Research Overview
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 the hormonal milieu in modulating hippocampal opioid systems and hippocampal responses to exogenous opiates (e.g., morphine) ; (2) the consequences of developmental ritalin exposure on brain monoaminergic, cholinergic and glutatameric systems as well as adult neurogenesis; and (3) the effects of gonadal steroids on modulating brainstem pathways important in cardiovascular control.
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. Drug addiction and relapse to drug taking require associative memory and motivational incentives, processes that critically involve hippocampal formation (HF) output to the mesolimbic reward system. In humans and animals, relapse susceptibility and HF-associated learning behaviors vary by gender, suggesting hormonal as well as sociocultural influences on addiction-linked processes. Opiate drugs of abuse (e.g., morphine) and ovarian steroids alter HF excitability and long-term potentiation (LTP), the primary model for learning, and neurogenesis that is involved in forms of associative learning. We are analyzing how the hormonal milieu modulates endogenous hippocampal opioid systems and hippocampal responses to exogenous opiates. For this, we will determine whether estrogens and progestins: a) affect levels of enkephalins and/or preproenkephalin mRNA in three subregions that critically integrate different afferent information; b) alter the subcellular distribution of mu and delta opioid receptors, which are on interneurons that regulate rhythmic output of excitatory projection neurons; and c) interact with opioids to facilitate LTP. We also will determine whether estrogen and progestin receptors are on: a) enkephalin-containing neurons, suggesting potential direct interactions of these systems; b) hilar mossy cells, major targets of enkephalin terminals and regulators of projection cell output; c) newly generated cells. We will determine if enkephalin-containing neurons, their targets, or newly generated neurons contain functional estrogen binding sites. The results will elucidate potential mechanisms and sites where ovarian steroids, by affecting HF opioid systems, may influence hippocampal-dependent learning relevant to drug abuse.
2. Developmental affects of ritalin on the brain. Ritalin (methylphenidate; MPH) is one of the most common drugs given to children with attention deficit hyperactivity disorder (ADHD). Several studies have shown that ritalin usage is increasing in the United States such that children diagnosed with ADHD often are maintained on the drug throughout late childhood and adolescence. Little is known, however, what the long term consequences of these therapeutic doses of MPH may be on the brain. Thus, we currently are developing a reliable and simple model for delivering MPH to developing rats to assess the effects of long-term developmental exposure to therapeutic doses of MPH in this model on the adult brain. For this, quantitative immunocytochemical methods will be employed and focus will be on (a) the dopamine system; (b) the ascending noradrenergic system; (c) the ascending serotonergic system; (d) the cholinergic basal forebrain system; (e) cortical glutamatergic systems; and (f) adult neurogenesis.
3. Cellular basis for estrogen effects in the medulla. 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.For more information, please visit our website at:http://www.cornellneurology.org/neurobiology
