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• Exercise had modest effects on behaviours. • Stopping exercise increased depression- and anxiety-behaviours. • Exercise cessation appeared to impair some cognitive-like behaviours. • Hippocampal gene expression (GE) was altered following exercise cessation. • Replication of results and translation into high quality clinical trials is needed. Regular exercise can reduce depression-, anxiety-, and impaired cognitive-like behaviours, and upregulate hippocampal genes associated with neuroplasticity. However, the effects of ceasing exercise on depression-, anxiety-, and cognitive-like behaviours, and hippocampal gene expression remain unknown. 12-week-old C57BL/6 mice (n = 12–16/group) were randomised to six months of exercise (exercise (EXC)), four months of exercise then two months of no exercise (exercise-cessation (EC)), or no-exercise control (CONT) until aged nine months. Depression-, anxiety-, and cognitive-like behaviours were tested with the forced swim test, open field and elevated zero maze, Y-maze, and Barnes maze. The expression of 75 hippocampal genes were investigated by high-throughput quantitative polymerase chain reaction (qPCR). Exercise cessation increased depression- and anxiety-like behaviours, and impaired spatial learning and cognitive flexibility compared to CONT and EXC mice. 10/75 hippocampal genes were differentially expressed in EC mice, including increased expression of neurogenesis associated genes (Ntrk1), and reduced expression of immune (Il10 , Gfap) and monoamine related genes (Htr1a) compared to CONT mice. Altered expression of nine genes including increased Slc6a4 and reduced Sirt1 expression were shown in EC mice compared to EXC mice. Exercise cessation increased depression- and anxiety-like behaviours and impaired some cognition-like behaviours with altered neurogenic, monoaminergic, and immune hippocampal gene expression consistent with the pathogenesis of depression and related anxiety described by the neurogenic, monoaminergic, and immune hypotheses of depression. Mice and humans share mammalian physiology, so these findings could be relevant to humans. These results require replication and possibly translation into high-quality pilot clinical trials. [ABSTRACT FROM AUTHOR]

Background Altered TNF levels are associated with cognitive impairment in depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). Exercise improves cognition-like behaviours, reduces the expression of tumour necrosis factor alpha (TNF), and increases expression of the soluble TNF receptors soluble TNFR1 (sTNFR1) and sTNFR2. We suggest TNF and its receptors are involved in cognitive function and dysfunction, and investigate whether exercise mediates its effects on cognitive function via TNF and its receptors. Methods We utilised C57BL/6, TNF −/− , TNFR1 −/− , and TNFR2 −/− mice to compare exercise to non-exercise control groups to investigate whether exercise exerts its effects on various types of cognition-like behaviours via TNF and its receptors. Results Recognition memory improved with exercise in WT mice, was impaired in TNFR1 −/− exercise mice, showed non-significant impairment with exercise in TNF −/− mice, and no changes in TNFR2 −/− mice. In spatial learning there were exercise related improvements in WT mice, non-significant but meaningful impairments evident in TNFR1 −/− exercise mice, modest improvement in TNF −/− exercise mice, and potentially meaningful non-significant improvements in TNFR2 −/− exercise mice. Moreover, WT and TNFR2 −/− mice displayed noteworthy non-significant improvements in spatial memory, whereas TNFR1 −/− exercise mice demonstrated non-significant spatial memory impairment. Exercise did not alter cognitive flexibility in any strain. Discussion TNF receptor signalling via the TNFR1 and TNFR2 appears to mediate the effects of exercise on cognitive-like behaviours. The potential for exercise to regulate human TNF and TNF signalling and cognitive dysfunction needs investigation under inflammatory conditions including depression and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Preclinical studies have demonstrated exercise improves various types of behaviours such as anxiety-like, depression-like, and cognition-like behaviours. However, these findings were largely conducted in studies utilising short-term exercise protocols, and the effects of lifetime exercise on these behaviours remain unknown. This study investigates the behavioural effects of lifetime exercise in normal healthy ageing C57BL/6 mice over the adult lifespan. 12 week-old C57BL/6 mice were randomly assigned to voluntary wheel running or non-exercise (control) groups. Exercise commenced at aged 3 months and behaviours were assessed in young adult (Y), early middle age (M), and old (O) mice (n = 11–17/group). The open field and elevated zero maze examined anxiety-like behaviours, depression-like behaviours were quantified with the forced swim test, and the Y maze and Barnes maze investigated cognition-like behaviours. The effects of lifetime exercise were not simply an extension of the effects of chronic exercise on anxiety-like, depression-like, and cognition-like behaviours. Exercise tended to reduce overt anxiety-like behaviours with ageing, and improved recognition memory and spatial learning in M mice as was expected. However, exercise also increased anxiety behaviours including greater freezing behaviour that extended spatial learning latencies in Y female mice in particular, while reduced distances travelled contributed to longer spatial memory and cognitive flexibility latencies in Y and O mice. Lifetime exercise may increase neurogenesis-associated anxiety. This could be an evolutionary conserved adaptation that nevertheless has adverse impacts on cognition-like function, with particularly pronounced effects in Y female mice with intact sex hormones. These issues require careful investigation in future rodent studies. [ABSTRACT FROM AUTHOR]

• Tumor necrosis factor (TNF) signaling via its two receptors TNFR1 and TNFR2 mediates cognition and affective-like behaviors. • Physical exercise (PE) has been shown to improve cognition and affective-like behaviors in middle-aged mice. • TNF signaling via its two receptors and PE mediate cognition and affective-like behaviors independent of each other. We recently reported that tumor necrosis factor (TNF) signaling via the TNFR1 and TNFR2 receptors mediates the effects of long-term exercise on locomotion, cognition and anxiety, but not depressive-like behavior. We now investigated whether the TNF signaling via its receptors also mediates the effects of short-term exercise on cognition, anxiety and depressive-like behaviors. Thirteen-month-old C57BL/6 (WT), TNF−/−, TNFR1−/−, and TNFR2−/− mice were provided with 4 weeks of voluntary wheel running followed by behavioral testing using an established behavioral battery. Each genotype had a respective non-exercise control. There was no interaction between genotype and exercise in any of the tests but the main effect of genotype, and not exercise, were found to be significant in the open field (OF), forced-swim test (FST) and Barnes maze (BM). In the OF, the control and exercise TNFR2−/− mice spent significantly less time in the inner zone than mice in the control and exercise WT and TNF−/− cohorts. In the FST, control and exercise WT mice showed significantly higher immobility time than their control and exercise TNF−/−, TNFR1−/− and TNFR2−/− cohorts. In the BM, the latency to escape over 4 days of training was significantly higher in all KO groups compared to WT, irrespective of exercise. Also, the latency to escape to the original location during the probe trial was higher for control and exercise WT compared to corresponding TNFR1−/− mice. In contrast, the latency to escape to the new location was lower for control and exercise WT compared to control and exercise TNFR1−/− and TNFR2−/− mice. The latency to escape to the new location in exercise groups was longer compared to control within all genotypes. While TNF signaling via the TNF receptors mediates cognition, anxiety and depressive-like behaviors independently, it does not mediate the effects of short-term exercise on these behaviors in middle-aged mice. [ABSTRACT FROM AUTHOR]