The consequences of youth violence and aggression pose a significant public health problem, and the risk of later psychopathologies such as drug abuse, mood disorders, and abusive parenting is increased in individuals with a history of aggressive behavior during adolescence. However, much remains unknown about the neural substrates involved in aggression and its development. The work proposed here will use isolation rearing, an animal model of adolescent social adversity, to explore the role of the medial prefrontal cortex (mPFC) in aggression in male and female rats, focusing on glutamate and dopamine (DA) neurotransmission as potential mechanisms for the dysregulation of social behavior that occurs as a consequence of isolation rearing. Glutamate and DA modulate each other bidirectionally and are crucial for plasticity and proper mPFC function. The mPFC is critically important for executive function, including appropriate social behavior, and much of the development of the mPFC occurs during adolescence and into early adulthood. Although some of the effects of isolation rearing on social behavior have been shown to be reversible simply by rehousing isolates with a group, this is not likely to be a valid model of how socialization occurs in humans, as clinical evidence indicates that many aggressive adolescents become aggressive adults. Therefore we will assess the effects of single or repeated social experience after either isolation or group rearing of adolescent rats. The proposed work asks whether the activation of immediate early gene protein products (c-fos and Arc) and the plasticity-related protein PSD-95, all of which are sensitive to or involved in glutamate and DA signaling, are altered after isolatio rearing in response to subsequent social interaction with a novel same-sex rat, and whether changes in these proteins are related to the increase in aggression observed after isolation rearing. Alterations in postsynaptic interactions of DA and glutamate signaling and the role of PSD-95 in these interactions will be explored by assessing colocalization of DA D1 and glutamate NMDA receptors with PSD-95 using immunoflurorescence and confocal microscopy. Experiments will explore presynaptic changes produced by isolation rearing and subsequent social experience in the neurotransmitters glutamate and DA using in vivo microdialysis. In addition, mPFC microinjections of NMDA receptor (D-cycloserine) and DA D1 receptor (SKF 38393) agonists will be used to determine whether these neurotransmitter systems act in the mPFC to mediate the increased aggression observed in isolation reared rats. This will be done with 3 Specific Aims.
Specific Aim 1 is to determine social-interaction induced changes in mPFC functional activation and plasticity after isolation rearing in male and female rats.
Specific Aim i s to determine the role of mPFC glutamate and NMDA receptors in aggressive behavior after isolation rearing in male and female rats.
Specific Aim 3 is to determine the role of mPFC DA and DA D1 receptors in aggressive behavior after isolation rearing in male and female rats.

Public Health Relevance

This proposal explores the effects of social deprivation during adolescence on subsequent social and aggressive behavior as well as the neural substrates of these effects in male and female rats. The results have the potential to increase our understanding of the antecedents of aggressive behavior and may contribute to the development of behavioral and pharmacological interventions specific to at-risk individuals.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Academic Research Enhancement Awards (AREA) (R15)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Simmons, Janine M
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University of Colorado Denver
Schools of Arts and Sciences
United States
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