PURPOSE:Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function. METHODS AND MATERIALS:Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, whereas longitudinal magnetic resonance imaging, behavioral studies, and histologic analysis were performed to evaluate brain response to the treatment for up to 18 months. RESULTS:Stereotactic radiosurgery (SRS) resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, whereas all nontreated animals succumbed to the brain tumor. Behavioral impairment, as measured with a recognition memory test, was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, whereas tumor eradication was complicated by the persistent cognitive deficits. In addition, the results of magnetic resonance imaging were unremarkable in both groups, and histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss, or hemorrhage was detected in any of the groups. CONCLUSIONS:Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits; therefore, methods aiming at reducing inflammation after tumor eradication or other therapeutic methods should be sought.

Future long-duration space missions will involve travel outside of the Earth’s magnetosphere protection and will result in astronauts being exposed to high energy and charge (HZE) ions and protons. Exposure to this type of radiation can result in damage to the central nervous system and deficits in numerous cognitive domains that can jeopardize mission success. Social processing is a cognitive domain that is important for people living and working in groups, such as astronauts, but it has received little attention in terms of HZE ion exposure. In the current study, we assessed the effects of whole-body oxygen ion (16O; 1000 MeV/n) exposure (1 or 10 cGy) on social odor recognition memory in male Long-Evans rats at one and six months following exposure. Radiation exposure did not affect rats’ preferences for a novel social odor experienced during Habituation at either time point. However, rats exposed to 10 cGy displayed short and long-term deficits in 24-h social recognition. In contrast, rats exposed to 1 cGy only displayed long-term deficits in 24-h social recognition. While an age-related decrease in Ki67+ staining (a marker of cell proliferation) was found in the subventricular zone, it was unaffected by radiation exposure. At one month following exposure, plasma KC/GRO (CXCL1) levels were elevated in the 1 cGy rats, but not in the 10 cGy rats, suggesting that peripheral levels of this cytokine could be associated with intact social recognition at earlier time points following radiation exposure. These results have important implications for long-duration missions and demonstrate that behaviors related to social processing could be negatively affected by HZE ion exposure.

The hippocampus, medial dorsal thalamus and the perirhinal and entorhinal cortices are essential for visual recognition memory whereas the neural substrates underlying olfactory recognition memories are less well characterized. In the present study we combined chemogenetic inactivation with a social odor recognition memory (SORM) task to test the hypothesis that the medial prefrontal cortex (mPFC) is involved in recognition memory. We demonstrate that temporary chemogenetic inactivation of the mPFC prior to an encoding session impairs social odor recognition memory, whereas silencing the mPFC just prior to the recognition session was without effect. Our data support the critical role of the mPFC in the formation rather than retrieval of social odor memory.

Future long-duration space missions will involve travel outside of the Earth's magnetosphere, which will result in increased radiation exposure for astronauts. Exposure could permanently damage multiple tissues, including the central nervous system (CNS), and result in deleterious effects on cognition and behavior during and beyond the mission. Here, we assessed the effects of whole-body oxygen ion (16O; 1,000 MeV/n) exposure (5 or 25 cGy) on social odor recognition memory in male Long-Evans rats at one and six months after exposure. At one month postirradiation, all rats displayed a preference for a novel 1 (N1) social odor experienced during the habituation phase. When assessed for recognition memory 24 h later, only sham-irradiated rats spent more time exploring a second novel social odor (novel 2, N2), whereas rats irradiated with 5 or 25 cGy 16O ions did not show a preference for the N2 odor compared to the N1 odor experienced 24 h earlier, thus displaying a memory deficit for recall of the social odor encountered 24 h prior. At six months postirradiation, rats exposed to 25 cGy showed persistent deficits in 24 h recognition memory, while the 5 cGy-exposed rats did not. Thus, 24 h recognition memory was apparently recovered at six months postirradiation for the low, but not the higher, dose of 16O ions. Both irradiated groups displayed similar numbers of Ki67+ cells, a marker of cell proliferation, in the subventricular zone. These results further demonstrate that space-relevant 16O ion exposure has deleterious effects on the CNS, which are related to both radiation dose and time after exposure.

As the duration of manned missions outside of the Earth's protective shielding increase, astronauts are at risk for exposure to space radiation. Various organ systems may be damaged due to exposure. This study investigates the bone strength changes using finite element modeling of Long Evans rats (n=85) subjected to graded, head-only proton (0, 10, 25, and 100 cGy, 150 MeV/n) and 28silicon (0, 10, 25, and 50 cGy, 300 MeV/n) radiation. The strength of the femoral neck will be examined due its clinical relevance to hip fractures. It has been shown in previous studies that bone mineral density was not reduced at the site of fracture. These findings question whether measurements of bone mineral density may be used to assess risk of hip fracture. The mechanisms leading to the irregular relationship between bone density and strength are still uncertain within literature and investigated to greater extent in clinical applications. Finite element analysis within this study simulated physiological loading of the femoral neck. No significant changes in femoral neck strength were found across doses of proton or 28silicon head-only radiation. Future work includes performing mechanical testing of the bone samples. Moving from mouse to larger animal models may also provide the increased lifespan for assessing the long-term outcomes of radiation exposure.

Objective The medial prefrontal cortex (mPFC) is critical to mediating attention and social cognition, but its specific role in memory processing is unclear. In a rodent model of social odor recognition memory (SORM), we assessed the role of the prelimbic and infralimbic regions of the mPFC in social motivation and recognition memory at different stages of the memory process (encoding, consolidation, and retrieval). In the same animals, we also assessed the role of these subregions of the mPFC in sustained attention, using the rodent psychomotor vigilance test (rPVT). Methods The SORM task involves three phases (familiarization, habituation, and recognition), and requires olfactory‐based discrimination between familiar odors and novel odors from conspecifics, where failure to show preference for novel odors on the test phase indicates a memory deficit. The rPVT is a sustained attention test that measures accuracy, premature responding, and response times to the presence of a stimulus light that appears after a random waiting period between 3–10 seconds. Using pAAV‐hSyn‐hM4D(Gi)‐mCherry (“designer receptors,” DREADDs) injected bilaterally into the prelimbic or infralimbic regions of the mPFC, we remotely silenced these regions during behavioral testing via injections of the “designer drug,” clozapine‐N‐oxide (CNO). Results For the SORM test, injecting CNO (1 mg/kg, i.p.) 30 minutes prior to the habituation phase did not impair novel odor discrimination on this phase, but did result in impaired memory for a novel odor on the recognition test day 24‐hrs later. These effects were not a function of CNO administration alone because the impairment was found on the drug‐free test day 24‐hrs after the previous CNO injection. In a second study, injections of CNO (0–5 mg/kg, i.p.) were administered 30‐min prior to different rPVT sessions. CNO at 1 mg/kg had effects on premature responding in the rPVT, without impairing response times. Conclusions Silencing the prelimbic and infralimbic subregions of the mPFC impaired memory performance the recognition test phase of the SORM test, without inducing a motor impairment in the psychomotor vigilance test, indicating that the mPFC could be involved in encoding, and possibly consolidating, information about social odors acquired during habituation. Support or Funding Information This work was supported by a grant from NASA (NNX15AC71G) to CMD. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

As NASA quickly approaches the ability to embark on long‐term space travel, it becomes increasingly important to discover effective methods to shield astronauts from the damaging effects from exposure to space radiation. To investigate possible neuroprotective strategies for ameliorating radiation‐induced cognitive deficits, the present study describes the effects of erythropoietin (EPO) for attenuating proton‐induced deficits in sustained attention, obtained by measuring performance of rats on the rodent Psychomotor Vigilance Test (rPVT). The rPVT is a rodent version of the human PVT that is routinely used as a “fitness‐for‐duty” test across a wide range of professions. Performance on the human PVT requires responding to a visual stimulus as soon as it appears; a response terminates the stimulus presentation and the subject's reaction time is recorded and displayed. In the present study, male Long‐Evans rats were trained to perform the rPVT to baseline performance levels, defined as ≥75% correct and ≤ 25% premature responses. For 7 days before irradiation, rats received daily injections of human EPO (Epoetin alfa, human recombinant erythropoietin) at either of 1,000, 3,000, or 5,000 U/kg/day (7 total injections). Two control groups were also utilized: a sham‐irradiated group administered the EPO vehicle, and a sham‐irradiated group receiving 5,000 U/kg/day EPO. Rats were then irradiated with head‐only protons (150 MeV/n) at 100 cGy or sham‐irradiation. Similar to previous results, 100 cGy exposures induced deficits in accuracy and increased lapses in attention in a subgroup of rats on the rPVT; these rats were characterized as “radiation‐sensitive”. EPO dose‐dependently improved performance in “radiation‐sensitive” rats, producing higher performance accuracy and lower lapses in attention. EPO showed no effects on rPVT performance in radiation insensitive rats or in the sham‐irradiated rats. The data presented in the current study supports the role of vascular growth factors in ameliorating radiation‐induced cognitive deficits and the use of EPO as a treatment for ameliorating the CNS effects of radiation exposure for astronauts embarking on long‐term space travel.Support or Funding InformationThis work supported by NSBRI through NASA NCC 9‐58‐NBPF04201, NASA NNX15AC71G and an ASPET Summer Undergraduate Research Fellowship.

To investigate radiation‐induced cognitive deficits, the present report describes performance data obtained with the rPVT (rat Psychomotor Vigilance Test), an animal analog of the human PVT test currently employed in a variety of operational settings. The human PVT was developed as a highly sensitive and standardized assay capable of quantifying temporally dynamic changes in sustained attention, and requires responding to a light stimulus as soon as it appears. In the current study, rats were trained to perform the rPVT to baseline performance levels (≥75% correct and ≤25% premature responses) and were then irradiated with head‐only protons (150 MeV/n) at 25 or 100 cGy or sham‐irradiation. Following radiation exposure, rats were returned to Hopkins and continued daily rPVT assessments. At approximately 6 months post‐radiation exposure, rats were then characterized as radiation sensitive—i.e., those rats displaying radiation‐induced rPVT deficits, or radiation insensitive—i.e., irradiated rats performing the rPVT at sham‐irradiated control levels. Several different drugs were then assessed as countermeasures for these deficits in radiation sensitive rats, and were also assessed in radiation insensitive rats to determine if any performance disruptions would occur. d‐Amphetamine dose‐dependently improved performance in radiation sensitive rats, whereas it impaired rPVT performance in radiation insensitive rats at the two highest doses tested. Amphetamine's effects were decreased by the D1 antagonist, SCH 39166, but not the D2 antagonist, L‐741, 626. Atomoxetine and methylphenidate were also tested, but did not produce these differential effects. This data further supports the role of the dopamine neurotransmitter system in mediating individual differences in radiation‐induced deficits in neurobehavioral performance as assessed by the rPVT.Support or Funding InformationSupported by the NSBRI through NASA cooperative agreement NCC 9‐58, grants NBPF01604, NBPF02802, NBPF04201, and EO00010, and NASA NNX15AC71G

The human Psychomotor Vigilance Test (PVT) is a widely used procedure for measuring changes in fatigue and sustained attention. The present article describes a rodent version of the PVT—termed the "rPVT"—that measures similar aspects of attention (i.e., performance accuracy, motor speed, premature responding, and lapses in attention). Data are presented that demonstrate both the short- and long-term usefulness of the rPVT when employed with laboratory rats. Rats easily learn the rPVT, and learning to perform the basic procedure takes less than two weeks of training. Once acquired, rat performances in the rPVT show a high degree of similarity to these same performance measures in the human PVT, including similarities in, lapses in attention, reaction times, vigilance decrements across session time (i.e., the human "time-on-task" effects), and the response-stimulus interval (RSI) effect described for humans. Thus the rPVT can be an extremely valuable tool for assessing the effects of a wide range of variables on sustained attention quite similar to human PVT performances, and thus can be useful for developing novel treatments for neurobehavioral dysfunctions.

A previous report noted that rats receiving head-only radiation exposure displayed neurobehavioral deficits on the rodent psychomotor vigilance test (rPVT), including changes in accuracy and premature responding. These changes were only apparent in a subset of irradiated rats, such that radiation-sensitive and radiation-insensitive groups emerged. Group specific changes in levels of the dopamine D2 receptor and dopamine transporter (DAT) protein were also evident. To better understand the DA system in radiation sensitivity, rats were trained on the rPVT, irradiated, and post-IR rPVT data were acquired. All rats were then observed for quinpirole-induced yawning under food-restricted and free-feeding conditions using a cumulative dosing procedure. The D2 receptor antagonist, L-741626 (0.32-1.0 mg/kg) was used to assess group differences in antagonism of the descending limb of the yawning curve. Since the hippocampus is sensitive to radiation, group differences in downstream hippocampal cholinergic mediation of quinpirole-induced yawning were assessed with the muscarinic antagonist, scopolamine (0.001-0.01 mg/kg). Quinpirole-induced hypothermia and its antagonism were assessed immediately following all yawning observations. Differences in quinpirole-induced yawning appear to be indicative of differential changes in D2/3 receptors between radiation-sensitive and insensitive rats following the highest dose of radiation exposure. Funding: NASA NCC 9-58-PF02602 and 9-58-NBPF02802; Mylan Internships program.

The current report assessed the effects of low-level proton irradiation in inbred adult male Fischer 344 and Lewis rats performing an analog of the human Psychomotor Vigilance Test (PVT), commonly utilized as an object risk assessment tool to quantify fatigue and sustained attention in laboratory, clinical, and operational settings. These strains were used to determine if genetic differences in dopaminergic function would impact radiation-induced deficits in sustained attention. Exposure to head-only proton irradiation (25 or 100 cGy) disrupted rPVT performance in a strain-specific manner, with 25 cGy-exposed Fischer 344 rats displaying the most severe deficits in sustained attention (i.e., decreased accuracy and increased premature responding); Lewis rats did not display behavioral deficits following radiation. Fischer 344 rats displayed greater tyrosine hydroxylase and dopamine transporter levels in the frontal cortex compared to the Lewis rats, even though radiation exposure increased both of these proteins in the Lewis rats only. Tyrosine hydroxylase was decreased in the parietal cortex of both rat strains following radiation exposure, regardless of proton dose. Strain-specific cytokine changes were also found in the frontal cortex, with the Lewis rats displaying increased levels of putative neurotrophic cytokines (e.g., CNTF). These data support the hypothesis that basal dopaminergic function impacts the severity of radiation-induced deficits in sustained attention.

Background: The human Psychomotor Vigilance Test (PVT) is commonly utilized as an objective risk assessment tool to quantify fatigue and sustained attention in laboratory, clinical, and operational settings.New method: Recent studies have employed a rodent version of the PVT (rPVT) to measure various aspects of attention (lapses in attention, reaction times) under varying experimental conditions.Results: Data are presented here to evaluate the short- and long-term utility of the rPVT adapted for laboratory rats designed to track the same types of performance variables as the human PVT-i.e., motor speed, inhibitory control ("impulsivity"), and attention/inattention. Results indicate that the rPVT is readily learned by rats and requires less than two weeks of training to acquire the basic procedure. Additional data are also presented on the effects of radiation exposure on these performance measures that indicate the utility of the procedure for assessing changes in neurobehavioral function in rodents across their lifespans.Comparison with existing method(s): Once stable performances are obtained, rats evidence a high degree of similarity to human performance measures, and include similarities in terms of lapses and reaction times, in addition to percent correct and premature responding. Similar to humans, rats display both a vigilance decrement across time on task and a response-stimulus interval effect.Conclusions: The rPVT is a useful tool in the investigation of the effects of a wide range of variables on vigilance performance that compares favorably to the human PVT and for developing potential prophylactics, countermeasures, and treatments for neurobehavioral dysfunctions. (C) 2015 Elsevier B.V. All rights reserved.

To assess the possible neurobehavioral performance risks to astronauts from living in a space radiation environment during long-duration exploration missions, the effects of head-only proton irradiation (150 MeV/n) at low levels (25-50 cGy, approximating an astronaut's exposure during a 2-year planetary mission) were examined in adult male Long-Evans rats performing an analog of the human psychomotor vigilance test (PVT). The rodent version of PVT or rPVT tracks performance variables analogous to the human PVT, including selective attention/inattention, inhibitory control ("impulsivity") and psychomotor speed. Exposure to head-only proton radiation (25, 50, 100 or 200 cGy) disrupted rPVT performance (i.e., decreased accuracy, increased premature responding, elevated lapses in attention and slowed reaction times) over the 250 day testing period. However, the performance decrements only occurred in a subgroup of animals at each exposure level, that is, the severity of the rPVT performance deficit was unrelated to proton exposure level. Analysis of brain tissue from irradiated and control rats indicated that only rats with rPVT performance deficits displayed changes in the levels of the dopamine transporter and, to a lesser extent, the D₂ receptor. Additional animals trained to perform a line discrimination task measuring basic and reversal learning showed no behavioral effects over the same exposure levels, suggesting a specificity of the proton exposure effects to attentional deficits and supporting the rPVT as a sensitive neurobehavioral assay.

A previous report noted that rats receiving head‐only radiation exposure displayed neurobehavioral deficits on the rodent psychomotor vigilance task (rPVT), including changes in accuracy and premature responding. These changes were only apparent in a subset of irradiated rats, such that radiation‐sensitive and radiation‐insensitive groups emerged. Group specific changes in levels of the dopamine D2 receptor and dopamine transporter (DAT) protein were also evident, in addition to differential sensitivity to the rate‐decreasing effects of quinpirole on schedule‐controlled responding.To better understand DA system differences in radiation sensitivity, a cohort of rats was trained to perform the rPVT and then trained on a fixed‐ratio 30 fixed‐interval 2‐min schedule of reinforcement; dopaminergic compounds were administered prior to the FR‐FI session to determine the rate‐altering effects of these drugs in individual subjects. A second cohort of rats was trained to perform the rPVT and was then observed for quinpirole‐induced yawning. Pre‐irradiation rPVT, FR/FI, and yawning data was compared to post‐irradiation data in the same animals, in order to determine how radiation might impact the dopamine system as measured by these behaviors induced by administration of dopaminergic compounds.Grant Funding Source: This work was funded by NSBRI through NASA NCC 9‐58‐PF02602 and 9‐58‐NBPF02802.

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.

A previous report noted that rats receiving head‐only exposure to iron ions (56Fe, a form of ionizing radiation) displayed neurobehavioral deficits on the rodent psychomotor vigilance task (rPVT), including changes in accuracy and premature responding, that were only apparent in a subset of exposed rats; i.e., radiation‐sensitive and insensitive groups emerged. Group‐specific changes in dopamine (DA) protein levels were also evident.To better understand DA system differences in radiation sensitivity, these radiation‐sensitive and insensitive groups and a sham‐irradiated control group were subsequently trained to press a lever for food pellets on a fixed‐ratio 30 schedule of reinforcement. The D2 receptor agonist quinpirole (0.01–1.0 mg/kg) dose‐dependently decreased response rates in all groups; irradiated groups were more sensitive than controls (i.e., showed greater decreases). The D2 receptor antagonist amisulpride (0.1–2.0 mg/kg) alone had no effect on performance, but did antagonize quinpirole's effects. The results show that the DA system is sensitive to radiation‐induced changes that alter behavior as exemplified by the DA system's response to drug administration, which could impact treatment of radiation‐induced cognitive deficits. This work was funded by NSBRI through NASA NCC 9–58‐PF02602 and 9–58‐NBPF02802.

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals.

psychomotor vigilance task (rPVT) following low-dose proton and 56 Fe exposure. The rPVT is an animal analog of the human PVT, a highly sensitive and standardized assay, currently employed in a variety of operational settings as a “fitness-for-duty” self-test. Approximately 50% of our sample were behaviorally “radiation-sensitive” and also displayed changes in dopamine (DA) protein levels. The current work further examines the effect of proton radiation on neurobehavioral function in two inbred strains of rats, the Fischer 344 (F344) and Lewis (LEW) rats with differences in dopamine function that are characterized by a lower density of dopamine-transporter (DAT) levels in the striatum, nucleus accumbens, and olfactory tubercle of LEW rats compared to F344 rats, a lower density of DA D2 receptor levels in the striatum and nucleus accumbens of LEW rats, and a slower in vivo clearance of DA, all of which suggests lower basal DAT function in LEW rats. Thus these two strains were used as subjects in order to test the importance of differences in DA system function in the behavioral and molecular responses to radiation.

The human psychomotor vigilance task (PVT) was developed as a sensitive and standardized assay capable of quantifying changes in sustained attention. The procedure requires subjects to respond to a light stimulus as soon as it appears; a response extinguishes the stimulus and displays the subject's reaction time. The PVT is widely used in risk assessments in operational environments to provide feedback on fatigue levels and alertness.Given the importance and widespread use of the PVT, we have adapted a rodent PVT (rPVT) for use in the laboratory, primarily to detect drug‐ and radiation‐induced changes in neurobehavioral function in rats. Rats performing on the rPVT and humans on the PVT display similar mean reaction times, lapses in attention, premature responding, and normal variations in sustained attention. Amphetamine altered performances in a manner similar to the effects of psychostimulants; Zolpidem produced dose‐dependent decreases in rPVT performance. Further, rPVT performance is sensitive to individual differences in dopamine function following head‐only radiation exposure: rats showing significant changes in dopamine protein levels displayed performance deficits. Future work is focused on further examining the neurochemical systems involved in performing the rPVT and developing therapeutic strategies aimed at improving performance degraded by various environmental manipulations.