Biology subjects

Eisch, A. J.

Publications and source records attributed to Eisch, A. J..

14 recordsLinked to original sources

bioRxiv2026

Automated behavioral segmentation and markerless pose tracking of mice during spaceflight

The NASA Rodent Habitat aboard the International Space Station enabled long-duration studies of behavioral responses to spaceflight, but video-based behavioral analysis has relied on laborious manual annotation. No study has tested whether deep learning tools can automate this analysis under the demanding imaging conditions of orbital vivaria. We applied pose estimation (SLEAP) and behavioral segmentation (DeepEthogram) to archival footage from the Rodent Research-1 mission. Nine labelers annotated 3,249 pose labels across 2,063 frames, and three behaviorists labeled 411,194 frames across 66 videos. Pose tracking accuracy approximated human inter-annotator variability despite progressive lens soiling, grid occlusions, and spherical aberration. Behavioral classification across eight categories achieved accuracy of 0.86-0.90 and suggests progressive behavioral adaptations to microgravity. Kinematic reconstruction of circling estimated centripetal accelerations periodically approaching 1g. This is the first application of deep learning-based pose estimation and behavioral segmentation to rodents in spaceflight, establishing benchmarks for future monitoring systems. One-Sentence SummaryDeep learning-based pose estimation and behavioral segmentation of ISS video reveal progressive behavioral adaptations of mice to microgravity

neuroscience↗

bioRxiv2026

Circuit-selective cognitive vulnerability to environmental stress: multi-domain assessment of space radiation in both sexes reveals countermeasure trade-offs

Environmental stressors rarely affect just one brain circuit. Most studies assess single cognitive endpoints, obscuring whether vulnerabilities are global or circuit-selective and how effects distribute across interconnected systems. To address this, we used galactic cosmic radiation (GCR), a Mars mission-relevant stressor that disrupts the hippocampal-nucleus accumbens-prefrontal circuit. C57BL/6J mice received 33-ion GCR simulation (33-GCR, 0.75 Gy) or sham radiation with the Nrf2-activating compound CDDO-EA or vehicle, followed by multi-domain behavioral testing in both sexes. Under very high memory load, male Veh/33-GCR mice showed enhanced pattern separation compared to Veh/Sham males, an effect normalized by CDDO-EA. Female mice showed no radiation-induced changes in pattern separation but weighed 9-18% more than Veh/Sham females and had reduced locomotor activity. Reward-based learning differed by sex: males showed no changes, while female Veh/33-GCR mice displayed enhanced reward anticipation that was further increased by CDDO-EA alone, with both treatments contributing to elevated goal-tracking. For behavioral flexibility, CDDO-EA impaired reversal learning in males regardless of radiation, while 33-GCR impaired reversal learning in females regardless of CDDO-EA. Principal component analysis revealed that treatments disrupted specific circuit relationships while leaving others intact, consistent with selective rather than global cognitive effects. Fiber photometry showed enhanced dentate gyrus encoding activity in irradiated males under high memory load. Combined CDDO-EA/33-GCR selectively reduced dentate gyrus progenitors in females. Males and females showed distinct, circuit-selective vulnerability patterns, demonstrating that multi-domain, both-sex assessment is necessary to capture how stressors and interventions affect integrated brain function. CDDO-EA proved to be a double-edged sword: protecting one cognitive domain while impairing another, a trade-off invisible to single-endpoint assessment. This framework has immediate relevance for astronaut risk assessment and extends to any context where neuroprotective interventions are evaluated against environmental stressors.

animal behavior and cognition↗

bioRxiv2025

Paradoxical ventral tegmental area GABA signaling drives enhanced morphine reward after adolescent nicotine

BackgroundAn important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction. MethodsMale and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP. ResultsIn adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based oral morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels. ConclusionsThese data reveal an electrophysiological mechanism by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.

neuroscience↗

bioRxiv2024

The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: implications for deep space missions, female crews, and potential antioxidant countermeasures

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment is lacking. Here we asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received the antioxidant CDDO-EA (400 {micro}g/g of food) or a control diet (vehicle, Veh) for 5 days and either Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: 1) location discrimination reversal (which tests behavior pattern separation and cognitive flexibility, two abilities reliant on the dentate gyrus) and 2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment end (14.25-month post-IRR), neurogenesis was assessed (doublecortin-immunoreactive [DCX+] dentate gyrus neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. Notably, one radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had worse stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice show normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change in neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crews longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.

neuroscience↗

bioRxiv2023

Microglial depletion worsens lesion in female but not male C57BL/6J mice after P10 hypoxia-ischemia

BackgroundRodent models for perinatal hypoxic ischemic (HI) encephalopathy have reported sex differences such as the same injury causing larger lesions in the brains of males compared to females. Microglia, the resident immune cells of the brain that have sex-dependent developmental trajectories and gene expression patterns, likely play a different role in females and males following HI. However, there is conflicting literature on whether depletion of microglia worsens or improves HI-induced lesions and whether this differs by sex. Here we tested the effect of pharmacologic microglia depletion on HI lesion size in male and female mice. MethodsAn initial cohort of C57BL/6J mouse pups underwent HI at postnatal day 10 (P10) using a modified Vannucci procedure or a Sham insult followed by brain collection at P13. Another cohort of mice received daily intraperitoneal injections from P7 to P12 of either 25mg/kg PLX3397 (PLX, a CSF1R inhibitor) or vehicle (Veh). These mice also underwent HI or Sham at P10, resulting in four groups (Veh-Sham, Veh-HI, PLX-Sham, PLX-HI). All groups included female and male mice. Behavioral testing was performed both pre-HI (forelimb grasping [P8, P9]) and post-HI (open field traversal [P12], behavior and appearance observations [P13]). P13 brain sections underwent immunohistochemistry for Iba1 or cresyl violet staining for lesion scoring. ResultsP13 HI hippocampal sections had more Iba1 signal than Sham, with more variance in Male-HI vs Female-HI mice. PLX led to >95% depletion of Iba1+ cells at P10 or P13, and effective elimination of microglia did not differ by sex. In the hippocampus, Female-PLX-HI mice had worse lesion scores than Female-Veh-HI mice; this was not true in male mice, where there was a trend in the opposite direction. Female-PLX-HI mice also had worse lesion scores than Male-PLX-HI mice. In contrast to this sex-dependent effect of PLX on lesion score, there was no difference among groups in developmental milestones. ConclusionPLX3397 injection P7-P9 or P7-P12 effectively depletes microglia by P10 or P13, respectively. Microglial depletion via PLX worsens HI-induced injury in female mice but not in male mice.

neuroscience↗

bioRxiv2023

Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

Behavioral pattern separation and cognitive flexibility are essential cognitive abilities which are disrupted in many brain disorders. Better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on integrity of the hippocampal dentate gyrus (DG) which both receive glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). Inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here we asked if the activity of LEC fan cells that directly project to the DG (LECDG neurons) regulates behavioral pattern separation or cognitive flexibility. C57BL6/J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA); this approach increases the activity of LECDG neurons. Four weeks later, mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based Location Discrimination Reversal [LDR] task) and innate fear of open spaces (elevated plus maze [EPM]) followed by counting of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). TRIP8b and SCR shRNA mice performed similarly in general touchscreen training and LDR training. However, in late LDR testing, TRIP8b shRNA mice reached the first reversal more quickly and had more accurate discrimination vs. SCR shRNA mice, specifically when pattern separation was challenging (lit squares close together or "small separation"). Also, TRIP8b shRNA mice achieved more reversals in late LDR testing vs. SCR shRNA mice. Supporting a specific influence on cognitive behavior, SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis vs. SCR shRNA mice. This work advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival -- behavioral pattern separation and cognitive flexibility -- and suggests the activity of LECDG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output.

animal behavior and cognition↗

bioRxiv2021

Iba1+ cell density and morphology classification at postnatal day 10 in four hippocampal subregions of female and male C57BL/6J mice

Microglia, the resident immune cells of the brain, support normal brain function and the brains response to disease and injury. The hippocampal dentate gyrus (DG) is an area of microglial study due to its central role in many behavioral and cognitive functions. Interestingly, microglia and related cells are distinct in female vs. male rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia have been reported in certain hippocampal subregions at specific ages. However, sex differences in the DG have not yet been assessed at P10, a rodent developmental time point translationally relevant to human term gestation. To address this knowledge gap, Iba1+ cells in the DG (which are enriched in the Hilus and Molecular Layer) in female and male C57BL/6J mice were analyzed for their number (via stereology) and density (via stereology and via sampling). Next, Iba1+ cells were classified into published morphology categories. Finally, the percent of Iba1+ cells in each morphology category was multiplied by total cell number to generate a total number of Iba1+ cells in each morphological category. Results show no sex difference in Iba1+ cell number, density, or morphology in the P10 Hilus or Molecular Layer. The lack of sex difference in Iba1+ cells in P10 DG using commonly-employed methodologies (sampling, stereology, morphology classification) provides a baseline from which to interpret microglia changes seen after injury. HIGHLIGHTSO_LISex differences in Iba1+ cells were assessed in the dentate gyrus (DG) of P10 mice C_LIO_LIIba1+ cells were assessed in DG microglia-rich subregions: Hilus and Molecular Layer C_LIO_LIBoth stereology and sampling approaches were used to quantify Iba1+ cells C_LIO_LINo sex difference found in Iba1+ cell number, density, or morphology in P10 mice DG C_LI

neuroscience↗

bioRxiv2021

Effects of a 33-sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a vehicle formulation alone or with the antioxidant/anti-inflammatory compound CDDO-EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures.

animal behavior and cognition↗

bioRxiv2021

Multi-domain touchscreen-based cognitive assessment of C57BL/6J female mice shows whole body exposure to 56Fe particle space radiation in maturity improves discrimination learning yet impairs stimulus-response habit learning

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like 56Fe. Preclinical studies with mature, "astronaut-aged" rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed 56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As other preclinical work suggests the female rodent brain may be relatively resistant to charged particle-induced injury, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to whole-body 56Fe irradiation (3 x 6.7cGy 56Fe over 5 days, 600MeV/n) would improve performance vs.Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function (e.g. location discrimination reversal [LDR] and extinction, respectively). In LDR, 56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However, 56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal rule-based learning (visuomotor conditional learning). Interestingly, 56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an 56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASAs risk assessments from being based on a single cognitive domain.

animal behavior and cognition↗

bioRxiv2020

Mild traumatic brain injury induces transient, sequential increases in proliferation, neurogenesis, and cell survival: a time course study in the male mouse dentate gyrus

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically-relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data suggest this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which are suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.

neuroscience↗

bioRxiv2020

Chronic systemic injection of DREADD agonists Clozapine-N-oxide and Compound 21 does not change behavior relevant to locomotion, exploration, anxiety, or affect in male mice

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools commonly-used to manipulate brain activity. The most widely-used synthetic DREADD ligand, clozapine-N-oxide (CNO), is back-metabolized to clozapine which can itself activate endogenous receptors. Studies in non-DREADD-expressing rodents suggest CNO or a DREADD agonist that lacks active metabolites, such as Compound 21 (C21), change rodent behavior (e.g. decrease locomotion), but chronic injection of CNO does not change locomotion. However, it is unknown if chronic CNO changes behaviors relevant to locomotion, exploration, anxiety, and depression, or if chronic C21 changes any aspect of mouse behavior. Here non-DREADD-expressing mice received i.p. Vehicle (Veh), CNO, or C21 (1mg/kg) 5 days/week for 16 weeks and behaviors were assessed over time. Veh, CNO, and C21 mice had similar weight gain over the 16-week-experiment. During the 3rd injection week, CNO and C21 mice explored more than Veh mice in a novel context and had more open field center entries; however, groups were similar in other measures of locomotion and anxiety. During the 14th-16th injection weeks, Veh, CNO, and C21 mice had similar locomotion and anxiety-like behaviors. We interpret these data as showing chronic Veh, CNO, and C21 injections given to male non-DREADD-expressing mice largely lack behavioral effects. These data may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists. HighlightsO_LIAcute injection of CNO changes behavior of non-DREADD-expressing mice C_LIO_LIIts not known if chronic CNO or alternative agonist C21 also changes mouse behavior C_LIO_LIDREADD agonists or Veh were given chronically to non-DREADD-expressing mice C_LIO_LICNO and C21 dont change locomotion and have a mixed effect on anxiety-like behavior C_LIO_LI1 mg/kg CNO and C21 can be injected repeatedly without non-specific behavior effects C_LI

animal behavior and cognition↗

bioRxiv2020

Maternal Continuous Oral Oxycodone Self-Administration Alters Pup Affective/Social Communication but not Spatial Learning or Sensory-Motor Function

The broad use and misuse of prescription opioids during pregnancy has resulted in a surge of infants diagnosed with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are hallmarks of NOWS, but the long-term consequences are unknown. Our newly-developed preclinical model of oxycodone self-administration enables adult female rats to readily drink oxycodone (0.06-0.12 mg/ml, [~]10/mg/kg/day) continuously before and during pregnancy and after delivery, to achieve similar liquid intake in oxycodone moms relative to water-only controls. Oxycodone levels were detected in the serum of mothers and pups. Growth parameters in dams and pups, and litter mass and size were similar to controls. Maternal behavior at postnatal day 1 (PN1) was unchanged by perinatal oxycodone consumption. Regarding the plantar thermal response, there were no differences in paw retraction latency between oxycodone and control pups at PN2 or PN14. Oxycodone and control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in oxycodone pups relative to controls. Finally, during naltrexone precipitated withdrawal at PN9, oxycodone males vocalized more than control pups, consistent with a previously-published withdrawal phenotype. Thus, our rat model of continuous oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and locomotion. Our preclinical, high face validity NOWS model reproduces key aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring. HIGHLIGHTSO_LIFemale rats self-administered oxycodone at clinically relevant doses before and during pregnancy and for the first two weeks after parturition. C_LIO_LIBoth dams and pups, for the14 day postnatal experimental period, had detectable levels of oxycodone in their blood C_LIO_LIDams drinking oxycodone only or water only did not differ in weight gain, water intake, or the number of pups born and their pups did not differ in weight throughout. C_LIO_LISensory and motor function in the pups was not altered, nor was hippocampal dependent spatial learning. C_LIO_LIOxycodone exposed pups were physically dependent and displayed increased withdrawal behaviors with or without the opioid antagonist naltrexone. C_LIO_LIPups expressed more negative affect, expressed by increased ultrasonic vocalizations, following naltrexone precipitated withdrawal or when separated from their mother. C_LI

pharmacology and toxicology↗

bioRxiv2019

Multi-domain cognitive assessment of male mice reveals whole body exposure to space radiation is not detrimental to high-level cognition and actually improves pattern separation.

Astronauts on interplanetary space missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies with mature, \"astronaut-aged\" rodents show space radiation decreases performance in low- and some high-level cognitive tasks. Given the prevalence of touchscreens in astronaut training and in-mission assessment, and the ability of rodent touchscreen tasks to assess the functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, it is surprising the effect of space radiation on rodent touchscreen performance is unknown. To fill this knowledge gap, 6-month-old C57BL/6J male mice were exposed to whole-body space radiation and assessed on a touchscreen battery starting 1-month later. Relative to Sham, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation led to better performance on a dentate gyrus-reliant task of pattern separation ability. Irradiated mice discriminated similar visual cues in [~]40% fewer days and [~]40% more accurately than control mice. Improved pattern separation was not touchscreen-, radiation-particle, or neurogenesis-dependent, as both 56Fe and 28Si irradiation led to faster context discrimination (e.g. Sham Block 5 vs. 56Fe Block 2) in a non-touchscreen task and 56Fe led to fewer new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.\n\nSIGNIFICANCE STATEMENTAstronauts on an interplanetary mission - such as to Mars - will be unavoidably exposed to galactic cosmic radiation, a spectrum of highly-charged, fast-moving particles. Rodent studies suggest space radiation is detrimental to cognition. However, here we show this is not universally true. Mature mice that received whole body exposure to Mars-relevant space radiation perform similarly to control mice on high-level cognitive tasks, reflecting the functional integrity of key neural circuits. Even more surprisingly, irradiated mice perform better than controls in both appetitive and aversive tests of pattern separation, a mission-critical task reliant on dentate gyrus integrity. Notably, improved pattern separation was not touchscreen-, radiation-particle-, or neurogenesis-dependent. Our work urges revisitation of the generally-accepted conclusion that space radiation is detrimental to cognition.

neuroscience↗

bioRxiv2019

Development and validation of a novel oral oxycodone self-administration protocol for female and male rats

The increased abuse of opioids - such as oxycodone - poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by continuous, voluntary, oral intake, and sex differences. Therefore the field would benefit from a preclinical in-depth characterization of sex differences in a chronic oral voluntary, free choice, and continuous access paradigm. Here we show in an oral oxycodone continuous access two-bottle choice paradigm sex-dependent voluntary drug intake, dependence, and motivation to take the drug. Adult female and male Long-Evans rats were given unlimited, continuous home cage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental). Most experimental rats voluntarily drank oxycodone ([~]10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater blood levels of oxycodone, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentration of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Thus, female rats consumed and preferred oxycodone more than males in this chronic two-bottle oral choice paradigm. Both sexes displayed many features of human oxycodone abuse, and behavioral pre-screening predicted parameters of intake and withdrawal. This model provides an additional paradigm for understanding mechanisms that mediate long-term voluntary drug use and for exploring potential treatment options.\n\nHIGHLIGHTSAdult rats offered continuous choice of oral oxycodone vs. water preferred oxycodone\n\nRats self-titrated oxycodone, yet females preferred and escalated more than males\n\nBoth sexes were motivated to drink oxycodone, as shown by a citric acid aversion test\n\nBoth sexes became dependent on oxycodone, as shown by precipitated withdrawal\n\nBehavioral prescreening predicted later aspects of oxycodone intake and dependence

neuroscience↗