Author ORCID Identifier

https://orcid.org/0000-0003-1724-5349

Date of Award

12-12-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Angela Mabb, PhD

Second Advisor

Daniel Cox, PhD

Third Advisor

Jordan Hamm, PhD

Fourth Advisor

Jenny Yang, PhD

Fifth Advisor

Hiroyuki Okuno, PhD

Abstract

Behavioral flexibility, or the adaptation of behavior to changing task contingencies, is an essential adaptive function across species. Behavioral inflexibility is a common endophenotype for many human neuropsychiatric disorders which severely impacts quality of life. While previous work has made inroads towards describing the neurobiological basis of flexible behaviors, further delineation of a coherent model that integrates molecular, cellular, and ensemble dynamics is imperative. We recently showed evidence that the immediate early gene (IEG) Arc, and its temporally regulated turnover via the ubiquitin proteasome pathway, may contribute a key regulatory role in spatial reversal learning. However, the precise intracellular changes resulting in this phenotype were unknown. Using a model in which the ubiquitination sites on Arc are mutated (ArcKR) and an endoplasmic reticulum (ER)-localized calcium indicator, we show that disrupted Arc turnover results in dysregulated ER-mediated Ca2+ release in response to activation of metabotropic glutamate receptors in-vitro. This phenotype is correlated with changes in calcium/calmodulin-dependent protein kinase II signaling and association with Arc, changes in Arc self-association, and enhanced interaction with the integral ER membrane protein Calnexin. Next, we use a photoconvertible Ca2+ indicator to explore IEG expression profiles in active and inactive hippocampal neuron populations during a spatial reversal learning-dependent task. Recapitulated deficiencies in ArcKR spatial reversal learning are paired with altered gross hippocampal activity and differential expression of both Arc and the IEG c-Fos. We also provide evidence that varying task demands across epochs of behavior may engage neural ensembles with discrete IEG profiles. We find that c-Fos is associated with the engagement of new ensembles during acquisition of a location-reward association, while heterogeneity in Arc expression is absent between active and inactive neurons during initial reversal learning in ArcKR mice. This suggests a unique role for Arc in reversal behavior. This work thus illustrates that Arc ubiquitination acts as an essential regulator of hippocampus-dependent behavioral flexibility by tuning Ca2+ signaling pathways and regulating ensemble dynamics during spatial reversal learning.

DOI

https://doi.org/10.57709/32591456

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