Social stress has adverse consequences for physical and mental health throughout life and its impact may be particularly relevant during adolescence as this is a time of substantial growth and reorganization of brain circuits. To date, most basic research into the behavioral and physiological consequences of social stress has focused on adult male rodents. The proposed research uses a model of rat social stress, "the resident- intruder model", to characterize the neurobehavioral responses to, and consequences of, social stress at different stages of adolescent development compared to adulthood. This research also takes on the important challenge of investigating sex differences in the response to social stress or its consequences. The research program proposed here is based on preliminary data indicating that the defensive subordinate response to an aggressive conspecific develops throughout adolescence into adulthood. Temporally correlated to this is a shift away from active coping strategies in response to subsequent challenges. These age-related behavioral differences are associated with distinct changes in locus coeruleus (LC) neuronal activity. Therefore, this proposal tests the central hypothesis that social stress in early adolescence disrupts the ontogeny of specific neural pathways important for regulating the development of subordinate defensive behaviors and that this disruption has effects on behavior and cognition in adolescence that endure into adulthood. This hypothesis will be tested in three specific Aims.
Aim 1 will identify and compare neural circuits engaged by social stress at different stages of adolescence and in adulthood using a functional neuroanatomy approach and examining changes in peptide systems related to social behavior and stress.
Aim 2 will characterize and compare responses of LC neurons to the social stress at different stages of adolescence and in adulthood.
Aim 3 will examine specific behavioral and cognitive consequences of social stress during adolescence and evaluate the endurance of these effects. Because some of the neural substrates being investigated in Aims 1 and 2 have been implicated in the behavioral endpoints being tested in AIM 3, the studies are organized to reveal how the neural substrates and circuits involved in the initial response to social stress (the defensive behaviors) at a particularly time in development play a role in determining the subsequent acute and long-term consequences of social stress. Together, the proposed studies will provide critical information about developmental and sex differences in defensive behaviors and in the consequences of social stress. Given the impact of social stress on mental health these studies will advance our understanding of the development of psychiatric disorders in humans and on the neurobiological basis for gender differences in the onset and etiology of these diseases.)

Public Health Relevance

This proposal uses a rat model of social stress to elucidate the neurobiological mechanisms by which social stress occurring at specific times in adolescence shapes present and future behavioral responses to stress, social interactions and/or cognitive function. By performing studies in both male and female rats, the basis for sex differences in vulnerability to and the developmental trajectory of psychiatric disorders will be identified.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH093981-04
Application #
8708971
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Simmons, Janine M
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Wood, Susan K; Zhang, Xiao-Yan; Reyes, Beverly A S et al. (2013) Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. Biol Psychiatry 73:1087-94
Ver Hoeve, E S; Kelly, G; Luz, S et al. (2013) Short-term and long-term effects of repeated social defeat during adolescence or adulthood in female rats. Neuroscience 249:63-73
Valentino, Rita J; Reyes, Beverly; Van Bockstaele, Elisabeth et al. (2012) Molecular and cellular sex differences at the intersection of stress and arousal. Neuropharmacology 62:13-20