Item Details

title

The Consequences of Early Life Stress and Alcohol Consumption on Microglia Function and Dementia-related Pathologies

author

Gironda, Stephen

abstract

Early life stress (ELS) has lasting consequences on behavioral and physiological health. Existing literature suggests that ELS has a direct effect on microglia function. As resident immune cells of the brain, the primary objective of microglia is to maintain brain homeostasis. In development, microglia assist in regulating synapse maturation. This process ensures proper neuronal and circuit function later in life. As a result of ELS, microglia can alter their engagement with synapses leading to adaptations in reward processing and motivated behaviors. These types of changes may play a vital role in the relationship between ELS and an increased risk for excessive alcohol use and alcohol use disorder (AUD). AUD is known to elicit chronic inflammation and lead to global neurodegeneration. Evidence suggests that this process may be mediated by impaired microglial function. Therefore, the central questions to this dissertation are: 1) Are microglia necessary for the development of maladaptive drinking behaviors following ELS (Chapter II) and 2) does alterations in microglia function mediate the effects of alcohol on neurodegeneration in the context of dementia (Chapter III). In Chapter 2, we utilized an ELS model, early life psychosocial stress (PSS), to determine whether microglia are necessary for the development of maladaptive drinking behaviors following ELS. We found that 1) PSS evoked increases in binge-like ethanol consumption; 2) repeated binge-like ethanol ix consumption increased the number of microglia; 3) PSS altered microglial responsivity to repeated binge-like ethanol consumption; and 4) microglial inhibition during PSS was not sufficient to prevent escalations in ethanol consumption, but was effective at preventing the effects of PSS on microglia number following repeated binge-like ethanol consumption. In Chapter 3, we identified the effects of voluntary ethanol consumption on a mouse model of dementia. We found that voluntary ethanol consumption altered self-care related behaviors and increased amyloid plaque count in a region-specific manner. In the appendices, supplemental work provides evidence that voluntary ethanol consumption may exacerbate dementia-related changes in microglial function. As a result, we speculate that microglial inhibition during periods of ELS may conserve healthy microglia function later in life and prevent the onset of maladaptive behaviors that increase the risk for dementia.

subject

Alcohol Use Disorder

Development

Early Life Stress

Innate Immunity

Longevity

Microglia

contributor

Weiner, Jeffrey L (advisor)

Milligan, Carol J (committee member)

Raab-Graham, Kim F (committee member)

Macauley, Shannon L (committee member)

Carola, Valeria (committee member)

date

2025-03-12T08:36:47Z (accessioned)

2025-03-12T08:36:47Z (available)

2024 (issued)

degree

Neuroscience (discipline)

identifier

http://hdl.handle.net/10339/110321 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation