Chapter 8 Neuroendocrine Aspects of the Aging Brain

Chapter 8

Neuroendocrine Aspects of the Aging Brain PHYLLIS M. WISE. JAMES P. HERMAN. and PHILIP W . LANDFIELD

Introduction .......................................................... Neuroanatomy of the Corticotropin Releasing Hormone ( 0 System ........ Excitatory Afferents to CRH Neurons ..................................... Inhibitory Afferents to CRH Neurons ..................................... Aging of the CRH-ACTH-Adrenal Cortex Axis............................. Hypercorticoidism.Stress. and Aging ..................................... Aging and AdrenocorticosteroidActivity ........ : ......................... Effects of Aging on CRH Neurons ....................................... Aging and GlucocorticoidNegative Feedback .............................. Corticosteroid Actions on the Aging Brain ................................. Neuroanatomy of the Hypothalamic Gonadotropin Releasing Hormone (GnRH)System ....................................................... Excitatory Afferents to GnRH Neurons ................................... Inhibitory Afferentsto GnRH Neurons .................................... Aging of the GnRJ3-Luteinizing Hormone (LH)-Ovarian Axis ............... The Female ReproductiveSystem as a Model .............................. Preovulatory and Pulsatile Patterns of LH Secretion During Middle Age ......... Changes in NeurotransmitterActivity May Influence Patterns of GnRH and LH Secretion ..................................................... Advances in Cell Aging and Gerontology Volume 2. pages 193.241 Copyright Ca 1997by JAI Press Ioc All rights of reproduction in any form reserved

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Deterioration of the Circadian Clock May Explain Changes in Multiple Rhythms Estrogen Actions in the Aging Brain ..................................... Conclusion...........................................................

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INTRODUCTION Interest and suspicion that endocrine systems are involved in the process of aging date back to beginnings of endocrinology.Brown-Sequard’slegendary reports that he was able to rejuvenate himself using testicular extracts were not supported by objective data, but nevertheless they created a stir in the scientific community and led to further experimentation regarding the efficacy of steroid replacement to relieve symptoms associated with reproductive aging (Burstein, 1955). The fundamental importance of the brain and particularly the hypothalamus in integrating and communicating environmental and internal neural information to peripheral organ systems crystallized with Harris’ work in the 1950s (Harris, 1955). Since then several laboratories have approached the question of whether changes at the hypothalamic level can explain the alterations that occur in anterior pituitary and target organ function (Minaker et al., 1985). We will focus on two neuroendocrine axes, the hypothalamic-pituitary-adrenocortical (HPA) and the hypothalamic-pituitary-ovarianaxis (HPO), to illustrate approaches and findings that clearly establish that changes in hypothalamic/pituitary function are important during aging. We have chosen these two systems because a significant body of neuroanatomical, neurophysiological, cellular, and molecular data exist for each. These two neuroendocrine axes also serve as paradigms of complex neuroendocrine systems that require exquisitely balanced feedback systems for maintenance of function. By necessity most of the work has been performed in laboratory animals, since many of the methods are invasive or terminal. Nevertheless, in some cases, parallel changes appear to occur in humans during normal or pathological aging. For example, exposure to excess glucocorticoids leads to cell death in the hippocampus of rats with effects similar to those observed during aging in humans. Likewise, changes in the pattern of anterior pituitary luteinizing hormone (LH) secretion occur in aging women and likely reflect changes in patterns of hypothalamic gonadotropin releasing hormone (GnRH) secretion. Recent advances in the neuroendocrinology of aging have been facilitated by several methodological advances, including patch clamping single cells, which permits quantitativemeasurement of single channel activity; in sifu hybridization, which allows analysis of gene expression in individual cells; tract-tracing methods that enable investigators to follow neuronal pathways for considerable distances; and microdialysis of specific brain regions, which permits monitoring of neurochemical events over time in individual animals. Using such techniques, we are

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slowly beginning to decipher the neural events that regulate endocrine changes in the periphery. In summary, the goals of this chapter are to use two neuroendocrine axes to illustrate changes that occur in neuroendocrine systems and the methods used to attack critical questions regarding the mechanisms that drive these changes.

NEUROANATOMY OF THE CORTICOTROPIN RELEASING HORMONE (CRH) SYSTEM Regulation of HPA activity is primarily controlled by a discrete set of CRH neurons localized to the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons integrate a wealth of blood-borne and neuronal afferent information into appropriate secretion of ACTH, which then triggers release of glucocorticoidsfrom the adrenal cortex (Figure 1). Glucocorticoidsthen exert negative feedback inhibition of CRH secretion by direct and indirect actions on PVN CRH neurons. The impact of aging on the HPA axis is thus required to act through this important cell group. At present, mechanisms underlying the impact of aging on CRH neurons are ill-defined. Efforts to identify potential sites whereby aging affects neuroendocrine function demand a clear knowledge of neuronal pathways subserving excitation and inhibition of CRH secretion.

Excitatory Afferents to CRH Neurons Pathways mediating excitationof CRH release can be divided into three general classes: (1) brainstem projections, emanating primarily but not exclusively from noradrenergic neurons in the region of the nucleus of the solitary tract (A2); (2) circumventricularorgan afferents, relaying information from the peripheral circulation; and (3) limbic system pathways, prominently involving stress-relevant structures such as the amygdala and bed nucleus of the stria terminalis (Figure 2). While the role of these circuits in age-related changes in the HPA function remain to be defined, it is clear that several excitatory pathways are affected by age and may thus alter the activational state of CRH neurons.

Brainstem Pathways Brainstem catecholaminergic pathways are intimately involved in stimulation of CRH release. Noradrenergic and adrenergic neurons in the caudal medulla (A2 and ClICUC3 regions) project directly to CRH containingneurons of the paraventricular nucleus (PVN), illustrating the potential for direct interactions with CRH release. In line with this observation, central administration of norepinephrine (NEi) or epinephrine (E) promotes secretion of adrenocorticotropin (ACTH); actions are blocked by prazosin but not by propranolol, illustrating that effects on the CRH

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Figure 7. Schematic of the hypothalamo-pituitary-adrenocortical(HPAI axis. HPA responses to stress are initiated by hypophysiotrophic neurons localized in the medial parvocellular (mp) division of the hypothalamic paraventricular nucleus ( W N ) . These neurons project axons to the external lamina of the median eminence, where they release adrenocorticotropic hormone (ACTH) secretagogues such as corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). Secreted ACTH elicits synthesis and release of glucocorticoids at the adrenal cortex. Glucocorticoids access target organs via the systemic circulation. To limit the physiological impact of glucocorticoids, negative feedback inhibition of glucocorticoid release is elicited at the adrenal, pituitary, and brain level. Feedback at the level of brain appears to be the prime mediator of glucocorticoid secretion, and may occur directly at the PVN or use intermediary CNS pathways such as the hippocampus.

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system are mediated through a-1-adrenergic receptors (Plotsky, 1987; Szafarczyk et al., 1987). Medullary PVN-projecting adrenergic and noradrenergic cell groups coexpress and corelease a number of neuropeptides which may serve as adjuncts to catecholaminergic actions on the HPA axis. For example, brainstem NE-and E-containing neurons coexpresssubstancesknown to affect HPA activation, including neuropeptide Y (NPY) and substance P (Hokfelt et al., 1987). Thus, PVN projections from the brainstem may also influence HPA activationby way of peptidergic neuromodulation. Unfortunately, the contribution of brainstem peptidergic pathways to CRH secretion is difficult to detennjne, as numerous intrahypothalamic projection systems also utilize the same peptidergic neuromodulators. Serotonergic (5HT) neurons of the dorsal raphe nucleus have been associated with HPA excitation. For example, local administration of 5HT elicits increases in PVN neuronal activity that can be blocked by SHT-depletingdrugs (Saphier and Feldman, 1989). Conversely, lesion of dorsal raphe 5HT neurons reduce corticosterone and ACTH responsesto neural stimuli (Feldman et al., 1987).Pharmacological studies indicate that systemic administration of 5HT- 1A receptor agonists (e.g., 80H-DPAT) increases glucocorticoid secretion (Korte et al., 1991; Welch et al., 1993). However, injection of 5HT or 80H-DPAT into the third ventricle or directly into the PVN result in bimodal effects on glucocorticoid secretion (Feldman et al., 1987; Korte et al., 1991), suggesting complex actions on CRH neurons. Circumventricular Organs

Circumventricularorgans appear to provide the PVN with information on the contents of the systemic circulation. For example, information on circulating cytokine levels may affect CRH neurons by way of receptors in circumventricular organs, such as the area postrema. in which CRH release is modulated by way of ascending brainstem systems (Ericsson et al., 1994). Information on fluid and electrolyte balance and blood pressure are relayed to the PVN by way of bloodbrain barrier deficient neurons in the subfornical organ (Swanson, 1987).It remains to be determined whether input from circumventricular organs has any direct impact on age-related changes in CRH neuron function. Limbic Pathways

Numerous studies have demonstrated excitatory effects of the amygdala on the HPA axis. Extensive lesions of the amygdaloid complex have been shown to decrease the release of ACTH and corticosterone (Herman et al., 1996). Studies aimed at more restricted regions of this nucleus suggest allocationof CRH-relevant action to distinct amygdaloid subnuclei. For example, bilateral lesions of the central nucleus of the amygdala significantly reduce stress-induced ACTH secretion (Beaulieu et al., 1986) supporting an excitatory role in CRH release. This role is

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supported by subsequent studies indicating attenuation of glucocorticoid secretion induced by fear conditioning (van de Kar et al., 1991). Positive regulation of the HF'A axis by the central amygdaloid nucleus parallels known actions of this region on fear-related behaviors (Davis, 1992). It should be noted that the amygdala does not have substantial direct input into the PVN. Anterograde tracing studies indicate very few amygdaloid efferents to the PVN region, suggesting that actions on CRH release are trans-synaptic (Gray et al., 1989; Prewitt and Herman, 1995). In support of this notion, the amygdaloid nuclei heavily innervatethe bed nucleus of the stria terminalis (BST), preoptic area, anterior, and mediobasal hypothalamus (Price et al., 1987), which may in turn project to the PVN. The BST, a region frequently considered to be a rostra1 extension of the amygdala, also appears to play an excitatory role in HPA stress regulation. Stimulation of the lateral region increases glucocorticoid levels and produces behavioral changes qualitatively similar to those induced by acute restraint stress (Casada and Dafny, 1991). Conversely, lesions of this region diminish ACTH, glucocorticoid, and prolactin secretion in a conditioned fear paradigm (Gray et al., 1993). Results from Herman and colleagues (Herman et al., 1994) indicate that damage to this region of the BST decreases PVN CRH messenger RNA (-A) expression, supporting an excitatory action of the BST at the hypophysiotrophic neuron. Notably, PVN-projecting neurons of the anterolateral BST are in aposition to relay information from the central, medial, and posterior cortical amygdala (Prewitt and Herman, 1995), indicating a potential pathway connecting the amygdala and PVN through the BST.

Inhibitory Afferents to CRH Neurons Inhibitionof CRH neurons is accomplished by several alternativepaths: (1) local feedback,working directly upon the CRH neuron itself; (2) limbic pathways, which relay multimodal sensory information and/or glucocorticoid feedback into an inhibitory signal at the PVN; and (3) BST/preoptic areahypothalamic circuits, which translate information relevant to homeostatic balance into modulation of HPA axis activity (Figure 2). It should be noted that inhibitory pathways are responsible for glucocorticoid negative feedback inhibition of the HPA axis, and may thus contribute to feedback deficits characteristic of HPA aging (see below). Local Feedback

CRH-containingneurons of the PVN appear to be targets for direct glucocorticoid feedback inhibition of the ACTH secretion. Local implants of corticosterone or dexamethasone into the PVN region greatly diminish CRH and arginine vasopressin (AVP) mRNA expression and ACTH secretion following adrenalectomy (Kovacs et al., 1986; Sawchenko, 1987). Micro-injections of glucocorticoidsinto

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Figure 2. Excitatoryand inhibitorycircuitryregulatingCRH neurons. (A) Excitatorycircuits. Brainstem: CRH neurons receive direct input from norepinephrine (NE)-containingneurons in the region of the nucleus of the solitary tract (A2cell group). These neurons are known to cosynthesize neuropeptide Y (NW), which may also play a role in HPA excitation. CRH neurons also receive input from medullary cell groups synthesizingepinephrine(C1, C2 and C3) and from 5HT neurons in the dorsal raphe nucleus. Circumventricular Organs: CRH neurons receive direct excitatory projections from the subfornical organ, which appears to use angiotensin II as a neurotransmitter. Limbidforebrainstructures: The amygdala appears to have a trans-synapticexcitatoryinput onto CRH neurons. Amygdaloid efferentsmay excite CRH neuronsthroughexcitatoryinteractionswithlocalglutamate-containing(CLU)neurons, or alternatively through inhibitory interactions with local CABAergic neurons. Local circuit CLU and CABA projections to the WN arise from the medial preoptic area, bed nucleus of the stria terminalis (BST), and/or hypothalamus. (B) Inhibitory circuits. Local: CRH neurons possess glucocorticoid receptors and are thus sensitive to changes in circulating glucocorticoids. CRH neurons also receive direct input from neuropeptidergic neurons in the preopticarea, lateral hypothalamus, and arcuate nucleus(ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; ENK, enkephalin; DYN, dynorphin; P-END, beta endorphin). Limbidforebrainstructures: Likethe amygdala, the hippocampusand prefrontal cortex appear to have trans-synaptic influences on CRH neurons. In this case, excitatory outtlow from the hippocampus/prefrontalcortex is likely to be translated into inhibition by interactionswith CABAergic neurons in the preoptic area, BST and hypothalamus.

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this region inhibit median eminence-projecting neurons, further consistent with direct action on this cell population (Saphier and Feldman, 1990). Notably, chronic stress induces a down-regulation of glucocorticoid receptor (GR)mRNA expression in the parvocellular PVN (Herman et al., 1995a); these decreases are inversely correlated with CRH expression, suggesting an interaction mediated at the level of the PVN neuron itself. Finally, CRH neurons coexpress GR and CRH (Uht et al., 1988), further suggesting the capacity to directly respond to circulating glucocorticoids. However, PVN GRs cannot account for all aspects of negative feedback. Deafferentationsof the PVN result in enhancedexpressionof CRH and AVP mRNA despite normal levels of glucocorticoid secretion (Herman et al., 1990). indicating that biosynthetic tone of this cell population is mediated by afferent neuronal input. In addition, basal secretion of glucocorticoids is limited by binding to central mineralocorticoidreceptors (MR) (Clark et al., 1989; Dallman et al., 1989),which are not highly expressed in the parvocellular PVN (Herman, 1993). Forebrain Stress Relays

Several forebrain structures, including the hippocampus, prefrontal cortex, and septum, have been reported to inhibit stress responsiveness and thereby serve as B. Inhibitory Circuitry: CRH Neurons

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transducers of glucocorticoid action in brain. The hippocampus is perhaps the best known limbic inhibitor of HPA activation. Early studies noted that animals with hippocampal lesions hypersecrete glucocorticoids under both basal and stressed conditions (Jacobson and Sapolsky, 1991). These findings were further supported by experiments demonstrating that hippocampal stimulation actively inhibited basal and stress-induced glucocorticoid secretion in rat and human (Slusher and Hyde, 1961; Dunn and Orr,1984; Rubin et al., 1996).More recent studies indicate that hippocampal lesion enhances corticosteroneresponses to acute stress in both rat and monkey (Sapolsky et al., 1991).This effect is directed at PVN CRH neurons, as lesions of the hippocampus, fornix, or ventral subiculumincrease CRH and AVP mRNA expression in PVN neurons and increase ACTH secretagogue release into the pituitary portal circulation (Herman et al., 1989,1995b; Sapolsky et al., 1989). Interestingly, hippocampal lesions also reduce the ability of exogenous glucocorticoids to inhibit stress-inducedHPA activation(Magarinos et al., 1987),suggesting that the hippocampus interacts with negative feedback regulation of the HPA system. The latter observation is further bolstered by the presence of high levels of both MR and GR mRNA and protein in the hippocampal formation (Krozowski and Funder, 1983; Herman, 1993). Anatomical analyses indicate that while the hippocampus does not project to CRH-containing neurons, it may interconnect with the PVN by way of any of several bisynaptic relays. Cullinan and colleagues (Cullinan et al., 1993) have performed dual-labelinganalyses of hippocampal-PVNinteractions,using animals that received injectionsof the retrogradetracer Fluorogold in the region of the PVN, and anterograde tracer Phaseolus vulgaris-leucoagglutinininto the ipsilateral ventral subiculum. Results indicated that several forebrain sites are in a position to relay hippocampalinfluencesto the PVN, includingfhe BST,preoptic area, anterior hypothalamus, subparaventriculararea and the dorsomedial hypothalamic nucleus (Cullinan et al., 1993). With respect to the BST, subsequent combined in situ hybridizatiodtract-tracing studies revealed that a large proportion of PVN-projecting BST neurons contain the inhibitory neurotransmitter GABA (Cullinan et al., 1993), suggesting a change in balance from presumably excitatory hippocampal outflow to inhibitory input into the PVN region. These data are consistent with the inhibitory role of the ventral subiculum on HPA function, as outlined above. Like the hippocampus, the medial prefrontal cortex appears to have a prominent negative effect upon HPA activity. Ablation produces hypersecretionof both ACTH and glucocorticoidin response to stress. Conversely, corticosteroneimplants in this region block restraint-induced ACTH secretion @ion0 et al., 1993). Neither prefrontal cortex lesions nor corticosteroneimplants affected ACTH or glucocorticoid response to either exposure. This region demonstrates a robust immediate early gene induction following stress (Cullinan et al., 1995),further consistentwith a role in stress integration. However, the pathways by which prefrontal neurons might impact the HFA axis remain unclear, as the region lacks direct input to the PVN.

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BsTIPreoptic ArealHypothalamic Regions

The parvocellular PVN receives prominent innervation from medial subnuclei of the BST, the medial preoptic area, and several hypothalamic regions, prominently includingthe dorsomedial,anterior, lateral, and arcuate nuclei. Most of these structureshave been associated with inhibition of the CRH system. Consistent with this inhibitory action, all of these regions contain sizable populations of GABAergic neurons (Swanson and Sawchenko, 1983; Leonhardt et al., 1995). Medial subdivisions of the BST exert inhibitory actions on the PVN. For example, stimulation of this region decreases glucocorticoid secretion in response to fear conditioning (Dunn, 1987) and increases expression of CRH mRNA in the parvocellular PVN (Herman et al., 1994). This region of the BST provides an extensive innervation of the medial parvocellular PVN, the majority of which is GABAergic in phenotype (Cullinan et al., 1993). The preoptic area and the hypothalamus also appear to be involved in inhibitory regulation of CRH neurons. Lesions of the medial preoptic area enhance restraintinduced corticosterone secretion, suggesting inhibitory actions on the PVN. Interestingly, implants of corticosteronedirectly into this region inhibit stress-induced ACTH secretion, suggesting that preoptic area neurons may communicate glucocorticoid negative feedback information to PVN CRH neurons (Viau and Meaney, 1996). Similarly, the ventromedial, dorsomedial hypothalamus, and arcuate nuclei all inhibit basal and/or stress-induced secretion of glucocorticoids (Dolnikoff et al., 1988; King et al., 1988; Larsen et al., 1994), consistent inhibition of PVN HPA neurons. Notably, all these regions are predominantly GABAergic in nature and are CFOSpositive following stress (Cullinan et al., 1996), suggesting that PVN inhibition may occur through activation of these hypothalamic GABAergic neurons. The suprachiasmatic nucleus (SCN) has also been implicated in regulation of PVN CRH neurons. The SCN is primarily responsible for entraining diurnal corticosteronerhythms (Cascio et al., 1987). Damage to this region desynchronizes circadian rhythms of glucocorticoid secretion (Cascio et al., 1987) and increases stress-induced glucocorticoid secretion (Buijs et al., 1993a).Although the SCN has a quite limited input into the parvocellular PVN region, it projects heavily to the subparaventricular region and dorsomedial nucleus (Watts et al., 1987; Buijs et al., 1993b), two regions which have direct connections into the parvocellular PVN proper (Ter Horst and Luiten, 1987; Roland and Sawchenko, 1993). However, it is unclear whether the impact of SCN lesion on the HPA axis is due directly to interaction with CRH neurons, or if desynchronization of circadian rhythms represents a significant stressor in and of itself. At present, it is not completely clear which central pathway or pathways are critical for age-related changes in HPA function. Evidence reviewed below indicates a prominent role for the hippocampus in HF'A dysfunction; however, it is equally clear that alterations in GR feedback at the PVN, disruptions of intrahy-

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pothalamic integrative circuits, and/or hyperactivity among excitatory pathways may influence long-term activity of PVN neurons. Further, the effects of aging on the functional integrity of PVN CRH neurons have yet to be firmly established. Elucidation of the impact of aging on glucocorticoid homeostasis thus requires considerable research directed at regulation and afferent control of this critical cell population.

AGING OF THE CRH-ACTH-ADRENALCORTEX AXIS Hypercorticoidism,Stress, and Aging Despite the evidence of age-related imbalance or change in nearly every endocrine system yet studied (Minaker et d.,1985), it is uncertain whether any of these imbalances, apart from reproductive system changes, play a major role in modulating patterns of age-related physiological decline. However, one particular clinical endocrinologic syndrome, hypercorticoidism (Cushing’s syndrome), appears to mimic a wide range of aging changes in peripheral systems. The similarity of Cushing’s syndrome to normal aging was initially noted some time ago on the basis of clinical observations (Findlay, 1949; Solez, 1952). The analogy was strengthened further through Selye’s experimental work on stress-induced degenerative diseases, which appeared in part to be mediated by adrenal corticosteroids. Selye also subsequently emphasized similarities of chronic stress-related symptoms to patterns of age-related degeneration, and developed a multiple-stress hypothesis of aging (Selye and lhchweber, 1976). The list of degenerative symptoms or diseases common to both hypercorticoidism and aging is impressive. It includes, among others, muscular wasting, osteoporosis, atherosclerosis, diabetes, reproductive system dysfunction, immunological decline, and an increased incidence of cancer. Although Cushing’s syndrome does not mimic all aspects of mammalian aging, the above manifestations are clearly among the most debilitating aspects of senescence. We do not yet know how similar such steroid-induced changes are to aging changes at a cellular level, but the similarity of the overt patterns of dysfunction nevertheless seems striking. In a separate line of investigation,Robertson and Wexler (1959) showed that the life of a Pacific salmon normally is terminated after a single spawning by the catabolic effects of associated elevated adrenocorticoid activity. Wexler subsequentlyextended these studiesto mammalian aging by showing that male breeder rats, in comparison to virgin rats, were characterized by both elevated adrenocortical activity and early arteriosclerosis;virgin rats showed similar changes, but at later ages. Moreover, analogous cardiovascular degeneration could be produced by corticosteroid administration (see review in Wexler, 1976). These early studies and observations focused for the most part on the possibility that stress and elevated adrenal steroids could accelerate or exacerbate diseases

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associated with aging processes. However, they raised the interesting possibility that cumulative long-term effects of endogenous corticosteroids, even at nonstress levels, might participate directly in mediating basic aging processes (Landfield et al., 1978). Regardless of whether adrenal steroids interact with underlying basic aging-processes, however, these early concepts of stress and aging predict that elevated corticosteroids can contribute to the most debilitating manifestations of peripheral aging. Therefore, the question of whether adrenal corticosteroids normally rise during late adulthood and into the later stages of life has been of considerable interest. Aging and Adrenocorticosteroid Activity

A significant number of studies have reported that serum corticosterone concentrations in rats increase during aging, whether under conditions of rest, mild stress, or substantial stress (Lewis and Wexler, 1974; Landfield et al., 1978; Sapolsky et al., 1983; DeKosky et al., 1984). Not all of these studies have agreed on the conditionsunder which serum corticosteroidswere found to be elevated,but each study reported elevation with aging under at least some conditions. It also has been found that adrenal weight (Landfield et al., 1978) and stress levels of ACTH (Landfield et al., 1980) increase with aging in rats, suggestingthat chronic hyperstimulation of the adrenal glands by pituitary hormones may underlie the aging increase in corticosteroid levels. One reported age change in the HPA axis is an apparent elevated threshold for feedback suppression of ACTH by glucocorticoids (Riegle and Hess, 1972; Sapolsky et al.. 1983).In addition, several studies have shown that one of the more consistent aging changes in the adrenocortical axis of rats is a delayed return to baseline following stress (see review, McEwen, 1992). Not all investigators have found an age-related increase in basal corticosteroid activity (Britton et al., 1975; Hylka et al., 1984). Nevertheless, Sapolsky (1991) reviewed the rodent literature on basal levels and concluded that the majority of studies to that point suggested that, if stressful conditions were well controlled, basal corticosterone levels usually were found to be increased in aging male rats. Therefore, one possible explanation for inconsistentfindings is that aging changes in this axis are difficultto observe in rats because of variable degrees of uncontrolled stress and/or variation across the diurnal cycle (Meaney et al., 1992).Other possible reasons for the discrepancies include differences in animal husbandry, strain differences, or genetic drift (see discussion in Slusher and Hyde, 1961; Landfield and Eldridge, 1992). In humans, several early studies found that plasma cortisol concentrations did not change substantiallywith normal aging (Minakeret al., 1985).Again, however, the system is extremely labile and difficult to study, and careful time course studies. may be needed to detect possible subtle age changes. For example, studies in humans in which ACTH was examined over time (Blichert-Toft and Hummer,

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1976), or in which the diurnal rhythm of cortisol was carefully examined (Friedman et al., 1969), observed age-related increases in the activity of this axis. In the Blichert-Toft and Hummer (1976) study, metyrapone suppression of steroid pro-

duction was used to test the possibility that the elderly exhibited a reduced capacity to respond to metyrapone with high ACTH secretion. The investigators found no decrease in capacity and, in fact (although not emphasized), found an increase in ACTH activity in the elderly. More recent studies in humans have reported an aging-dependent increase in morning levels of cortisol (Waltman et al., 1991) or a phase shift in the diurnal cycle (Sherman et al., 1985). Careful studies of cortisol responses to suprapituitary and pharmacologic stimuli also indicate greater responsiveness in older human subjects (Raskind et al., 1994). Overall, therefore, recent studies suggest the HPA axis also is more responsive and/or less suppressible in aging humans (see review, Raskind et al., 1994). In Alzheimer’s disease (AD) it has been found consistently that cortisol levels are substantially elevated (Raskind et al., 1982; Baldin et al., 1983). Interestingly, an increasing degree of atrophy of the hippocampus in imaging studies has been correlated with higher plasma cortisol in AD subjects (de Leon et al., 1988).

Effects of Aging on CRH Neurons Age-related changes in HPA activation are associated with changes in PVN function. Aged Fischer 344 rats show a significant decrease in PVN CRH mRNA expression and reduced hypothalamic content of CRH peptide (Cizza et al., 1994). Interestingly, ACTH and corticosteroneresponses to CRH were increased in aged rats, suggesting increased pituitary responsiveness (Cizza et al., 1994). Hypothalamic explants for aged Fischerrats show decreased CRH release,furtherconsistent with an age-related loss of CRH tone (Cizza et al., 1994). Interestingly, expression of AVP mRNA was increased in the parvocellular PVN of aged rats, suggesting that enhanced HPA reactivity is due to increased vasopressinergic drive. However, other studies suggest that PVN tone is significantly enhanced in aged rats. For example, aged Fischer 344 rats show elevated basal CRH levels in portal blood and enhanced portal CRH secretion in response to hemorrhage (Hauger et al., 1994). CRH receptor expression is decreased in aged rats, also consistent with prolonged CRH release. Other investigators report increased CRH release from hypothalamic explants of aged rats (Scaccianoce et al., 1990), further consistent with age-related enhancement of CRH secretion. Finally, analysis of human post-mortem tissue reveals an apparent activation of hypophysiotrophic PVN neurons, marked by increases in number of CRH neurons and extent of AVP/CRH colocalization in aged individuals (Raadsheer et al., 1994a,b). In short, the effect of aging on PVN neurons is far from clear. However, despite disagreements among these studies, all see a similar potentiation of glucocorticoid release. Thus, it is possible that age-related glucocorticoid hypersecretion can be

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effected by multiple pathways. Alternatively,CRH up-regulation and loss of CRH tone may occur at different points in the aging process. Thus, while the PVN plays a central role in age-related HPA dysfunction, the cellular changes underlying this action remain to be definitively elucidated.

Aging and Clucocorticoid Negative Feedback Age-related HPA hypersecretion has been associated with decreased glucocorticoid negative feedback. For example,aged rats are less responsiveto the inhibitory effects of the synthetic glucocorticoid dexamethasone on corticosteronesecretion (Sapolsky et al., 1986a). In the human, both aged and normal subjects suppress HPA activity following dexamethasone injection; however, suppression was less pronounced in the aged, suggesting some degree of feedback loss (Heuser et al., 1994; Ferrari et al., 1995). The long-term loss of negative feedback inhibition of the HPA axis has been implicated as the principal cause of both basal and stress-induced glucocorticoid secretion (see Sapolsky, 1992). The majority of studies assessing age-related loss of negative feedback have focused on the hippocampus. As noted above, lesions of the hippocampus have been shown to increase central HPA tone, increase stress-induced CRH, ACTH, and corticosteronesecretion,and attentuated negativefeedbackinhibitionof ACTH secretion (Jacobson and Sapolsky, 1991). Arguments proposing the hippocampus as a site of negative feedback are further supported by the prominent expression of both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in this region (Schwartz et al., 1977).Notably, aging produces marked downward changes in hippocampal MR and GR binding (Figure 3) and mRNA expression. In aged Long-Evans, Sprague-Dawley,Brown-Norwayand Fischer 344 rats, type 1 and/or type 2 binding is significantly reduced in hippocampal homogenates (van Eekelen et al., 1991, 1992; Meaney et al., 1992; Rothuizen et al., 1993; Cintra et al., 1994; Cizza et al., 1994;Morano et al., 1994).The loss in receptor number correlateswith cell loss, stress hyperresponsivity, and memory impairment (Issa et al., 1990). Further, studies performed in aged Fischer 344 rats indicate that GR and/or MR mRNA expression are decreased in aged animals,suggestinga decrease in receptor biosynthesis at the level of gene transcription or RNA stability (Cizza et al., 1994; Morano et al., 1994). The loss of hippocampal adrenocorticosteroid receptors in aging is believed to be responsible for reduced efficacy of glucocorticoid negative feedback, and as such play an important role in post-stress glucocorticoid hypersecretion (Sapolsky et al., 1986a). The specific adrenocorticosteroid receptor most affected in aging is under debate. Studies aimed at examining effects of glucocorticocoids on cell death indicate a GR mechanism. However, across the aging process MR seems to be most consistently affected. In general, age-related decreases in type 1 binding and MR mRNA are quite pronounced, and one of the cellular populations showing the greatest age-related cell loss (CA3) contains abundant quantities of MR, but

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Figure3. Effects of age on upregulationof hippocampalcorticosteroid receptors (group means 2 SEM). Young animals were 3-4 months of age; aged animals were 24-26 months of age: young 2 days postADX (n = 101, aged 2 days (n = 9), young 7-10 days (n = 13), aged 7-10 days (n = 5). (A) Total receptor binding; age effect, F = 9.878, p c 0.005; time effect, F = 17.19, p < 0.001; (B) Type I binding; age and time effects, nonsignificant; (C): Type II binding; age effect, F = 6.829, p < 0.01; time effect, F = 15.415, p c 0.001. (From Eldridge et al., 1989, with permission.)

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relatively little GR (van Eekelen et al., 1992,1991; Meaney et al., 1992; Rothuizen et al., 1993; Cizza et al., 1994). Specific MR deficits appear to correlate with both baseline hypersecretion and impaired glucocorticoid negative feedback (van Eekelen et al., 1992, 1991; Rothuizen et al., 1993). It is also important to note that aging has differential effects on regulation of GR and MR binding. Aged rats show impaired down-regulation of hippocampal GR binding by glucocorticoids (Eldridgeet al., 1989).These data suggestthat aged animals maintain normal levels of GR binding even when confronted with high levels of circulating glucocorticoids, suggesting enhanced GR action at the cell nucleus and perhaps an exacerbation of GR-mediated neuronal endangerment. In general, the principal effects of aging on the HPA axis appear to be intimately tied to loss of negative feedback inhibition, which is manifest as increases in basal and/or stress-induced glucocorticoid secretion. In either case, the impact of aging is to increase the amount of glucocorticoid seen by the brain over time. This change in glucocorticoid status will produce alterations in adrenocorticosteroid signaling, due to enhanced GR activation and/or reduced MR action at the genome. The gradual unveiling of potentially damaging actions of the GR likely contributes to the spectrum of neuronal and physiologic dysfunctions seen in elderly individuals.

Corticosteroid Actions on the Aging Brain One current hypothesis of brain aging holds that endogenous glucocorticoids directly modulate brain aging by gradually eroding the integrity of corticosteroidreceptor containing neurons and enhancing the vulnerability of these neurons to a number of toxic influences. This general view has been under consideration for over 15 years (Landfield, 1978) and has withstood many experimental tests and undergone several modifications (for reviews see Landfield, 1981, 1987; Sapolslq et al., 1986b; McEwen, 1992; Landfield and Eldridge, 1994). Glucocorticoids normally exert a wide range of behavioral, neurochemical, and neurophysiological effects, mediated primarily through the brain’s adrenal corticosteroid receptor systems (for reviews see Slusher and Hyde, 1961). Adrenal steroids influence diurnal rhythmicity, catecholamine systems, salt appetite, and learningbehaviors, among other brain functions. Moreover,adrenal steroids modulate neurotransmitter actions on excitability, and do so differentially depending upon whether the type I MR only or both the type I MR and type I1 GR together are activated (Joels and deKloet, 1992). In humans, chronic glucocorticoid administration or elevation can result in a number of psychiatric syndromes (Holsboer et al., 1994; Wolfkowitz, 1994). With regard to aging of the brain, however, the key experimental issues appear to revolve around whether aging-like brain changes are induced or made more probable by glucocorticoids and whether cellular-level effects of adrenal steroids appear to be candidates for neurotoxic mechanisms relevant to brain aging.

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Effects on Correlates of Aging Several aspects of plasticity at behavioral and neuronal levels are consistently impaired with aging and similar processes can be altered by treatment with glucocorticoids. These include maze learning and electrophysiology (Barnes, 1994), axon sprouting (Scheff et al., 1980), dendritic remodeling (McEwen and Gould, 1990), and long-term potentiation (LTP) (for review see McEwen, 1994). Electrophysiological correlates of hippocampal aging can be accelerated by six months of chronic stress (Kerr et al., 1989), and related correlates can be reversed by treatment with a specific glucocorticoid antagonist (Talmi et al., 1996). Structural changes in the hippocampus have been among the more extensively studied correlates of brain aging in tests of glucocorticoid actions. Initially, plasma corticosterone and adrenal weights of healthy, barrier-reared F344 rats were found to increase with aging and to correlate positively with quantitative measures of hippocampal astrocyte reactivity, a marker of brain aging (Landfield et al., 1978, 1980). In addition, long-term studies were conducted in which mid-aged animals were adrenalectomized (ADX) and were compared after 6-9 months of ADX to same-age controls on markers of hippocampal aging, such as pyramidal neuron density (Figure 4) or astrocyte reactivity. These studies provided quantitative

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Figure4. Pyramidal cell density values, expressed as number of nucleoli (mean f SEMI per 100 pm of stratum pyramidale length, for young, rnidaged, and aged (nonstressedvs. stressed) rats. Main effects of age were observed, and chronic stress resulted in an increase in cell loss for the aged groups (From Kerr et al., 1991 with permission.)

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anatomical evidence that long-term ADX was protective against declining hippocampal neuronal density and other markers of brain aging (Landfield et al., 1981; Landfield, 1987). Conversely, chronic administration of high doses of corticosterone, although difficult to investigatebecause of severe toxic effects of high glucocorticoids in rats (e.g., loss of appetiteand weight loss leading to death), was examined in young adult rats for three months. In this study, hippocampal neurons with specific corticoid receptors were reduced in glucocorticoid-treated animals (Sapolsky et al., 1985). Another study found that six months of mild chronic stress reduced hippocampal cell density in aged rats, but not in younger or middle-aged rat (Kerr et al., 1991). Studies also have found that handling of neonatal rats reduced subsequent stress-inducedrelease of corticoids while protecting against decreased hippocampal cell density with aging (Meaney et al., 1988), and that direct infusion of corticosteroids into monkey hippocampus could cause early signs of neuronal toxicity (Sapolsky et al., 1990).Other studies have found that plasma levels of corticosterone were correlated with learning/memory impairment and decreased neuronal density in aged rats (Issa et al., 1990). On the other hand, several recent studies have found similar age-related deficits in maze learning in animals without neuron loss in the hippocampus (Rapp and Gallagher, 1996; Rasmussen et al., 1996). In vitro and in vivo studies have shown that elevated levels of circulating glucocorticoidscan exacerbateinjury to hippocampal and cortical neurons induced by excitotoxic, metabolic, and oxidative insults. Several of the alterations induced in the neurons are similar to those observed in age-related neurodegenerative conditions, such as stroke and Alzheimer’s disease. Corticosterone increased the vulnerability of hippocampal neurons to cytoskeletalalterationsin microtubule-associated proteins and to degeneration induced by excitotoxic (Elliott et al., 1993) and ischemic (Smith-Swintosky et al., 1996) injuries. Physiological stress also promotes excitotoxic neurodegenerative cascades in adult rats (Stein-Behrens et al., 1994). Studies of cultured rat hippocampal and cortical neurons have shown that glucocorticoidscan impair glucose transport (Homer et al., 1990), destabilize calcium homeostasis (Elliott and Sapolsky, 1993), and exacerbate free radical production in neurons exposed to oxidative insults (Goodman et al., 1996). Corticosterone increased the vulnerability of cultured rat hippocampal neurons to amyloid p-peptide toxicity, suggesting a role for glucocorticoidsin the pathogenic process in Alzheimer’s disease (Goodman et al., 1996). By enhancing oxidative processes in the aging brain, glucocorticoidscould accelerateboth the normal aging process and the many different neurodegenerative disorders that involve free radical-mediated damage. Possible Cellular Mechanisms A number of cellular and molecular effects of glucocorticoids that appear to be candidates for underlying toxic and/or aging-like mechanisms have been

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identified in brain neurons. In particular, a number of studies suggest that glucocorticoids may act in brain aging by altering calcium (Ca2+)homeostasis. Alterations in several aspects of Ca2+homeostasis, from resting Ca2+ concentrations in cells or synapses, to influx, buffering, and extrusion, have been found in aged mammalian neurons (for reviews see Gibson and Peterson, 1987; Khachaturian, 1989; Landfield et al., 1992). Because it is well established that elevated and/or dysregulated cytosolic Ca2+ can be toxic to a variety of excitable cells, including neurons (Campbell et al., 1996), there has been growing interest in the possibility that these alterations may play a critical role in brain aging and Alzheimer’s disease (AD) (for review see Disterhoft et al., 1993). Recently a link was found between corticosteroid activation of hippocampal neurons and an increase in voltage-sensitive Ca2+ influx (Figure 5). In the hippocampus, corticosteroidswere found to increasethe Ca2+-dependent afterhyperpolarization (AHP), the Ca2+ action potential, and voltage-activated Ca2+ currents (Joels and de Kloet, 1989; Kerr et al., 1989,1992),and each of these electrophysiological indicants of voltage-activated Ca2+ influx also has been found to be increased in hippocampal neurons of aged rats or rabbits (Landfield and Pitler, 1984; Pitler and Landfield, 1990; Moyer et al., 1992; Disterhoft et al., 1993; Campbell et al., 1996). These actions seem to be mediated by the type I1 glucocorticoid receptor (Joels and deKloet, 1992; Kerr et al., 1992). Moreover, corticosteroids exerted a greater impact on the Ca2+-dependentAHP in aged than in young hippocampal neurons (Kerr et al., 1989). New studies at the single channel level indicate that one of the basic concomitants of aging in hippocampal neurons is an increased density of L-type Ca2+ channels (Thibault and Landfield, 1996), which could account for many of the alterations in Ca2+influx noted above. Conceivably,therefore, this channel type is an important regulatory target for glucocorticoids. Another cellular mechanism through which glucocorticoids could alter Ca2+ homeostasis is through altered energy metabolism and/or glutamate clearance. This mechanism has been suggested based upon studies that show glucocorticoids can enhance glutamate-mediated excitotoxicityin brain cells, whereas glucose supplementation can counteract the neurotoxicity and the associated increases in intracellular Ca2+ (Elliott and Sapolsky, 1993; Sapolsky, 1993). Thus, these results raise the possibility that glucocorticoid activation and dysregulated calcium homeostasis may be sequential components of a complex brain aging process. Initially, glucocorticoid-mediatedincreases in Ca2+influx may only reversibly impair neuronal function. However, over the long term, the cumulative effects of consistently higher Ca2+ influx may gradually erode neuronal integrity and result in heightened susceptibility to irreversible deterioration,or cell death, particularly in the presence of toxic or neurodegenerative (e.g., Alzheimer’s disease) conditions.

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Figure 5. Representative calcium action potentials for cesium-loaded tetrodotoxintreated neurons in hippocampalslices exposed to either vehicle, a specific glucocorticoid agonist, or the agonist and cyclohexamide. Action potentials were triggered by depolarizingintracellular pulses and have an initial large amplitude, fast phase, and a late slow phase. Neurons exposed to a saturating dose of the agonist exhibited wider initial phases and longer duration and larger amplitude slow phases than did control neurons. Cycloheximide blocked the effect. (From Kerr et al. 1992, with permission.)

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NEUROANATOMY OF THE GONADOTROPIN RELEASING HORMONE (GnRH) SYSTEM The menstrual cycle of primates and the estrous cycle of other mammals result from the intricate orchestration of neurochemical events that climax in a preovulatory GnRH surge, which, in turn, stimulate preovulatory gonadotropin secretion, which then causes ovulation of one or more ripe follicles from the ovary (Figure 6). The ovary secretes two dominant steroids. estradiol and progesterone. and several ovarian peptides, which feed back both negatively and positively to the level of the brain and pituitary gland and regulate the pattern of secretion of GnRH and the gonadotropins. The synchronization and coordination of neurochemical and endocrine events in the young sexually mature animal remains a topic of intense study. The changes that occur with age and cause the onset of the perimenopausal transition that lead to ultimate demise of the ovarian follicular reserve and the menopause are even less clear. As in the CRH axis, an understanding of the neuronal pathways that stimulate and inhibit the GnRH neuron is prerequisite to understanding the effects of age on the female reproductive axis. Excitatory Afferents to CnRH Neurons

GnRH neurons are scattered throughout the medial preoptic area, organum vasculosum of the lamina terminalis (OVLT), and diagonal band of Broca (Figure 7). Axons of these neurons coalesce to innervate the lateral region of the external lamina of the median eminence, where GnRH is secreted into the hypophysial portal plexus. The diffuse organization of GnRH cell bodies has rendered anatomical study of the connectivity of this cell type quite difficult. Thus, the majority of work on stimulation of GnRH has been performed using phannacologic techniques; consequently, considerably less is known about neurocircuit regulation of the GnRH neuron than is the case for CRH cells. The importanceof neuronal input into GnRH neurons cannot be underestimated. These neurons are the final common pathway for LH release, integrating both positive and negative estrogen feedback into appropriate secretory activity. However, these neurons do not themselves express estrogen receptors (Herbison and Theodosis, 1992).As a result, GnRH neurons rely completely on afferent input for estrogen feedback information. Generally, studies of neuronal circuit regulation of GnRH have focused on two principal pathways: brainstem circuitry, primarily from monoaminergic neurons in the medulla and pons, and local circuit integration by way of cells in the hypothalamus and in immediate proximity to the GnRH neurons in question. Additional regulatory informationmay be conferred by nitric oxide and GnRH itself, although the exact roles of these molecular species remain to be definitively elucidated. We shall deal with these in turn.

Higher Brain Loci

Basal Forebrain

Figure 6. Schematic of the hypothalamo-pituitary-ovarianaxis. GnRH neuron cell

bodies exist in the septal/preoptic area in rodents. Axons traverse to the median eminence where GnRH is released into the hypophysial portal blood. CnRH, which reachesthe anterior pituitary, stimulates the synthesis and secretion of LH and FSH from gonadotrophs. LH and FSH elicit the synthesis and release of both estradiol and progesterone, depending upon the pattern and relative concentrationsof gonadotropin secretion and the developmental status of the follicles. Steroid negative and positive feedback occurs to the level of the ovary, pituitary, and brain.

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Brainstem Pathways

A considerable body of literature indicates powerful modulation of GnRH neurons by brainstem noradrenergic/NPY pathways. Destruction of norepinephrone (NE) neurons or local blockade of a- (but not 0-) adrenergic receptors decreases pulsatile release of GnRH, consistent with noradrenergic stimulation of

A. Elrcifafory Circuitry: GnRH Neurons Preoptic area Septnnddiagonal band

Anferownlml Preoptk Area

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Figure 7. Excitatory and inhibitory circuitry regulating CnRH neurons. (A) Excitatory circuitry. CnRH neurons are innervated by medullary norepinephrine-containingcell groups A1 and A2. These cells coexpress NPY and may act to stimulate CnRH release by direct interactions with GnRH cells, stimulation of local glutamatergic cell populations, or inhibition of local GABA cell groups. Local circuit excitation of CnRH cells may be conveyed by neurons in the preoptic area, septurddiagonalband of Broca, organum vasculosum of the lamina terminalis (OVLT), or perhaps arcuate nucleus. Additional stimulatory input may be derived from dopamine neurons of the anteroventral regions of the preoptic area or by input from other GnRH neurons. (B) Inhibitory circuitry. Inhibition of CnRH release prominently involves CABAergic and neuropeptidergic inputs from preoptic area and hypothalamic cell groups (ANP, atrial natriuretic peptide; CNP, C-type natriureticpeptide; ENK, enkephalin; NT, neurotensin; P-END, beta endorphin). 5HT also inhibits CnRH secretion, either directly or by way of inhibition of local excitatory inputs.

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GnRH neurons. Endogenous GnRH secretion correlates with changes in pulsatile

NE and NPY release, suggesting that NE plays a role in driving endogenousGnRH

rhythms (Terasawa, 1995). Brainstem catecholamines play a prominent role in mediating the LH surge. Central administration of NE or E to estrogen-primed rats directly induces LH release. Conversely, blockade of a-adrenergic receptors inhibits LH secretion, again consistent with stimulation of GnRH neurons by central NE pathways (for review see Barraclough and Wise, 1982). Expression of GnRH mRNA is positively regulated by central noradrenergic neurotransmission, suggesting that NE also regulates GnRH biosynthesis (He et al., 1993; Kim et al., 1994). Catecholamine/GnRHinteractions may be mediated by direct and indirect pathways. Direct connections are confirmed by the presence of tyrosine hydroxylase ("€I)- and dopamine beta-hydroxylase(DBH)-containingsynapses on GnRH containing cell some and dendrites in the septudpreoptic area (Leranth et al., 1988; l'illet et al., 1989). However, TH and DBH synapses are also observed on GABAergic neuronspresentin this region (Leranthet al., 1988). Preopticarea GABA neurons are believed to mediate inhibition of GnRH neurons (see below), thus raising the possibility that NE works by multiple mechanisms to promote GnRH release.

B. Inhibitory Circuity GnRH Neurons Preoptic area Septuda7agonal bond

Arcuaie Preoptic area Septunddiagonalband

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Figure 7. Continued.

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As was the case for the CRH system, innervation of this region appears to emanate predominantly from the A2 and A1 regions of the brainstem, with a very small contribution from the locus coeruleus (Wright and Jennes, 1993a). A substantial proportion of these neurons colocalize NPY (Hokfelt et al., 1987). Notably, like NE,NPY has been shown to increase GnRH release (Bonavera et al., 1996), and NPY stimulates GnRH mRNA expression in the septudpreoptic area (Li et al., 1994). Moreover, electron microscopic studies indicate that NPYand DBH-containing afferents to GnRH neurons show similar morphology and distribution (Tillet et al., 1989), consistent with corelease from brainstem NE neurons. However, NPY is also synthesized in other cell groups projecting to the region of GnRH cells (Swanson, 1987), making it difficult to define the source of NPY innervation. The development of an immortalized line of GnRH neurons (GT1 cells) has permitted detailed analysis of the pharmacology of GnRH regulation. Both NPY and NE (Martinezde la Escaleraet al., 1992a;Segovia et al., 1996) promote GnRH release in GT1 cells, consistentwith in vivo data. However, in GT1 cells stimulation of GnRH is conferred through P-adrenergic receptors (Martinez de la Escalera et al., 1992b; Segovia et al., 1996). The significance of these results remains to be determined.

Local Circuits The lion’s share of GnRH regulation appears to be accomplished by local circuit neurons. Anatomicalstudies suggestthat GnRH neurons are extensivelyinnervated by neurons intrinsic to the preoptic area and septum. Included in this category are dopamine (DA) neurons of the anteroventral periventricular nucleus, which appear to directly innervateGnRH neurons, and excitatory amino acid containing neurons presumptively scattered in the vicinity of GnRH containing neurons. Several studies indicate that DA enhancesGnRH release. Central administration of IDA has been shown to increase GnRH release in vivo, and DA elicits GnRH release from GT1 cells through D1 dopamine receptor subtypes (Martinez de la Escalera et al., 1992b). Dopaminergic innervation of GnRH neurons appears to be mediated by way of TH-positive neurons localized to the anteroventral periventricular nucleus (Horvath et al., 1993). The excitatoryamino acid N-methyl-D-aspartate (NMDA) elicits GnRH release and enhances preoptic area GnRH mRNA and protein expression (Carbone et al., 1992; Lee et al., 1993; Gore and Roberts, 1994), consistent with coordinate excitation of secretion and gene expression in this cell population. Actions of NMDA on GnRH neurons may be mediated in part through interactions with noradrenergic neurotransmission (Suh et al., 1994).Notably, release of glutamate and aspartate was increased in the preoptic area prior to and during the LH surge, consistent with a physiologic role of excitatory amino acids in LH release (Jarry et al., 1995). Interestingly, no changes were evident at the level of the mediobasal

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hypothalamus, suggesting that the site of action was proximal to neuronal cell bodies, rather than median eminence terminal fields. Recent data suggest that nitric oxide (NO) regulates GnRH release. Anatomical data indicate the presence of NO synthase in GnRH-containing regions of the preoptic area and OVLT, as well as cell groups projecting to this region. GnRH neurons do not appear to express NO synthase, suggesting that actions are communicated by afferent input (Bhat et al., 1991). It should be noted that the actions of NO on GnRH release are unclear. In vivo studies suggest that NO is in fact permissive for excitatory amino acid, NPY,and prostaglandin-induced excitation of GnRH release (Bhat ef al., 1991; Moretto et al., 1993; Rettori et al., 1993; Bonavera et al., 1996). Conversely, other studies suggest that NO inhibits GnRH release; for example, incubation of GTl cells with the NO precursor L-arginine blocks NE-induced GnRH secretion (Sortino et al., 1994). The exact role of NO in GnRH regulation remains to be definitively elucidated. Electron microscopic data indicate that GnRH neurons receive afferent input from other GnRH synthesizing neurons, suggesting the capacity for ultrashort feedback effects of GnRH on GnRH neurons (Pelletier, 1987).The nature of GnRH autoregulation is presently unclear. Notably, some studies suggest that intercommunication between GnRH cells may be importantfor synchronizedfiring (Silverman et al., 1985; Hiruma and Kimura, 1995), consistent with involvement in the LH surge. Due to the diffuse nature of the GnRH system, very little information is available regarding the effectsof specificlesionson synthesisand secretion.Availablestudies indicate that lesions of the anteroventral periventricular region and SCN attenuate LH surges in intact rats and estrogen-progesteronetreated ovariectomized rats, consistent with excitatory input from these structures. GnRH mRNA was also reduced in the preoptic area of lesioned rats, suggesting generalized down-regulation of GnRH neurons (Ma et al., 1990). Inhibitory Afferents to CnRH Neurons As was the case for excitation,inhibition of GnRH release has been extensively characterized at the local level (Figure 7). Evidence for inhibitory regulation through the brainstem is limited to the serotonergic system, and little information is available on integration by cortical or limbic forebrain inputs. Brainstem Pathways

The contribution of the brainstem to inhibition of GnRH neurons is primarily mediated through 5HT neurons of the dorsal and median raphe nuclei in the midbrain and pons. For example, injection of 5HT into the preoptic area significantly decreases GnRH mRNA expression; conversely, antagonists of 5HT1 and 5HT2 receptors potentiate GnRH mRNA levels (Li and Pelletier, 1995). Similarly,

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5I-IT1 and 5HT2 receptor antagonists increase release of GnRH from mediobasal hypothalamic/preopticaredmedian eminence explants (Meyer et al., 1992). Anatomical substrates of 5HT action are indicated by the presence of serotonin-containing terminals on GnRH neuronal perikarya and dendrites (Kiss and Halasz, 1985; l'illet et al., 1989). However, dual-label in siru hybridization studies suggest that SHTlA, 1C and 2 receptors are not expressed in GnRH neurons, suggesting that serotonergic action may be mediated by neighboring neurons or alternative receptor species (Wright and Jennes, 1993b). local Circuits

Inhibition of GnRH neurons appears to be mediated predominantly at the local level. Decreases in GnRH secretion and synthesis are driven by the inhibitory neurotransmitter GABA and peptidergic neuromodulators. Inhibition occurs via both direct action on GnRH neurons and by modulation of NE-driven excitation. Brain regions containing GnRH neurons receive a host of afferents from preoptic/hypothalamic cell groups expressing GABA (Okamura et al., 1990). GnRH neurons are directly (Leranth et al., 1985) contacted by GABAergic synapses, consistent with a direct action on GnRH cells. Interestingly, in sheep preoptic area GABA neurons contain estrogen receptors (Herbison et al., 1993), suggesting that GABA cells may relay steroid feedback information to GnRHcontaining neurons. In vivo microdialysis studies note a pronounced decrease in preoptic area GABA levels prior to and during the LH surge, indicating that LH release coincides with decreased GABAergic inhibition (Jany et al., 1995). The actions of GABA on GnRH secretion and synthesis may also be exerted by modulation of noradrenergic neurotransmission. For example, intraventricular or preoptic area administration of the GABA-A antagonist bicuculline or the GABAB antagonistphacolfen greatly enhanced the ability of centralNE to promote GnRH release (Hartman et al., 1990). Conversely, electron microscopic studies have verified the presence of TH terminals on preoptic area GABAergic neurons, suggesting that NE may modulate GABAergicinhibition of GnRH release (Leranth et al., 1988). Inhibition of GnRH release may also be accomplishedby a number of neuropeptide-containing local circuit systems. For example, A",CRH, neurotensin, and opioid peptides all inhibit in vivo and/or in v i m GnRH release (Leposavic et al., 1991;Leshin et al., 1991; Rivest et al., 1993).Again, due to the diffuse localization of GnRH cells and the rich hypothalamic distribution of peptidergic neurons, the precise pathways involved remain to be elucidated. However, it is clear that A", neurotensin, and CRH are localized within the septudpreoptic area and could easily affect GnRH release by local circuit neurons, similar to mechanisms proposed for GABA and excitatory amino acids.

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AGING OF THE GnRH LUTElNlZlNG HORMONE (LH)-OVARIANAXIS The Female Reproductive System as a Model The menopause is the definitive cessation of reproductive cycles in primates. Since an increasing number of women will spend a larger proportion of their lives in a hypoestrogenic state, an understanding of the mechanisms that govern the menopausal transition becomes even more important. For many years, it has been accepted that the menopause resulted simply from an exhaustion of the ovarian follicular reserve (vom Saal et al., 1994) and that the hypothalamic/pituimy alterationsoccurred merely in responseto changing ovarian function. However, recent findings suggest that both the brain and the ovaries are involved in female reproductive senescence. It is true that ovarian follicles are completely depleted in postmenopausalwomen (Block, 1952; Costoff and Mahesh, 1975). But what is most intriguing about follicular loss is that the rate of loss acceleratesduring the decadeprior to the menopause, leading to completedepletion of thz follicular endowment by the time women are in their fifties (Figure 8) (Richardson et al., 1987; Gougeon et al., 1994). What leads to this accelerated loss of follicles during middle age? Are there neural changes that impact upon ovarian function during the early stages of reproductive aging? Recently, several lines of evidence have led some investigators to believe that the brain contributes to the sequence of events that lead to reproductive decline. According to this alternative perspective, deterioration at the hypothalamic level plays a major role in the cascade of events that leads to the menopause. Thus, subtle changes in the temporal pattern and synchrony of neural signals, which are detectable in both women (Matt et al., 1994) and animal models (Wise et al., 1991) prior to the cessation of reproductive cycles, may contribute to the accelerated loss of follicles that occurs during the middle-age transition to acyclicity and infertility. Some of the earliest evidence that the hypothalamus plays a role in reproductive aging came from classic studies using two experimentalapproaches. In one, ovaries of old animals were transplanted to the kidney capsule of young, regularly cycling but previously ovariectomized females hosts. The investigators found that young animals that received ovaries of senescent rats showed follicular developmentand ovulation, suggesting that the depletion of ovarian oocytes is not the cause of the acyclic state (Krohn, 1955,1962,1966; Peng and Huang, 1972; Aschheim, 1983). In addition, grafts of fetal hypothalamus placed into the third ventricle of old hosts restored ovarian weight and the appearance of follicles at various stages of development, as well as corpora lutea (Matsumoto et al., 1984; Huang, 1988). Similarrestorative effects have been induced by neural transplants when measuring male reproductive function (Huang et al., 1987). In the second method, administration of drugs that restore the level of activity of monoaminergic neurotransmitters (Clemenset al., 1969; Quadri et al., 1973; Huang et al., 1976; Clemens andBennett,

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Figure 8. Ovarian follicular depletion in human females with respect to age. The rate of depletion greatly accelerates duringthe fourth decade. (Adaptedfrom Richardson et at. 1987, with permission.)

1977; Cooper, 1977;Cooper and Walker, 1979) or progesteronetreatment (Everett, 1940, 1943, 1980; Clemens et al., 1969; Everett and Tyrey, 1982) reinstates LH surges, estrous cyclicity, and ovulation. Electrochemical stimulationof the preoptic area of old, constant estrous rats enhances LH secretion (Clemens and Bennett, 1977) and results in ovulation, followed by a brief period of estrous cyclicity (Clemens et al., 1969). These results implicate changing hypothalamic function as a crucial element in reproductive decline. More recent studies that concentrate on the middle-age period suggest that hypothalamic changes, albeit subtle, may contribute to the transition to acyclicity (for review see Wise, 1997).

Preovulatory and Pulsatile Patterns of LH Secretion During Middle Age The preovulatory LH surge is both delayed and attenuated in middle-aged rats prior to overt changes in the length or regularity of the LH surge (Figure 9) (Cooper

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Figure 9. Plasma LH concentrationsin young and middle-agedrats on proestrous. Rats were cannulated to the level of the right atrium early in the morning and bled during the day. (From Wise, 1982a, with permission.)

et al., 1980;Wise, 1982a;Nass et al., 1984).Nass and colleagues mass et al., 1984) found that regularly cycling rats that became irregular cyclers soon after the cycle in which LH was monitored exhibited a more delayed and attenuated LH surge than rats that would continue to cycle for at least the following six months. Changes in pulsatile gonadotropin secretion have also been documented in middle-aged laboratory animals and in women. Scarbrough and coworkers (Scarbrough and Wise, 1990)assessed changes in the LH pulse generator in middle-aged rats that were chronologically matched, yet exhibited progressive stages of reproductive senescence. They found that the amplitude of LH pulses decreased with age and with reproductive decline,and the inter-pulseinterval and averageduration of individual pulses increased. These data strongly suggest that subtle changes in the integrity of the GnRH pulse generator occur early, prior to the transition from regular to irregular cycles, and may be a component of the cascade of events that contribute to reproductive aging.

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Studies performed with middle-aged women who maintained menstrual cycles of normal length demonstratethat some, but not all, of the alterationsin the patterns of LH secretion are similar to those observed in laboratory animals (Sherman et al., 1976; Matt et al., 1994). Matt and colleagues (1994) observed a significant increase in the inter-pulse interval and the duration of individual LH pulses in middle-aged women during the mid to late follicular phase of menstrual cycles that were of normal length and in which plasma estradiol levels were normal and follicle stimulating hormone (FSH) concentrations were elevated. These data have been interpreted to suggest that the initial alterations in the hypothalamic-pituitary axis precede the loss of regular cyclicity in women, as well as in rodent models. Whether there are intrinsic age-related changes in GnRH neurons has been a difficultquestion to answer for several reasons. As discussed in the previous section of this chapter, GnRH neurons are few in number and diffusely distributed through the septo-preoptico-infundibularpathway of rodents and the medial basal hypothalamus of humans (Silverman, 1994). Furthermore, GnRH neurons may serve multiple functions, not all of which are directly related to gonadotropin secretion. Unfortunately, it has been difficult to identify anatomically or morphologically discrete subpopulations of GnRH neurons that are specifically dedicated to regulatingLH and FSH, although recent data(Petersen et al., 1995; Rance and Uswandi, 1996) suggest that they may exist. For all of these reasons, it has been difficult to quantify GnRH release patterns over time in individual animals under controlled experimental conditions; although a few investigators have successfully achieved this technically challenging feat in rats (e.g., Levine and Ramirez, 1982; Levine and Duffy, 1988; Rubin and Bridges, 1989). Aging studies have utlilized semiquantitative in situ hybridization to assess gene expression in individual cells and dual label immunocytochemistryto identify activatedGnRH neurons. Investigators (Lloyd et al., 1994; Rubin et al., 1995) have sought to determinewhether alterations in the timing and amplitude of the proestrous LH surge involve alterations in the GnRH neuronal activation as assessed by the expression of Fos within the nuclei of GnRH neurons. In young animals,Fos is expressed in GnRH neurons coincident with both proestrous and steroid-induced LH surges (Lee et al., 1990, 1992). In middle-aged proestrous rats that maintain regular cycles, the intensity of Fos staining in GnRH neurons is lower, the percent of Fos-expressing GnRH neurons is dramatically lower than in young animals around the time of peak LH release (Figure lo), the neuroanatomical distribution of activated GnRH neurons is different, and the extent of activation no longer correlates with serum LH levels. This suggests an age-related desynchronization of the mechanisms involved in generating the proestrous LH surge. Rubin and Bridges (1989) reported alterations in GnRH release from the mediobasal hypothalamus of steroid-primed middle-aged rats, as detected by push-pull cannula methods. These functional changes become apparent prior to any detectablechange in the morphology or distribution of GnRH neurons of aging male rats (Witkin, 1987) or any age-related differences in the distribution of GnRH-immunoreactive forms expressed in GnRH neurons (Hoff-

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man and Finch, 1986). Thus, functional changes in GnRH neurons appear to occur prior to changes in the ability to maintain regular estrous cyclicity and appear to be a more sensitive measure of the status of GnRH neuronal activity than morphological criteria. Studies measuring GnRH have been performed in postmenopausal human females; but none have followed GnRH neuronal changes during the perimenopausal period. Parker and colleagues (Parker and Porter, 1984) showed that radioimmunoassayable GnRH concentrations in the mediobasal hypothalamus were lower in postmenopausal women than in young women. In contrast, Rance and Uswandi (1996) found that GnRH mRNA levels in the tuberoinfundibular region were elevated in postmenopausal women. A possible interpretation of these apparently contradictory findings is that transcription of the GnRH gene is elevated in response to the lack of estrogen and peptide release increases, such that steady state mRNA levels are elevated, but the stored pool of GnRH in the mediobasal hypothalamus is still lower than in young women. Obviously many more studies

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will need to be done before one can clearly interpret these data or draw firm conclusions.

Changes in the Neurotransmitter Activity May Influence Patterns of GnRH and LH Secretion Changes in the pattern of GnRH synthesis and secretion may be due to changes in the pattern of stimulatory and/or inhibitory modulators of GnRH neuronal activity. R e n t y years ago, Simpkins and colleagues (1977) proposed that alterations in catecholamine activity in the hypothalamus of old males may account for changes in gonadotropin secretion. We later reported changes in the rhythm of NE turnover rates in specific hypothalamic nuclei on proestrus (Wise, 1982b) and in estradiol-treated ovariectomized (wise, 1984) middle-aged rats. Similar changes have been confirmed using push-pull cannulae (Mohankumar et al., 1994). During the past ten years, we have examined several aspects of some of the neurotransmitters that are thought to modulate GnRH release: turnover rates, neurotransmitter receptor densities, and gene expression. The theme that repeats itself is that the daily rhythmicity in the activity of many neurotransmitters (Wise, 1982b, 1984;Cohen and Wise, 1988),density of theirreceptors (Weiland and Wise, 1990), or the level of gene expression (Figure 11) (Weiland et al., 1992) dampens or changes with age in hypothalamic regions involved in regulating GnRH synthesis or secretion. We observed alterations when animals were middle-aged, as they were entering the transition to irregular cycles. Sometimes the change was progressive and more exaggerated in older rats that had completed the transition to acyclicity;other times, the change was completeby the time rats were middle-aged. These changes are subtle and may not be detectable if endpoints are measured at only one or two times of day. In one case, for example, we monitored the rhythm in proopiomelanocortin (POMC) gene expression, since data from several laboratories demonstratesthat P-endorphinsuppressesLH secretion,and that release from this inhibition during the afternoon contributes to GnRH secretion by permitting stimulatory neuromodulatory signals to influence GnRH neurons (Kalra, 1986). POMC is the precursor of P-endorphin; therefore, we examined the rhythm of POMC gene expression in the arcuate nucleus of young, middle-aged, and old rats atseventimesaday over a24-hourperiod(Figure ll)(Weilandetal., 1992).POMC mRNA levels exhibited a daily rhythm in estradiol-treated ovariectomized young rats. In marked contrast, the rhythm of expression was completely absent and the overall average mRNA level was suppressed by the time rats reach middle-age; no further decrease occurred in older rats. Nelson and coworkers (1988) reported similar decreases in average level of POMC mRNA in aging mice. Disruption of the coordination of multiple neural signals that together result in the precise timing of GnRH release may ultimately lead to profound changes in the ability of rats to maintain regular estrous cycles. It is clear from the elegant work of Everett and colleagues (1949), over 50 years ago, that small changes in the

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Time of Day (h) Figure 71. POMC mRNA levels in the arcuate nuclei of young, middle-aged, and old ovariectomized,estradiol-treated rats. (From Weiland et at., 1992, with permission.) temporal integrity of neurochemical events become greatly magnified in terns of the ability to maintain regular estrous cycles.This effect is different from the effects of timing on any other neuroendocrine system, which can be shifted by several hours without any major compoundingimpact on the peripheral endocrinerhythms that they drive. For example, desynchronization of neurochemical messages does not cause the CWACWglucocorticoid rhythm to skip an entire day.

Deterioration of the Circadian Clock May Explain Changes in Multiple Rhythms Multiple rhythms change with age (Brock, 1991; Tbrek et al., 1995). It is possible that fundamental changes at the level of the “biological clock” or the coupling to its outputs may cause increasing temporal desynchronization of neurotransmitter rhythms that are critical for stable, precise, and regular reproductive cycles. The suprachiasmatic nucleus (SCN)of the hypothalamus is the master circadian pacemaker, or biological clock, in mammals (Moore-Me et al., 1982; n r e k and Van Cauter, 1994). These bilateral nuclei exhibit endogenous circadian

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rhythmicity: they continue to exhibit circadian electrophysiological activity and neuropeptide secretion patterns when maintained in v i m (Turek, 1985), unlike any other region of the brain. Efferent connections to various regions of the brain communicate temporal information and drive outputs, resulting in a pervasive circadian rhythmicity in most physiological functions. When the SCN is lesioned, virtually all circadian rhythms (e.g., drinking, restlactivity, endocrine, temperature, metabolic) are abolished. We speculate that decay in the neural circadian pacemaker may lead to desynchronization in the timing of neurotransmitter signals that must be coordinated to trigger an LH surge or to maintain LH pulses of normal duration, amplitude, and frequency. Increased variability of diurnal hormone release may, in turn, lead to estrous cycles of irregular and unpredictable length, and ultimately to acyclicity. Support for this hypothesis comes from studies that demonstrate that transplantation of fetal SCN into the third ventricle of middle-aged animals restores the light-induced pattern of Fos immunoreactivity to one resembling that of young animals, both temporally and anatomically (Cai et al., 1997). Second, suppression of a key neuropeptide in the SCN which communicates with GnRH neurons can mimic the effects of age on the estradiolinduced surges of LH (Harney et al., 1996).

Estrogen Adions in the Aging Brain It is becoming increasingly clear that estrogenshave a major impact on age-related deterioration of cell functions and pathological processes that occur in many different organ systems, including the brain. Postmenopausal women who take estrogen replacement therapy have greatly reduced risks for bone loss (Prestwood et al., 1995), atherosclerosis (Schwartz et al., 1995), and certain forms of cancer (Vogel, 1996). Importantly, the lifespan of women who take estrogen replacement therapy is increased significantly (Ettinger et al., 1996). Recent findings from several different studies have shown that estrogens reduce the risk of developing Alzheimer’s disease (Henderson et al.. 1994: Tang et al., 1996) and retard the decline in cognitive performance that occurs during “normal” aging (Sherwin, 1994). The mechanisms whereby estrogens prevent or delay brain aging are not established, but may involve both direct actions in neurons and indirect effects resulting from beneficial actions of the cerebral vasculature. Cell culture studies have shown that estrogens (17pestradiol and estriol) can protect hippocampal neurons from being damaged and killed by oxidative insults, including exposure to amyloid bpeptide (Goodman et al., 1996). The latter studies showed that estrogens suppressmembrane lipid peroxidation and stabilizecalcium homeostasis in neurons exposed to FeS04 and amyloid /3-peptide, and further showed that estrogens possess inherent antioxidant activity. These findings are consistent with studies showingthat estrogenscan suppressfreeradical-mediated injury to vascular endothelial cells induced by oxidized low density lipoprotein (Keaney et al., 1994). The neuroprotective actions of estrogens were not mediated by the classic steroid

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receptor-transcription pathway because high concentrations of estrogens were required and the estrogens were effective in the presence of RNA and protein synthesis inhibitors (Goodman et al., 1996). Additional transcription-dependent mechanisms of action of estrogens may also contribute to their neuroprotective actions, as suggested by data showing that estrogen induces the expression of neurotrophic factors in the rodent brain in vivo (Singh et al., 1995). In addition to having direct cytoprotective actions in neurons, estrogens may also retard brain aging by allaying the development of atheroscleroticchanges in the cerebrovasculature (see chapter by de la Torre in this volume).

CONCLUSION We have provided an overview of two neuroendocrine systems which have been studied in the context of the aging brain. It is clear that significant progress has been made, particularly within the past twenty years, as the interest in aging processes increases. It should also be clear that we have only begun to scratch the surface of information that must be obtained to have a clear understanding of the mechanisms involved. Much of the information remains correlational; that is, changes have been observed, but it is unclear whether these are the primary changes or secondary repercussions to events upstream. Furthermore, in many cases it is unclear whether changes in the anatomical substrate precede or cause neurochemical alterations; moreover, the physiological repercussions of such alterations are unknown.

SUMMARY The neuroendocrine system exhibits dramatic changes with age. We here consider the hypothalamic-pituitary-adrenalcortex and the hypothalamic-pituitary-ovarian axis as models to illustrate the various parameters that change, the repercussions of such change in terms of adrenocortical and ovarian steroid secretion, and the feedback loops that are altered. A deeper understanding of the mechanisms that govern the aging of these two neuroendocrine axes will be important to gerontologists interested in brain aging because, if the central nervous system is a key driver of neuroendocrine senescence, then studying the hypothalamic-pituitary-a~enalcortex and -ovarian axes may allow us to gain a clearer view of the fundamental process of brain aging. The female reproductive system is unique in that, in many species including humans, it undergoes striking and irreversible changes relatively early during the aging process. Therefore, this system may afford us the opportunity to address importantquestionsconcerning the biology of aging, in the absenceof confounding pathological changes that make it so difficult to interpret many aging studies.

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Hamey. J.P., Scarbrough, K.. Rosewell. K.L. & Wise, P.M. (1996). In vivo antisense antagonism of vasoactive intestinal peptide in the suprachiasmatic nucleus causes aging-lie changes in the estradiol-induced LH and prolactin surge. Endocrinology 137,3696-3701. Harris, G.W. (1955). N e d Control of the Pituitary Gland. Arnold, London. Hartman. R.D., He, J.R. & Barraclough, C.A. (1990). Gamma-aminobutyricacid-A and -B receptor antagonists increase luteinizing hormone-releasing hormone neuronal responsiveness to intracerebroventricularnorepinephrinein ovariectomizedestrogen-treatedrats. Endocrinology 127,1336-1345. Hauger, RL., Thrivilnaman, K.V. & Plotsky, P.M. (1994). Age-related alteration of hypothalamic-pituitary-adrenalaxis function in male Fischer 344 rats. Endocrinology 134, 1528-1536. He, J.R., Molnar, J. & Banaclough, C.A. (1993).Morphineamplifiesnorepinephrine(NE)-inducedLH release but blocks NE-stimulatedincreases in LHRH mRNA levels: comparison of responses obtained in ovariectomized, estrogen-treated normal and androgen-sterilizedrats. Brain Res. Mol. Brain Res. 20.71-78. Henderson,V. W., Paganini-Hill,A., Emanuel,C. K., Dunn, M. E. &Buckwalter,J. G. (1994). Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch. Neurol. 51,896-900. Herbison, A.E., Robinson, J.E. & Skinner, D.C. (1993). Distribution of estrogen receptor-immunoreactivecells in the preoptic area of the ewe: co-localization with glutamic acid decarboxylase but not luteiniziing hormone-releasing hormone. Neuroendocrinology57, 751-759. Herbison, A.E. & Theodosis, D.T. (1992). Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasinghormone in the male and female rat. Neuroscience 50,283-298. Herman, J.P. (1993). Regulation of adrenocorticosteroidreceptor mRNA expression in the central nervous system. Cell. Molec. Neurobiol. 13,349-372. Herman, J.P.. Schafer, M.K.-H.. Young, E.A., Thompson, R.. Douglass. J., Akil, H. &Watson, S.J. (1989). Evidence for hippocampd regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis. I. Neurosci. 9,3072-3082. Herman, J.P., Wiegand, S.J. & Watson, SJ. (1990). Regulation of basal corticotropin-releasing hormone and arginine vasopressin messenger ribonucleic acid expression in the paraventricular nucleus: effects of selective hypothalamic deafferentations. Endocrinology 127,2408-2417. Herman, J.P., Cullinan, W.E. & Watson, S.J. (1994). Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression. Neuroendocrinology6,433-442. Herman, J.P., Adams, D. & Prewitt, C. (1995a). Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 61, 180-190. Herman, J.P., Cullinan, W.E., Morano, M.L. Akil,H. & Watson, S.J. (1995b). Contribution of the ventral subiculumto inhibitory regulation of the hypothalomo-pituitary-adrenocorticalaxis. J. Neuroendocrinol. 7,475482. Herman, J.P., Prewitt, C.M.F. & Cullinan, W.E. (1996). Neuronal circuit regulation of the hypothalomo-pituitary-&nocortical stress axis. Crit. Rev. Neurobiol. 11,371-394. Heuser, I.J., Golthardt, U.,Schweigher, U.,Scbmider, J. & Lammers,C.H (1994). Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. Neurobiol. Aging 15,227-231. Hiruma, H. & Kimura, F. (1995). Luteinizing hormone-releasing hormone is a putative factor that causes LHRH neurons to fire synchronouslyin ovariectomizedrats. Neuroendocrinology61, 509-516.

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