I received my PhD in Behavioral and Neural Sciences from the Institute of Animal Behavior at Rutgers University in Newark, NJ in 1989. I then spent three years as a post-doctoral fellow at the Rockefeller University in New York, NY and one year as a National Research Council Fellow at the National Institutes of Health, before joining the faculty at the University of Maryland. I am a member of the University of Maryland Graduate School and the Center for Studies in Reproduction I am also a member of the Society for Behavioral Neuroendocrinology, the Society for Neuroscience, the American Physiological Association and the Endocrine Society.
My research program focuses on the influence of steroid hormones on the developing brain. During perinatal life, there is a sensitive period for hormone exposure during which permanent cytoarchitechtural changes are established. Males and females are exposed to different hormonal milieus and this results in sex differences in the brain. These differences include alterations in the volumes of particular brain nuclei and patterns of synaptic connectivity. The mechanisms by which sexually dimorphic structures are formed in the brain remains poorly understood.
We are currently investigating four broad areas:
STEROID MODULATION OF PROSTAGLANDINS IN THE BRAIN
A few years ago we made the surprising discovery that prostaglandins, in particular PGE2, are regulated in the brain by gonadal steroids and have a major impact on the masculinization of a particular region called the preoptic area. Prostaglandins are of enormous interest since their synthesis is the target of the most prevalent over the counter and prescribed drugs on the market today, the NSAIDs, or COX inhibitors. These include aspirin, Aleve, Vioxx, Coxib and many many more. We are now extending our initial findings to other brain regions and other functional outcomes.
RELEVANCE OF SEX DIFFERENCES IN THE BRAIN TO MENTAL HEALTH DISORDERS
An individuals gender is a major predictive factor of relative risk to develop specific neurologic or mental health disorders. The incidence of autism, attention deficit disorder, Tourettes and early on-set schizophrenia are all significantly greater in males. Conversely, the frequency of major depressive disorder, general anxiety disorder, obsessive compulsive disorder and disorders of eating are all greater in females. An important distinction between these two cohorts of disorders is that those which are male biased tend to occur early in development, whereas those that are more prevalent in females generally do not occur until after puberty. By understanding the basic mechanisms establishing sex differences in the brain, we hope to provide novel insight into the etiology of these devastating conditions.
SEX DIFFERENCES IN PEDIATRIC BRAIN DAMAGE
A major source of brain damage to both premature and full-term babies is stroke, and males tend to fare worse in outcomes than females to the same injury. We have found that the gonadal steroid, estradiol, is a potent regulator of the response to injury in the developing brain, being neuroprotective under circumstances and actually exacerbating injury under others. We use calcium imaging of cultured neurons to investigate the detailed cellular mechanisms by which these changes occur.
STEROID MODULATION OF GLIA
We have found that the morphology of a subclass of glia, known as astrocytes, is markedly influenced by the hormonal milieu of the developing brain. Changes in the morphology of these cells has important consequences for the synaptic patterns established on the developing neurons. Astrocyte-to-neuron communication has emerged as a major regulatory feature of the establishment of sex differences in the brain.
Lab Techniques and Equipment
We use a broad range of techniques, from behavioral analysis to the molecular level. Behavioral tests include tests of anxiety, sexual and maternal behaviors, learning and memory. We also frequently exploit the use of in vivo antisense oligonucleotide technology to alter gene expression during development. The detection of specific proteins in individual neurons by immunocytochemistry is routinely utilized, as real time PCR, Western blots and various other molecular approaches.
In collaboration which colleagues in the Department of Physiology we also conduct experiments on calcium imaging, fluorescent microscopy and live cell imaging. Recently we have been gaining expertise in electrophysiology.
- Bridget Nugent - Graduate student
- Jessica Knutson - Graduate student exploring a postnatal developmental sensitive period within the cerebellum during which there is an increased risk for developing autistic-like behaviors when a PGE2-E2 signaling pathway is disrupted.
- Kathy Kight - Graduate Student
- Michael Bowers - Postdoctoral fellow studying the Foxp2 gene and how it influences the developmental signaling pathways that are important for higher cognitive functions in human language and animal communication.
- Kathryn Lenz - Postdoctoral fellow focuses on the role that microglia, cytokines, and immune system signaling play in brain sexual differentiation.
- Christopher Wright - Postdoctoral fellow
- N. Shalon Edwards - Laboratory Technician
- Kevin Barnett - Laboratory Technician
- Clint Roby - Research Assistant
Selected Recent Publications
S.K. Amateau and M.M. McCarthy (2004) Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nature Neuroscience 7:643-650*
* Topic of Editorial - COX inhibitors and sexual development, 7:563 (2004) and News and Views - Brain Gender: prostaglandins have their say. 7: 570-571. Nature Neuroscience.
J.L. Nunez, L.L. Bambrick, B.K. Krueger and M.M. McCarthy (2005) Prolongation and enhancement of gamma-aminobutyric acidA receptor mediated excitation by estradiol in developing hippocampal neurons. European Journal of Neuroscience, 21: 3251-3261.
G.D. Hilton, J.L. Nunez, L. Bambrick, S.M. Thompson, M.M. McCarthy (2006) Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR and prevented by estradiol. European Journal of Neuroscience 24: 3008-3016.
B.J. Todd, J.M. Schwarz, J.A. Mong and M.M. McCarthy (2007) Glutamate AMPA/Kainate receptors, not GABAA receptors, mediate estradiol-induced sex differences in hypothalamic dendritic spines. Developmental Neurobiology 67: 304-315.
S.R. Burks, C.L. Wright, M.M. McCarthy (2007) Exploration of EP receptor subtype regulating estradiol and PGE2 induction of spinophillin in developing POA neurons. Neuroscience 146: 1117-1127
D.B. Speert, A.T.M. Konkle, S.L. Zup, J.A. Schwarz, C. Shiroor, M. Taylor and M.M. McCarthy (2007) Focal adhesion kinase and paxillin: novel regulators of brain sexual differentiation? Endocrinology 148: 3391-3401.
M.M. McCarthy and A.P. Arnold (2007) Sex differences in the brain: What's old and what's new. In: Sex on the Brain: From Genes to Behavior, (Eds) J.B. Becker, K.J. Berkley, N. Geary, E. Hampson, J. Herman and E. Young. Oxford University Press.
J.M. Schwarz, S.-L. Liang, S.M Thompson and M.M. McCarthy (2008) Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: A mechanism for organizational sex differences. Neuron, 58: 584-598.
M.M. McCarthy (2008) Estradiol and the developing brain. Physiological Reviews*, 88: 91-124 (*cover illustration)
C.L. Wright and M.M. McCarthy (2009) PGE2-induced masculinization of brain and behavior requires protein kinase A, AMPA/Kainate and metabotropic glutamate receptor signaling. Journal of Neuroscience, 29(42):13274-82.
D.L. Krebs-Kraft, M.N. Hill, C.J. Hillard, and M.M. McCarthy (2010) Cannabinoids mediate a sex difference in cell proliferation in the developing amygdala with implications for social behavior. Proceedings of the National Academy of Sciences, 107:20535-20540.
B.M. Nugent, J.M. Schwarz and M.M. McCarthy (2010) Hormonally mediated epigenetic changes to steroid receptors in the developing brain: Implications for sexual differentiation. Hormones and Behavior, 59: 338-344.
M.M. McCarthy (2011) Sex and the Developing Brain. Morgan & Claypool, Ed.
M.M. McCarthy, series The Developing Brain.
J Neurosci. 2012 Jan 11;32(2):593-8.
Curr Top Behav Neurosci. 2012;9:341-60.
PLoS One. 2011;6(8):e23020. Epub 2011 Aug 19.
Nat Neurosci. 2011 Jun;14(6):677-83. Epub 2011 May 25. Review.
Endocrinology. 2011 Jul;152(7):2760-7. Epub 2011 May 17 PLoS One. 2011 Apr 7;6(4):e18500.
Biol Sex Differ. 2010 Nov 22;1(1):8.
Brain Res. 2011 Mar 16;1379:109-18. Epub 2010 Dec 4. Review.
Endocrinology. 2011 Jan;152(1):223-35. Epub 2010 Nov 10.
Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20535-40. Epub 2010 Nov 8.