Regulation of behavioral responses by corticotropin-releasing factor

General and Comparative Endocrinology 146 (2006) 19–27 www.elsevier.com/locate/ygcen

Minireview

Regulation of behavioral responses by corticotropin-releasing factor Christopher A. Lowry a, Frank L. Moore b,¤ a

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol BS1 3NY, UK b Department of Zoology, Oregon State University, Corvallis, OR 97331-2914, USA Received 25 July 2005; revised 1 December 2005; accepted 5 December 2005 Available online 19 January 2006

Abstract In the wild, animals survive by responding to perceived threats with adaptive and appropriate changes in their behaviors and physiological states. The exact nature of these responses depends on species-speciWc factors plus the external context and internal physiological states associated with the stressful condition. The neuroendocrine mechanisms that control context-dependent stress responses are poorly understood for most animals, but some progress has been made recently. Corticotropin-releasing factor (CRF) plays an important role in mediating neuroendocrine, autonomic, and behavioral responses to stress. Across many vertebrate taxa, CRF not only stimulates the HPA axis by increasing the secretion of ACTH and glucocorticoid hormones, but also acts centrally by modifying neurotransmitter systems and behaviors. CRF or one of several CRF-related neuropeptides acts to stimulate locomotor activity during periods of acute stress. This behavioral activation consists of anxiety-related non-ambulatory motor activity, ambulatory locomotion, or swimming depending on the species and context. CRF-related neuropeptides increase swimming behaviors in amphibians and Wsh, apparently by activating brainstem serotonergic systems because the administration of Xuoxetine (a selective serotonin re-uptake inhibitor) greatly enhances CRFinduced locomotor activity. Thus, our working model is that CRF, in part via interactions with brainstem serotonergic systems, modulates context-dependent behavioral responses to perceived threats, including both anxiety-related risk assessment behaviors and Wght-or-Xight locomotor responses.  2005 Elsevier Inc. All rights reserved. Keywords: CRF; CRH; Serotonin; Behavior; Anxiety; Locomotion

1. Introduction Corticotropin-releasing factor (CRF) and related neuropeptides (e.g., urotensins/urocortins) can have powerful behavioral eVects in diverse vertebrate species including Wsh, amphibians, birds, and mammals. The behavioral eVects of CRF or urocortins in mammals have been discussed in several excellent reviews (Contarino et al., 1999; Dunn and Berridge, 1990; Heinrichs and Koob, 2004; Maier and Watkins, 2005; Smagin et al., 2001). Recent advances have also been made in describing the behavioral eVects of CRF in Wsh, amphibians, and birds and lead to some novel perspectives on potential neural mechanisms

underlying CRF-mediated behavioral responses in vertebrates, particularly a potential role for brainstem serotonergic systems in CRF-induced modulation of behavior. This minireview discusses these recent Wndings with an emphasis on the role of CRF in the regulation of locomotor activity. CRF has potent stimulatory eVects on behavioral arousal and locomotor activity in all vertebrates that have been studied and a comparative approach oVers unique opportunities for understanding neural mechanisms underlying neuropeptide regulation of behavior and revealing which of the mechanisms are evolutionarily conserved in vertebrates. 2. The CRF family of neuropeptides and their receptors

*

Corresponding author. Fax: +1 541 737 0501. E-mail address: [email protected] (F.L. Moore).

0016-6480/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygcen.2005.12.006

CRF is a 41-amino acid neuropeptide originally characterized based on its ability to elicit the release of ACTH and

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-endorphin from the anterior pituitary gland in rodents (Vale et al., 1981). The principal source of CRF for hypophysiotropic regulation of ACTH release is the paraventricular nucleus of the hypothalamus (PVN). CRF, synthesized by neurons in the PVN, is transported axonally to the median eminence where it is released into the portal circulation. In the pituitary, CRF binds to receptors on corticotrophs and stimulates release of ACTH into the general circulation. ACTH in turn induces release of glucocorticoid hormones from the adrenal gland or its equivalent (i.e., interrenal gland in Wsh and amphibians). A role for CRF in stress-related regulation of the hypothalamic–pituitary–adrenal (HPA) or hypothalamic–pituitary–interrenal (HPI) axis in vertebrates has been supported by Wndings that stress increases the expression of CRF mRNA or protein within the PVN of mammals (Turnbull and Rivier, 1997) and within the non-mammalian homologue of the PVN, the preoptic area, in Wsh (Doyon et al., 2003, 2005; Huising et al., 2004) and amphibians (Boorse and Denver, 2004; Yao et al., 2004). It also has become clear that, as described initially in mammals, CRF is a potent secretagogue for ACTH in Wsh (Baker et al., 1996; Fryer et al., 1984, 1985; Weld et al., 1987), amphibians (Tonon et al., 1986), and birds (Carsia et al., 1986). The Wnding that CRF-expressing neurons and neuronal Wbers are widely distributed in mammalian brain in hypothalamic and extra-hypothalamic sites not directly involved in HPA regulation suggested that CRF has diverse physiological and behavioral functions (Merchenthaler, 1984; Sakanaka et al., 1987). Although the extra-hypothalamic distribution of CRF in non-mammalian vertebrates has not received as much attention, it is clear that CRF-expressing neurons and Wbers are also present in extra-hypothalamic neuronal circuits in Wsh, (Coto-Montes et al., 1994; Zupanc et al., 1999), amphibians (Bhargava and Rao, 1993; Tonon et al., 1985), reptiles (Mancera et al., 1991), and birds (Ball et al., 1989; Bons et al., 1988; Jozsa et al., 1984; Knigge and Piekut, 1985; Panzica et al., 1986; Richard et al., 2004; Yamada and Mikami, 1985). Together these studies support the hypothesis that CRF, in addition to its hypophysiotrophic role, also functions as a neuromodulator within the central nervous system in representative species from all vertebrate classes. Comparative evolutionary studies have led to the recognition that the CRF family of neuropeptides includes a urotensin-I/sauvagine/urocortin series and a CRF series of neuropeptides in vertebrates (Lovejoy and Balment, 1999). The CRF-related neuropeptides and their receptors have been most thoroughly characterized in mammals. In mammals, three additional members of the CRF family of neuropeptides, each with a unique distribution within the central nervous system, have been cloned and characterized, Ucn 1, Ucn 2, and Ucn 3 (reviewed by Reul and Holsboer, 2002). Mammalian CRF-related neuropeptides diVer in their aYnities for binding to the two known CRF receptor subtypes, CRF type I (CRF1) and CRF type II (CRF2) receptors. Although CRF is relatively selective for

CRF1 receptors compared to CRF2 receptors, Ucn 1 binds both receptor subtypes with high aYnity (Chen et al., 1993; Lovenberg et al., 1995), and Ucn 2 and Ucn 3 bind selectively with high aYnity to CRF2 receptors (Hsu and Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001). CRF receptor signaling mechanisms may be highly conserved among vertebrates as CRF1 and CRF2 receptors also have been characterized in Wsh (Arai et al., 2001; Pohl et al., 2001), amphibians (Dautzenberg et al., 1997), and birds (de Groef et al., 2004; Yu et al., 1996). In all cases, Ucn 1, Ucn 2, Ucn 3, and sauvagine bind CRF2 receptors with high aYnity, while mammalian CRF peptides bind CRF2 receptors with approximately a 10-fold lower aYnity (Arai et al., 2001; Dautzenberg et al., 1997; Hillhouse et al., 2002; Perrin and Vale, 1999; Pohl et al., 2001). In addition, a soluble CRF binding protein (CRFBP) has been characterized in rats and humans (Lowry, 1993; Potter et al., 1991), and in non-mammalian vertebrates including Wsh, amphibians, and birds (Seasholtz et al., 2002). Although this protein does not appear to act as a receptor, it may be required for some receptor signaling mechanisms within the central nervous system (Ungless et al., 2003). Up to three diVerent CRF receptors have been identiWed in Wsh (Arai et al., 2001; Cardoso et al., 2003; Huising et al., 2004; Pohl et al., 2001). The identiWcation of three CRF receptor subtypes in a diploid catWsh (cf) species, Ameiurus nebulosus (Arai et al., 2001), raises the possibility that other vertebrates, including mammals, may have as yet uncharacterized genes that encode other CRF receptor subtypes, but this remains to be determined. The cfCRF1 receptor is a 446-amino acid protein with high homology to mouse CRF1 receptor (93% identical) and binds CRF with high aYnity. The cfCRF2 receptor is a 406-amino acid protein with high homology to mouse CRF2 receptor (88% identical) and preferentially binds sauvagine [a neuropeptide with high aYnity for mammalian CRF2 receptors (Mazur et al., 2004)]. The cfCRF3 receptor is a 428-amino acid protein similar in sequence to cfCRF1 (85% identical) and also binds CRF with high aYnity. These Wndings and the presence of multiple CRF receptor subtypes in representative species of other non-mammalian vertebrates (Dautzenberg et al., 1997, 2001a,b) point toward complexity in the CRF family of neuropeptides as well as the receptor signaling mechanisms in vertebrates. 3. Behavioral responses to administration of CRF Comparative approaches to understanding the relationships between neuropeptides and behavior often provide unique opportunities to investigate the neural mechanisms involved and the ethological relevance of neuropeptide action. Comparative studies also can provide a unique perspective on the adaptive value of speciWc behavioral responses. In the case of CRF-induced behavioral responses, there is a remarkable degree of conservation among vertebrates with respect to the eVects of CRF on several behaviors that have been studied including, notably,

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ingestive, and reproductive behaviors. CRF decreases ingestive behaviors in Wsh (reviewed in Bernier and Peter (2001); VolkoV et al. (2005)), amphibians (Crespi and Denver, 2004; Crespi et al., 2004), birds (Denbow et al., 1999; Furuse et al., 1997; Ohgushi et al., 2001; Richardson et al., 2000; Zhang et al., 2001a,b), and mammals (reviewed in (Dunn and Berridge, 1990)). In amphibians, this has been extended to include prey-catching behaviors (Carr et al., 2002). Although it has not been extensively studied in nonmammalian vertebrates, CRF decreases reproductive behaviors in wild-caught female white-crowned sparrows, an eVect that parallels the eVects of CRF on reproductive behaviors in rodents (Sirinathsinghji, 1985, 1987). One of the most profound and reproducible eVects of CRF in vertebrates is the eVect on behavioral arousal and locomotor activity (Table 1). Evidence from diverse vertebrate species suggests that the eVects of CRF on locomotor activity are mediated within the central nervous system. CRF increases locomotor activity in both intact and hypophysectomized roughskin newts, Taricha granulosa (Moore et al., 1984), and in intact and hypophysectomized rats (Eaves et al., 1985), suggesting that the behavioral responses are not due to CRF actions on the pituitary gland. These Wndings are consistent with studies in juvenile salmon in which intracerebroventricular (i.c.v.) injections of CRF at behaviorally active doses have no eVect on plasma concentrations of cortisol (Clements et al., 2002), and Wndings in the Western spadefoot toad (Spea hammondii) that co-treatment with the glucocorticoid receptor antagonist RU486 has no eVect on CRF-induced swimming behavior (Crespi et al., 2004). The speciWc site or sites within the central nervous system that mediate CRF-induced increases in locomotor activity are not clear. Evidence suggests, however, that sites in the forebrain are necessary for CRF-induced increases in locomotor activity in rats. For example, blockade of the cerebral aqueduct at the level of the midbrain prevents CRF-induced increases in locomotor

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activity (as determined by photocell counts) following CRF injections into the cisterna magna, but not following CRF injections into the lateral ventricle (Tazi et al., 1987). This is not to suggest that brainstem structures are not involved, but conversely that CRF actions on the forebrain are a necessary component of the neural mechanism mediating the behavioral responses. It is likely that CRF-induced increases in locomotor activity are the product of direct and indirect actions on a distributed neural system, including brainstem neuromodulatory systems (see below), that together facilitate the behavioral response, much like what has been proposed for the eVects of anxiogenic drugs on anxiety-related behavior (Abrams et al., 2005; Singewald et al., 2003; Singewald and Sharp, 2000). This hypothesis is consistent with the Wnding in the Western spadefoot toad that injections of the CRF receptor antagonist helical-CRF9–41 decreases spontaneous swimming behavior following injections in either the third ventricle or the fourth ventricle (Crespi et al., 2004). Studies involving administration of CRF receptor antagonists support a role for endogenous CRF, or CRFrelated neuropeptides, in behavioral responses to stressors. For example, in roughskin newts, a brief period of handling (30 s) increases locomotion and this behavioral response is prevented by prior treatment with a general CRF antagonist, -helical-CRF9–41 (Lowry and Moore, 1991). A similar response to -helical-CRF9–41 is observed following exposure to warm water. Newts respond to warm water with an increase in locomotion and this is attenuated by prior treatment with -helical-CRF9–41 (Lowry and Moore, 1991). Similarly, -helical-CRF9–41 decreases baseline swimming behavior in prometamorphic S. hammondii tadpoles (Crespi et al., 2004), suggesting that either (1) CRF-related peptides play a role in stress- or novelty-induced swimming behaviors associated with the testing environment, or (2) CRF-related peptides play a role in baseline swimming behaviors at this stage of development in this species. As

Table 1 EVects of CRF on locomotor activity Class

Species

Ligand

Dose

Behavioral response

Reference

Fish

Oncorhynchus tshawytscha

oCRF

500 ng, 1 g, and 2 g

"Swimming

Amphibian

Taricha granulosa

oCRF

12.5, 25, 50, 100, and 150 ng

"Swimming and walking

Bird

Spea hammondii Gallus domesticus

oCRF oCRF

0.2, 2, and 20 ng/g body weight 100 ng

"Swimming "Stepping

Mammal

Rattus rattus

N.S. r/hCRF oCRF oCRF N.S. oCRF r/hCRF oCRF

0.5, 1, and 10 g

"Locomotor activity "Photocell counts

Clements et al. (2002, 2003); Clements and Schreck (2004a,b) Moore et al. (1984); Lowry et al. (1990, 1996, 2001); Lowry and Moore (1991) Crespi and Denver (2004) Ohgushi et al. (2001); Zhang et al. (2001a) Zhang et al. (2004) Sutton et al. (1982); Britton et al. (1986a,b); Koob et al. (1984); Kalivas et al. (1987); Matsuzaki et al. (1989)

Rattus rattus Rattus rattus

3 g 0.3 ug

Abbreviations: oCRF, ovine CRF; N.S., not speciWed; r/hCRF, rat/human CRF.

"Walking "Burying and exploring behaviors in the home cage

Sherman and Kalin (1987) Korte et al. (1993)

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described for other neuropeptidergic systems (Coddington and Moore, 2003), CRF-induced behaviors are likely to be modulated by the physiological context. For example, administration of the opioid receptor antagonist naloxone can potentiate CRF-induced locomotion in T. granulosa, an eVect that may be mediated by endogenous opioid peptides acting on -opioid receptors (Lowry et al., 1990). The behavioral activating eVects of CRF in rodents may involve CRF actions on diVerent neural circuits mediating diVerent ethologically relevant behavioral responses. Direct microinjection of CRF into the brainstem noradrenergic locus coeruleus in rats increases behavioral arousal as measured in photocell cages (Butler et al., 1990). The increase in behavioral arousal consists of increases in non-ambulatory motor activity, but not increases in locomotion. The same treatment increased anxiety-related behavior as measured by the amount of time spent in a darkened compartment in an open Weld, and by measures of exploration in an open Weld (Butler et al., 1990), suggesting that the increases in non-ambulatory motor activity may reXect an increase in anxiety state. We have observed increases in non-ambulatory motor activity in rats tested in their home cages in response to treatment with multiple anxiogenic drugs including the adenosine receptor antagonist caVeine, the serotonin 5-HT2A/2C receptor agonist m-chlorophenyl piperazine (mCPP), the 2-adrenoreceptor antagonist yohimbine, and the benzodiazepine receptor partial inverse agonist N-methyl-
-carboline-3-carboxamide (FG-7142) (Abrams et al., 2005). Although these drugs (with the notable exception of mCPP, as described previously (Kennett and Curzon, 1988)) also increased ambulatory locomotion, this represented a small proportion of the overall increase in behavioral activity (Abrams et al., 2005). Likewise, we have found that i.c.v. injections of CRF in rats housed in their home cages induce similar behavioral responses, that is, dramatic increases in non-ambulatory motor activity, and small, but signiWcant, increases in ambulatory locomotion (Lowry et al., unpublished). As observed by Butler and colleagues (1990), the non-ambulatory motor activity consists of head movements associated with visual scanning of the environment, non-ambulatory movements of the limbs, and shifts in body position. This behavior may represent an increase in anxiety state and “risk assessment” behaviors (Blanchard and Blanchard, 1989). It is possible, therefore, that some aspects of the CRF-induced behavioral activation observed in rodents are qualitatively diVerent from the increases in rhythmic locomotion that have been observed in Wsh, amphibians, and birds (Table 1), and that the neural mechanisms underlying the behavioral responses are diVerent. For example, it is possible that non-ambulatory motor activity in rodents reXects an underlying anxiety state, while increases in ambulatory locomotion in non-mammalian vertebrates reXect a Wght-or-Xight response. It is also possible that in rodents, diVerent neural mechanisms are involved in mediating CRF-induced increases in diVerent forms of behavioral activation (e.g., non-ambulatory motor activity and rhythmic locomotion). For example, these

diVerent forms of behavioral arousal may be due to interactions between CRF and the two major motor control systems of vertebrate brain that converge on premotor interneurons, as outlined by Holstege, the “somatic motor system,” and the “emotional motor system” (Holstege, 1995). Consistent with the possibility that CRF may modulate the activity of multiple neural circuits mediating motor function, early studies in rats determined that the behavioral eVects of administration of exogenous CRF are dependent on the environmental context. For example, rats tested in a familiar environment (photocell cages to which the rats had been habituated to prior to the behavioral testing), responded with increases in locomotor activity (i.e., photocell beam interruptions). In contrast, rats tested in an unfamiliar environment (an open Weld test arena) responded with decreases in locomotor activity as judged by decreases in the number of line crossings (Sutton et al., 1982). The latter eVect was interpreted as a CRF-induced increase in emotionality in a novel or stressful environment. Likewise, juvenile Chinook salmon, Oncorhynchus tshawytscha, tested in an artiWcial stream respond to CRF with an increased probability of swimming downstream from the release site. However, a high proportion of CRFtreated salmon fails to enter a novel environment (a trap which is accessed through a narrow opening), similar to juvenile salmonids that are stressed during their downstream migration (Clements and Schreck, 2004a). These studies indicate that the environmental context is an important determinant of the behavioral outcome following CRF administration. In other words, CRF does not appear to drive speciWc motor patterns, but to modify behavioral responses that are elicited by environmental cues. One mechanism through which CRF could modulate behavioral responses to diVerent environmental cues is via eVects on brainstem neuromodulatory systems such as adrenergic, noradrenergic, dopaminergic, or serotonergic systems. 4. Neural mechanisms underlying CRF-induced behavioral activation Early attempts to determine a role for brainstem monoaminergic systems in CRF-induced behavioral activation focused on dopaminergic systems. Although direct psychostimulants, e.g., apomorphine or bromocriptine, and indirect psychostimulants, e.g., amphetamine or cocaine, induce motor activity via dopaminergic mechanisms involving the basal ganglia, including the ventral striatum (nucleus accumbens) and globus pallidus, as well as the substantia innominata or “ventral pallidum” (Groenewegen and Russchen, 1984; Mogensen et al., 1983; Swerdlow et al., 1986), several lines of evidence suggest that CRF-induced motor activation is not dependent upon activation of mesolimbic dopaminergic systems (Kalivas et al., 1987; Koob et al., 1984; Swerdlow and Koob, 1985; Swerdlow et al., 1986). This conclusion is consistent with studies in juvenile Chinook salmon in which neither the dopamine receptor

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antagonist haloperidol nor the dopamine uptake inhibitor (4⬘,4⬙-diXuoro-3--[diphenylmethoxy] tropane hydrochloride) [DUI] altered CRF-induced swimming behavior. Evidence for or against a role of noradrenergic systems in CRF-induced behavioral activation has been more equivocal. As mentioned above, direct injection of CRF into the rat noradrenergic locus coeruleus increases behavioral activity, but this is in the form of non-ambulatory motor activity, not ambulatory motor activity, and may reXect an increase in anxiety state (Butler et al., 1990) as opposed to, for example, a Wght-or-Xight response. Studies investigating the behavioral eVects of i.c.v. CRF injections found that i.c.v. injections of the adrenergic receptor antagonists phentolamine (1, 2) and yohimbine (2) blocked the behavioral activating eVects of CRF (Imaki et al., 1987). As these tests were conducted using an automated system, it is not possible to determine if the behavioral activation consisted of non-ambulatory or ambulatory motor activity. In contrast, studies in roughskin newts demonstrated that the 2 adrenergic agonist clonidine, which would be expected to suppress the neuronal Wring rates of locus coeruleus noradrenergic neurons (Aghajanian and Wang, 1986, 1987), suppressed spontaneous but not CRF-induced ambulatory locomotion (Lowry and Moore, 1991). 4.1. A role for brainstem serotonergic systems in CRF-induced modulation of locomotor activity Behavioral studies in juvenile Chinook salmon and the roughskin newt point toward a potential role for serotonergic systems in CRF-induced increases in rhythmic locomotion. In both juvenile Chinook salmon (Clements et al., 2003; Clements and Schreck, 2004b) and the roughskin newt (Lowry et al., 1993), co-administration of the selective serotonin re-uptake inhibitor Xuoxetine, which is believed to enhance synaptic concentrations of serotonin and consequently serotonergic neurotransmission, dramatically potentiates CRF-induced locomotion. The hypothesis that CRF-induced locomotion involves activation of brainstem serotonergic systems is supported by the Wnding that the 5HT1A receptor antagonist NAN-190 dose dependently inhibits CRF-induced locomotion (Clements et al., 2003). These Wndings are consistent with electrophysiological (Kirby et al., 2000; Lowry et al., 1996, 2000; Price et al., 1998) and neurochemical studies (de Groote et al., 2005; Singh et al., 1992) in rodents demonstrating that CRF can modulate ascending serotonergic neurotransmission arising from the dorsal raphe nucleus and median raphe nucleus. It is unclear, however, whether the eVects of CRF on rhythmic locomotion are due to interactions between CRF and ascending serotonergic systems, such as those arising from the dorsal and median raphe nuclei, or to interactions between CRF and descending serotonergic systems, such as those arising from the medullary raphe nuclei that innervate spinal networks regulating rhythmic locomotion. In vivo electrophysiology in behaving roughskin newts demonstrated that CRF-induced walking and swimming

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behaviors are associated with increases in the Wring rates of neurons within the midline raphe nucleus (Lowry et al., 1996). However, it is unclear from this study whether the raphe neurons studied projected to forebrain or brainstem targets. Although the neuronal Wring rates of serotonergic neurons within the dorsal raphe nucleus are highly correlated with the level of behavioral arousal (Jacobs and Azmitia, 1992; Jacobs and Fornal, 1993, 1995, 1999), it is the neuronal Wring rates of medullary serotonergic neurons, for example those in the raphe obscurus and raphe pallidus nuclei, and not serotonergic neurons in the dorsal raphe nucleus that display increased Wring rates directly related to treadmill speed during rhythmic locomotion in freely moving cats (Veasey et al., 1995, 1997). These Wndings are consistent with the observation that rhythmic locomotion in rats is associated with increases in serotonin and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) within the ventral funiculus of the spinal cord (Gerin et al., 1995). Indeed, serotonin facilitates locomotion in vertebrates by actions at caudal brainstem and spinal levels (Cazalets et al., 1992; Grillner et al., 1987; Harris-Warrick and Cohen, 1985), eVects that may involve potentiation of the Wring rates of reticulospinal neurons in the presence of excitatory input (Viana Di Prisco et al., 1992). Stimulation of reticulospinal neurons can induce locomotion in vertebrates (Grillner et al., 1988; Ross and Sinnamon, 1984) and, at least in the lamprey model, serotonergic Wbers appear to be in direct synaptic contact with locomotion-inducing reticulospinal neurons (Di Prisco et al., 1994). Whether or not CRF-induced increases in rhythmic locomotion in vertebrates involve interactions with these medullary and spinal serotonergic signaling pathways remains an interesting question for future studies. As medullary serotonergic neurons express CRF receptor-like immunoreactivity (Fig. 1) it is possible that CRF or other CRF-related neuropeptides have direct, indirect, or both direct and indirect eVects on medullary serotonergic systems. 5. Endogenous CRF-related peptides mediating stress-related behavioral responses It is unknown which of the endogenous CRF-related neuropeptides is involved in stress-related behavioral activation (either non-ambulatory motor activity or ambulatory locomotion) in vertebrates. This remains an interesting question for future studies. The Wnding that mice lacking the CRF gene exhibit normal stress-induced behavior, including locomotor activity as measured using photocell counts in an open Weld environment (Weninger et al., 1999), suggests that CRF is not necessary for stress-induced behavioral activation in mice. This leaves open the possibility that other CRF-related neuropeptides are involved, including, for example, Ucn 1. Lovejoy and Balment (1999) have hypothesized that the urotensin-I/Ucn 1 system that gives rise to descending projections in vertebrates plays a role in the modulation of spinal motor circuits.

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Fig. 1. CRF receptor-immunoreactive neurons are located within the rat medullary raphe pallidus nucleus. (A) CRF-immunoreactive cell proWles (arrows) and proximal dendrites are visible throughout the rat medullary raphe pallidus nucleus. (B) Double immunostaining for CRF receptor (blue)/tryptophan hydroxylase (brown) reveals that CRF receptor immunoreactivity is visible on both serotonergic (solid arrowhead) and non-serotonergic (open arrowhead) neurons. A polyclonal anti-CRF receptor antiserum was generated in goat, against a 20-amino acid peptide sequence (Santa Cruz Biotechnology, Santa Cruz, CA). The synthetic peptide antigen, comprising the C-terminus of CRF1 receptor (SIPTSPTRVSFHSIKQSTAV), corresponds to amino acids 396–415 of human CRF1 receptor, identical with amino acids 396–415 of mouse and rat CRF1 receptor. This sequence diVers by three amino acids from the corresponding portions of mouse CRF2 (392–411), mouse CRF2
(411–430), rat CRF2 (392–411), and rat CRF2
(412–431). This antibody recognizes a single band of approximately 80 KDa in Western blot analysis of cell lysates prepared from mouse hypothalamus and cerebellum (Chen et al., 2000) in good agreement with the molecular weight of mouse brain CRF1 protein (Radulovic et al., 1998). Immunostaining for CRF receptor was conducted using a 1:200 dilution of primary antibody, a biotinylated rabbit anti-goat secondary antibody (1:1000; Vector Laboratories, Burlingame, CA), and an avidin–biotin–horseradish peroxidase complex (ABC; 1:200) reaction using Vector SG as substrate. For methods for immunostaining tryptophan hydroxylase in double immunostaining procedures, see (Abrams et al., 2005). Photographs from ¡11.60 mm relative to Bregma. Abbreviations: py, pyramidal tract. Scale bar, 50 m. Lowry et al., unpublished.

6. CRF receptors mediating CRF-induced behavioral activation It is also unknown which of the CRF receptor subtypes (CRF1, CRF2 or CRF3 in catWsh) mediate CRF-induced increases in behavioral activation. It is possible that multiple CRF receptor subtypes mediate the eVects of CRF-related neuropeptides in diVerent neural circuits or in diVerent context-dependent forms of behavioral activation. 7. Summary Corticotropin-releasing factor (CRF) has highly conserved eVects on behavior in representatives from multiple vertebrate taxa. The eVects of CRF on behavioral activation are particularly robust and reproducible in all vertebrate species that have been studied. Here, we have highlighted the importance of distinguishing the type of behavioral activation being studied. DiVerent forms of CRF-induced behavioral activation may be associated with diVerent species-speciWc, ethologically relevant behaviors. In addition, in the same species, the type of CRF-induced behavioral activation is dependent on context, including the external environment and the internal physiological state. DiVerent types of behavioral activation (non-ambulatory versus ambulatory motor activity, for example) may involve interactions between diVerent CRF-related neuropeptides, diVerent CRF receptor subtypes, and diVerent neural circuits. Evidence is accumulating that serotonergic systems may play a role in CRF-induced increases in rhythmic locomotion in vertebrates, possibly via actions on 5HT1A receptors. The speciWc endogenous CRF-related neuropeptides mediating stress-induced behavioral activa-

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