Our aim is to understand the neural circuit underlying the cognitive control over the mal-adaptive behaviors that stem from stress-induced anxiety, especially among female adolescents. We also aim to understand why adolescent females are more vulnerable than males, adults and children to mental illnesses that are co-morbid with anxiety disorders. We have shown that adolescent female rodents that are exposed to the stress of food restriction (FR) exhibit individual differences in vulnerability to an anxiety disorer-like behavior, consisting of abnormality on the elevated plus maze, voluntary food restriction and excessive exercise, the latter of which contribute to severe weight loss and for some, death. This compilation of FR-evoked abnormalities, called activity-based anorexia (ABA) differs widely among individuals and correlate strongly with changes in the GABAergic inhibitory system (axons and alpha4betadelta-GABA receptors) in the prefrontal cortex and hippocampus. What remains unknown is whether the behavioral and anatomical changes are causally linked and if so, the mechanism for the stress (in this study, FR)-evoked up-regulation of the GABAergic system that protects animals from the mal-adaptive behavior. We hypothesize that (1) up-regulation to the GABAergic system of the prefrontal cortex and hippocampus is causal to the animal's ability to make decisions regarding responses to stressful environments (e.g., to eat or to run) that are more adaptive and to regulate the stress-evoked anxiety;and (2) individual differences in the GABAergic system of the prefrontal cortex and hippocampus arise from gonadal hormone fluctuations at puberty and the activity-dependent BDNF release. We will test these hypotheses by (1) determining the extent to which experimentally boosting the GABA system in the hippocampus and prefrontal cortex reduces ABA vulnerability and trait anxiety;and (2) determining whether systemic progesterone or the systemic or local alterations of BDNF level increase the strength of the GABA system and with it, reductions in the mal-adaptive behavior of voluntary FR, excessive exercise, and anxiety measures on the elevated plus maze. These goals will be achieved by quantifying the mal-adaptive behaviors of mice that are globally or locally knocked down of or boosted of the expression of GABAR subunits or of the GABA synthesizing enzyme or of BDNF and verifying the ultrastructure of GABAergic synapses by electron microscopy.
We will identify the cellular and molecular basis for individual differences in the cognitive control over mal-adaptive behaviors that are evoked by anxiety and stress during adolescence, and especially among females. These findings will help build design treatments of mental illnesses with comorbidity of anxiety disorders.
|Chen, Yi-Wen; Wable, Gauri Satish; Chowdhury, Tara Gunkali et al. (2016) Enlargement of Axo-Somatic Contacts Formed by GAD-Immunoreactive Axon Terminals onto Layer V Pyramidal Neurons in the Medial Prefrontal Cortex of Adolescent Female Mice Is Associated with Suppression of Food Restriction-Evoked Hyperactivity and Resilience Cereb Cortex 26:2574-89|
|Mitre, Mariela; Marlin, Bianca J; Schiavo, Jennifer K et al. (2016) A Distributed Network for Social Cognition Enriched for Oxytocin Receptors. J Neurosci 36:2517-35|
|Wable, G S; Chen, Y-W; Rashid, S et al. (2015) Exogenous progesterone exacerbates running response of adolescent female mice to repeated food restriction stress by changing Î±4-GABAA receptor activity of hippocampal pyramidal cells. Neuroscience 310:322-41|
|Chowdhury, Tara Gunkali; Chen, Yi-Wen; Aoki, Chiye (2015) Using the Activity-based Anorexia Rodent Model to Study the Neurobiological Basis of Anorexia Nervosa. J Vis Exp :e52927|
|Wable, Gauri S; Min, Jung-Yun; Chen, Yi-Wen et al. (2015) Anxiety is correlated with running in adolescent female mice undergoing activity-based anorexia. Behav Neurosci 129:170-82|
|Petr, Geraldine T; Sun, Yan; Frederick, Natalie M et al. (2015) Conditional deletion of the glutamate transporter GLT-1 reveals that astrocytic GLT-1 protects against fatal epilepsy while neuronal GLT-1 contributes significantly to glutamate uptake into synaptosomes. J Neurosci 35:5187-201|