Dissertations, Theses, and Capstone Projects

Date of Degree

9-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Allyson Friedman

Committee Members

Mitchell Goldfarb

Patrizia Casaccia

Susana Mingote

Jia Liu

Kristen Pleil

Subject Categories

Other Neuroscience and Neurobiology

Keywords

BNST, VTA, stress, resilience, GABA

Abstract

Chronic stress has detrimental effects on psychological and physiological health. Incapability to adapt to chronic stress can lead to depression, anxiety disorders, and addiction. The brain regions critical for reward processing share diverse physiological and molecular changes linked to depressive-like behaviors as a result of chronic stress. Cumulative evidence shows that counteraction or prevention of these alterations in neurons, occasionally in a projection-specific manner, can enhance stress adaptation or resilience.

Chronic stress induces various changes in the brain, including in the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA). The neural projections from the BNST to the VTA have been shown to be vital for regulating behaviors linked to stress-reward interactions. Specifically, the intrinsic membrane properties of these neurons are important as they set the threshold for action potentials. Based on electrophysiological features, the BNST has diverse neuronal types: Type I, Type II, and Type III, each potentially possessing distinct sensitivity and responses to chronic stress. These properties shape the neurons' firing patterns, which govern signal transduction and ultimately affect behavioral outcomes, including stress susceptibility or stress resilience. The diversity and plasticity within this pathway offer an intriguing opportunity for exploring the mechanisms that underpin resilience.

In this dissertation, I offer evidence that chronic stress differently affects the electrophysiological properties of the VTA-projecting BNST neurons, and the changes are related to stress susceptibility and resilience. First, I establish a comprehensive characterization of electrophysiologically diverse VTA-projecting BNST neurons in mice by utilizing retrograde viral-mediated neuronal labeling combined with whole-cell patch-clamp recording. This set of experiments discovered previously unseen Type III neurons in mice. Further, I show that quantified electrophysiological parameters can be used to classify BNST neurons in an unsupervised way. Next, I demonstrate the unique sensitivity of Type III neurons to chronic stress. The excitability of Type III neurons is altered as a result of chronic stress, and this physiological change is correlated with stress-related behaviors. Given dense GABAergic projections from the BNST to VTA, the higher excitability of Type III neurons may contribute to the hyperactivity of VTA dopaminergic neurons, a signature of susceptibility, through disinhibition.

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