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Adaptations in Locus Coeruleus Induced by Post-Traumatic Stress Disorder

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Annual rept. 1 Nov 2012-31 Oct 2013

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PTSD and related anxiety disorders are a major health problem for veterans, as well as the general population. There is compelling experimental support for the proposition that elevated NA release in the brain is a major contributing factor in PTSD. This elevation in norepinephrine is thought to promote arousal as well as the persistence and enhanced retrieval of traumatic memories core phenomena in PTSD. The principal source of norepinephrine in forebrain and amygdalar circuits is the locus ceruleus LC. In spite of its centrality to theories of the neural mechanisms underlying PTSD, relatively little is known about the factors governing its activity and how these change in PTSD. The central hypothesis of this proposal is that the intrinsic and extrinsic synaptic properties of LC neurons are remodeled in PTSD, and this remodeling plays a major role in triggering the pathological changes in forebrain circuits mediating symptoms in the disorder. The studies to be conducted will test this core hypothesis in two animal model of PTSD, filling key gaps in our understanding of the mechanisms governing PTSD. The core hypothesis is broken down into three specific aims, each of which has a guiding, working hypothesis. The studies outlined in the first specific aim will test the hypothesis that the induction of PTSD-like state in mice will result in an elevation of autonomous intrinsically generated spiking in LC neurons. The studies outlined for the second specific aim will test the hypothesis that the induction of PTSD-like state in mice will result in strengthening of synaptic connections of LC neurons that arise from the cerebral cortex and amygdala, creating a means by which fear-evoking stimuli lead to an abnormal elevation of LC activity. Our lab has a well-developed expertise in the characterization of synaptic connections using both conventional electrical and optogenetic approaches.

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  • Medicine and Medical Research

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