Despite the vast number of medications available to treat major depressive disorder (MDD), 30% of depressed patients never achieve remission even with multiple treatment trials and different medications. Thus there is a need to understand better the biological mechanisms underlying the disease and to identify new targets for drug development. Recent studies in biomedical research have found inflammation to be a common feature in the pathophysiology of many diseases including cardiovascular disease, diabetes, cancer and most recently in psychiatric disease. Elevated levels of pro-inflammatory cytokines can be found in the serum of patients with psychiatric disease including MDD, schizophrenia, and bipolar disorder. Elevation in the levels of pro-inflammatory cytokines can cause a disturbance in the balance of pro- and anti-inflammatory cytokines and serve as an additional stressor to activate and even disrupt HPA axis function. Furthermore, immunotherapy of patients for the treatment of malignancies, viral infections, multiple sclerosis and skin conditions is commonly associated with neuropsychiatric side effects, particularly symptoms of depression.
The overarching goal of our research is to understand how elevated peripheral and central pro-inflammatory cytokines mediate behavioral changes associated with mood disorders and to use these insights to identify novel targets for treating patients with inflammation related MDD. To achieve this goal we have established and validated a mouse model of chronic inflammation using treatment with Bacille Calmette Guérin (BCG) to stimulate the innate immune response which results in chronic elevation of pro-inflammatory cytokines and is accompanied by increased depressive-like behaviors. We are assessing BCG-induced changes in miRNA and mRNA using molecular profiling of total RNA from microdissected brain regions in order to understand the neuroadaptive mechanisms that are altered by chronic elevation of pro-inflammatory cytokines and contribute to the depressive phenotype.
In addition, we are assessing the effects of chronically elevated pro-inflammatory cytokines on neurotransmitter function, synaptic plasticity, HPA axis function, anxiety-like behavior and pain sensitivity in an attempt to identify the mechanisms underlying the behavioral changes in this model. It is anticipated that the use of this model will reveal new insights into mechanisms underlying psychiatric diseases including MDD and identify novel candidate drug targets to address the needs of those patients who respond poorly to currently available treatments.
"A depressive phenotype induced by Bacille Calmette Guerin in 'susceptible' animals: Sensitivity to antidepressants."
Platt B, Schulenberg J, Klee N, Nizami M, Clark JA
Psychopharmacology DOI: 10.1007/s00213-012-2923-6. 2012.
"Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test."
Clark JA, Alves S, Gundlah C, Rocha B, Cai S-J, Flick R, Hayes E, Ho K, Warrier S, Pai L-P, Yudkovitz J, Fleischer R, Colwell L, Li S, Wilkinson H, Schaeffer J, Wilkening R, Mattingly E, Hammond M, and Rohrer SP
Neuropharmacol. 63: 1051-1063, 2012.
"Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/BI6 mice"
Clark JA, Flick RB, Pai L-Y, Szalyyova I, Key S, Conley RK, Deutch AY, Hutson PH, and Mezey E
Mol. Psych. 13: 498-506, 2008.
"Estrogen receptor-beta (ER-β) regulates tryptophan hydroxylase expression in the murine dorsal raphe"
Gundlah C, Alves SE, Clark JA., Pai L-Y, Schaeffer JM and Rohrer SP
Biol. Psych. 57: 938-942, 2005.
"Differential hormonal regulation of TPH2 mRNA in the murine dorsal raphe nucleus"
Clark JA, Pai L-Y., Flick RB, and Rohrer SP
Biol. Psych. 57: 943-946, 2005.
"Distribution of the GABAB receptor subunit gb2 in rat CNS"
Clark JA, Mezey Ế, Lam AS, and Bonner TI
Brain Res. 860: 41-52, 2000.
"Identification fo a GABAB receptor subunit, gb2, required for functional GABAB receptor activity"
*Clark JA., *Ng GYK, Coulombe N, Ethier N, Hebert TE, Sullivan R, Kargman S, Chateauneuf A, Tsukamoto N, McDonald T, Whiting P, Mezey Ế, Johnson MP, Liu Q, Kolakowski LF, Jr., Evans JF, Bonner TI, and O'Neill GP (*co–first authors)
J. Biol. Chem. 274: 7607-7610, 1999.