurochemical signals. However, these binding techniques do not afford cellular resolution and it is likely that considerable heterogeneity exists with respect to the receptor profiles of subpopulations of hypothalamic neurons. For example, the AVPV receives a dense innervation by fibers that contain substance P immunoreactivity that is distributed throughout the nucleus, but it is not known if each of the many neurotransmitter-specific cell types found in the AVPV express substance P receptors. The cloning of cDNAs that encode neurotransmitter receptors and the use of in situ hybridization histochemistry, together with generation of receptor subunit-specific antibodies, has made possible the localization of receptor expression to individual neurons. It is a common observation in histochemical studies that some, but not all, neurons in a hypothalamic nucleus express particular receptors, but more colocalization studies are needed in order to determine if the pattern of expression represents distinct populations of neurons. In addition, cell-type-specific patterns of receptor regulation may subdivide further the functional classes of hypothalamic neurons and provide for additional mechanisms whereby the flow of information through functionally distinct circuits is regulated. Because it is likely that individual neurons receive multiple neurochemically distinct inputs it will be important to determine if synapse-specific regulation of neuronal responsiveness such as that demonstrated for neurons in the hippocampus (Malinow et al., 2000) exists in hypothalamic circuits. It has been shown that hormonal modification of synaptic organization (Matsumoto, 1991; Segarra and McEwen, 1991; Garcia-Segura et al., 1994; Mong et al., 2001) and intracellular receptor distribution (Coirini et al., 1989; Eckersell et al., 1998) occur, demonstrating that such cellular plasticity is likely to be a common aspect of cellular integration of multiple signals in the hypothalamus. Neural pathways from neurons responding to leptin may converge onto neurons in the paraventricular nucleus and contribute to cellular integration of chemically specific signals related to food intake. Neuropeptide Y (NPY) and agouti-related peptide (AGRP) are coexpressed within arcuate neurons and their projections. Together with melanocortin peptides, such as α-MSH, NPY, and AGRP represent key regulatory peptides since they are orexigenic and melanocortins are anorexigenic. AGRP is a potent antagonist of melanocortin signaling at MC4 melanocortin receptors, and in the paraventricular nucleus this interaction is likely presynaptic since MC4 receptors do not appear to be expressed on paraventricular neurons in abundance (Cowley et al., 1999). Moreover, melanocortins and NPY appear to be functional antagonists in the

paraventricular nucleus and have opposing actions on GABA-evoked currents within individual paraventricular nucleus neurons (Cowley et al., 1999). Thus, it has been proposed that POMC and NPY/AGRP neurons in the arcuate nucleus project to GABAergic neurons in the paraventricular nucleus to regulate GABA release. Since both NPY/AGRP and POMC neurons respond to leptin, their coordinate action on GABA release in the paraventricular nucleus provides an efficient means of integrating orexigenic and anorexigenic signals at the level of individual paraventricular nucleus neurons. Despite the complexity of cellular interactions in the hypothalamus some of the mechanisms underlying neurohumoral integration are beginning to emerge. It is already clear that subpopulations of neurotransmitterspecific neurons have unique signal transduction properties. For instance, progesterone treatment appears to cause an induction of the immediate early gene c-fos in a subpopulation of gonadotropin-releasing hormone neurons (Lee et al., 1990), and estrogen and progesterone cause changes in noradrenergic neurotransmission at both the receptor and the second messenger level (Petitti and Etgen, 1990). Estrogen can also alter neuronal responsiveness to GABA and glutamate (Wong and Moss, 1992; Moss et al., 1997; Gu et al., 1999a, 1999b), indicating that information transmitted by these neurotransmitters can have quite different effects on populations of hypothalamic neurons depending on whether they possess the ability to respond to changes in circulating levels of estrogen. Similarly, the leptin-sensitive NPY and POMC containing neurons in the arcuate nucleus that innervate melanocortin and hypocretin/orexin neurons in the lateral hypothalamus show different cellular responses to leptin (Elias et al., 1999). Thus, hypothalamic nuclei may be composed of distinct compartments that are made up of subpopulations of neurons with different regulatory profiles and response characteristics. It is also important to keep in mind that different parts of the hypothalamus may have unique compliments of glial cells. The increasing appreciation of the diverse roles played by glial cells in regulating microenvironments and cell–cell communication (Chowen et al., 2000; Araque et al., 2001; Bezzi and Volterra, 2001) provides a broad array of cellular mechanisms for specifying regionally distinct aspects of cellular integration. Integration at the Molecular Level Given the diverse array of environmental stimuli that affect neuropeptide gene expression in the hypothalamus, the molecular mechanisms underlying transcriptional activation in hypothalamic neurons will prove to be exceedingly complex. This is not surprising since

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hypothalamic neural circuits are made up of neurons that have much in common with neurons in other parts of the brain, and progress toward understanding how neurons integrate diverse signals at the molecular level is proceeding rapidly. The ability of a particular stimulus to alter gene expression depends on the presence of the appropriate signal transduction pathway, including the expression of molecules to initiate signaling (e.g., neurotransmitter or hormone receptors), an appropriate complement of transcription factors that couple the stimulus with the genome, and the presence of corresponding enhancer elements in the promoter region of the target gene (Goodman, 1990; Habener, 1990; Herdegen and Leah, 1998). For example, responsiveness to direct activation of gene expression by steroid and thyroid hormones can be dependent on the presence of the hormone receptor and a hormone response element in the hormone-sensitive gene (Yamamoto, 1985; Evans, 1988; Tsai and O’Malley, 1994; Beato and Sanchez-Pacheco, 1996; Jenster et al., 1997; Zhang and Lazar, 2000; Aranda and Pascual, 2001). Similarly, genes that display transynaptic transcriptional activation generally contain binding sites for sequence-specific trans-acting factors that respond to changes in levels of intracellular second messengers such as cAMP and calcium (Montminy, 1997; De Cesare and Sassone-Corsi, 2000). This traditional view of hormonal and transynaptic regulation of gene expression remains essentially valid, but the isolation of proteins that function as coregulators of transcription through multiple protein–protein interactions has revealed regulatory mechanisms that profoundly complicate our understanding of transcriptional control. Although little is known regarding the role of transcription factors and coregulators in hypothalamic pathways, considerable progress is being made toward understanding stimulus transcription coupling in clonal cell lines, and emerging evidence suggests new molecular mechanisms for the integration of diverse stimuli at the level of individual genes. Just as diverse neural pathways can converge onto single neurons, distinct signal transduction cascades transmitting a variety of stimuli can converge at the molecular level. One of the most dramatic examples of this type of convergence leads to the activation of the cAMP response element binding protein (CREB), which is a stimulus-induced transcription factor that plays an important role in transynaptic regulation of gene expression (Montminy, 1997). CREB is a member of the bZip superfamily of proteins and is a target of multiple signaling pathways activated by a diverse array of stimuli through phosphorylation at a specific serine residue (see Shaywitz and Greenberg, 1999, for review). In addition, CREB can integrate signaling events by

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forming heterodimers with other bZip factors, such as ATF-1 and CREM, or through protein–protein interactions with CREB binding protein (see below). Cross talk between signal transduction pathways that link extracellular signals with the nucleus represents another important mechanism for integration of homeostatic processes. For example, CREB phosphorylation is induced by protein kinase A in response to elevated levels of cAMP caused by G protein-coupled receptor activation. CREB phosphorylation is also induced by calcium acting through multiple calcium/calmodulindependent kinases, thereby providing a means of linking membrane depolarization with CREB activation. CREB also plays an important role in mediating growth factor induction of transcription by serving as a target for members of the Ras–MAP kinase cascade or through cooperation with other growth factorinduced transcription factors such as those that act at serum response elements. An additional level of communication between distinct signaling pathways is suggested by the observation that estrogen can induce phosphorylation of MAP kinases and extracellularsignal-regulated kinases in vitro and in vivo (Singer et al., 1999; Singh et al., 1999; Toran-Allerand et al., 1999). Thus, it is likely that in hypothalamic cells the nucleus is linked to afferent signals conveyed by hormones, growth factors, and neurotransmitters through multiple interacting signal transduction pathways such as those that lead to CREB phosphorylation. Of particular importance for the control of gene expression in the hypothalamus is the role of steroid and thyroid hormones. Because the hypothalamus regulates secretion of the tropic hormones that control the activity of the peripheral endocrine organs, steroid and thyroid hormones secreted by the adrenal gland, gonad, or thyroid gland exert some of their strongest central effects on hypothalamic circuits. Steroid and thyroid hormone receptors bind to hormone response elements, which function like transcriptional enhancers. But, unlike other enhancers, their activity depends on the presence or absence of ligand. For instance, when estrogen and thyroid hormone receptors bind their cognate hormones the hormone–receptor complex acts as a trans-acting transcription factor that binds to cisacting enhancer-like hormone response elements located within or near responsive genes to influence promoter activity. Because the capacity of these ligand-activated hormone receptors to recognize and regulate target genes is often determined by their ability to bind hormone response elements of hormone-sensitive genes, similarities in the structure of the DNA binding domains of related receptors implies that such receptors may activate overlapping sets of genes by acting through common response elements. For instance, the thyroid

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hormone receptor can bind to the estrogen response element with high affinity in vitro, but fails to activate transcription from these same elements in vivo (Umesono et al., 1988). Moreover, thyroid hormone receptors are capable of inhibiting the ability of estrogen to activate transcription (Glass et al., 1988). In vivo data supporting similar receptor interactions have been reported in the hypothalamus with clear implications for the molecular control of behavior (Pfaff et al., 2000). For example, pretreatment of female rats with thyroid hormone inhibits the actions of estrogen on proenkephalin gene expression (Zhu et al., 2001), and receptor-specific activities of thyroid hormone receptor subtypes influence copulatory behavior (Dellovade et al., 2000). On the other hand, two distinct adrenal steroid hormone receptors, the glucocorticoid receptor and the mineralocorticoid receptor, bind corticosterone with different affinities and can activate gene expression from common promoters (Arriza et al., 1988; Evans and Arriza, 1989; Reichardt and Schutz, 1998). Estrogen can also affect gene expression by binding to different forms of the estrogen receptor, which are coexpressed in several hypothalamic sites, but differ somewhat in their ability to regulate hormoneresponsive genes (Paech et al., 1997; Shughrue et al., 1997; Pettersson and Gustafsson, 2001). Thus, the codistribution of neurons that express related receptors with such interactive properties suggests that coexpression of these trans-acting factors by individual neurons provides considerable combinatorial potential for regulation of gene expression by different endocrine systems. Despite documented effects of steroid hormones on gene expression, in many cases the hormone-responsive genes lack consensus hormone response elements, suggesting that observed regulatory patterns are not due to direct action of the hormone-bound receptors on transcription of such genes. The lack of distinct hormone response elements in hormone-sensitive neurotransmitter genes may relate to the diversity and cellspecific regulation of interactions between steroid hormone receptors and other nuclear trans-acting factors, neurotransmitter receptors, and second messengers that respond to a variety of hormonal and neural cues. For example, estrogen and progesterone have been shown to induce expression of Fos immunoreactivity in the hypothalamus (Hoffman et al., 1990; Insel, 1990; Le et al., 1999), and together with the coordinately expressed protooncogene c-jun, are thought to be representative of general transcription factors (designated Fos or Jun) that are induced by environmental signals and which bind to DNA at regulatory sites termed activator-protein-1 (AP-1) regulatory elements (Morgan and Curran, 1991). CREB may also mediate hormonal regulation of gene expression since phosphorylation of

CREB can be regulated by estrogen (Gu et al., 1996; Zhou et al., 1996), progesterone (Gu et al., 1996), and glucocorticoids (Kovács and Sawchenko, 1996). Thus, the induction of trans-acting factors such as Fos or CREB may mediate the induction of hormone-sensitive genes that lack conventional hormone response elements. The action of hormones like estrogen may converge with transduction pathways that act at AP-1 sites through molecular interactions between estrogen receptors and Fos or Jun (Kushner et al., 2000; Pettersson and Gustafsson, 2001). More central to the action of steroid hormone receptors are coregulators that function as coactivators to increase transactivation by steroid hormone receptors or as corepressors to lower transcriptional activity of target genes (Shibata et al., 1997; McKenna et al., 1999). Cell-type-specific patterns of expression of these coregulators allow different populations of hypothalamic cells to integrate the activity of hormone-activated gene networks with a diverse array of environmental signals. Interaction between families of transcription factors that coordinately regulate gene expression is perhaps best illustrated by the CREB binding protein (CBP) and its close relative p300 (Goodman and Smolik, 2000). These important proteins have binding sites for a wide variety of transcription factors, including not only CREB, but also Fos and Jun (Vo and Goodman, 2001). The observation that CBP can also bind estrogen and thyroid hormone receptors indicates that these protein–protein interactions represent a powerful means of integrating diverse molecular signals at the transcriptional level. Although these mechanisms of molecular integration are only now beginning to be clearly defined, the evidence to date indicates that the activity of a given gene is controlled by changes in the relative ratios of interacting transcription factors expressed within a cell, each of which may respond to distinct cellular signaling pathways in a cell-type-specific manner according to the activity of coexpressed factors. Thus, neurons within the hypothalamus of the rat (and likely most other mammals) possess the potential to receive convergent sensory information from the environment and to integrate this information with neural and humoral signals related to the internal state of the animal. This process is mediated through a variety of complex neurological, cellular, and molecular mechanisms that collectively provide the required breadth and accuracy of adaptive responses necessary for the survival and propagation of the species.

Acknowledgments I thank Drs. Larry Swanson and Paul Sawchenko for providing illustrations and Mara Nelson for preparing the manuscript. Work in

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the author’s laboratory is supported by NIH Grants NS37952, DK55819, and RR00163.

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