There is an urgent need for new antidepressants that work in adolescents. Depression phenomenology is different in adolescents, but the reasons for this are not known. One possible explanation for lack of efficacy of many antidepressants and different phenomenology is that there is a difference in the pathophysiology of depression in adolescents. The long-term goal of our research is to determine how pathophysiology of the amygdala contributes to symptoms of depressive disorders. The short-term goal of these experiments is to test whether differences in specific amygdala output pathways underlie differences between adolescent and adult depressive behavior. The basolateral amygdala (BLA) guides many anxiety and appetitive behaviors via outputs to different neural regions. The relative activity between these BLA outputs balances anxiety and appetitive behavior. This project will test the hypothesis that the activity of major BLA output pathways is different in adolescents, and this leads to a favoring of appetitive behaviors. Repeated stress mimics several symptoms of depression, including anhedonia and anxiety. This project will also test the hypothesis that repeated stress shifts the balance of major BLA outputs towards those involved with anxiety and away from those that guide hedonic behaviors, but via different mechanisms in adults and adolescents. Using electrophysiological, behavioral and genetic approaches, this project aims to determine the relative activity of BLA outputs in adolescents and adults, to determine if repeated stress exerts age-dependent actions on two major BLA outputs, and to determine their contribution to behavioral effects of stress. Furthermore, this study will directly compare the mechanisms for the effects of repeated stress in adults and adolescents. This project is significant because it can demonstrate a novel neurobiological mechanism for differences in the balance of anxiety and hedonic behaviors across age, and provide novel targetable mechanisms for the development of new antidepressants for adolescents. These experiments are innovative because they will test the function of specific BLA neuronal populations in the context of their place in behaviorally important circuits across age. This approach will yield exciting new information about the behavioral importance of BLA circuits and novel insight into the formation of a psychiatric syndrome via an imbalance in the activity of BLA outputs. Understanding of the mechanism that underlies this imbalance in adolescents is expected to uncover alternative pharmacological approaches to treat depression in adolescents.

Public Health Relevance

The proposed project is relevant to public health because depressive symptoms in adolescents are surprisingly common, with prevalence ranging between approximately 8 - 22% in different populations. However, treatment options are severely limited compared to adult populations, leading to a large unmet need for new antidepressant medications to treat adolescent depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH084970-07
Application #
9128060
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Simmons, Janine M
Project Start
2008-12-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rosalind Franklin University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Selleck, Ryan A; Zhang, Wei; Samberg, Hannah D et al. (2018) Limited prefrontal cortical regulation over the basolateral amygdala in adolescent rats. Sci Rep 8:17171
Munshi, Soumyabrata; Rosenkranz, J Amiel (2018) Effects of Peripheral Immune Challenge on In Vivo Firing of Basolateral Amygdala Neurons in Adult Male Rats. Neuroscience 390:174-186
Twining, Robert C; Vantrease, Jaime E; Love, Skyelar et al. (2017) An intra-amygdala circuit specifically regulates social fear learning. Nat Neurosci 20:459-469
Zhang, Wei; Rosenkranz, J Amiel (2016) Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala. Neuropsychopharmacology 41:2309-23
Adams, Thomas; Rosenkranz, J Amiel (2016) Social Isolation During Postweaning Development Causes Hypoactivity of Neurons in the Medial Nucleus of the Male Rat Amygdala. Neuropsychopharmacology 41:1929-40
Jaisinghani, Suraj; Rosenkranz, J Amiel (2015) Repeated social defeat stress enhances the anxiogenic effect of bright light on operant reward-seeking behavior in rats. Behav Brain Res 290:172-9
Padival, M A; Blume, S R; Vantrease, J E et al. (2015) Qualitatively different effect of repeated stress during adolescence on principal neuron morphology across lateral and basal nuclei of the rat amygdala. Neuroscience 291:128-45
Hetzel, Andrea; Rosenkranz, J Amiel (2014) Distinct effects of repeated restraint stress on basolateral amygdala neuronal membrane properties in resilient adolescent and adult rats. Neuropsychopharmacology 39:2114-30
Zhang, Wei; Hetzel, Andrea; Shah, Bijal et al. (2014) Greater physiological and behavioral effects of interrupted stress pattern compared to daily restraint stress in rats. PLoS One 9:e102247
Padival, M A; Blume, S R; Rosenkranz, J A (2013) Repeated restraint stress exerts different impact on structure of neurons in the lateral and basal nuclei of the amygdala. Neuroscience 246:230-42

Showing the most recent 10 out of 19 publications