INDIVIDUAL RESEARCHERLauren Jacobson , A.B. , Ph. D.
Education1989 - Ph. D. from University of California, San Francisco
1981 - A.B. from Vassar College
We are currently funded by NIH to test whether the depression-like phenotype and response to antidepressants of the forebrain glucocorticoid receptor knockout (FBGRKO) mouse is due to the loss of glucocorticoid receptors or to the increase in glucocorticoids resulting from forebrain glucocorticoid receptor deletion. FBGRKO mice reproduce many common features of depression, including despair- and anhedonia-like behaviors and elevated basal hypothalamic-pituitary-adrenal (HPA) axis activity, which are normalized by antidepressant treatment [Boyle et al., PNAS 102 (2005):473]. However, it is unclear if behavioral deficits in FBGRKO mice are caused by elevated glucocorticoids acting at MR or remaining GR, or if antidepressant effects on depression behaviors are due to inhibition of glucocorticoid secretion. We will discriminate these possibilities by testing basal and antidepressant-induced behavior after controlling glucocorticoids. We are further testing the behavioral impact of virally-transduced glucocorticoid receptor gene deletion in selected brain regions of mice with a floxed glucocorticoid receptor gene. These studies will indicate if glucocorticoids, which often increase in depression, might contribute to depression symptoms or influence antidepressant effects. This information could ultimately help to identify more effective treatment for depressed patients with abnormal glucocorticoid levels.
Role of glucocorticoids in behavioral and physiological regulation, including depression, diabetes, and obesity.
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, cognitive and emotional disturbances). 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.
- Bowens N, Heydendael W, Bhatnagar S, Jacobson L. Lack of elevations in glucocorticoids correlates with dysphoria-like behavior after repeated social defeat. Physiol. Behav. 2011; 105: 958-965
- Mukherjee K, Jacobson L. Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity and thymus weight in male C57BL/6 mice. Endocrinology 2004; 145:4185-91
- Kier A, Han J, Jacobson L Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression. Endocrinology 2005; 146:1338-1347
- Heydendael, Jacobson L. Differential effects of imipramine and phenelzine on corticosteroid receptor gene expression in mouse brain: potential relevance to antidepressant response. Brain Res. 2008; 1238:93-107
- Heydendael, Jacobson L. Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphé tryptophan hydroxylase gene expression. Brain Res. 2009; 1288:69-78
- Heydendael W, Jacobson L. Widespread HPA axis- and mood-relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice. Eur. J. Neuroscience 2010; 31: 892-902.
- Jacobson, L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 34:271-292, 2005.