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INDIVIDUAL RESEARCHER

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


Education

1989 - Ph. D. from University of California, San Francisco
1981 - A.B. from Vassar College


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.  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. 



Research Interests

Role of glucocorticoids in behavioral and physiological regulation, including depression, diabetes, and obesity.



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 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. Fluoxetine ("Prozac") had effects that encompassed those of both tricyclic and monoamine oxidase inhibitor antidepressants, potentially explaining its wide utility for treating a variety of depression subtypes. 
 
     Overall, our findings suggest that glucocorticoid action in brain plays a role in the therapeutic effects of antidepressants and potentially in the psychopathology of depression.  We are currently testing this theory by determining if the depression-like phenotype of the forebrain glucocorticoid receptor (GR) knockout (FBGRKO) mouse [Boyle et al., PNAS 102 (2005):473] is due to the loss of glucocorticoid receptors or to the increase in glucocorticoids resulting from the loss of feedback inhibition by forebrain glucocorticoid receptors. Findings from this research could indicate ways in which tests of HPA function could be used to improve the selection and efficacy of treatments for depression. 
 
 
    Past research projects have included:
(1) Glucocorticoids effects on neural defenses against hypoglycemia. Glucocorticoids increase glucose themselves, but can also inhibit sympathetic nervous system activity to increase glucose. We used CRH knockout mice, which are selectively deficient in glucocorticoids, to show that glucocorticoid effects on glucose requirements and glycogen stores are more important than their impact on sympathetic nervous system activity in maintaining plasma glucose levels.
(2) Glucocorticoids effects on 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.
(3) Effects of perinatal hypoxia stress and glucocorticoid exposure on the maturation of hypothalamic-pituitary-adrenocortical axis (HPA) function. We have found that hypoxia elevates glucocorticoid secretion in neonates, leading to inhibition of HPA activity that could be exacerbated by the routine use of synthetic glucocorticoids to treat neonatal respiratory disease. Perinatal hypoxia also alters HPA regulation in the adult, suggesting that neonatal respiratory distress could have long-lasting effects on stress and homeostatic responses.

 

 



PubMed Publications

  1. Radley JJ, Kabbaj M, Jacobson L, Heydendael W, Yehuda R, Herman JP 2011 Stress risk factors and stress-related pathology: neuroplasticity, epigenetics and endophenotypes. Stress 14:481-97


  2. 39. Vincent MY, Hussain RJ, Zampi ME, Sheeran K, Solomon MB, Herman JP, Jacobson L. Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. Brain Res. 1525:1-15; 2013.


  3. 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


  4. 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


  5. 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


  6. 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


  7. 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


  8. 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.



References

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