Dissertations, Theses, and Capstone Projects

Date of Degree

2-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Ekaterina Likhtik

Committee Members

Susana Mingote

Allyson Friedman

Andrew Delamater

Robert Froemke

Subject Categories

Behavior and Behavior Mechanisms | Mental Disorders | Nervous System

Keywords

infralimbic, basal forebrain, basolateral amygdala, fear extinction, theta, learning

Abstract

The medial prefrontal cortex (mPFC) is a key region for emotion regulation, and its failure to regulate extinction of aversive memories is associated with Post Traumatic Stress Disorder. Study of how the Infralimbic cortex (IL), a subregion of the mPFC, directly communicates with the Basolateral Amygdala (IL-BLA), has thus far failed to uncover the circuit mechanisms that lead to mPFC-mediated amygdala suppression of firing and diminished fear responses during extinction retrieval. One problem of this model is that it doesn’t incorporate indirect IL communication with the BLA. A key region to help understand how IL modulates extinction is the basal forebrain (BF).

The BF both provides and receives input from IL and BLA and has been implicated in attention and learning, including in protocols encompassing inhibition of fear responses such as fear discrimination. The role of BF-BLA communication in fear and the role of IL-BLA in extinction communication have been heavily investigated. However, how IL-BF communication contributes to extinction processing and BLA activity has never been addressed.

In this dissertation, we characterize IL-BF activity and compare it to the classically studied IL-BLA projection. First, we studied the anatomical distribution of BF and BLA projectors from the mPFC using retrograde tracers. We found that the BF is preferentially innervated from deeper layers, whereas BLA projectors do not present a laminar differentiation. Then, via projection-specific cFos immunostaining we probed whether these pathways were differentially engaged in fear compared to extinction retrieval. We found that, in line with previous work, the IL-BLA was engaged in Extinction Retrieval, whereas the IL-BF was more involved in Extinction Acquisition. Then, we turned to local field potential recordings to study IL-BF-BLA communication throughout fear and extinction. We demonstrated that theta is present in all regions during states of high fear, but only correlates with freezing after fear conditioning. Further, whereas IL prominently leads BLA since late Extinction Acquisition stages, IL-BF communication is more prominent on Extinction Acquisition, starting with a bidirectional communication that evolves into a strong lead of BF by IL. Finally, we wanted to test whether IL-BF activity during early trials of Extinction Acquisition is sufficient and necessary to extinction processing. We found that mice with an inhibited IL-BF pathway displayed increased same-day and Retrieval defensive freezing, whereas no difference was found when this pathway was activated, suggesting that IL-BF activity is needed but insufficient for Extinction acquisition. We also investigated excitability changes in IL-BF projectors between Extinction Acquisition and Retrieval via whole-cell patch clamp recordings and found no difference. This suggests that the increased engagement of IL-BF during Extinction Acquisition likely derives from increased input at this timepoint, instead of from intrinsic changes in excitability.

Altogether, this dissertation opens the possibility that IL contains two neural populations, “Extinction Acquisition” and “Extinction Retrieval”, each harboring distinct connectivity to downstream regions and contributing to different phases of Extinction processing. More broadly, we hope this works is useful to uncover novel targets for the treatment of psychiatric disorders related to extinction deficits, and to inform how one is able to update previously learned responses to aversive cues in the face of altered environmental conditions.

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