In the United States, there is a 1 in 4 risk of developing depression by age 75, and by 2030 depression will be one of the leading causes of disease burden world-wide. For the past half-decade, the treatment of depression has been dominated by drugs that affect a group of molecules called the monoamines, with serotonin being the most commonly targeted. While effective for some people (30-50%), those that remain without relief have few options for therapy, as newer drug strategies have been hard to come by. Within the last few decades, it has become more and more apparent that changes in the activity and connections within the brain heavily influence the development of depression. Specifically, the hippocampus, a brain region important for emotion and memory, has been shown to be integral to depression's development. Our lab studies a unique protein in the brain called the Hyperpolarization-activated Cyclic-Nucleotide gated channel (HCN), which helps to regulate the flow of electricity from cell to cell. By doing this, the channel has an integral rolein solidifying and maintaining the connections between individual neurons and, ultimately, whole brain regions. Recently, we and others showed that a loss of these channels in the hippocampus has a distinct antidepressant-like effect in mice. Given this finding, we propose to study the roles of HCN in the development and treatment of depression, and hypothesize that HCN channels increase with depression-like behavior, and reduction of HCN channels correlate with a reduction in depression-like behavior. Specifically, we hypothesize that HCN is increased with depression-like behavior in chronically stressed mice (Aim1), that HCN subunit knock- out protects stressed mice from depression-like behavior (Aim 2.1), viral overexpression of HCN subunits in the hippocampus increase depression-like behavior (Aim 2.2), and antidepressants decrease HCN subunits (Aim 3).

Public Health Relevance

Major Depressive Disorder is a disease affecting 1 in 6 people worldwide, and current treatments are not effective in half of patients. Our research will describe the role of an important family of molecules (HCN channels) in the development of depression, with the goal of finding a new drug target for treating depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Driscoll, Jamie
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Northwestern University at Chicago
Schools of Medicine
United States
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Fisher, Daniel W; Han, Ye; Lyman, Kyle A et al. (2018) HCN channels in the hippocampus regulate active coping behavior. J Neurochem 146:753-766
Yan, Yan; Dominguez, Sky; Fisher, Daniel W et al. (2018) Sex differences in chronic stress responses and Alzheimer's disease. Neurobiol Stress 8:120-126
McClarty, Bryan M; Fisher, Daniel W; Dong, Hongxin (2018) Epigenetic Alterations Impact on Antipsychotic Treatment in Elderly Patients. Curr Treat Options Psychiatry 5:17-29
Fisher, Daniel W; Luu, Phillip; Agarwal, Neha et al. (2018) Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. PLoS One 13:e0193012
Montalvo-Ortiz, Janitza L; Fisher, Daniel W; Rodríguez, Guadalupe et al. (2017) Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice. Psychopharmacology (Berl) 234:2385-2398
Han, Y; Heuermann, R J; Lyman, K A et al. (2017) HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects. Mol Psychiatry 22:458-465