Friday, January 17, 2025
1/17/2025
Project Summary/Abstract Responses to potential threat and innate defensive behaviors are critical for survival. Nevertheless, an over- activation of the brain defensive network and, more importantly, an impairment in extinction (i.e., the ability to reduce threat responding upon repeated exposures in the absence of an aversive stimulus) can lead to behavioral maladaptation and neuropathological conditions associated with anxiety disorders. Thus, identification of the neuronal circuits and mechanisms underlying innate threat processing and, in particular, inhibition of defensive behaviors upon recurrent exposures, is fundamental for understanding the healthy brain response to threatening stimuli and also for insights into pathological conditions such as anxiety disorders. While most studies in laboratory animals have focused on conditioned responses to threat in non-naturalistic situations, exposure to an overhead dark visual looming stimulus (VLS) naturally elicits innate defensive responses across multiple species. Recent studies have determined that the medial habenulo-interpeduncular nucleus (MHb-IPN) axis has been implicated in conditioned fear and may contribute specifically to extinction of freezing behavior induced by associations with a cue and/or context. However, whether the IPN specifically contributes to innate defensive responses is unknown. The goal of this application is to test the over-arching hypothesis that threat-processing and adaptive inhibitory learning require specific patterns of IPN GABAergic neuron activation and afferent cholinergic input from the laterodorsal tegmentum (LDTg), to modulate innate defensive responses. Aim 1 will combine calcium sensors, fiber photometry and optogenetic approaches to test the hypothesis that IPN GABAergic neurons are activated by multi-sensory evoked defensive behaviors and innate inhibitory learning; whereas, Aim 2 will use similar approaches to test if activation of IPN GABAergic neurons and innate defensive behaviors are modulated by excitatory input to the IPN from the LDTg. If borne out, the results of these experiments should reveal novel cellular and circuit mechanisms underlying the response to naturalistic fearful stimuli and the effect of these mechanisms on innate defensive behaviors.
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