The Role of CREB in Social Isolation and Natural Reward Behavior




Wallace, Deanna Lynette

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The role of CREB (cyclic AMP Response Element Binding protein) has been known to play a role in complex behaviors such as learning and memory, drug reward and depression. The work presented in this dissertation examines the role of CREB in an inactive stress paradigm, social isolation. Social isolation is a model which decreases CREB-mediated transcription in the nucleus accumbens and results in depressive- and anxiety- like phenotypes, all reversed by chronic but not acute administration of imipramine. In addition, aspects of social isolation can be mimicked in non-isolated animals by inhibition of CREB in the nucleus accumbens and certain deficits in isolated animals can be reversed by wildtype overexpression of CREB. However, other behavioral deficits observed in the isolated phenotype, while reversed by imipramine administration, are unaffected by CREB manipulation in the nucleus accumbens. Potential gene targets are explored by microarray analysis comparing control doublehoused animals and isolated animals, and these groups treated with wildtype CREB or chronic imipramine administration. The array analysis led to the discovery that social isolation alone increases expression of several types of potassium channels in the nucleus accumbens. Investigating the electrophysiological properties of these neurons, social isolation results in a greater hyperpolarization of the resting membrane potential, and decreased potassium channel-mediated membrane resistance. Lastly, it is shown that inhibiting CREB leads to increases of potassium channel expression, and the anxiety-like effects observed in isolated animals can be mimicked in non-isolated animals by overexpression of the inward rectifying potassium channel kir2.1. These studies further the field of depression and anxiety research with a model sensitive to chronic but not acute antidepressant treatment and reveal potential novel mechanisms for the reversal of anxiety-like behaviors.

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