Date of Degree

6-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Psychology

Advisor

Ekaterina Likhtik

Advisor

Nesha Burghardt

Committee Members

Glenn Schafe

Allyson Friedman

Sumantra Chattarji

Subject Categories

Animal Experimentation and Research | Behavior and Behavior Mechanisms | Cellular and Molecular Physiology | Experimental Analysis of Behavior | Mental Disorders | Psychological Phenomena and Processes

Keywords

chronic stress, safety, generalized fear, basolateral amygdala, prelimbic cortex, basal forebrain

Abstract

Chronic stress increases generalization of fear to non-threatening cues, a key symptom in numerous psychiatric mood disorders. However, the mechanisms through which stress impacts safety learning remain poorly understood. To probe the relationship between stress and safety learning, this dissertation employed multiple behaviors, in conjunction with in-vivo multisite physiology during explicit safety and fear discrimination learning. In Chapter 1, I outline the role of chronic stress in driving neurological adaptations that result in generalized fear and highlight how this occurs because of impaired safety cue encoding. In Chapter 2, I show that chronic stress in the form of social defeat impairs encoding of a safety cue in a manner that causes a population wide shift towards failed safety signaling. Communication between the prelimbic cortex (PL) of the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have been shown to be necessary for threat discrimination. In Chapter 3, I use local field potential (LFP) recordings in the PL and BLA to show that following chronic stress, safety cues evoke elevated theta power in the PL, the threatening context evokes increased theta power in the BLA, and PL-BLA theta synchrony is diminished during safety memory retrieval. In Chapter 4, I demonstrate that following chronic stress, explicit safety learning can improve subsequent fear discrimination. Finally, in Chapter 5, I show that chronic restraint stress impacts fear generalization similarly to chronic social defeat stress, and I integrate the basal forebrain (BF) into the fear discrimination circuit. I demonstrate that fewer BF parvalbumin-expressing (PV) cells are active in mice that display generalized fear, and that inhibition of cholinergic afferents from the BF to the PL during discrimination learning disrupts discrimination retrieval, mimicking stress-induced fear generalization. Overall, this work demonstrates that chronic stress impairs explicit safety learning, breaks down PL-BLA theta synchrony during safety recall, and increases generalized fear. Additionally, while there has been no prior exploration of PV cells in the BF in relation to fear discrimination, my results indicate that this cellular population is crucial for regulating specificity of the threat response. Finally, I show that explicit safety training alleviates stress-induced impairments in discrimination, which has potential therapeutic implications for disorders that include generalized fear.

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