Hcrt And Stress

As reviewed above, HCRT increases arousal level and arousal-related behaviors in a circadian-independent manner. These actions are of particular relevance for the current discussion given the prominent role of arousal in stress. Combined, these observations suggest the hypothesis that HCRT may participate in the induction of a high-arousal, and possibly stress-like, behavioral state. In support of this hypothesis are a variety of observations indicating actions of HCRT on stress-related circuits and stress-related behavior, as reviewed below.

5.1. Stress-Like Physiological and Behavioral Actions of HCRT.

HCRT fibers and receptors are found within a variety of brain structures implicated in behavioral and physiological responding in stress. These include, the noradrenergic nucleus, LC; dopaminergic nuclei (e.g. ventral tegmental area, VTA); the bed nucleus of the stria terminalis, the amygdala, and the pvn.25,37,38,65,77,81 As reviewed above, the LC-NE system is activated in stress and plays a prominent role in behavioral responding in stress.3,10,73,90 Thus, in the context of this discussion, it is of interest that HCRT-1 and HCRT-2 increase LC neuronal discharge rates.17,42,47,51,53 Similarly, HCRT exerts an excitatory action on dopaminergic VTA neurons in vitro.56 Additionally, ICV administered HCRT elicits a robust and stress-like increase in rates of DA release within the prefrontal cortex, as measured by in vivo microdialysis.99 Finally, in studies utilizing immunohistochemical measures of c-fos expression, HCRT modulates neuronal activity in a variety of stress-related structures, including the PVN, LC, VTA, BST and the central nucleus of the amygdala.1,25,37,58,80

The above-described observations suggest the possible action of HCRT on stress-related circuits. Consistent with this hypothesis are certain stress-like behavioral actions of HCRT. Across multiple species, various behavioral responses are observed during stress, including chewing or gnawing of inedible material, grooming and fighting, and motor activity (e.g. displacement behaviors).2,10,32,43,55,59,68,96 These behaviors act to attenuate stressor-induced activation of a variety of central and peripheral physiological systems. Interestingly, ICV and basal forebrain administration of HCRT elicits a majority of these behaviors, including grooming,48,49 chewing of inedible material,37 and locomotor activity.35-37,67

In addition to the above-described actions of HCRT on neuronal activity and behavior, HCRT also promotes a variety of autonomic processes associated with stress and/or high levels of arousal. These include elevation of mean arterial blood pressure, heart rate, oxygen consumption, and body temperature.23,62,83,88,101 Combined, these observations begin to suggest that HCRT simultaneously activates a variety of neural circuits that coordinate physiological and behavioral responding in stress and possibly other high-arousal states.

5.2. Effects of Stress On c-Fos Expression in HCRT-Synthesizing and HCRT-Receptive Neurons.

The above-described observations suggest the hypothesis that HCRT systems may be activated under high-arousal, stress-like conditions. To better assess this hypothesis, and as part of studies examining the circadian dependency of rates of HCRT neurotransmission described above' we examined Fos-ir levels in animals exposed to a

Figure 5 Photomicrographs depicting the effects of varying behavioral state/environmental condition on Fos-ir (brown) within prepro-HCRT-ir neurons (gray-blue) and non-prepro-HCRT-ir neurons within LH. Shown are diurnal sleeping (SLP), nocturnal spontaneous waking (NSW) and high-arousal waking (HAW). Neither diurnal sleeping nor diurnal spontaneous waking was associated with increased Fos-ir within LH. Relative to diurnal sleeping' nocturnal spontaneous waking was associated with a slight increase in Fos-ir within prepro-HCRT-ir neurons and non-prepro-HCRT-ir neurons. In contrast' high-arousal waking was associated with a substantial increase in Fos-ir nuclei within prepro-HCRT-ir neurons and non-prepro-HCRT-ir neurons relative to diurnal sleeping, diurnal spontaneous waking and nocturnal spontaneous waking. Modified from. 37

Figure 5 Photomicrographs depicting the effects of varying behavioral state/environmental condition on Fos-ir (brown) within prepro-HCRT-ir neurons (gray-blue) and non-prepro-HCRT-ir neurons within LH. Shown are diurnal sleeping (SLP), nocturnal spontaneous waking (NSW) and high-arousal waking (HAW). Neither diurnal sleeping nor diurnal spontaneous waking was associated with increased Fos-ir within LH. Relative to diurnal sleeping' nocturnal spontaneous waking was associated with a slight increase in Fos-ir within prepro-HCRT-ir neurons and non-prepro-HCRT-ir neurons. In contrast' high-arousal waking was associated with a substantial increase in Fos-ir nuclei within prepro-HCRT-ir neurons and non-prepro-HCRT-ir neurons relative to diurnal sleeping, diurnal spontaneous waking and nocturnal spontaneous waking. Modified from. 37

stress-inducing, brightly lit novel environment.14'43 It was observed that novelty-stress increased Fos-ir levels within HCRT-synthesizing neurons as well as HCRTr1-expressing neurons located within LC, MPOA, MS, and SI (Figure 4 and 5).37 Interestingly, the magnitude of the novelty-stress-induced Fos-response within HCRT-receptive neurons was similar to that observed following ICV HCRT-administration. This latter observation further suggests the possibility that HCRT administration elicits at least a subset of stress-like actions within the brain. Similar activating effects on Fos expression within HCRT-synthesizing neurons have been observed following cold exposure, food deprivation, foot-shock, and immobilization stress.49'80'82'103 Consistent with these observations, limited evidence indicates an increase in levels of HCRT mRNA within LH following immobilization stress.49 Interestingly, although foot-shock increases Fos within

HCRT neurons, the conditioned stimulus that predicts the foot-shock, a stressor itself, does not alter Fos within these neurons.103 Together, these observations indicate that presentation of some, but not all stressors, results in increased activity of HCRT neurons.

5.3. Activating Actions of HCRT on CRH Neurotransmission.

CRF plays a prominent role in coordinating the constellation of behavioral and physiological responses that define the state of stress.30,54 Given this, it is of interest that HCRT fibers are located within close proximity of CRF neurons within the PVN and amygdala. Innervation of these structures by HCRT efferents suggests the possibility that HCRT may interact with central CRF systems to regulate the HPA axis and other stress-related processes. In support of this hypothesis, bath application of HCRT-1 elicits depolarization and increased spike frequency of magno- and parvocellular PVN neurons.84,87 Consistent with this, HCRT-1 increases cortisol and corticosterone secretion from human and adrenocortical cells, respectively.63,69 Similarly, in vivo, acute ICV HCRT-1 administration increases plasma levels of both corticosterone and adrenocorticotropin hormone (ACTH) release.1,49,52,58,63,75,84 Together, these observations indicate that HCRT efferents exert excitatory actions on CRF PVN neurons. It remains to be determined whether HCRT modulates activity of extrahypothalamic CRF neurons.

Similar to that observed with HCRT, central administration of CRF and ACTH elicit a variety of behavioral responses observed in stress, including locomotion, grooming and chewing of inedible objects.31,40 Combined, these observations suggest a possible interaction between HCRT and CRF in the regulation of stress-related behaviors. To test this hypothesis, Ida and colleagues49 examined the effects of a CRF antagonist (alpha-helical CRF9-41) on HCRT-induced grooming and locomotor activity. In these studies, treatment with alpha-helical CRF, reduced HCRT-induced grooming and face washing for the two hours following injection. Interestingly, the magnitude of HCRT-induced increases in locomotor activity was also reduced.

To further characterize the contribution of CRF systems to HCRT-induced arousal we have begun to examine the degree to which CRF participates in HCRT-induced waking and arousal-related behavioral activity. In these studies, animals were pretreated with vehicle or a CRF antagonist (alpha-helical CRF12-41) 30-min prior to HCRT administration. All infusions were made via a remote-controlled infusion pump and thus the behavioral state of the animal was not influenced by the infusion procedures per se. Consistent with previous observations,11,35,42,78 in animals pretreated with vehicle, HCRT-1 (0.7 nmol) increased EEG/EMG and behavioral indices of waking (Figure 6). In contrast, pretreatment with 15.0 nmol of the CRF antagonist attenuated HCRT-induced waking. Additionally, the CRF antagonist reduced HCRT-induced locomotion (rears and quadrant entries) and grooming (data not shown). Combined, evidence suggests the HCRT system may act, in part, to modulate behavioral and physiological processes under high arousal, stress-like, conditions and that at least a subset of these actions involves an interaction between HCRT and CRF systems.

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