INDIVIDUAL RESEARCHER
Lauren Jacobson
, A.B.
, Ph. D.
Associate Professor
e-mail: JACOBSL@mail.amc.edu
Education
1981 - A.B. from Vassar College1989 - Ph. D. from University of California, San Francisco
Current Research
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. 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.
Research Summary
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.
My laboratory is currently exploring the possibility that the contradictory range of hypothalamic-pituitary-adrenocortical (HPA) abnormalities in depression might be exploited to improve depression treatment. HPA activity has been of interest as a biomarker for antidepressant response because it is often elevated in depression and returns to normal after successful treatment. However, the predictive value of HPA activity is severely limited by the relatively high proportion of depressed patients that have either normal or even low HPA activity. We have demonstrated evidence in mice that antidepressants effective for depression subtypes such as melancholic depression, in which HPA activity is typically elevated, will facilitate glucocorticoid feedback inhibition of HPA activity, while antidepressants effective for subtypes such as atypical depression, in which HPA activity is usually not elevated, will have the opposite effect. The representative tricyclic antidepressant imipramine, which has been used to treat a variety of depression subtypes but is notably less effective for atypical depression, increased glucocorticoid receptors in forebrain areas related to glucocorticoid feedback, whereas phenelzine, a monoamine oxidase inhibitor antidepressant that is more efficacious for atypical depression decreased glucocorticoid receptor expression in these same forebrain regions. In the brainstem, both antidepressants decreased glucocorticoid receptor expression, but did so in different regions. Imipramine-induced decreases in glucocorticoid receptor expression in the dorsal raphé correlated with increases in gene expression of tryptophan hydroxylase-2, the rate-limiting enzyme for serotonin synthesis. Phenelzine had no effect in the dorsal raphé but decreased glucocorticoid receptors and increased expression of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis, in the noradrenergic locus coeruleus. These results are consistent with antidepressant reversal of glucocorticoid inhibition of tryptophan hydroxylase-2 or tyrosine hydroxylase expression, and suggest novel, glucocorticoid-related mechanisms by which antidepressants cause therapeutic increases in serotonin or norepinephrine in depression. Overall, our findings suggest that differences in HPA activity might be used to improve the selection and efficacy of treatments for depression.
Past research projects have included:
(1) How glucocorticoids influence neural defenses against hypoglycemia. Glucocorticoids increase glucose themselves, but can also inhibit sympathetic nervous system actions that increase glucose. We used corticotropin-releasing hormone knockout mice, which are selectively deficient in glucocorticoids, to show that glucocorticoid actions to maintain glucose levels are probably more important than their impact on sympathetic nervous system activity. These findings suggest that targeting glucocorticoids is unlikely to be an effective solution to preventing hypoglycemia unawareness, a potentially fatal loss of physiological defenses against low blood sugar in insulin-dependent diabetes.
(2) How glucocorticoids affect 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.
PubMed Publications
- 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, 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
- 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
- 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
