Thalamolimbic circuit mechanisms for social threat processing

Patients with posttraumatic stress disorder (PTSD) experience debilitating deficits in threat inhibition, resulting in hypervigilance, reexperiencing traumatic events, and severe sleep disturbances. Supported by a growing body of scientific evidence, it is apparent that these symptoms result from maladaptive stress responses that derail

threat neurocircuitry. Therefore, regions of overlap in stress and threat networks - where trauma could jeopardize the integrity of adaptive threat processing - warrant thorough scientific examination. I recently discovered a population of anterior central medial thalamic (aCMT) cells that expresses the well-characterized stress signaling

neuropeptide, corticotropin-releasing hormone (Crh) and densely innervates the anterior basolateral amygdala (aBLA) - a brain area with a recognized role in fear expression and extinction. In mice, experiencing social trauma in the form of translational chronic social defeat stress (CSDS) promotes extreme defensiveness toward safe

social partners. This maladaptive defensive behavior is associated with hypoactivity in Crh+ aCMT neurons and can be relieved through optogenetic stimulation of this cell population; conversely, optogenetic inhibition of Crh+ aCMT neurons severely disrupts sociability in CSDS-naïve mice. As such, I propose that the aCMT is an

important “missing link” in our understanding of intersecting stress and fear neurocircuitries and that aBLA- projecting aCMT (aCMTaBLA) cells contribute to persistent maladaptive defensiveness after social trauma. With access to the Ressler Laboratories’ extensive expertise in genetic and molecular techniques and Pavlovian fear

conditioning, I will systematically examine the dynamic effects of CSDS on aCMTaBLA neural activity using cutting- edge transcriptional, molecular and behavioral neuroscience approaches. For Aim 1, I will use fiber photometry in behaving mice to record from Crh+ aCMTaBLA cells as social defense develops after CSDS exposure. I

hypothesize that defensive social behaviors will negatively correlate with aCMTaBLA neural activity and I expect neural activity to recover during social fear extinction learning. For Aim 2, I will use Targeted Recombination of Activated cell Populations (TRAP2) to isolate aCMTaBLA cells that are activated during social interactions before

CSDS – this social ensemble can be accessed genetically to recover adaptive interactions following exposure to social trauma. This cutting-edge genetic methodology will be leveraged to examine the effects of CSDS on aCMT and aBLA social ensembles. To recover sociability after CSDS, aberrant neural activity during social

defensiveness will trigger closed-loop optogenetic stimulations that target TRAPed aCMTaBLA cells. Thalamolimbic social ensembles will be isolated in Exploratory Aim 3 to identify transcriptional repercussions of CSDS. In summary, this work will critically examine the effects of social trauma on a novel thalamolimbic pathway

- aCMTaBLA - that intersects with stress and fear neurocircuits. Closed-loop optogenetics will target aberrant social stress-induced neural activity in aCMTaBLA social cell ensembles to recover adaptive sociability.