Role of HCN channels in Behavioral Responses to Psychosocial StressPublic Deposited
Psychosocial stress is part of everyday life, and while ubiquitous, stress plays a huge role disease development and treatment. Though the stressor’s intensity, predictability, and frequency (acute vs chronic) are important determinants of disease development, interactions with one’s genetic and epigenetic make-up also play a causal role. Major Depressive Disorder (MDD) is influenced by stress, and MDD is best described as a disease of aberrant neural connectivity. Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important molecular regulators of neural excitability influencing connectivity, and ablation of HCN channels in the dorsal hippocampus lead to antidepressant-like behavior in mice. However, HCN channels’ role in response to psychosocial stress is unknown. In this thesis, hippocampal HCN channels and their behavioral effects are characterized after acute and chronic stress in mice. Data presented here suggests that HCN channels do not change expression or function after Chronic Social Defeat (CSD) in the dorsal hippocampus of mice, nor does loss of HCN channel localizing protein, Tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), protect mice from CSD. However, loss of TRIP8b or HCN channels in the dorsal CA1 leads to persistent active coping behavior, which in humans prevents the development of certain diseases while improving outcomes to treatment. In all, the data shown here suggest that HCN Channels may not be specific targets for MDD but instead may more broadly applied to numerous disease where improving adaptive responses to stress would greatly benefit patients. This thesis additionally explores the phenotype of a novel HCN2 mutation in mice that leads to complete ablation of this protein. Like other HCN2 ablation mice, these mice display ataxia, tremor, infertility, persistent absence epilepsy-like spike-wave discharges, antidepressant-like behavior, and severe growth restriction. Data here shows that the extreme growth restriction is unlikely to be due to hormone dysfunction of the pancreas, pituitary, or thyroid and more likely to be due to malnutrition secondary to slowed GI motility.
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