Abstract
Orexins (OX), also known as hypocretins, are excitatory neuropeptides with well-described roles in regulation of wakefulness, arousal, energy homeostasis, and anxiety. An additional and recently recognized role of OX is modulation of fear responses. We studied the OX neurons of the perifornical hypothalamus (PeF) which send projections to the amygdala, a region critical in fear learning and fear expression. Within the amygdala, the highest density of OX-positive fibers was detected in the central nucleus (CeA). The specific mechanisms underlying OX neurotransmission within the CeA were explored utilizing rat brain slice electrophysiology, pharmacology, and chemogenetic stimulation. We show that OX induces postsynaptic depolarization of medial CeA neurons that is mediated by OX receptor 1 (OXR1) but not OX receptor 2 (OXR2). We further characterized the mechanism of CeA depolarization by OX as phospholipase C (PLC)- and sodium-calcium exchanger (NCX)- dependent. Selective chemogenetic stimulation of OX PeF fibers recapitulated OXR1 dependent depolarization of CeA neurons. We also observed that OXR1 activity modified presynaptic release of glutamate within the CeA. Finally, either systemic or intra-CeA perfusion of OXR1 antagonist reduced the expression of conditioned fear. Together, these data suggest the PeF-CeA orexinergic pathway can modulate conditioned fear through a signal transduction mechanism involving PLC and NCX activity and that selective OXR1 antagonism may be a putative treatment for fear-related disorders.
Highlights
Deregulation of fear responses are thought to contribute to a number of anxiety disorders, including posttraumatic stress disorder, panic, and phobias associated with panic disorder (Milad et al, 2006; Herry et al, 2008; Hofmann, 2008; Holmes and Singewald, 2013)
Application of 200 nM OX A significantly depolarized central nucleus (CeA) neurons compared to vehicle and 1 μM OX A significantly depolarized CeA neurons compared to 200 nM OX A and vehicle conditions (Sidak’s between subjects p ≤ 0.0003, within subjects p ≤ 0.0008) (Figure 1D)
We have demonstrated that CeA depolarization and control of synaptic transmission is dependent upon OX receptor 1 (OXR1) but not OX receptor 2 (OXR2) activity, so we aimed to determine the effects of OXR antagonism on fear expression
Summary
Deregulation of fear responses are thought to contribute to a number of anxiety disorders, including posttraumatic stress disorder, panic, and phobias associated with panic disorder (Milad et al, 2006; Herry et al, 2008; Hofmann, 2008; Holmes and Singewald, 2013). These disorders can have severe consequences on quality of life and are accompanied with serious economic burden for society (Olesen et al, 2012). Multiple previous studies have implicated the OX system in modulating fear responses: intracerebroventricular injection of OXR1 antagonists enhances fear extinction in rats (Flores et al, 2014); OXR1 knockout mice display impaired freezing responses and reduced amygdala neuron activity (Soya et al, 2013); dual OX antagonist almorexant reduces fear-potentiated startle response (Steiner et al, 2012); immobility time after footshock positively correlates with prepro-OX mRNA expression and is attenuated by treatment with a dual OX antagonist (Chen et al, 2014); and increased OX neuron activity is correlated to higher freezing levels and resistant fear extinction (Sharko et al, 2016)
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