Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice

Highlights

• Low dose cosmic irradiation causes significant adverse effects on CNS function.

• Functional CNS disruptions occur over times commensurate with a trip to Mars.

• Impairments to cognition and neural circuitry persisted 1 year after exposure.

• Prolonged functional deficits were associated with elevated 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 behavior. 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 spontaneous 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 exposure. 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 protracted post-irradiation intervals.

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 whole body and/or brain exposure to charged particles can elicit various behavioral decrements that can be linked to impairments in the hippocampus (Britten et al. 2012; Britten et al. 2016a; Britten et al. 2016b; Cherry et al. 2012; Haley et al. 2013; Tseng et al. 2014), amygdala (Parihar et al. 2016; Rabin et al. 2014), basal forebrain (Britten et al. 2014), medial prefrontal cortex (mPFC) (Britten et al. 2014; Parihar et al. 2015a; Parihar et al. 2016) and other brain domains (Davis et al. 2015; Davis et al. 2014; Lonart et al. 2012). Individual animals often exhibit deficits in multiple behavioral paradigms implicating different brain regions (Britten et al. 2016b; Parihar et al. 2015a; Parihar et al. 2016), and while this is consistent with the mode of exposure, the nature of the deficits found at low dose suggest that irradiation is capable of disrupting network activity on a more global scale. Cognitive changes transpiring over 6–15 weeks have now been found to coincide with a marked structural plasticity and elevated neuroinflammation that track with poor cognitive performance (Parihar et al. 2015a; Parihar et al. 2016). Increased yields of activated microglia found 15 weeks after exposure may also contribute to the reshaping of the synaptic environment (Parihar et al. 2016), by pruning dendritic branches and spines thereby reducing the structural complexity of neurons throughout distinct regions of the brain.

Recent and past work has highlighted how radiation-induced oxidative stress and inflammation might disrupt neurotransmission (Parihar et al. 2015b; Tseng et al. 2014), and new evidence has now shown that charged particles may disrupt cognition through selective changes in synaptic function that regulate GABA release in the hippocampal CA1 microcircuit (Lee et al. 2017). However, much of this prior work was performed at a single time point and after relatively brief post-irradiation intervals that may not approximate effects encountered during an extended deep space mission to Mars. Therefore, to gain much needed insight concerning the time course of cosmic radiation-induced alterations, we sought to determine whether changes in cognition measured over extended times might be associated with disruptions in network circuit activity and emergent pathology capable of compromising neurotransmission and cognition. Here we report our findings demonstrating that helium ion exposure at space-relevant doses elicits prolonged cognitive dysfunction measured over the course of one year following exposure. Importantly, behavioral deficits were accompanied by marked alterations in perirhinal network excitability, which, together with the presence of elevated inflammatory markers reveal the remarkably persistent nature of the effects of cosmic radiation on the brain.