The role of astrocytes in probabilistic decision-making

ORCID

https://orcid.org0000-0003-3615-1890

Date of Award

2-4-2025

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

To flexibly navigate an uncertain world, animals need to be able to maintain internal representations of the values of good and bad things in the environment and to flexibly update their internal representations from experience. The purpose of this thesis work is to 1) develop tools and methodology to quantitatively study aversion-motivated behavior, and to 2) investigate the role of astrocytes, a non-neuronal brain cell type, in mediating experience-guided decision- making. The first part of this thesis describes a novel paradigm we developed to use dermal laser stimulation as an aversive stimulus for quantitatively studying motivated behavior in rodents and non-human primates. We trained head-fixed mice on a paradigm where auditory cues predicted sucrose water rewards or dermal laser punishments. We show that mice learn the meanings of these cues and show differential anticipatory behavior between rewards and laser punishments. Our paradigm reveals a novel use of dermal laser stimulation as a temporally precise, easily titratable aversive stimulus that can be used to measure motivational processes on a trial-by-trial basis. vii The second part of this thesis aims to investigate the role of astrocytes in outcome-guided decision-making. This behavior is thought to depend on basal ganglia circuitry, particularly dopamine-dependent synaptic plasticity in the striatum. Even as the field gains insight into how different neural cell types in striatum contribute to RL computations, the role of astrocytes remains unclear. Astrocytes are known to respond to neurotransmitters and neuromodulators such as glutamate and dopamine, and they have strong intracellular calcium responses that can lead to the release of gliotransmitters capable of modulating synaptic plasticity and behavior. However, whether and how astrocyte function is important for RL is not yet known. To investigate this, we attenuated astrocyte calcium signaling across different regions of striatum while mice performed a probabilistic decision-making task. Agents performing task must continuously update their value representations based on the history of outcomes they receive. We found that mice with astrocyte activity attenuated in ventral striatum show significantly worse performance post-injection compared to pre-injection, and that this decrease in performance correlates with a decrease in win-stay behavior. In contrast, mice with astrocyte activity attenuated in the dorsolateral and dorsomedial striatum, or with control manipulations, did not show this effect. To further characterize computations that may underlie this behavioral change, we fit mice’s behavior with a Q-learning model of reinforcement learning. We found that VS astrocyte attenuated mice show significantly noisier decision-making reflected through decreased inverse temperature parameters, but no significant change in learning rates. These results suggest that astrocytes in VS may not directly control value updating per se, but are involved in shaping the effect of learned values on the decision-making process.

Language

English (en)

Chair and Committee

Ilya Monosov

Committee Members

Andrew Huang; Indira Mysorekar; Kory Lavine; Philip Williams; Todd Margolis

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