Teresa Milner



Influence of gonadal steroids and drugs on brain systems

Interests: Morphological correlates of functional interactions between neurons. Three ongoing projects are: (1) the effects of stress and sex in modulating hippocampal opioid systems and hippocampal responses to exogenous opiates (e.g., oxycodone); (2) understanding the mechanisms by which hormonal changes in menopause affect hypertension susceptibility.

All the studies employ: (1) quantitative light microscopic immunocytochemical techniques; (2) electron microscopic dual labeling techniques performed on single brain sections for localizing either two antigens or a single antigen in combination with tract-tracers; (3) electrophysiological recordings in single cells and in brain slices.

1. Estrogen and opioid interactions in the hippocampus.  Women are more susceptible than men to several aspects of drug addiction, including relapse due to stressful events.  Addictive mechanisms require associative memory processes that critically involve hippocampal circuits, including the opioid system.  Our light and electron microscopic (EM) studies have revealed notable sex and estrous cycle differences in the hippocampal opioid system: enkephalins, mu opioid receptors (MORs) and delta opioid receptors (DORs) are subcellularly positioned in neurons in the mossy fiber circuitry to enhance excitability and learning processes in females with elevated estrogen states.  Moreover, unlike males, females in high estrogen states exhibit a long-term potentiation (LTP) evoked by low frequency stimulation of the mossy fibers that is regulated by DORs. We have shown that chronic immobilization stress (CIS) in males essentially “shuts off” the hippocampal opioid system.  Conversely, CIS in females, regardless of estrogen state, “primes” the opioid system for greater excitation of CA3 pyramidal cells and for enhanced drug-related learning.  Our newest studies are exploring the mechanisms by which chronic stress-induced changes in the opioid system in females could advance associative memory processes important for drug addiction, particularly to oxycodone.

2. Menopausal changes in hypothalamus and hypertension susceptibility. After menopause, blood pressure and cardiovascular risk increases. In the periphery, gonadal steroids contribute to cardiovascular regulation by influencing the function of the renin-angiotensin system (RAS) through genomic [via nuclear estrogen, progesterone and androgen receptors (ERs, PRs and ARs)] and non-genomic (via membrane ERs, PRs and ARs) mechanisms. These effects may involve alterations in the number or plasmalemmal targeting of angiotensin 1 (AT1) receptors, or in AT1 receptor-linked signaling mechanisms, including NAD(P)H oxidase. Similarly, in the CNS, gonadal steroids may influence cardiovascular function by affecting angiotensin II (Ang II) actions in the rostral ventrolateral medulla (RVLM), an area crucial for the control of arterial pressure. Our central hypothesis is that estrogens, progestins and androgens differentially modulate central blood pressure regulation, in part by altering the excitability and Ang II responses of RVLM C1 bulbospinal neurons, and that these effects involve both genomic and non-genomic mechanisms. For this, we are examining whether: (1) ERs, PRs and ARs are positioned to have genomic and/or non-genomic effects on neuronal circuits in the RVLM relevant to central cardiovascular regulation; (2) estrogens, progestins and androgens affect the function of C1 bulbospinal neurons including their responses to Ang II and glutamate; and (3) gonadal steroids influence the membrane targeting of AT1 receptors and NAD(P)H oxidase subunits in C1 neurons. A better understanding of gender-specific blood pressure regulation will contribute to the design of more effective therapeutic strategies for post-menopausal cardiovascular disorders.

Research Topics

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