Depression can involve disrupted pro-inflammatory TNF signaling via the TNF receptors TNFR1 and TNFR2, or the soluble TNF receptors sTNFR1 and sTNFR2. However, exercise might attenuate pro-inflammatory signaling in depression and related anxiety. We hypothesized that six months voluntary wheel running exercise would improve depression-like and anxiety-like behaviours in WT and TNFR1-/- mice, but not in TNF-/- and TNFR2-/- mice compared to their respective control mice. METHODS:We investigated the effects of six months voluntary wheel running exercise on open field (OF) and elevated zero maze (EZM) anxiety-like behaviours, and forced swim test (FST) depression-like behaviours in control and exercise WT, TNF-/-, TNFR1-/-, and TNFR2-/- mice with two-way ANOVAs. RESULTS:Exercise reduced of anxiety-like behaviours in TNFR2-/- exercise mice compared to their respective controls. Compared to WT control mice, WT exercise mice displayed significantly reduced EZM anxiety-like behaviours. There were no exercise related changes in FST immobility time. Between-strains analyses found WT control and exercise mice displayed reduced EZM anxiety-like behaviours compared to TNF-/- and TNFR1-/- control and exercise mice, and WT exercise mice displayed reduced anxiety-like behavior compared to TNFR2-/- exercise mice. DISCUSSION:Exercise associated TNFR1 and TNFR2 signaling in concert in WT exercise mice mediated reductions in aspects of anxiety-like behaviours. These findings are consistent with the current view that imbalances in TNF signaling are involved in disrupted affect. Additional studies are needed to further explore the roles of exercise related TNFR1 and TNFR2 signaling in anxiety-like and depression-like behaviours.