NOTE: End date change to 9/30/2012 (from 4/30/2012) per NSBRI (Ed., 1/24/2012)

Aim #1: To assess the effects of space radiation across a range of neurobehavioral functions in rodents, including assessments of general motor function and speed, inhibitory control ( impulsivity ), timing, learning, selective attention, and motivation. Aim #2: To assess the long-term effects of radiation across a range of cognitive/behavioral functions via extended post-exposure testing for potential performance deficits. Aim #3: To assess both the acute and long-term effects of radiation on the neurochemical mechanisms underlying changes in neurobehavioral functions by examining the integrity of the neurotransmitter systems known to mediate those neurobehavioral functions found impaired.

(2) Key Findings

Results from the project have demonstrated the reliability and validity of the neurobehavioral procedures in detecting behavioral changes following radiation, and that such procedures can be used to effectively track changes in neurobehavioral function over extended intervals following radiation exposure. Using a version of the human Psychomotor Vigilance Test (PVT) adapted for use in rats (the rodent PVT, or rPVT), head-only exposure to radiation (including both protons and 56Fe particles) has been shown to significantly impair neurobehavioral function (e.g., decreased accuracy, increased impulsivity, increased lapses in attention) and slow motor function. These findings support the success of the rPVT as a rodent model for studying the risks of living in the space radiation environment due to changes in neurobehavioral function.

Specific findings from the past year include:

1. Demonstrating that individual differences in susceptibility to the effects of radiation exist, with 56% of rats exposed to proton radiation showing a radiation sensitivity as indicated by marked neurobehavioral deficits, with these deficits being independent of dose (i.e., 25 cGy produced effects similar to 50 – 200 cGy). Importantly, only radiation-sensitive animals showed significant changes in proteins associated with the levels of dopamine (DA) D2 receptors as well as dopamine transporter (DAT) in the brain, suggesting that DA level differences may play an important role in how an organism responds to radiation neurobehaviorally, and have important implications for possible screening of radiation sensitivity and future development of radioprotectants.

2. Demonstrating that exposure to 56Fe ions at 10, 25, and 50 cGy produces highly specific effects on vigilance. Similar to the effects of proton radiation, 56Fe ion exposures produced an "individual differences" effect in that only a subset of irradiated animals showed neurobehavioral deficits (i.e., were "radiation sensitive"), with these deficits also being independent of dose. In contrast to proton radiation, 56Fe radiation did not produce deficits in inattention or motor function, and 56Fe radiation produced deficits in only 15% of the exposed animals.

3. Assessing the initial inflammatory response in the brain following proton irradiation by examining the expression of translocator protein 18 kDa (TSPO), a sensitive marker of reactive gliosis in proton-exposed rats. TSPO levels were significantly elevated in the forebrain, cerebellum, and whole brain tissue following proton exposure up to 14 days post-exposure, suggesting that proton radiation causes immediate damage to the brain via inflammation and reactive gliosis, and that the immediate inflammatory response and likely subsequent glial cell death and extended brain inflammation could underlie such neurobehavioral changes following proton exposure and impact an individual's sensitivity to proton radiation.

4. Studies supported by this grant were conducted by Dr. Catherine Davis as part of her newly-funded NSBRI Postdoctoral Fellowship to determine the degree to which radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic function. Using inbred rats with inherent differences in dopamine (DA) function (Fischer 344 and Lewis rats), radiation-sensitive rats were found in the inbred Fischer rats, a strain with greater functioning DA system compared to Lewis rats but not yet in the Lewis strain, indicating again a possible involvement of the dopaminergic system in an individual's susceptibility to radiation-induced neurobehavioral damage to the CNS.

(3) Impact of Findings

The present results demonstrate the sensitivity of tests such as the rPVT for assessing the effects of head-only space radiation on cognitive neurobehavioral function. Such deficits could significantly impact routine performances in operational environments during long-duration exploratory missions, and also negatively affect post-mission adjustment upon return to Earth. These findings support the likely continued success of the rodent model for studying the cognitive, neurobehavioral, and CNS risks associated with living in the space radiation environment while providing an innovative experimental platform for exploring the bases of individual vulnerability to radiation-induced impairments and evaluating potential prophylactics, countermeasures, and treatments.

(4) Plan for the Coming Year

Plans for the first year of this newly-funded project (will be a new project with the same title, "Detection and Prevention of Neurobehavioral Vulnerability to Space Radiation," with new period of performance) include 1) starting new behavioral pharmacology studies to determine the degree to which pre-existing individual differences in neurotransmitter function may be predictive of the observed differential neurobehavioral susceptibility of individuals following radiation, and 2) neurotransmitter protein level studies to determine the degree to which the observed neurotransmitter changes are restricted to specific brain regions. Additionally, this project will support Dr. Catherine Davis' NSBRI Postdoctoral Fellowship studies designed to determine the radioprotective effectiveness of dietary flaxseed to mitigate the deleterious effects of low-dose proton radiation on neurobehavioral function.

• Determinations of Individual differences in susceptibility to the effects of radiation exist, with 56% of rats exposed to proton radiation showing a radiation sensitivity as indicated by marked behavioral deficits in rPVT performance measures, with these deficits being relatively independent of dose.

• Findings of radiation-sensitive animals showing significantly higher levels of dopamine D2 receptors as well as dopamine transporter (DAT) in the brain, with non-sensitive-but-exposed rats as well as control rats showing no such changes in DA protein levels, suggesting that DA level differences may play an important role in how an organism responds to radiation neurobehaviorally, and may have important implications for possible screening of radiation sensitivity and future development of radioprotectants.

• Findings showing that exposure to 56Fe ions at 10, 25, and 50 cGy also produce highly specific effects on vigilance, including impairments in accuracy and impulsivity, and that a subset of the irradiated animals showed strong neurobehavioral deficits, and thus appeared to be quite "radiation sensitive."

• Discovery that the initial inflammatory response in the brain is elevated in the forebrain, cerebellum, and whole brain tissue following proton exposure immediately following and up to 14 days post-exposure. This inflammatory response continues for a significant amount of time following irradiation and that could possibly lead to cellular changes and negatively impact neurobehavioral function, and suggests that the immediate inflammatory response and likely subsequent glial cell death and extended brain inflammation could underlie such neurobehavioral changes following proton exposure and impact an individual's sensitivity to proton radiation.

• Dr. Catherine Davis' NSBRI Postdoctoral Fellowship study showing that radiation-induced deficits in neurobehavioral function differ as a function of basal dopaminergic function when examined in Inbred strains of rats with inherent differences in dopamine (DA) function, and indicating a likely involvement of the dopaminergic system in determining an individual's susceptibility to radiation-induced neurobehavioral damage to the CNS.

Aim #1: To assess the effects of space radiation across a range of neurobehavioral functions in rodents. Performance measures include assessments of general motor function and speed, fine motor control, inhibitory control ("impulsivity"), timing, short-term memory, spatial working memory, learning and selective attention, and motivation. Groups of animals are separately trained on different tasks, exposed at Brookhaven National Laboratory to high-energy radiation at levels that astronauts would likely experience during lunar or planetary surface activities, and then immediately re-tested.

Aim #2: To assess the long-term effects of radiation across a range of cognitive/behavioral functions via extended post-exposure testing for potential performance deficits.

Aim #3: To assess both the acute and long-term effects of radiation on the neurochemical mechanisms underlying changes in neurobehavioral functions by examining the integrity of the neurotransmitter systems known to mediate those neurobehavioral functions found impaired.

(2) Key Findings of the Project

Results from the project have demonstrated the reliability and validity of the neurobehavioral procedures in detecting behavioral changes following radiation, and that such procedures can be used to effectively track changes in neurobehavioral function over extended intervals following radiation exposure. Specifically, the results have shown that head-only proton radiation produces discrete neurobehavioral changes by significantly impairing aspects of sustained attention (e.g., decreased accuracy, increased impulsivity, increased lapses in attention) and motor function (i.e., a slowing in reaction times). These findings support the likely success of the rodent model for studying the risks of living in the space radiation environment due to changes in neurobehavioral function.

During the current year studies continued to track daily performances on the rat psychomotor vigilance test (rPVT), which is an animal analog of the Psychomotor Vigilance Test (PVT) used to study sustained attention in humans. Following irradiation, performances on the rPVT were disrupted at all exposure levels studied (i.e., 25, 50, 100, and 200 cGy protons). Changes in motor function were manifested as consistent, significant increases (i.e., a slowing) in reaction times, indicative of a decrease in sustained attention. Other changes in sustained attention included decreases in accuracy, increases in performance lapses, and increases in impulsivity. New pilot studies of the effects of additional circadian disruptions on these rodent PVT performances have been conducted to determine the degree to which the observed radiation effects on neurobehavioral function may be compounded when disruptions in sleep/wake schedules occur (i.e., as under conditions of heavy workload and/or extended-duration exploration missions). Initial data indicates that disruptions in circadian rhythms has the potential to exacerbate ongoing radiation-induced neurobehavioral impairments, with radiation-exposed animals showing pronounced increases in sustained attention greater than those observed with radiation alone. Additionally, in a new study designed to measure impulsive choice behaviors in rodents, exposure to 200 cGy produced an increase in impulsivity compared to controls, indicating this may be an additional fruitful model for investigating biological consequences of radiation exposure as well as pharmacotherapy and other countermeasures aimed at preventing these radiation-induced brain and behavioral changes.

To summarize, the data obtained during the current year demonstrate that significant changes in sustained attention, impulsivity, and motor function can be shown to occur following proton exposures as low as 25 cGy for the exposure groups as a whole. Importantly, significant variations in responding to these proton doses occurred among animals within groups that indicate that these "average" effects of proton irradiation may not be indicative of all animals. In animals that respond significantly to proton irradiations, all exposure doses produced similar effects on accuracy, lapses, and reaction times. Finally, the changes in sustained attention were tracked over time for up to 1 year post-exposure and found to persist over this extended time period.

(3) Impact of these Findings

The present results demonstrate the sensitivity of tests such as the rPVT for assessing the effects of head-only space radiation on cognitive neurobehavioral function. Such deficits could significantly impact routine performances in operational environments during long-duration exploratory missions, and also negatively affect post-mission adjustment upon return to Earth. These findings support the likely continued success of the rodent model for studying the cognitive, neurobehavioral, and CNS risks associated with living in the space radiation environment while providing an innovative experimental platform for exploring the bases of individual vulnerability to radiation-induced impairments and evaluating potential prophylactics, countermeasures, and treatments.

(4) Proposed Research Plan for the Coming Year

Animals are currently being trained in the rodent version of the PVT. Once training is completed, they will be transported and exposed in May 2011 at Brookhaven National Laboratory to iron ions over a dose range of 0 - 150 cGy, and then returned for extensive post-radiation testing. Studies of the effects of circadian disruptions as well as the effects of both stimulants and depressants, in combination with irradiations, will be completed. Additional data will be obtained via neuropathological imaging of the tissue with the translocator protein TSPO (Dr. Guilarte), as well as data on the integrity of the dopaminergic (DA) system using Western blot analyses (in collaboration with Dr. De Cicco-Skinner).

Moreover, the human Psychomotor Vigilance Test (PVT) is a standardized and widely validated objective measure of neurobehavioral status not only employed by NASA, but also utilized in a variety of settings such as clinical neuropsychiatric assessment, military, shiftwork, and aviation. As such, the present rodent analog of the PVT provides a direct translational link to performance capacity on Earth. Once validated, the rPVT model developed here may be used as a basic and translational research tool to predict performance deficits induced by radiation or other CNS insults while providing an innovative experimental platform for exploring the bases of individual vulnerability to performance impairments and evaluating potential prophylactics, countermeasures, and treatments.

- With a rodent version of the human psychomotor vigilance test (PVT), proton radiation exposures of 25 cGy and higher result in increased reaction times. Recently, the effects of additional circadian disruptions on these PVT performances have been shown to exacerbate these effects, with radiation-exposed animals (200 cGy) showing pronounced decreases in sustained greater than those observed with radiation alone.

- Studies of the effects of stimulant and sedative compounds were begun, with the effects of amphetamine currently being examined on rodent PVT performances for irradiated and non-irradiated subjects. Once complete, these studies will be combined with the circadian disruption protocol to determine the interactive effects of stimulants and sedatives on PVT performances in irradiated rats before and after circadian disruptions.

- Continued study of the effects of radiation exposure on choice impulsivity as measured by a "delayed discounting" procedure have demonstrated that 200 cGy proton exposures produce deficits in choice impulsivity as well, vis-à-vis the "motor impulsivity" effects previously shown with the rodent PVT procedure.

- A collaboration with Drs. Strangman and Zeffiro of MGH was established to assess the effects of radiation on CNS structural changes through advanced neuroimaging. The imaging of these brains is currently underway.

- During the quarter an additional 30 animals were transported to Brookhaven National Laboratory for proton radiation exposure, with subgroups being euthanized at 1, 3, 5, 7, and 14 days post-exposure. Brain tissue was sent to Dr. Tomas Guilarte (Columbia Univ.) who is employing the translocator protein TSPO, a sensitive biomarker of reactive gliosis and inflammation, for neuropathological imaging of the tissue. Preliminary analyses of the images indicate that there are definite areas that have increased TSPO expression. These analyses are continuing.

- A new collaboration with Dr. Kathleen DiCicco-Skinner (American University) has been established to assess neurotransmitter function in rodent brain tissue for both irradiated and non-irradiated control animals. During this quarter tissue samples have been prepared in the laboratory and sent to Dr. De Cicco-Skinner's laboratory, where she is now examining the integrity of the dopaminergic (DA) system using Western blot analyses to quantify levels of DA proteins (e.g., receptors, DA tranporter) and the extent of degradation of DA terminals and upregulation of other proteins, including stress and inflammatory markers commonly active following brain trauma.

Aim #1: To assess the effects of space radiation across a range of cognitive/behavioral functions in rodents. Performance measures include assessments of general motor function and speed, fine motor control, inhibitory control ("impulsivity"), timing, short-term memory, spatial working memory, learning and selective attention, motivation, and basic sensory function. Groups of animals are separately trained on different tasks, exposed at Brookhaven National Laboratory to high-energy radiation at levels that astronauts would likely experience during lunar or planetary surface activities, and then immediately re-tested.

Aim #2: To assess the long-term effects of radiation across a range of cognitive/behavioral functions via extended post-exposure testing for potential performance deficits.

Aim #3: To assess both the acute and long-term effects of radiation on the neurochemical mechanisms underlying changes in cognitive/behavioral functions by examining the integrity of the neurotransmitter systems known to mediate those neurobehavioral functions found impaired.

(2) Key Findings of the Project

Results from the project thus far demonstrate the reliability and validity of the neurobehavioral procedures in detecting behavioral changes following radiation, that analogs of human psychomotor performance assessment procedures can be employed with rodents to automatically assess neurobehavioral function on a daily basis, and that such procedures can be used to effectively track changes in neurobehavioral function over extended intervals following radiation exposure. Specifically, the results have shown that head-only radiation produces discrete neurobehavioral changes by significantly decreasing discrimination accuracy and increasing false alarms in the reaction time procedure, with the latter result being indicative of a decrease in inhibitory control. These findings support the likely success of the rodent model for studying the risks of living in the space radiation environment due to changes in cognitive/neurobehavioral function.

During the current reporting year, an additional 60 rats were trained in a simple reaction time (RT) and another 60 rats trained in a line orientation discrimination (LD) task. Following training, rats were exposed to head-only radiation to isolate the possible CNS effects from whole-body effects. Rats were irradiated with high-energy (150 MeV) protons generated at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), as this energy of protons is prevalent in the deep space environment. Control rats were sham-exposed using the same anesthesia protocol, but not brought into the beam line. The RT task required rats to depress a lever for a random (1-3 sec) time, and to release the lever within 1.5 sec of a 'reaction time' stimulus (correct trial) to receive a food pellet. Lever releases prior to the release stimulus terminated the trial and were considered errors. The LD task required rats to learn to discriminate vertical from horizontal line stimuli, and then to learn the reverse discrimination. The LD task measures basic learning, reversal learning, and perseverative responding. Additionally, a 'recognition memory' test that requires no training was used after radiation exposure test the degree to which rats explore wooden beads impregnated with either their own odors, or with the odors of novel, unfamiliar rats.

Results indicated that performances following exposure to 200 cGy showed a consistent, significant increase in reaction times for the irradiated animals that has persisted and shows no signs of recovery at 11 months post-exposure. For the first 6 months post-exposure, no significant changes were observed in discrimination accuracy, vigilance, or food intake. During the last 5 months, however, decrements in both accuracy and vigilance have been observed. For animals that learned the basic line orientation discrimination and repeated the discrimination following radiation exposure, no significant differences were observed between control and radiated animals. However, the odor recognition memory tests revealed differences in recognition memory performances for irradiated vs. control groups. The results of these experiments confirm the feasibility of an animal model approach for assessing neurobehavioral risks associated with living in a space radiation environment, and demonstrate the sensitivity of cognitive/behavioral test measures to the effects of head-only radiation that produce highly specific effects on neurobehavioral function.

(3) Impact of these Findings

Very little is known about the brain's response to HZE particle radiation encountered in space. The present research addresses several important questions of relevance to NASA's mission (Risk Number 29, Acute and Late CNS Risks, as described in the Bioastronautics Roadmap). To address these questions, the work is providing for the development and application of the acquisition and long-term performance of a number of neurobehavioral tasks in a cognitive/behavioral animal test battery in rodents, and additionally for the demonstration of the validity and reliability of the procedures to measure critical cognitive/behavioral functions following specific interventions (e.g., pharmacologic disruptions). The research will provide critically needed dose-response data on the effects of high-energy (HZE) radiation (protons, GCRs, SPEs) on a range of cognitive/behavioral functions.

(4) Proposed Research Plan for the Coming Year

Animals are currently being trained in new neurobehavioral tasks that are designed to detect changes in choice impulsivity. Once completed, they will be transported and exposed in late April at Brookhaven National Laboratory to protons. Within the next year, approximately 120 rats will undergo this training/exposure/post-testing protocol, covering a dose range of 0 - 200 cGy.

Results indicated that performances following exposure to 200 cGy showed a consistent, significant increase in reaction times for the irradiated animals that has persisted and shows no signs of recovery at 11 months post-exposure. For the first 6 months post-exposure, no significant changes were observed in discrimination accuracy, vigilance, or food intake. During the last 5 months, however, decrements in both accuracy and vigilance have been observed. For animals that learned the basic line orientation discrimination and repeated the discrimination following radiation exposure, no significant differences were observed between control and radiated animals. However, the odor recognition memory tests revealed differences in recognition memory performances for irradiated vs. control groups. The results of these experiments confirm the ability of an animal model to assess neurobehavioral risks associated with living in a space radiation environment, and demonstrate the sensitivity of the test measures to the effects of head-only radiation.

In sum, exposure to proton radiation produces discrete neurobehavioral changes in reaction time and impulsivity, with the latter result being indicative of a decrease in inhibitory control. Such effects are being successfully tracked over the life span of these animals, and suggest the occurrence of permanent changes in neurobehavioral function over extended intervals following radiation exposure. These findings support the likely continued success of the rodent model for studying the cognitive, neurobehavioral, and CNS risks associated with living in the space radiation environment.

Aim #1: To assess the effects of space radiation across a range of cognitive/behavioral functions in rodents. Performance measures include assessments of general motor function and speed, fine motor control, inhibitory control ('impulsivity'), timing, short-term memory, spatial working memory, learning and selective attention, motivation, and basic sensory function. Groups of animals are separately trained on different tasks, exposed at Brookhaven National Laboratory to high-energy radiation at levels that astronauts would likely experience during lunar or planetary surface activities, and then immediately re-tested.

Aim #2: To assess the long-term effects of radiation across a range of cognitive/behavioral functions via extended post-exposure testing for potential performance deficits.

Aim #3: To assess both the acute and long-term effects of radiation on the neurochemical mechanisms underlying changes in cognitive/behavioral functions by examining the integrity of the neurotransmitter systems known to mediate those neurobehavioral functions found impaired.

(2) Key Findings of the Project

Results from the project thus far demonstrate the ability to establish an automated training and testing facility for assessing cognitive and behavioral function in the rodent model, and indicate that rodents are readily trainable in the cognitive/behavioral testing procedures, and readily learn to perform simple reaction time procedures, delayed-estimation/motor preparation tasks, and complex visual discriminations. Data obtained on changes in cognitive/behavioral performances following 5-Gy gamma radiation demonstrated the reliability and validity of the procedures in detecting behavioral changes following radiation, that an analog of a human psychomotor performance assessment procedure can be employed with rodents to automatically assess neurobehavioral function on a daily basis, and that such a procedure can be used to effectively track changes in neurobehavioral function over extended intervals following radiation exposure. Specifically, the results showed that head-only radiation produces discrete neurobehavioral changes by significantly decreasing discrimination accuracy and increasing false alarms in the reaction time procedure, with the latter result being indicative of a decrease in inhibitory control. These findings support the likely success of the rodent model for studying the risks from living in the space radiation environment in terms of damage to the CNS and changes in cognitive/behavioral function.

During the current reporting year, rats were trained to perform an intradimensional/extradimensional (ID-ED) task that is a computerized analog of the Wisconsin card sort task used to test category abstraction, and is similar in function to non-automated tests of set shifting in rats that use odor, texture or color as stimulus dimensions. Set shifting tasks measure learning, reversal learning, perseverative responding, and the ability to switch attentional sets between categories. Following training, experimental rats were exposed to head-only x-ray irradiation (2.3 Gy), while control rats were sham-exposed using the same anesthesia protocol. Initial data with this procedure indicates that the procedure can clearly detect radiation-induced changes in standard discrimination and discrimination learning reversal in rats. Additionally, differences in error rates of the rats' also differentiated between different discrimination conditions, thus indicating that the ID-ED procedure can track a rat's ability to shift attention between different stimulus dimensions. The results of these experiments confirm the feasibility of an animal model approach for assessing neurobehavioral risks associated with living in a space radiation environment, and demonstrate the sensitivity of differing neurobehavioral test measures to the effects of radiation that produce highly specific effects on neurobehavioral function.

(3) Impact of these Findings

Very little is known about the brain's response to HZE particle radiation encountered in space. The present research addresses several important questions of relevance to NASA's mission (Risk Number 29, Acute and Late CNS Risks, as described in the Bioastronautics Roadmap). To address these questions, the work is providing for the development and application of the acquisition and long-term performance of a number of neurobehavioral tasks in a cognitive/behavioral animal test battery in rodents, and additionally for the demonstration of the validity and reliability of the procedures to measure critical cognitive/behavioral functions following specific interventions (e.g., pharmacologic disruptions). The research will provide critically needed dose-response data on the effects of high-energy (HZE) radiation (protons, GCR's, SPE's) on a range of cognitive/behavioral functions.

(4) Proposed Research Plan for the Coming Year

Animals are currently being trained in selected neurobehavioral tasks for subsequent transport and exposure at Brookhaven National Laboratory to protons. Within the next year, approximately 120 rats will undergo this training/exposure/post-testing protocol, covering a dose range of 0 - 200 cGy.

The rodent training and testing facility has been developed to provide for automated, computerized assessments of cognitive, behavioral, sensory, and motor function in research subjects on a daily basis. The facility supports both the exportation of groups of well-trained subjects to NASA-related radiation exposure testing facilities (e.g., Brookhaven National Laboratory, the Department of Radiation Oncology of the Johns Hopkins Hospital) as well as the importation of radiation-exposed rodents from such facilities for detailed, long-term neurobehavioral risk assessments at the testing facility.

Initial data with an intradimensional-extradimensional (ID-ED) set shifting procedure indicates that the procedure can clearly detect changes in standard discrimination and discrimination learning reversal in rats. Additionally, differences in error rates of the rats' performances also differentiate between different discrimination conditions, thus indicating that the ID-ED procedure can track a rat's ability to shift attention between different stimulus dimensions. During this initial year of funding, 16 experimental rats were exposed to head-only x-ray irradiation (2.3 Gy), while control rats were sham-exposed using the same anesthesia protocol. Initial data with this procedure indicates that the procedure can clearly detect radiation-induced changes in standard discrimination and discrimination learning reversal in rats. Additionally, differences in error rates of the rats' performances also differentiated between different discrimination conditions, thus indicating that the ID-ED procedure can track a rat's ability to shift attention between different stimulus dimensions.

The results of these experiments confirm the feasibility of an animal model approach for assessing neurobehavioral risks associated with living in a space radiation environment, and demonstrate the sensitivity of cognitive/behavioral test measures to the effects of head-only radiation that produce highly specific effects on neurobehavioral function.

This project addresses this need via the application of a comprehensive animal model to determine the effects of radiation exposure on a range of neurobehavioral functions and the likely mechanisms of damage to the CNS following radiation exposure (e.g., radiation-induced changes in neurotransmitter system function).

Specific Aims

1) To assess the likelihood of space radiation producing immediate and/or long-term functional changes in the CNS, neurobehavioral functions will be measured in rodents via animal tests analogous to the human Cambridge Neuropsychological Test Automated Battery (CANTAB);

2) To cover a range of human neurobehavioral functions relevant to astronaut mission performance effectiveness, performance measures will include assessments of general motor function and speed, fine motor control, discrimination accuracy, inhibitory control (impulsivity), timing, short-term memory, spatial working memory, motivation, and basic sensory function. Groups of animals will be separately trained on each of these tasks, following which they will be exposed to radiation and then immediately re-tested as well as re-tested periodically for up to 18 months post-exposure to assess potential long-term performance deficits; and

3) To determine likely mechanisms of damage to the CNS following radiation exposure, pre-radiation and post-radiation pharmacologic assessments of the integrity of the relevant neurotransmitter systems will be conducted, as well as autoradiographic analyses of the integrity of different neurotransmitter systems.