The pro-inflammatory cytokine tumor necrosis factor alpha (TNF-1) regulates cell differentiation and apoptosis in the immune system. However, TNF-1 and its receptors are also found in the central nervous system. Increased levels of TNF-1 have been implicated in depression and anxiety. However, it is unclear whether ambient/physiological levels of TNF-1 (in the absence of pathological inflammation) play a role in anxiety and depression or other neuropsychiatric disease. Our laboratory has recently found that TNF-1 knockout (KO) mice display reduced avoidance of fearful and increased exploration of novel environments, behaviors consistent with reduced anxiety- like behavior. Genetic inactivation of other factors implicated in anxiety such as the 5- HT transporter, 5-HT1A receptor and brain derived neurotrophic factor (BDNF) in contrast results in an anxiogenic-like effect. These data suggest that anxiety levels are bi- directionally modulated by genes and that increased or decreased anxiety could be the result of an imbalance between these or similar gene effects. In searching for a neuronal mechanism that could be associated with the expression of specific manifestations of anxiety (avoidance and exploration of a novel and fear inducing environment), we identified proliferation of neuronal precursors during early postnatal life as a potential contributing factor. Indeed proliferation and the level of anxiety were inversely correlated in TNF KO mice.
The aims of this application are to specify the cell source of TNF (aim 1), the developmental time of TNF's action (aim 2) and the neuronal and molecular mechanisms of TNF-mediated regulation of proliferation and anxiety levels (aim 3). An additional goal is to causally link postnatal neuronal precursor proliferation to specific manifestations of anxiety using genetic and pharmacological rescue strategies (aim 4).
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