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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH105846-01
Application #
8809593
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Rossi, Andrew
Project Start
2014-09-25
Project End
2016-07-31
Budget Start
2014-09-25
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$264,706
Indirect Cost
$89,706
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Santiago, Adrienne N; Lim, Kayla Y; Opendak, Maya et al. (2018) Early life trauma increases threat response of peri-weaning rats, reduction of axo-somatic synapses formed by parvalbumin cells and perineuronal net in the basolateral nucleus of amygdala. J Comp Neurol 526:2647-2664
Aoki, Chiye; Chen, Yi-Wen; Chowdhury, Tara Gunkali et al. (2018) ?4??-GABAA receptors in dorsal hippocampal CA1 of adolescent female rats traffic to the plasma membrane of dendritic spines following voluntary exercise and contribute to protection of animals from activity-based anorexia through localization at excitator J Neurosci Res 96:1450-1466
Chen, Yi-Wen; Actor-Engel, Hannah; Aoki, Chiye (2018) ?4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males. Mol Cell Neurosci 90:33-48
Shen, Hui; Sabaliauskas, Nicole; Yang, Lie et al. (2017) Role of ?4-containing GABAA receptors in limiting synaptic plasticity and spatial learning of female mice during the pubertal period. Brain Res 1654:116-122
Chen, Yi-Wen; Surgent, Olivia; Rana, Barkha S et al. (2017) Variant BDNF-Val66Met Polymorphism is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia. Cereb Cortex 27:3980-3993
Aoki, Chiye; Chowdhury, Tara G; Wable, Gauri S et al. (2017) Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa. Brain Res 1654:102-115
Nedelescu, Hermina; Chowdhury, Tara G; Wable, Gauri S et al. (2017) Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their association with resilience to activity-based anorexia. Brain Struct Funct 222:317-339
Chen, Yi-Wen; Actor-Engel, Hannah; Sherpa, Ang Doma et al. (2017) NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise. Brain Struct Funct 222:2271-2294
Santiago, Adrienne; Aoki, Chiye; Sullivan, Regina M (2017) From attachment to independence: Stress hormone control of ecologically relevant emergence of infants' responses to threat. Curr Opin Behav Sci 14:78-85
Aoki, Chiye (2016) THE NEUROBIOLOGICAL ROOTS OF INDIVIDUALITY AND ANXIETY. Scientia (Bristol) 107:18-22

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