The Teresa A. Milner laboratory aims to understand estrogen influences on the brain function over the life-cycle.
Tracey Van Kempen (graduate student)
Jose Da Silva Marques Lopes (Post-doc)
To test the hypothesis that chronic stress leads to adaptive changes in the hippocampal opioid system of females to promote CA3 long-term potentiation and other plastic processes that support drug-related associative learning. This study uses a combination of immuno-electron microscopic and physiological approaches in rats.
To test the central hypothesis that changes in postsynaptic NMDA receptors and associated signaling pathways with estrogen receptor-beta neurons in the paraventricular hypothalamic nucleus during menopause predispose these neurons to increase excitability in response to hypertensive challenges. This study uses a combination of immuno-electron microscopic, molecular and physiological approaches in transgenic mice.
Throughout the life cycle, estrogens and other gonadal steroids can influence many brain functions. In addition to regulating reproductive functions and homeostasis, estrogens can affect cognitive and emotional processes and autonomic functions. My research focuses on delineating the mechanisms by which estrogens influence cognition, particularly that related to drug abuse, and cardiovascular functions during menopause.
Women are more susceptible to several aspects of drug addiction than men, including relapse following stressful events. The hippocampus is a brain region that is critically involved in learning relevant to drug abuse. Moreover, estrogens and opioid peptides by binding to select receptors can modulate learning processes in the hippocampus. Over the years, my lab has localized estrogen and opioid receptors in rodents using electron microscopic immunocytochemical methods to help elucidate the mechanisms by which estrogens and opioids interact to impact learning relevant to drug abuse. In particular, we have found that estrogen receptors (ERs) are not only found in nuclei where they can influence genomic events but also are located in synapses where they can influence rapid communication between nerve cells. We also have demonstrated that the mu- and delta-opioid receptors (MOR and DORs, respectively) are present on select subtypes of hippocampal neurons where they can influence the balance of excitation and inhibition. My most recent studies indicate that estrogens regulate endogenous hippocampal opioid peptides and MORs and DORs in a manner that could promote learning processes relevant to drug abuse and relapse after chronic stress.
After menopause, hypertension and stress reactivity increases in women. My lab investigates the central mechanisms by which estrogens regulate blood pressure in rodents to help understand the development of hypertension and stress reactivity in menopause. We have shown that receptors for estrogens and other ovarian steroids have a regionally selective location relative to cardiovascular brain circuits. Using combined neuroanatomical and physiological approaches, we have shown that estrogens, primarily via ER beta, regulate angiotensin-signaling in the rostral ventrolateral medulla, a brain region crucial for the regulation of blood pressure. My most recent research utilizes a new “accelerated ovarian failure” model of menopause to study the mechanisms by which changes in estrogen levels during menopause influences cells the hypothalamic paraventricular nucleus, a brain region critical for integrating and coordinating neurohumoral responses involved in blood pressure regulation. These studies have contributed importantly to understanding changes in the brain during menopause that contribute to the increase susceptibility to hypertension.
Using immuno-electron microscopy we discovered that estrogen and progestin receptors are found at extranuclear sites in dendritic spines, terminals and glia where they can affect local cell signaling.
Using a multidisciplinary approach our studies have shown that the opioid system in the female hippocampus is primed for enhance associative learning processes after chronic stress.
We have characterized a novel mouse model of menopause and are currently using it to elucidate mechanisms of hypertension maintenance in the hypothalamus.
Marques-Lopes, J., Van Kempen, T.A., Waters, E.M., Pickel, V.M., Iadecola, C., and Milner, T.A.: Slow-pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor beta-containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent. J. Comp. Neurol. (2014) in press
Adjunct Professor, Laboratory of Neuroendocrinology, The Rockefeller University