Hypocretin (orexin) neuromodulation of stress and reward pathways

Abstract

Hypocretin (also known as orexin) is a peptide neuromodulator that is expressed exclusively in the lateral hypothalamic area and plays a fundamental role in wakefulness and arousal. Chronic stress and compulsive drug-seeking are two examples of dysregulated states of hyperarousal that are influenced by hypocretin transmission throughout hypothalamic, extended amygdala, brainstem, and mesolimbic pathways. Here, we review current advances in the understanding of hypocretin's modulatory actions underlying conditions of negative and positive emotional valence, focusing particularly on mechanisms that facilitate adaptive (and maladaptive) responses to stressful or rewarding environmental stimuli. We conclude by discussing progress toward integrated theories for hypocretin modulation of divergent behavioral domains.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

LH-Hcrt neurons project widely, including to the PVN, BNST, CeA, BLA, LC, VTA, and NAcc. Recent evidence implicates Hcrt modulation of CRF neurons of the PVN, BNST, and CeA in the negative affective states associated with anhedonia, drug withdrawal, HPA-axis activation, and anxiogenesis. Primarily glutamatergic vs. GABAergic phenotypes of PVN-CRF vs. BNST-CRF neurons provide diverse mechanisms for Hcrt modulation of stress circuitry. Preliminary evidence implicates BLA-HcrtR2 signaling in anxiolysis rather than anxiogenesis. Hcrt innervation of LC-NE neurons participates in sleep-to-wake transitions, and strengthens fear memories via subsequent LC-NE release in the amygdala. Hcrt modulation of excitatory synaptic plasticity in VTA-DA neurons is well-studied. Together with potentiation of DA release at the level of the NAcc shell, Hcrt may promote motivational responding and drug-seeking behavior via enhanced DA receptor signaling.