Neuronal circuits regulating aversive salience, defensive behavior, and hyperarousal

Southeast Louisiana Veterans Health Care, New Orleans LA

Investigators

Abstract

Emotional behaviors, such as defensive responses to threat, are often dysregulated in mental illness. Currently, there is a poor understanding of the neural mechanisms that influence and control diverse types and magnitudes of defensive responding. Obtaining such knowledge will provide significant progress toward providing foundational knowledge used for the development of better therapeutics for mental illness. The overall objective of this application is to identify how distributed neuronal circuits control salience assignment during fear learning to influence defen- sive behavior intensity. The central hypothesis is that cholinergic neuromodulatory inputs from the Basal Forebrain (BF) to the Basolateral Amygdala (BLA) and Medial Prefrontal Cortex (mPFC) assist in encoding stimulus salience to inform future defensive responses. The rationale that un- derlies this proposal is that an enhanced understanding of these complex behavioral states and circuits will provide key data for understanding multiple psychiatric disorders emerging from mal- adaptive responses to stress. The proposed research evaluates the central hypothesis with three specific aims: 1) Identify the functional role of specific projection pathways in defining salience during complex fear learning; 2) Determine how cholinergic projection neurons encode stimuli of differing salience; and 3) Define the role of the system in the acquisition of a traumatic memory. The first aim will use viral vector delivery strategies and optogenetics to target and manipulate specific output pathways of the BF. The second aim will use retrograde targeting strategies and fiber photometry to monitor neural activity patterns in specific BF projection neurons while mice transition through escalating levels of defensive responding. Finally, the third aim will use chemo- genetics during an ethologically valid trauma exposure paradigm and measure its effects on phys- iological measures of hyperarousal. The proposed research is innovative because it substantially departs from the status quo by investigating how the brain encodes aversive salience to coordi- nate transitions between defensive behaviors. This will be significant because it will lay a founda- tion that facilitates understanding of the neuronal circuit basis of the maladaptive responses as- sociated with mental illness. Indeed, this systems neuroscience approach to understanding how fear states are encoded will open new avenues of research into the neurobiological underpinnings of anxiety- and trauma-related mental health disorders, such as posttraumatic stress and panic disorder.