Hypocretin (orexin) neuromodulation of stress and reward pathways
Introduction
The hypocretins (also known as orexins) are two secreted neuropeptides (Hcrt1, Hcrt2) derived from the same preprohypocretin gene that bind to two G-protein-coupled receptors (HcrtR1, HcrtR2) [1, 2, 3]. Both hypocretins are expressed exclusively in the lateral hypothalamic area (LH), therefore both are referred to here as hypocretin (Hcrt). LH-Hcrt neurons are inactive during sleep, but become activated during wakefulness, likely to promote goal-oriented behavior and energy homeostasis [4, 5]. Direct manipulations of LH-Hcrt neurons using in vivo optogenetics revealed their key role in increasing the probability of sleep-to-wake transitions through HcrtR signaling in norepinephrine (NE) neurons of the locus coeruleus (LC) [6, 7••]. While LH-Hcrt neurons project widely [8], this review covers Hcrt's modulatory actions within the paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), central and basolateral nuclei of the amygdala (CeA, BLA), LC, ventral tegmental area (VTA), and nucleus accumbens (NAcc). Rather than providing a comprehensive summary of the literature, we focus on articles published in the last three years that examine Hcrt neuromodulation of stress-related and addiction-related phenomena.
Multiple lines of evidence identify Hcrt as a pro-stress modulator, adding complexity to the prevailing view of Hcrt as a reward-related signal. For example, intracerebroventricular (i.c.v.) Hcrt administration enhances anxiety-like behavior [9] and decreases brain reward function, reflected by increased thresholds in the classical intracranial self-stimulation (ICSS) procedure [10]. Interestingly, Hcrt's effects on the ICSS threshold are mediated by corticotropin-releasing factor (CRF), the prototypical stress neuropeptide [11•]. CRF released from the PVN activates the hypothalamic–pituitary–adrenal (HPA) stress axis, resulting in increased levels of adrenocorticotropin hormone (ACTH) and corticosterone (or cortisol; CORT). Hcrt administered i.c.v. also elevates ACTH and CORT levels [12], supporting the hypothesis that Hcrt possesses CRF-dependent anti-reward properties [11•]. Yet, an extensive literature describes Hcrt-mediated positive modulation of the mesolimbic VTA dopamine (DA) reward system. Hcrt robustly innervates the VTA [13], induces excitatory synaptic plasticity in VTA-DA neurons [14, 15], and causes DA release in VTA target regions [16, 17]. Reward-seeking behavior (i.e., expression of conditioned place preference, operant self-administration, or reinstatement of either) is associated with activation of Hcrt neurons, and largely attenuated by systemic HcrtR blockade [18, 19].
Thus, Hcrt is anatomically and functionally poised to modulate neural activity in arousal-related conditions of both negative and positive emotional valence. In reviewing the most recent findings on this topic, we discuss several mechanisms by which dysfunction of Hcrt modulation could underlie behavioral states associated with stress-related and addiction-related psychiatric disorders.
Section snippets
Hypocretin interactions with CRF stress pathways
Hcrt-containing efferents of the LH target the hypothalamus and extended amygdala, particularly the CRF-enriched nuclei of the PVN, BNST, and CeA [20, 21, 22]. I.c.v. infusion of Hcrt activates PVN-CRF neurons [23] and elevates HPA hormones [12], suggesting that Hcrt directly modulates the CRF-mediated neuroendocrine output. Furthermore, the anxiolytic effects of HcrtR1 blockade are associated with reduced neural activation in the BNST and CeA [24]. Together with the CRF-dependent effects of
Hypocretin modulation in the BNST and amygdala
As with the PVN, the BNST connects reciprocally with Hcrt neurons [8, 29]. However, while PVN-CRF neurons are mostly glutamatergic, BNST-CRF neurons are primarily GABAergic [30], thereby offering diverse mechanisms for Hcrt modulation of stress circuits. In one recent study, slice application of Hcrt to neurons in the CRF-enriched dorsolateral BNST (dlBNST) of adult mice depressed excitatory post-synaptic currents (EPSCs) in a HcrtR1-specific manner [31]. Interestingly, these effects on
Hypocretin modulation in the LC
LC-NE neurons are a major target of Hcrt neurons, and combinatorial optogenetics revealed the necessity of LC-NE activity for Hcrt-mediated awakenings [7••]. Additionally, LC-NE neurons play a critical role in the stress response [38]. NE-induced plasticity at GABAergic synapses in the PVN regulates HPA-axis activity [39], and the relevance of BNST-NE signaling to stress and reward function has been reviewed [40]. In one recent study of Hcrt-NE interactions, Sears et al. used optogenetic and
Hypocretin modulation in the VTA
VTA-DA neuron burst firing is sufficient to produce conditioned reward [42], and Hcrt neurons project strongly to the VTA [13], forming appositional contacts with DA neurons [43]. VTA-DA neurons demonstrate increased EPSC amplitudes and firing rates upon Hcrt application, and display HcrtR1-dependent excitatory synaptic plasticity following cocaine exposure. The precise mechanisms underlying these forms of modulation have been reviewed elsewhere in detail [14, 15]. Intra-VTA infusion of Hcrt
Hypocretin modulation in the NAcc
In addition to modulating DA activity at the level of the VTA, two new studies examine how Hcrt inputs to the NAcc could further amplify reward-related effects associated with striatal DA release. Mori et al. described a subpopulation of neurons in the NAcc shell that displayed a synergistic increase in firing rate upon combinatorial application of Hcrt and DA, relative to Hcrt alone [46]. Patyal et al. used voltammetry in NAcc shell slices to reveal a glutamate-dependent mechanism in which
Conclusions
Recent studies on Hcrt modulation have identified diverse mechanisms that point toward both pro-stress (PVN, BNST, CeA, LC) and anti-stress/pro-reward (BLA, VTA, NAcc) behavioral consequences (Figure 1). Future investigation of the discussed pathways may shed light on clinical findings that highlight Hcrt's involvement in the response to both negative and positive motivational situations. For example, Hcrt-deficient patients display impaired amygdala activation following exposure to conditioned
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Drs. Ada D. Eban-Rothschild and Andrew J. Whittle for helpful comments on this manuscript. Grant support from the National Institutes of Health was provided to WJG (F32 AA022832) and LdL (R01 MH83702, R01 MH87592).
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