Biomedical Sciences ETDs
Publication Date
Spring 5-2026
Abstract
Behavioral flexibility—the ability to adapt behavior when contingencies change—is a fundamental executive function supported by orbitofrontal–striatal circuitry. This dissertation examined molecular, motivational, and circuit mechanisms underlying flexibility and its restoration after prenatal alcohol exposure (PAE). In healthy mice, GluN2B-containing NMDA receptors in the orbitofrontal cortex increased during outcome updating, while AMPA receptor subunits in the dorsal striatum rose during new learning, defining temporally distinct plasticity processes. PAE impaired reversal learning under low-reward conditions, but not when motivation was high, indicating altered thresholds for circuit engagement rather than permanent loss. Finally, optogenetic stimulation of OFC→dorsal striatum projections rescued flexibility in PAE mice, revealing preserved but under-recruited circuitry. Together, these studies identify dynamic glutamatergic mechanisms that support adaptive learning, demonstrate how motivation gates cognitive expression of developmental insult, and show that circuit activation can restore flexibility, highlighting latent neural resilience.
Keywords
behavioral flexibility, prenatal alcohol exposure, optogenetic rescue, orbitofrontal–striatal circuitry, glutamatergic receptor dynamics, reversal learning
Document Type
Dissertation
Language
English
Degree Name
Biomedical Sciences
Level of Degree
Doctoral
Department Name
Biomedical Sciences Graduate Program
First Committee Member (Chair)
Jonathan L. Brigman
Second Committee Member
Carlos Fernando Valenzuela
Third Committee Member
Nora Perrone Bizzozero
Fourth Committee Member
Erin Milligan
Fifth Committee Member
David Linsenbardt
Sixth Committee Member
Derek Hamilton
Recommended Citation
Chandrasekaran, Jayapriya. "From Synapse to circuit: Mechanisms of behavioral flexibility and its restoration after Prenatal alcohol exposure." (2026). https://digitalrepository.unm.edu/biom_etds/317
Comments
Behavioral flexibility—the ability to adapt behavior when contingencies change—is a fundamental executive function supported by orbitofrontal–striatal circuitry. This dissertation examined molecular, motivational, and circuit mechanisms underlying flexibility and its restoration after prenatal alcohol exposure (PAE). In healthy mice, GluN2B-containing NMDA receptors in the orbitofrontal cortex increased during outcome updating, while AMPA receptor subunits in the dorsal striatum rose during new learning, defining temporally distinct plasticity processes. PAE impaired reversal learning under low-reward conditions, but not when motivation was high, indicating altered thresholds for circuit engagement rather than permanent loss. Finally, optogenetic stimulation of OFC→dorsal striatum projections rescued flexibility in PAE mice, revealing preserved but under-recruited circuitry. Together, these studies identify dynamic glutamatergic mechanisms that support adaptive learning, demonstrate how motivation gates cognitive expression of developmental insult, and show that circuit activation can restore flexibility, highlighting latent neural resilience.