Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring’s brain physiology and cognitive behavior.

It is known that intergenerational inheritance can be induced by environmental changes in parents. These studies usually focus on negative stressors that affect the offspring adversely. There is increasing evidence that exercise improves learning and memory in humans and mice. These beneficial effects could be mediated by enhanced hippocampal neurogenesis. Whether these effects could be inherited by future generations remains to be seen. This study analysed if paternal exercise training could facilitate hippocampal‐dependent novel object recognition memory and pattern separation performance in offspring. Firstly, male progenitors were subjected to a forced moderate exercise protocol for eight weeks before mating. All male experimental animals underwent the following behavioural protocols: an activity cage and two different protocols of a novel object recognition memory test and a pattern separation test, both protocols differing in the level of difficulty. Regarding basal motor activity, no differences were found between experimental groups in a known environment. As for the novel object recognition and pattern separation tests, only male progenitors that had undergone the exercise protocol were able to discriminate the novel object and the change of pattern in the difficult protocols. No significant differences were found in postnatal behaviour. However, the behavioural outcomes in adulthood showed that only the offspring of male progenitors that had undergone physical exercise displayed facilitation in novel object recognition memory and pattern separation performance. In order to assess adult hippocampal neurogenesis, immunohistochemistry against different neurogenesis markers was performed. Furthermore, whole‐genome sequence analyses showed differential gene expression among experimental groups. These results suggest that beneficial effects of exercise training on learning and memory can be inherited.Support or Funding InformationWork was supported by project grants from Spanish Ministry of Economy and Competitiveness BFU2013‐48907‐R and BFU2016‐77162‐R (to J.L.T.). A.F. was funded by a JaE‐DOC CSIC grant, I.L.T. was funded by an FPI grant, and K.R.McG. was funded by a contract associated with the project grants above mentioned (to J.L.T.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.