Date of Degree

9-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Allyson K Friedman

Committee Members

Mitchel Goldfarb

Ekaterina Likhtik

Paul Forlano

Teresa Milner

Troy Roepke

Subject Categories

Behavioral Neurobiology | Biology | Molecular and Cellular Neuroscience | Neuroscience and Neurobiology

Keywords

Estrogen, Dopamine, Stress, Pharmacology, Electrophysiology, Estrous

Abstract

The behavioral output of different animals, or even the same animal in different contexts, is remarkably variable in response to the same external stimulus. This behavioral diversity is due to the complex integration of external and internal stimuli, through both neuronal and hormonal signals that selects the best behavioral response. By their nature as long-distance signaling molecules, hormones play a critical role in communicating information about internal states across the organism. Many hormones produced in the periphery target the central nervous system to modulate animal behavior, selecting for behaviors that are appropriate over behaviors that are maladaptive in that specific situation. These hormones generally communicate the internal state of the organism, such as reproductive status, or stress.

Sex steroid hormones are a diverse class of hormones that include estrogens, progestogens, and androgens. These hormones are released from the gonads and act on the brain to control a range of behaviors s involved in reproduction. Decades of research demonstrate both short- and long-term actions of these signaling molecules that directly affect the physiology of neurons in various regions of the brain. In addition to brain regions controlling behaviors involved in reproduction, these changes have also been found in regions important for controlling non-reproductive behaviors, such as memory, cognition, and motivation.

Estrogens are a class of steroid hormones that activate estrogen receptors (ERs) and have a strong influence on neuronal activity throughout the brain and periphery. While estrogens are typically associated with the female reproductive cycle, more than 50 years of research shows that ERs are expressed throughout the brain in both sexes and modulate behavior and cognition not typically associated with reproductive behavior, such as memory and motivation. Moreover, estrogen signaling has a role in modulating motivation and mood in humans, non-human primates, and rodents, indicating a conserved role for estrogen signaling across species. The ventral tegmental area (VTA) is a dopaminergic nucleus in the midbrain that is associated with motivation is also highly conserved across species. Shifting of motivation through modulation of the dopaminergic hub of the brain is important for behavioral plasticity that determines an appropriate behavioral response based on the external and internal environment.

Motivation refers to the drive to perform a behavior to obtain a goal (Simpson and Balsam, 2016). Strong primary motivations include obtaining food and shelter, finding a mate to reproduce, or avoiding dangerous situations. Motivated behaviors are triggered by an external event, such as a reward or a cue paired a reward. The behavioral response to a motivating cue is also modified by an internal state. Classic in vivo recordings of dopamine neurons in the VTA show increases in firing rate in response to both rewarding and aversive external stimuli. These responses are not limited to the reward or aversive stimuli, but also with neutral stimuli that have been paired with the reward or punishment. Research has revealed that the reward system, including the VTA, is modulated by estrogen signaling. However, much of the research in this area focuses on the effects of estrous cycle and estrogen signaling in regions that receive projections from the VTA, such as the striatum, the hippocampus, and the prefrontal cortex, while little research exists examining the role of estrogen in directly modulating the physiology of dopamine neurons in the VTA.

Motivation is a component of mood, and a change in motivation to obtain reward is a hallmark of mood disorders such as depression. Women are up to twice as likely to be diagnosed with major depressive disorder (MDD) than men (Noble, 2005). In many women, changes in the menstrual cycle can lead to changes in mood and motivation. Several depressive disorders and modifiers of MDD in the Diagnostic and Statistical Manual V (DSM-V) are associated with fluctuations in hormones. These include premenstrual dysphoric disorder (PMDD), postpartum depression, and mood changes during perimenopause. Moreover, depression treated with medication can lead to changes in menstrual cycle length and regularity, suggesting an interaction between mood and hormone fluctuations (Rowland et al., 2002). Additionally, rodent models of stress susceptibility provide evidence that the dopaminergic response to stress is sex- and hormone dependent.

In this dissertation, I will present experimental evidence that estrogen signaling in the VTA is an important modulator of dopamine neuron physiology, which leads to differences in the behavioral response to stress in female mice. I show that the physiology of dopamine neurons in the VTA of female mice changes across the estrous cycle. These changes are at least partially caused by changes in estrogen signaling, as shown by pharmacological manipulation of estrogen signaling in in vitro slice preparation. Moreover, estrogen signaling in the VTA is involved in the behavioral response to stress, as pharmacological manipulation of estrogen signaling in intact female mice changes the behavioral response to stress.

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