Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Research Paper Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice Vipan K. Parihar a,1 , Mattia Maroso b,c,1 , Amber Syage a , Barrett D. Allen a , Maria C. Angulo a , Ivan Soltesz b,c, ⁎ , Charles L. Limoli a, ⁎⁎ a Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA b Department of Neurosurgery, Stanford University, Palo Alto, CA 94305, USA c Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA 94305, USA ARTICLE INFO Keywords: Cosmic radiation Radiation-induced cognitive dysfunction Hippocampal-cortical connectivity Neuroinflammation ABSTRACT Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic- radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like beha- vior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spon- taneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation ex- posure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly pro- tracted post-irradiation intervals. 1. Introduction Deep space travel presents an assortment of problems that challenge the ingenuity of humankind, and one of the many obstacles that must be confronted involves the health risks associated with exposure to the space radiation environment (Nelson 2016). Acute and chronic tissue alterations arise from the damaging effects of highly energetic charged particles that penetrate the spacecraft and traverse though the tissues of the body. These fully ionized nuclei are derived chiefly from solar ejection events (e.g. protons) or galactic cosmic rays (GCR) composed of light and heavy ions (Z from 1 to 26). Measurements of the radiation fields in space have provided considerable information concerning the types, fluences and energies of charged particles that contribute to the expected doses astronauts would incur within and beyond the Earth's protective magnetosphere (Nelson 2016). Based on the measured dose rates and mission duration for a roundtrip mission to Mars, total doses are not expected to exceed 0.3–4 Gy, where the majority (~80%) of whole body exposures will be due to lighter particles (e.g. protons and helium ions) (Nelson 2016). Terrestrial based simulations of the space radiation environment have provided invaluable information concerning the biological effects of cosmic rays and have begun to identify how such exposures can compromise the functionality of the central nervous system (CNS) (Cucinotta et al. 2014). Past work with rodents has demonstrated that https://doi.org/10.1016/j.expneurol.2018.03.009 Received 9 January 2018; Received in revised form 16 February 2018; Accepted 9 March 2018 ⁎ Correspondence to: I. Soltesz, Department of Neurosurgery, Stanford University, Palo Alto, CA 94305, USA. ⁎⁎ Correspondence to: C.L. Limoli, Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA. 1 These authors contributed equally to this work. E-mail addresses: isoltesz@stanford.edu (I. Soltesz), climoli@uci.edu (C.L. Limoli). Experimental Neurology 305 (2018) 44–55 Available online 11 March 2018 0014-4886/ © 2018 Elsevier Inc. All rights reserved. T