The neurologic origins of both normal and pathological social behavior remain poorly understood. The study of naturally occurring sex differences in social behavior provides an opportunity for discovery of unique variables that would never be revealed by the study of one sex in isolation. The amygdala is a brain region critically involved in emotional and social behaviors and characterized by a complexly regulated sexually dimorphic profile that varies across the lifespan. Little attention has been focused on the cellular mechanisms by which sex differences in the amygdala arise and the consequences this might have for social behavior. We recently made the novel discovery of a sex difference in cell genesis in the developing amygdala of the neonatal rat, observing more new cells being generated in female pups compared to their male littermates. We further observed that while most of the new cells being born postnatally in both sexes will become neurons, the higher rate of cell genesis in females is the result of more astrocytes being generated. Astrocytes are critical partners in synaptogenesis and neural functioning. We also made the surprising discovery that males have a higher overall endocannabinoid tone in the developing amygdala and that pharmacologically increasing the tone in females reduces the rate of cell genesis to that of males. Endocannabinoids are lipid derived signaling molecules that ubiquitously regulate synaptic function and are only recently being recognized for their role in cell proliferation. Lasty, the same treatment that increases endocannabinoid tone and cell genesis in newborn females masculinizes their social play behavior as juveniles. We now propose three specific aims to 1) determine whether gonadal steroid hormones mediate the sex difference in endocannabinoid tone, 2) identify the signal transduction pathway(s) mediating the sex difference in cell genesis and its regulation by endocannabinoids and 3) determine the impact of the higher rate of astrocyte proliferation in females on amygdala neuron synaptic profile and its correlation with control of juvenile social play. Standard techniques will be used to quantify cell genesis (BrdU incorporation), neuron and astrocyte morphology (Golgi/Cox, immunocytochemistry, confocal microscopy), endocannabinoids and associated enzymes (GS/MS, Western blot) and to pharmacologically manipulate the endocannabinoid system and associated kinase pathways and measure social behavior. The data generated by these experiments will greatly expand our understanding of the neural control of social behavior and identify novel nodes of importance which may provide new targets for prevention and therapeutic intervention.

Public Health Relevance

The neurological underpinnings of both normal and abnormal social behavior remain poorly understood yet aberrant social communication and responding is a hallmark of numerous disorders of mental health. Identifying the origins of naturally occurring sex differences in social behavior provides a unique opportunity for discovery of novel sources of variation in this complex behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH052716-18
Application #
8644882
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Panchision, David M
Project Start
1995-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
$383,750
Indirect Cost
$133,750
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
McCarthy, Margaret M; Wright, Christopher L (2016) Convergence of Sex Differences and the Neuroimmune System in Autism Spectrum Disorder. Biol Psychiatry :
Nugent, Bridget M; Wright, Christopher L; Shetty, Amol C et al. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci 18:690-7
Argue, Kathryn J; McCarthy, Margaret M (2015) Characterization of juvenile play in rats: importance of sex of self and sex of partner. Biol Sex Differ 6:16
Lenz, Kathryn M; McCarthy, Margaret M (2015) A starring role for microglia in brain sex differences. Neuroscientist 21:306-21
McCarthy, Margaret M; Nugent, Bridget M (2015) At the frontier of epigenetics of brain sex differences. Front Behav Neurosci 9:221
Argue, Kathryn J; McCarthy, Margaret M (2015) Utilization of same- vs. mixed-sex dyads impacts the observation of sex differences in juvenile social play behavior. Curr Neurobiol 6:17-23
McCarthy, Margaret M (2015) Incorporating Sex as a Variable in Preclinical Neuropsychiatric Research. Schizophr Bull 41:1016-20
McCarthy, Margaret M; Pickett, Lindsay A; VanRyzin, Jonathan W et al. (2015) Surprising origins of sex differences in the brain. Horm Behav 76:3-10
Kight, Katherine E; McCarthy, Margaret M (2014) Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis. Neurobiol Dis 72 Pt B:136-43
Ball, Gregory F; Balthazart, Jacques; McCarthy, Margaret M (2014) Is it useful to view the brain as a secondary sexual characteristic? Neurosci Biobehav Rev 46 Pt 4:628-38

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