DESCRIPTION (provided by applicant): Clinical imaging studies have suggested that nicotinic acetylcholine receptor (nAChR) occupancy by acetylcholine (ACh) is increased in the brains of human subjects with depression. In addition, blockade of either nicotinic or muscarinic ACh receptors can have antidepressant effects in human subjects. Thus, changes in ACh levels in specific brain regions could be critical for the control of circuits involved in mood regulation. W have recently shown that blocking ACh degradation in the hippocampus increases anxiety- and depression-like behaviors in mice, and increases susceptibility to social stress, all of which can be reversed by treatment with fluoxetine, an antidepressant effective in human depressed individuals. This suggests that cholinergic regulation of the hippocampus is critical for behaviors related to depression, but the necessity of hippocampal cholinergic innervation in stress-induced behaviors related to depression, and the role of different cholinergic circuitry in depression-like behavior remains unknown. Using novel technologies, we will silence or activate the cholinergic neurons innervating the hippocampus and measure the effects of these manipulations on the ability of a social stressor to increase depression-like behavior in mice, or the effects on mouse models of depression-like behavior at baseline. We will control cholinergic neuronal firing by expressing Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in cholinergic neurons using viral-mediated gene transfer to infuse conditional DREADD constructs locally in mice expressing Cre recombinase under the control of the choline acetyltransferase promoter. We will first determine whether silencing the activity of the cholinergic neurons from the medial septum and the diagonal band of Broca (MS/VDB; the primary cholinergic input to the hippocampus) can block the effects of social stress on the development of social avoidance, a phenotype sensitive to chronic treatment with antidepressant medications. To determine the anatomical specificity of this effect, we will also silence another source of hippocampal ACh, the sparse cholinergic neurons intrinsic to the hippocampus. In a second set of studies, we will determine whether activating ACh neurons in the MS/VDB is sufficient to induce depression-like behaviors, and whether this can be also observed by activating the intrinsic cholinergic neurons of the hippocampus. These experiments take advantage of novel and innovative techniques that allow local control of the activity of specific ACh neurons. These results will determine whether stress-induced firing of cholinergic inputs to the hippocampus mediate effects of a social stressor on depression-like behavior. These studies will be important in determining whether medications that target the cholinergic system could be useful for treating depression.

PUBLIC HEALTH RELEVANCE: Between 35-50% of depressed patients are not helped by existing antidepressant medications. Identification of another neurotransmitter system involved in depression could help clarify the brain mechanisms leading to depression, provide novel strategies for the development of new medication and lead to better diagnostics for subtypes of depression by identifying potential risk factors for the disorder.