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.