RESUMEN
This study has established the impact that 1-15 cGy 600 MeV/n 28Si radiation had on cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of â¼10-month-old (at the time of irradiation) male Wistar rats. Exposure to 1 cGy 600 MeV/n 28Si ions resulted in significantly impaired performance in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment. Should similar effects occur in astronauts, the impairment of SD performance would result in a decreased ability to identify and learn the "rules" required to respond to new tasks/situations, while the impaired CD performance would result in a decreased ability to identify and maintain focus on relevant aspects of the task being conducted. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. Extracellular recordings of field excitatory postsynaptic potentials revealed that radiation significantly decreased long-term depression in layer L5. Patch-clamp whole cell recordings in pyramidal neurons of the L2-3 revealed reduced frequency of spontaneous excitatory postsynaptic currents indicating alterations in presynaptic glutamate release and impaired neuronal spiking (e.g., decreased action potential amplitudes) in irradiated neurons. However, there was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.
Asunto(s)
Cognición/efectos de la radiación , Corteza Prefrontal/efectos de la radiación , Silicio/administración & dosificación , Animales , Conducta Animal/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Masculino , Técnicas de Placa-Clamp , Corteza Prefrontal/fisiología , Ratas , Ratas WistarRESUMEN
Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3 month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1-1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post-irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid ß (Aß) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (TNFα, IL-1ß, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased Aß deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased Aß deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.
Asunto(s)
Enfermedad de Alzheimer/patología , Modelos Animales de Enfermedad , Protones , Vuelo Espacial , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Conducta Animal/efectos de la radiación , Biomarcadores/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de la radiación , Citocinas/metabolismo , Relación Dosis-Respuesta en la Radiación , Masculino , Ratones , Ratones Transgénicos , Sinaptofisina/metabolismoRESUMEN
Astronauts traveling outside Earth's magnetosphere risk exposure to charged particle radiation that may cause neurophysiological changes and behavioral deficits. Although proton particles comprise a large portion of the space radiation environment, little has been published on the effects of low-dose proton radiation on central nervous system function. In the current study, we irradiated young male mice with 0.5 Gy 150 MeV protons and assessed the effects on behavior and hippocampal neurophysiology. Spatial learning ability, a sensitive behavioral marker of hippocampal damage, was assessed using the water maze and Barnes maze before irradiation and repeatedly 3 and 6 months after irradiation. Evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes, long-term potentiation (LTP) and spontaneous oscillations (SOs) triggered by incubation with Mg(2+)-free media (reflecting interictal epileptiform activity) were assessed 9 months after irradiation in vitro in hippocampal slice preparations. Irradiated mice exhibited impaired reversal learning in the water maze compared to control mice 6 months after irradiation. Proton radiation did not affect LTP, but significantly increased fEPSP slopes and reduced the incidence of SOs 9 months after irradiation. These findings suggest that a single exposure to low-dose proton radiation can increase synaptic excitability and suppress the propensity for epileptiform activity. Such findings of functional alterations in the irradiated mouse hippocampus have implications for extended manned space missions planned in the near future.
Asunto(s)
Conducta Animal/efectos de la radiación , Hipocampo/efectos de la radiación , Protones , Radiación , Animales , Astronautas , Relación Dosis-Respuesta en la Radiación , Electrofisiología , Hipocampo/fisiopatología , Masculino , Ratones , Neuronas/patología , Neuronas/efectos de la radiación , Radiación Ionizante , Irradiación Corporal TotalRESUMEN
The space radiation environment consists of multiple species of high-energy charge particles (HZE), including (56)Fe and (28)Si nuclei, that may impact neuronal cells, but their damaging effects on the central nervous system (CNS) have been poorly defined. Hippocampus-dependent memory functions have been shown to be highly sensitive to (56)Fe HZE particles, which poses a significant risk to the cognitive performance of astronauts during space missions. While low doses of (56)Fe radiation do not induce cell death of mature neurons, they affect synaptic plasticity in the CA1 region, the principal neuronal output of the hippocampal formation involved in memory formation. The effects of (28)Si on the CNS have not been defined. Compared to behaviorally naïve mice, cognitive testing might affect synaptic plasticity and the effects of (28)Si radiation on synaptic plasticity might be modulated by prior cognitive testing. Therefore, in the current study, we quantified the effects of whole-body (28)Si radiation (600 MeV/n, 0.25 and 1 Gy) on hippocampus-dependent contextual freezing and synaptic plasticity in the CA1 region of animals not exposed (behaviorally naïve mice) and animals exposed to the contextual freezing test (cognitively tested mice). In behaviorally naïve mice exposed to 0.25 and 1 Gy of (28)Si radiation, the magnitude of long-term potentiation (LTP) was enhanced. However, in mice irradiated with 0.25 Gy contextual fear conditioning was enhanced and was associated with a further enhancement of the LTP magnitude. Such increase in synaptic plasticity was not seen in cognitively tested mice irradiated with 1 Gy. Thus, low dose (28)Si radiation has effects on synaptic plasticity in the CA1 region of the hippocampus and these effects are modulated by cognitive testing in a contextual fear-conditioning test.
Asunto(s)
Hipocampo/efectos de la radiación , Plasticidad Neuronal/efectos de la radiación , Radioisótopos/farmacología , Silicio/farmacología , Animales , Radiación Cósmica , Potenciación a Largo Plazo , Ratones , Ratones Endogámicos C57BLRESUMEN
An unavoidable complication of space travel is exposure to radiation consisting of high-energy charged particles (HZE), such as Fe and Si nuclei. HZE radiation can affect neuronal functions at the level of the synapse or neuronal soma without inducing significant neuronal death. Different radiation species impart distinct patterns of radiation damage depending on their track structure, dose rate and fluence. Moreover, structural differences exist along the dorsoventral axis of the hippocampus that may underlie different radiosensitivities within the same neuronal field (e.g., the CA1 pyramidal cell population of the hippocampus). In this study we tested the functional effects of low doses of (28)Si radiation on excitability and synaptic plasticity in hippocampal slices prepared strictly from the ventral hippocampus. We used extracellular electrophysiological techniques to record field excitatory postsynaptic potentials (EPSPs) and population spikes in hippocampal CA1 neurons from C57BL/6J male mice 3 months after exposure to (28)Si radiation (600 MeV/n; 0.25 and 1 Gy, whole body). In irradiated mice we found prominent decrements in population spike amplitudes and reduced maximal neuronal output without changes in dendritic field EPSP. Reduced field EPSP vs. population spike ratios indicate radiation-induced impairment of the EPSP-spike (E-S) coupling. This effect was not associated with significant changes in the magnitude of short- and long-term synaptic plasticity [long-term potentiation (LTP)]. These data confirm that irradiation with (28)Si particles at relatively low doses alters the properties of the hippocampal network, which can limit its connectivity with other brain centers.
Asunto(s)
Región CA1 Hipocampal/efectos de la radiación , Neuronas/efectos de la radiación , Radioisótopos/farmacología , Silicio/farmacología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Dendritas/efectos de los fármacos , Dendritas/fisiología , Dendritas/efectos de la radiación , Potenciales Postsinápticos Excitadores , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacosRESUMEN
Traumatic brain injury (TBI) affects many infants and children, and results in enduring motor and cognitive impairments with accompanying changes in white matter tracts, yet few experimental studies in rodent juvenile models of TBI (jTBI) have examined the timeline and nature of these deficits, histologically and functionally. We used a single controlled cortical impact (CCI) injury to the parietal cortex of rats at post-natal day (P) 17 to evaluate behavioral alterations, injury volume, and morphological and molecular changes in gray and white matter, with accompanying measures of electrophysiological function. At 60 days post-injury (dpi), we found that jTBI animals displayed behavioral deficits in foot-fault and rotarod tests, along with a left turn bias throughout their early developmental stages and into adulthood. In addition, anxiety-like behaviors on the zero maze emerged in jTBI animals at 60 dpi. The final lesion constituted only â¼3% of brain volume, and morphological tissue changes were evaluated using MRI, as well as immunohistochemistry for neuronal nuclei (NeuN), myelin basic protein (MBP), neurofilament-200 (NF200), and oligodendrocytes (CNPase). White matter morphological changes were associated with a global increase in MBP immunostaining and reduced compound action potential amplitudes at 60 dpi. These results suggest that brain injury early in life can induce long-term white matter dysfunction, occurring in parallel with the delayed development and persistence of behavioral deficits, thus modeling clinical and longitudinal TBI observations.