The aim of this proposal is to investigate sex differences in social interaction behavior and to examine the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Another focus of this study is to determine the upstream and downstream molecular targets of zif268 that are relevant to sex differences in social interaction. Our preliminary data show that male rats exhibit higher social interaction (SI) than female rats -regardless of their estrus cycle-. Interestingly, the basal expression of zif268 in the medial prefrontal cortex (mPFC) varied between the sexes in that males had higher levels of zif268 expression in this region when compared to females. Through the use of zif268 antisense oligodeoxynucleotides (zif268 ASO), we induced a temporary down-regulation of zif268 expression in the mPFC of male rats and compared their SI behavior to both control males and females infused with zif268 missense oligodeoxynucleotides (zif268 MSO). Upon doing this, we found that zif268 ASO males displayed significantly less SI (and therefore, were more anxious) than control males and, in fact, displayed levels of SI which were similar to control females. In essence, down-regulation of zif268 expression in the mPFC of male rats eliminated the sex differences previously found in anxiety-like behavior in the SI test. Our novel findings have led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety-like behavior in the SI test, which has a strong social component. In this application we would like to explore further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in social interaction and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.

Public Health Relevance

The aim of this proposal is to investigate sex differences in social interaction behavior and to examine the role of the immediate early gene zif268 in the medial prefrontal cortex (mPFC) in mediating these behaviors in male and female rats. Our preliminary data implicate zif268 in sex differences in anxiety and led us to hypothesize that sexually-dimorphic zif268 expression in the mPFC is a key molecular factor in mediating sex-specific anxiety. In this application we would like to explore further the hypothesis that zif268 in the medial prefrontal cortex play a major role in determining sex differences in anxiety and determine the upstream and downstream targets of zif268 in the mPFC that play a major role in these sex differences in anxiety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087583-03
Application #
8247156
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Simmons, Janine M
Project Start
2010-07-05
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$353,686
Indirect Cost
$106,186
Name
Florida State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
Duclot, Florian; Perez-Taboada, Iara; Wright, Katherine N et al. (2016) Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine. Neuropharmacology 109:293-305
Sarkar, Ambalika; Kabbaj, Mohamed (2016) Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats. Biol Psychiatry 80:448-56
Saland, Samantha K; Schoepfer, Kristin J; Kabbaj, Mohamed (2016) Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. Sci Rep 6:21322
Duclot, F; Wang, H; Youssef, C et al. (2016) Trichostatin A (TSA) facilitates formation of partner preference in male prairie voles (Microtus ochrogaster). Horm Behav 81:68-73
Carrier, Nicole; Saland, Samantha K; Duclot, Florian et al. (2015) The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats. Biol Psychiatry 78:259-69
Duclot, Florian; Kabbaj, Mohamed (2015) Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants. J Exp Biol 218:21-31
Duclot, Florian; Kabbaj, Mohamed (2015) The estrous cycle surpasses sex differences in regulating the transcriptome in the rat medial prefrontal cortex and reveals an underlying role of early growth response 1. Genome Biol 16:256
Wright, Katherine N; Hollis, Fiona; Duclot, Florian et al. (2015) Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner. J Neurosci 35:8948-58
McHenry, Jenna; Carrier, Nicole; Hull, Elaine et al. (2014) Sex differences in anxiety and depression: role of testosterone. Front Neuroendocrinol 35:42-57
Duclot, Florian; Kabbaj, Mohamed (2013) Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression. J Neurosci 33:11048-60

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