Research

INDIVIDUAL RESEARCHER

Lauren Jacobson , Ph. D.
Associate Professor
e-mail: JACOBSL@mail.amc.edu

Education

1989 - Ph. D. from University of California, San Francisco

Current Research

Research in my laboratory focuses on the neural effects of glucocorticoid steroids from the adrenal cortex, in order to understand communication between the brain and the rest of the body. Glucocorticoids are necessary for survival, and have a variety of effects to increase blood glucose, increase blood pressure, limit immune system reactivity, enhance appetite, and influence cognition and mood. Glucocorticoid secretion is ultimately controlled by the brain, via a classic hypothalamic-anterior pituitary neuroendocrine axis that responds to stress and circadian cues. The best-characterized neural action of glucocorticoids is negative feedback, whereby glucocorticoids control their own secretion by inhibiting the hypothalamic factors stimulating glucocorticoid release. Appropriate feedback inhibition is the main mechanism preventing deleterious effects from glucocorticoid deficiency (hypoglycemia, cardiovascular collapse, autoimmunity) or glucocorticoid excess (diabetes, hypertension, immune suppression). We employ integrative approaches spanning molecular biology, physiology, and behavioral monitoring to test the hypothesis that alterations in the CNS actions of glucocorticoids contribute to metabolic and mental health disorders. Using mouse models, we analyze changes in hormones, metabolites, behavior, and neuronal gene expression to define the neural mechanisms for, and the impacts of, abnormal glucocorticoid levels. Some of the issues we are investigating include: 1.) How antidepressants alter CNS glucocorticoid actions. We have found opposing effects of two classes of antidepressants on glucocorticoid feedback and CNS glucocorticoid receptor expression. The effects could indicate strategies to improve treatment of depressed patients exhibiting abnormal regulation of glucocorticoids. 2.) How glucocorticoids influence neural defenses against hypoglycemia. Glucocorticoids have complex effects on defenses against hypoglycemia (low blood sugar), acting both to increase glucose themselves and potentially to inhibit sympathetic nervous system actions that increase glucose. We are using knockout mice with selective glucocorticoid deficiency to identify glucocorticoid effects on neural and hormonal responses to acute and repeated hypoglycemia. These studies could aid in preventing hypoglycemia unawareness, a potentially fatal loss of physiological defenses against low blood sugar in insulin-dependent diabetes. 3.) How glucocorticoids affect neural control of appetite and body weight. We have found that glucocorticoids increase appetite and body fat independently of major regulators of food intake and metabolism, such as leptin. These results suggest that glucocorticoids could contribute to altered body weight regulation during stress or other conditions, such as aging or depression that increase glucocorticoid levels. Recent publications and abstracts 1. Jacobson L, Ansari T, McGuinness O 2006 Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically-cannulated mice. Am J Physiol Endocrinol Metab In press. 2. Heydendael W, Jacobson L 2005 Evidence that the antidepressant/ neuroleptic amoxapine inhibits adrenocortical activity: implications for treating psychotic depression. Program of the 35th Annual Meeting of the Society for Neuroscience, Washington, D. C., Abstract no. 637.9 3. Jacobson L, Pacak K 2005 Counterregulatory responses after repeated hypoglycemia are not enhanced by combined corticotropin-releasing hormone and glucocorticoid deficiency in mice. Metabolism 54:1259-1265 4. Heydendael W, Jacobson L 2005 The monoamine oxidase inhibitor phenelzine decreases glucocorticoid receptor gene expression in the mouse paraventricular hypothalamus: relevance to atypical depression. Program of the 87th Annual Meeting of the Endocrine Society, San Diego, CA, Abstract no. P1-117 5. Kier A, Han J, Jacobson L 2005 Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression. Endocrinology 146:1338-1347 6. Jacobson L 2005 Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292 7. Mukherjee K, Knisely A, Jacobson L 2004 Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight and hippocampal glucocorticoid receptors in male C57BL/6 mice. Endocrinology 145:4185-4191 8. Jacobson L 2002 Middle-aged C57BL/6 mice have impaired responses to leptin that are not improved by calorie restriction. Am J Physiol 282:E786-793

References

1. Kier, A., J. Han, and L. Jacobson. Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression. Endocrinology 146: 1338-47, 2005.



2. Mukherjee, K., A. Knisely, and L. Jacobson. Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight and hippocampal glucocorticoid receptors in male C57BL/6 mice. Endocrinology 145: 4185-4191, 2004.



3. Jacobson, L., and K. Pacak. Counterregulatory responses after repeated hypoglycemia are not enhanced by combined corticotropin-releasing hormone and glucocorticoid deficiency in mice. Metabolism 54: 1259-65, 2005.



4. Jacobson, L. Middle-aged C57BL/6 mice have impaired responses to leptin that are not improved by calorie restriction. Am J Physiol 282: E786-93, 2002.



5. Jacobson, L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, 2005.