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.
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.
|Lenz, Kathryn M; Nugent, Bridget M; Haliyur, Rachana et al. (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33:2761-72|
|Dean, Shannon L; Knutson, Jessica F; Krebs-Kraft, Desiree L et al. (2012) Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period. Eur J Neurosci 35:1218-29|
|McCarthy, Margaret M; Arnold, Arthur P; Ball, Gregory F et al. (2012) Sex differences in the brain: the not so inconvenient truth. J Neurosci 32:2241-7|
|McCarthy, Margaret M; Arnold, Arthur P (2011) Reframing sexual differentiation of the brain. Nat Neurosci 14:677-83|
|Matsuda, Ken Ichi; Mori, Hiroko; Nugent, Bridget M et al. (2011) Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. Endocrinology 152:2760-7|
|Lenz, Kathryn M; Wright, Christopher L; Martin, Ryan C et al. (2011) Prostaglandin E? regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation. PLoS One 6:e18500|
|Nugent, Bridget M; Schwarz, Jaclyn M; McCarthy, Margaret M (2011) Hormonally mediated epigenetic changes to steroid receptors in the developing brain: implications for sexual differentiation. Horm Behav 59:338-44|
|Krebs-Kraft, Desiree L; Hill, Matthew N; Hillard, Cecilia J et al. (2010) Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior. Proc Natl Acad Sci U S A 107:20535-40|
|Wright, Christopher L; Schwarz, Jaclyn S; Dean, Shannon L et al. (2010) Cellular mechanisms of estradiol-mediated sexual differentiation of the brain. Trends Endocrinol Metab 21:553-61|
|Schwarz, Jaclyn M; Nugent, Bridget M; McCarthy, Margaret M (2010) Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 151:4871-81|
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