ARTICLE IN PRESS JID: NEUPSY [m6+;November 24, 2018;20:52] European Neuropsychopharmacology xxx (xxxx) xxx www.elsevier.com/locate/euroneuro Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes N. Kokras a,b,1 , I. Sotiropoulos c,d,a,1 , D. Besinis a , E.L. Tzouveka a , O.F.X. Almeida e , N. Sousa c,d , C. Dalla a,* a Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece b First Department of Psychiatry, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece c Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal d ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal e Max Planck Institute of Psychiatry, Munich, Germany Received 6 March 2018; received in revised form 1 November 2018; accepted 9 November 2018 Available online xxx KEYWORDS Sex differences; Enriched environment; Hippocampus; Receptors; Serotonin; Dopamine Abstract Environmental enrichment (EE), comprising positive physical (exercise) and cognitive stimuli, influences neuronal structure and usually improves brain function. The promise of EE as a pre- ventative strategy against neuropsychiatric disease is especially high during early postnatal development when the brain is still amenable to reorganization. Despite the fact that male and female brains differ in terms of connectivity and function that may reflect early life ex- periences, knowledge of the neural substrates and mechanisms by which such changes arise remains limited. This study compared the impact of EE combined with physical activity on neu- roplasticity and its functional consequences in adult male and female rats; EE was provided during the first 3 months of life and our analysis focused on the hippocampus, an area impli- cated in cognitive behavior as well as the neuroendocrine response to stress. Both male and female rats reared in EE displayed better object recognition memory than their control counter- parts. Interestingly, sex differences were revealed in the effects of EE on time spent exploring the objects during this test. Independently of sex, EE increased hippocampal turnover rates of dopamine and serotonin and reduced expression of 5-HT 1A receptors; in addition, EE upreg- ulated expression of synaptophysin, a presynaptic protein, in the hippocampus. As compared ∗ Corresponding author. E-mail address: cdalla@med.uoa.gr (C. Dalla). 1 Both the authors contributed equally to this work. https://doi.org/10.1016/j.euroneuro.2018.11.1107 0924-977X/© 2018 Elsevier B.V. and ECNP. All rights reserved. Please cite this article as: N. Kokras, I. Sotiropoulos and D. Besinis et al., Neuroplasticity-related correlates of environmental enrichment combined with physical activity differ between the sexes, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro. 2018.11.1107