Intergenerational transmission of the positive effects of physical exercise on brain and cognition

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.We thank Cesar Cobaleda [Centre of Molecular Biology Severo Ochoa (CBMSO), Spanish National Research Council/Autonomous University of Madrid (CSIC/UAM), Madrid, Spain] and Alberto González-de la Vega (MegaLab, Madrid, Spain) for expert assistance and advice of the RNAseq, DAVID, and GSEA analysis; María Llorens-Martín (CBMSO, CSIC/UAM, Madrid, Spain) for useful discussions; Silvia Fernández (Cellular and Molecular Biology Unit, Cajal Institute, Madrid, Spain) and Laude Garmendia (Animal House, Cajal Institute, Madrid, Spain) for volunteer help and advice; the Image Analysis Unit of the Cajal Institute; Carmen Sandi (Brain Mind Institute, Lausanne, Switzerland) for helpful and useful advice and assistance; and all members of the National Centre for Biotechnology Mouse Embryo Cryopreservation Facility— María Jesús del Hierro, Marta Castrillo, and Lluís Montoliu—for their huge efforts and impressive involvement in the IVF experiments. This work was supported by the Spanish Ministry of Economy and Competitiveness Project Grants BFU2013-48907-R and BFU2016-77162-R (to J.L.T.), SAF2016-78845-R (to S.R.F.), RYC-2012-10193 and AGL2014-85739-R (to P.B.Á.), CP14/00105 and PI15/00134 (to A.M.-M.); by the Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness; and by the European Regional Development Fund Grant PT17/0009/0019 (to A.E.-C). Á.F.-L. was funded by a CSIC JAE-Doc Programme grant and VPlan Propio US-Acceso Grant, I.L.-T. was funded by a predoctoral fellowship (FPI) grant, and K.R.M. was funded by a contract associated with the above-mentioned project grants awarded to J.L.T