The life long consequences of developmental events is becoming increasingly apparent. The hippocampus is a critical brain region for integrating external stimuli to promote learning and memory or induce stress and anxiety, and it may serve this role in some capacity as early as the first week of life. The early postnatal period is a sensitive window for the organization of brain sex differences and many hippocampal-related functions and/or associated pathologies exhibit strong gender biases. The goal of this proposal is to explore the novel observation of higher rates of cell genesis in the neonatal male rat hippocampus compared to the female, and an increase in cell genesis by exogenous estradiol treatment. We propose that this period of cell genesis is unique compared to embryonic and adult neurogenesis and we hypothesize that the greater rate in males is the mechanism establishing the larger hippocampus observed in this sex. We also speculate that this early neurogenesis may underlie sex differences in very early learning and enduring consequences of maternal deprivation. We will identify the source of origin of new cells to the hippocampus and determine whether the sex difference and effect of estradiol on new cells are the result of changes in proliferation and/or cell survival. We will further determine whether cell genesis promotes the development of neurons and/or glia. Finally, we will test the hypothesis that sex differences in depolarizing GABA action and enhancement of this response by estradiol is the mechanistic basis for increased cell proliferation and/or survival in the neonatal male hippocampus. We will use BrdU incorporation into new cells, microinjection of cell tracker dye, double label immunofluorescent confocal microscopy, electrophysiology of organotypic slice cultures and single cell calcium imaging to complete nine specific aims that test three distinct hypotheses. Results of this work will provide new therapeutic avenues for prevention, intervention and treatment of developmental neurological disorders and diseases and brain damage.
The hippocampus is a critical brain region regulating cognition and emotionality. Parameters that impact on hippocampal development are essential to understanding adult function and provide insight into the select vulnerability of the hippocampus to damage and disease. The studies proposed here explore the novel observation of increased cell genesis in the newborn male rat hippocampus compared to that of the female. We seek to elucidate the cellular mechanisms mediating this sex difference as a valuable tool for the identification of new targets for therapeutic intervention and prevention.
|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|
|Zup, S L; Edwards, N S; McCarthy, M M (2014) Sex- and age-dependent effects of androgens on glutamate-induced cell death and intracellular calcium regulation in the developing hippocampus. Neuroscience 281:77-87|
|Liang, Shu-Ling; Alger, Bradley E; McCarthy, Margaret M (2014) Developmental increase in hippocampal endocannabinoid mobilization: role of metabotropic glutamate receptor subtype 5 and phospholipase C. J Neurophysiol 112:2605-15|
|Bowers, J Michael; Perez-Pouchoulen, Miguel; Roby, Clinton R et al. (2014) Androgen modulation of Foxp1 and Foxp2 in the developing rat brain: impact on sex specific vocalization. Endocrinology 155:4881-94|
|Bowers, J Michael; Perez-Pouchoulen, Miguel; Edwards, N Shalon et al. (2013) Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval. J Neurosci 33:3276-83|
|Waddell, Jaylyn; Bowers, J Michael; Edwards, N Shalon et al. (2013) Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat. Horm Behav 64:144-52|
|Waddell, Jaylyn; McCarthy, Margaret M (2012) Sexual differentiation of the brain and ADHD: what is a sex difference in prevalence telling us? Curr Top Behav Neurosci 9:341-60|
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