Anxiety and fear disorders involve alterations of fear processing, due in part to persistent changes in emotional processing circuits in the brain. The overall goal of the current proposal is to elucidate the role of the hypothalamic orexin (hypocretin) system in emotional learning. There is strong evidence that orexins mediate stress and arousal responses to aversive stimuli, which may be required for the formation of negative emotional memories. A well established brain area for the formation, storage and retrieval of these memories, and the first logical target for orexin activity, is the lateral nucleus of the amygdala (LA). However, consistent with low receptor expression in this area, direct pharmacological manipulations of orexin receptor-1 (OrxR1) in LA do not affect aversive learning. Preliminary data suggest that both central and direct locus coeruleus (LC) administration of the orexin receptor-1 (OrxR1) antagonist SB 334867 impairs the acquisition of aversive memories. Indeed, the LC, a major source of brain norepinephrine (NE), receives dense projections from orexin neurons, expresses high levels of OrxR1, and LC neurons are excited by orexins. Based on evidence that locus coeruleus LC and orexin neurons are co-activated in response to aversive stimuli, and that orexins directly excite LC neurons, I hypothesize that orexins can enhance NE release in the LA. Indeed, data from our lab strongly implicate NE signaling through beta-adrenergic receptors (betaARs) in the LA in the learning of fear associations. The current proposal seeks to demonstrate an unexplored interaction between the hypothalamic orexin system and brain regions that are critical for emotional learning. Specifically, I hypothesize that orexins enhance aversive memory formation through positive modulation of the LC during the unconditioned stimulus (US, or stimulus that triggers an innate response) in cued conditioning. First, I will test orexin activity in the LC with an OrxR1 antagonist (SB 334867) pre-training period (acquisition of a memory) and post- training period (consolidation of a memory). Second, to demonstrate a hypothalamus (orexin)->LC(OrxR1)->LA(betaAR) pathway, I will pharmacologically ?disconnect? the circuit using contralateral infusions of SB 334867 in the LC and propranolol in LA. Third, I will use a light-activated channel, Archaerhodopsin-3 (Arch) to inhibit orexin neurons during either the conditioned stimulus (CS, i.e. a tone) or the US to examine when during training orexin modulates LC activity. I hypothesize that orexin neuron inhibition during the US, but not the CS, will facilitate aversive learning. Clinical evidence suggests that people deficient in orexins show impairments in aversive memory formation. Dysregulation of the orexin system may explain susceptibility to fear and anxiety disorders and provide both a diagnostic measure and treatment target for these disorders.
Strong, fearful memories can lead to fear and anxiety disorders that have a negative impact on individuals and their quality of life. By investigating the brain neuromodulatory systems that enhance fear memories, the current proposal may lead to novel diagnoses and treatments for fear, panic, stress and anxiety disorders in susceptible individuals.
|Sears, Robert M; Fink, Ann E; Wigestrand, Mattis B et al. (2013) Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci U S A 110:20260-5|