Dissertation Defense (IPN): Valerie Lewitus

Name: Valerie J. Lewitus

Degree: Ph.D. in Neuroscience

Program: Interdisciplinary Program in Neuroscience

Dissertation title: The Effect of Estradiol on Striatal Synaptic Plasticity Underlying Goal-Directed Learning

Committee members: Dr. Kim T. Blackwell (committee chair), Dr. Theodore Dumas, Dr. Greta Ann Herin, and Dr. David M. Lovinger

Abstract:

Estradiol (E2), the predominant form of estrogen, has many neurological effects throughout the brain including in learning and memory. One area of the brain in which it exerts its effects is the dorsal striatum, a region of the basal ganglia associated with several functions including motor control and instrumental conditioning. Maladaptive learning in the basal ganglia underlies substance use disorder, which involves changes in control over drug use between the two striatal subregions: from dorsomedial striatum (DMS)-based goal-directed learning to dorsomedial striatum (DLS)-based habitual learning. Males and females exhibit differences in some striatal function, which may be related to known biological sex differences in substance use disorders. Furthermore, E2 has been found to impair several DMS- and DLS-based learning types, which may underpin the sex difference in striatal function. However, the hormone’s mechanisms of action are unclear. In particular, research on the effect of E2 on striatal synaptic plasticity, a cellular process underlying learning, is limited. This dissertation uses ex vivo electrophysiology in male and female mouse brain slices to uncover the role of cycling female sex hormones and E2 receptors in particular in inhibiting synaptic plasticity in the DMS. It also explores DMS and DLS differences in the role of brain-derived neurotrophic factor (BDNF) on synaptic plasticity. Finally, it reviews the current state of literature on sex, reproductive cycle, and E2 effects on dorsal striatal activity and learning, including its role in substance use disorders, to relate our physiology findings to sex differences in behavior.