Organization of spontaneous spatial behaviors under dark conditions is unaffected in adult male and female long-Evans rats after moderate prenatal alcohol exposure.

Prenatal alcohol exposure can produce disruptions in a wide range of cognitive functions, but it is especially detrimental to spatial navigation. In open environments, rodents organize their spatial behaviors around centralized locations, termed home bases, from which they make circuitous and slow locomotor trips (progressions) into the rest of the environment. Open-field behaviors are organized even under darkened test conditions, suggesting a role for self-motion cues (vestibular, motor, etc.). The impact of moderate prenatal alcohol exposure (mPAE) on the organization of spontaneous open-field behaviors under darkened conditions has not been investigated. Here we tested adult female and male rats with mPAE or saccharin control exposure in a circular open field for 30 min in a testing room that was made completely dark. While general locomotion, as measured by reductions in travel distance and increased stop duration, decreased across the test session, the organization of these behaviors, as measured by stop duration, home base establishment, home base stability, progression accuracy, and scaling of peak speeds with progression length, did not differ between mPAE and saccharin control rats. Together, the findings strongly suggest that spontaneous movement organization in relation to self-motion cues remains intact in adult mPAE rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach.

Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping antisense oligonucleotide that has a therapeutic effect in a mouse model of CLN3 Batten disease, a fatal pediatric lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach.

Impairments and compensation in string-pulling after middle cerebral artery occlusion in the rat.

Stroke is a leading cause of long-term disability in humans, and it is frequently associated with impairments in the skilled use of the arms and hands. Many human upper limb impairments and compensatory changes have been successfully modeled in rodent studies of neocortical stroke, especially those that evaluate single limb use in tasks, such as reaching for food. Humans also use their hands for bilaterally coordinated movements, dependent upon interhemispheric cortical projections, which are also compromised by unilateral stroke. This study describes middle cerebral artery occlusion (MCAO) dependent changes in the bilaterally dependent hand use behavior of string-pulling in the rat. The task involves making hand-over-hand movements to pull down a string that contains a food reward attached to its end. MCAO rats missed the string more often with both hands than Sham rats. When the string was missed on the contralateral to MCAO body side, rats continued to cycle through subcomponents of string-pulling behavior as if the string were grasped in the hand. Rats also failed to make a grasping motion with the contralateral to MCAO hand when the string was missed and instead, demonstrated an open-handed raking-like motions. Nevertheless, with repeated attempts, rats performed components of string-pulling well enough to obtain a reward on the end of the string. Thus, string-pulling behavior is sensitive to bilateral impairments but is achieved with compensatory adjustments following MCAO. These aspects of MCAO string-pulling provide a foundation for studies that investigate the efficacy of therapeutic intervention which might enhance neuroplasticity and recovery.

Spatial Disorientation Under Dark Conditions Across Development in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is associated with hippocampal neuropathology and cognitive impairments, including wandering behavior or becoming lost in a familiar environment. Wandering behavior is severe and manifests early in life for people with specific genetic mutations. Genetic mouse models of AD have been developed to characterize the onset and progression of behavioral deficits that represent human behaviors, such as wandering, to test the efficacy of therapeutics. It is not clear if current assessments of mouse models capture the onset of AD or a snapshot of its progression. Sequential analysis of open field behavior provides a robust, quick test to dissociate navigation cues that contribute to spatial disorientation, a feature of wandering. Despite potential utility in evaluating this feature of AD, little work has been reported using animal models of dementia in this task. Thus, we examined the use of different sources of information to maintain spatial orientation at two prodromal ages in female transgenic CRND8 AD (n = 17) and Control mice (n = 16). These mice exhibit amyloid plaques, a hallmark neuropathological feature of AD, that are associated with cognitive dysfunction at ∼three months of age. Spatial disorientation was observed at two months and more severely at four months under dark conditions, but performance was spared when visual environmental cues were available. This study provides documentation of impaired self-movement cue processing in AD mice, establishing the dark open field as a behavioral tool to characterize spatial disorientation associated with AD. These findings may accelerate future assessments of novel therapeutic interventions for neurological disorders.

Fine motor deficits exhibited in rat string-pulling behavior following exposure to sleep fragmentation and deep space radiation.

Deep space flight missions will expose astronauts to multiple stressors, including sleep fragmentation and space radiation. There is debate over whether sleep disruptions are an issue in deep space. While these stressors independently impair sensorimotor function, the combined effects on performance are currently unknown. String-pulling behavior involves highly organized bimanual reach-to-grasp and withdraw movements. This behavior was examined under rested wakeful conditions and immediately following one session of sleep fragmentation in Sham and irradiated rats 3 months after exposure (10 cGy 4Helium or 5-ion simulated Galactic Cosmic Radiation). Sleep fragmentation disrupted several aspects of string-pulling behavior, such that rats' ability to grasp the string was reduced, reach endpoint concentration was more variable, and distance traveled by the nose increased in the Y-range compared to rested wakeful performance. Overall, irradiated rats missed the string more than Sham rats 3 months post-exposure. Irradiated rats also exhibited differential impairments at 3 months, with additional deficits unveiled after sleep fragmentation. 4Helium-exposed rats took longer to approach the string after sleep fragmentation. Further, rats exposed to 4Helium traveled shorter withdraw distances 3 months after irradiation, while this only emerged in the other irradiated group after sleep fragmentation. These findings identify sleep fragmentation as a risk for fine motor dysfunction in Sham and irradiated conditions, in addition to radiation exposure. There may be complex temporal alterations in performance that are stressor- and ion-dependent. Thus, it is critical to implement appropriate models of multi-flight stressors and performance assessments in preparation for future deep space flight missions.

Testosterone treatment restores vestibular function by enhancing neuronal survival in an experimental closed-head repetitive mild traumatic brain injury model.

Repetitive mild traumatic brain injury (rmTBI) results in a myriad of symptoms, including vestibular impairment. The mechanisms underlying vestibular dysfunction in rmTBI patients remain poorly understood. Concomitantly, acute hypogonadism occurs following TBI and can persist chronically in many patients. Using a repetitive mild closed-head animal model of TBI, the role of testosterone on vestibular function was tested. Male Long Evans Hooded rats were randomly divided into sham or rmTBI groups. Significant vestibular deficits were observed both acutely and chronically in the rmTBI groups. Systemic testosterone was administered after the development of chronic vestibular dysfunction. rmTBI animals given testosterone showed improved vestibular function that was sustained for 175 days post-rmTBI. Significant vestibular neuronal cell loss was, however, observed in the rmTBI animals compared to Sham animals at 175 days post-rmTBI and testosterone treatment significantly improved vestibular neuronal survival. Taken together, these data demonstrate a critical restorative role of testosterone in vestibular function following rmTBI. This study has important clinical implications because it identifies testosterone treatment as a viable therapeutic strategy for the long-term recovery of vestibular function following TBI.

Rapid loss of fine motor skills after low dose space radiation exposure.

Sensorimotor function, motivation, and attentional processes are fundamental aspects of behavioral organization during skilled tasks. NASA's planned expedition to Mars will expose astronauts to space radiation (SR) that has the potential to impair performance in mission critical tasks. Impairments in task accuracy and movement kinematics have been previously reported during string-pulling behavior ~7 months after SR exposure. If similar SR-induced sensorimotor deficits emerge at earlier times, then astronauts may have compromised in-flight performance disruptions while performing skilled tasks in critical situations, such as when manipulating controls or performing seat egress. Due to the possibility that such performance losses may compromise mission success, it is critical to determine if sensorimotor, motivation, or attentional deficits occur acutely after SR exposure at a time point that corresponds to in-flight performance. Male Wistar rats were thus exposed to either 10 cGy simplified galactic cosmic radiation (GCRsim), 10 cGy 4Helium (4He), or no radiation at all (Sham), and string-pulling behavior was assessed approximately 72 h later. Following exposure to SR, rats (4He) took more time to approach the string to initiate string-pulling behavior and to pull in the string to reach the Cheerio (4He and GCRsim) relative to Sham rats. 4He-exposed rats also exhibited a greater number of misses and less contacts relative to both Sham and GCRsim-exposed rats. Further, rats exposed to 4He demonstrated less concentrated reach endpoints with both the left and right hands compared to GCR-exposed rats. This work suggests that sensorimotor function and motivation and/or attentional processes were impaired 72 h after 4He-radiation exposure.

Exposure to 5 cGy 28Si Particles Induces Long-Term Microglial Activation in the Striatum and Subventricular Zone and Concomitant Neurogenic Suppression.

The proposed mission to Mars will expose astronauts to space radiation that is known to adversely affect cognition and tasks that rely on fine sensorimotor function. Space radiation has also been shown to affect the microglial and neurogenic responses in the central nervous system (CNS). We recently reported that a low dose of 5 cGy 600 MeV/n 28Si results in impaired cognition and skilled motor behavior in adult rats. Since these tasks rely at least in part on the proper functioning of the striatum, we examined striatal microglial cells in these same subjects. Using morphometric analysis, we found that 28Si exposure increased activated microglial cells in the striatum. The majority of these striatal Iba1+ microglia were ED1-, indicating that they were in an alternatively activated state, where microglia do not have phagocytic activity but may be releasing cytokines that could negatively impact neuronal function. In the other areas studied, Iba1+ microglial cells were increased in the subventricular zone (SVZ), but not in the dentate gyrus (DG). Additionally, we examined the relationship between the microglial response and neurogenesis. An analysis of new neurons in the DG revealed an increase in doublecortin-positive (DCX+) hilar ectopic granule cells (hEGC) which correlated with Iba1+ cells, suggesting that microglial cells contributed to this aberrant distribution which may adversely affect hippocampal function. Taken together, these results indicate that a single dose of 28Si radiation results in persistent cellular effects in the CNS that may impact astronauts both in the short and long-term following deep space missions.

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) can produce deficits in a wide range of cognitive functions but is especially detrimental to behaviors requiring accurate spatial information processing. In open field environments, spatial behavior is organized such that animals establish "home bases" marked by long stops focused around one location. Progressions away from the home base are circuitous and slow, while progressions directed toward the home base are non-circuitous and fast. The impact of PAE on the organization of open field behavior has not been experimentally investigated. METHODS: In the present study, adult female and male rats with moderate PAE or saccharin exposure locomoted a circular high walled open field for 30 minutes under lighted conditions. RESULTS: The findings indicate that PAE and sex influence the organization of open field behavior. Consistent with previous literature, PAE rats exhibited greater locomotion in the open field. Novel findings from the current study indicate that PAE and sex also impact open field measures specific to spatial orientation. While all rats established a home base on the periphery of the open field, PAE rats, particularly males, exhibited significantly less clustered home base stopping with smaller changes in heading between stops. PAE also impaired progression measures specific to distance estimation, while sex alone impacted progression measures specific to direction estimation. CONCLUSIONS: These findings support the conclusion that adult male rats have an increased susceptibility to the effects of PAE on the organization of open field behavior.

Effects of Dietary Soy Protein Isolate Versus Isoflavones Alone on Poststroke Skilled Ladder Rung Walking and Cortical mRNA Expression Differ in Adult Male Rats.

Dietary soy protein isolate (SPI) and the isoflavones daidzein and genistein have been shown to provide neuroprotection from stroke. However, the mechanisms remain uncertain. We sought to determine whether the addition of isoflavones to a diet containing caseinate (CAS) as the protein source would induce behavioral neuroprotection similar to that seen previously in rats fed SPI. Furthermore, we aimed to characterize the baseline and poststroke expression of mRNAs involved in pathways previously published as perhaps mediating soy-based neuroprotection from stroke and other markers of neuronal plasticity, oxidative stress, and inflammation. Adult male rats were fed a semipurified diet containing (1) sodium caseinate (CAS), (2) CAS plus daidzein and genistein (CAS+ISO), or (3) SPI for 2 weeks. A subset of rats was euthanized, and tissue was collected for quantitative real-time PCR (qPCR). Remaining rats underwent a middle cerebral artery occlusion to induce a stroke. Samples for qPCR were collected on day 3 poststroke. Rats fed SPI made fewer errors on the skilled ladder rung walking task after stroke compared to rats fed CAS (P < .05). Rats fed CAS+ISO were not different from rats fed CAS or SPI. Significant effects of diet were found at day 0 for Syp, Pparg, and Ywhae and at day 3 for Rtn4 expression. We concluded that the benefits of SPI are not solely attributable to daidzein and genistein.

Organization of exploratory behavior under dark conditions in female and male rats.

Sexually dimorphic performance has been observed across humans and rodents in many spatial tasks. In general, these spatial tasks do not dissociate the use of environmental and self-movement cues. Previous work has demonstrated a role for self-movement cue processing in organizing open field behavior; however, these studies have not directly compared female and male movement characteristics. The current study examined the organization of open field behavior under dark conditions in female and male rats. Significant differences between female and male rats were observed in the location of stopping behavior relative to a cue and the topography exhibited during lateral movements. In contrast, no sex differences were observed on measures used to detect self-movement cue processing deficits. These results provide evidence that female and male rats are similar in their use of self-movement cues to organize open field behavior; however, other factors may be contributing to differences in performance.

Effects of acquired vestibular pathology on the organization of mouse exploratory behavior.

Rodent open field behavior is highly organized and occurs spontaneously in novel environments. This organization is disrupted in mice with vestibular pathology, suggesting vestibular signals provide important contributions to this behavior. A caveat to this interpretation is that previous studies have investigated open field behavior in adult mice with congenital vestibular dysfunction, and the observed deficits may have resulted from developmental changes instead of the lack of vestibular signals. To determine which aspects of open field behavior depend specifically on vestibular signals, mouse movement organization was examined under dark and light conditions at two time points, 1 and 2 months, after bilateral chemical labyrinthectomy. Our results show that acquired vestibular damage selectively disrupted the organization of open field behavior. Access to visual environmental cues attenuated, but did not eliminate, these significant group differences. Improvement in movement organization from the first to the second testing session was limited to progression path circuity. These observations provide evidence for the role of the vestibular system in maintaining spatial orientation and establishes a foundation to investigate neuroplasticity in brain systems that process self-movement information.

Skilled movement and posture deficits in rat string-pulling behavior following low dose space radiation (28Si) exposure.

Deep space flight missions beyond the Van Allen belt have the potential to expose astronauts to space radiation which may damage the central nervous system and impair function. The proposed mission to Mars will be the longest mission-to-date and identifying mission critical tasks that are sensitive to space radiation is important for developing and evaluating the efficacy of counter measures. Fine motor control has been assessed in humans, rats, and many other species using string-pulling behavior. For example, focal cortical damage has been previously shown to disrupt the topographic (i.e., path circuity) and kinematic (i.e., moment-to-moment speed) organization of rat string-pulling behavior count to compromise task accuracy. In the current study, rats were exposed to a ground-based model of simulated space radiation (5 cGy 28Silicon), and string-pulling behavior was used to assess fine motor control. Irradiated rats initially took longer to pull an unweighted string into a cage, exhibited impaired accuracy in grasping the string, and displayed postural deficits. Once rats were switched to a weighted string, some deficits lessened but postural instability remained. These results demonstrate that a single exposure to a low dose of space radiation disrupts skilled hand movements and posture, suggestive of neural impairment. This work establishes a foundation for future studies to investigate the neural structures and circuits involved in fine motor control and to examine the effectiveness of counter measures to attenuate the effects of space radiation on fine motor control.

Effects of string length on the organization of rat string-pulling behavior.

The string-pulling paradigm has been adapted to investigate many psychological phenomena across a range of animal species. Although varying string length has been shown to influence performance, the nature of the representation remains to be determined. Across three experiments, rats were shaped to pull string to receive food reinforcement. Either string length or reinforcement rate was manipulated to examine the influence on string-pulling behavior. Experiment 1 demonstrated that varied string length was sufficient to elicit an odor discrimination. Subsequent experiments provided evidence that varying string length (Experiment 2) and reinforcement rate (Experiment 3) produced qualitatively distinct patterns of string-pulling behavior. In Experiment 2 rats that received a long string were more likely to pull in the probe string to the end, yet no differences were observed in approach time between short and long groups. However, in Experiment 3 rats that received low reinforcement were less likely to pull in the probe string to the end and were slower to approach the string to begin pulling. These results are consistent with rats using temporal and motivational characteristics to guide responding during string-pulling behavior.

Human string-pulling with and without a string: movement, sensory control, and memory.

String-pulling is a behavior that is allied to many daily acts and is an easily performed action featuring hand-over-hand movements to reel in a string (or rope). String-pulling has been used as a test of perceptual and cognitive functions in many animal species, including human children, but its movements and sensory control have not been characterized. Male and female university students (n = 68) performed target-based or memory-based string-pulling in which they pulled down a string suspended on an overhead pulley and immediately afterwards attempted to make the same movement in a memory-based test. Frame-by-frame video scoring was used to describe movements, eye-tracking and visual occluding glasses were used to assess sensory control, and a Matlab video-analysis procedure was used to describe kinematics. The string was advanced using five arm/hand movements: with lift and advance comprising fast up movements, and grasp, pull and push comprising slow down movements. Fingers closed 5 (pinky) through 1 (thumb) to make a whole-hand grasp and release in target-based string pulling but moved in a reverse sequence for the memory-based task. Target-based string pulling was not visually guided unless participants were instructed to grasp at a cue, and then vision featured eye-tracking of the target and pupil dilation with the grasp, but there was no relation between eye events for memory-based string-pulling. For target-based string-pulling the left and right hands advanced the string with both independent and concurrent movement but only independent movements were featured in a more symmetrical memory-based movement. The results are discussed in relation to the sensory control of hand movements, contemporary theories of the neural control of hand movements, and species differences in string-pulling.

Making waves: Comparing Morris water task performance in rats and prairie voles.

Spatial processing is a critical component for survival. This domain of information processing has been extensively studied in rats and mice. Limited work has examined the capacity of other rodent species, like the prairie vole (Microtus ochrogaster), to process spatial information. The Morris water task (MWT) is a classic spatial task that has been used to examine spatial cognition in rodents. This task involves an animal developing configural relationships between extra-maze cues and the location of a hidden platform to successfully escape from a pool of water. The current study compared performance in the MWT between rats and prairie voles. Rats were observed to outperform prairie voles in key aspects of the task including latency to find the platform, directness of swim paths to the platform, and degrees of heading error. These results may be attributed to potential interspecies differences in spatial cognition, stress reactivity, physiology, or motivation. This study provides the foundation for future work investigating the spatial cognition of prairie voles and the factors that contribute to water task performance in rodents.

The structure of arm and hand movements in a spontaneous and food rewarded on-line string-pulling task by the mouse.

Arm and hand use by the mouse have been studied in a variety of tasks in order to understand the structure of skilled movements and motor learning, the anatomy and function of neural pathways, and to develop animal models of neurological conditions. The present study describes string-pulling by the mouse, a behavior in which a mouse uses hand-over-hand movements to pull down a string that hangs from the top of a test cage. Mice both spontaneously string-pull and also string-pull to obtain cashew nuts tied to the end of the string as food reward. To string-pull, mice sat upright and tracked the string with their nose and then made hand-over-hand movements to reel in the string. A string-pull movement consists of four arm movements (Advance to make purchase, Pull, Push to draw the string down and Lift to return the hand for the next Advance) and four hand movements (Collect to aim the hand, Overgrasp to position the hand, and Grasp to make purchase, and Release). The kinematic profiles of the string-pull movement are distinctive with each hand making similar movements at a rate of 4 cycles per second and with the Lift and Advance movements occurring at a higher speed than Pull and Push movements. The results are discussed in relation to the antecedent repertoire of mouse behavior that lends itself to string-pulling, with respect to the utility of using string-pulling to investigate motor systems and adapting string-pulling to model neurological conditions in mice.

Antisense oligonucleotide therapy rescues disruptions in organization of exploratory movements associated with Usher syndrome type 1C in mice.

Usher syndrome, Type 1C (USH1C) is an autosomal recessive inherited disorder in which a mutation in the gene encoding harmonin is associated with multi-sensory deficits (i.e., auditory, vestibular, and visual). USH1C (Usher) mice, engineered with a human USH1C mutation, exhibit these multi-sensory deficits by circling behavior and lack of response to sound. Administration of an antisense oligonucleotide (ASO) therapeutic that corrects expression of the mutated USH1C gene, has been shown to increase harmonin levels, reduce circling behavior, and improve vestibular and auditory function. The current study evaluates the organization of exploratory movements to assess spatial organization in Usher mice and determine the efficacy of ASO therapy in attenuating any such deficits. Usher and heterozygous mice received the therapeutic ASO, ASO-29, or a control, non-specific ASO treatment at postnatal day five. Organization of exploratory movements was assessed under dark and light conditions at two and six-months of age. Disruptions in exploratory movement organization observed in control-treated Usher mice were consistent with impaired use of self-movement and environmental cues. In general, ASO-29 treatment rescued organization of exploratory movements at two and six-month testing points. These observations are consistent with ASO-29 rescuing processing of multiple sources of information and demonstrate the potential of ASO therapies to ameliorate topographical disorientation associated with other genetic disorders.

Unilateral forelimb sensorimotor cortex devascularization disrupts the topographic and kinematic characteristics of hand movements while string-pulling for food in the rat.

String-pulling by the rat is a bimanual act, in which an upright animal retrieves a piece of food attached to the end of the string by downward hand-over-hand movements. The present study compared the movements of string-pulling, using topographic and kinematic measures of hand movement, in control rats and rats with unilateral sensorimotor motor cortex lesion produced by removal of the pia matter. In the first week following devascularization, the rhythmicity and accuracy of string-pulling movements decomposed; however, thereafter the rhythm of bilateral alternation was restored. Over 70days of testing, distance traveled decreased for both hands in the control and lesion groups, suggesting that both groups displayed an increase in string-pulling efficiency. Nevertheless, the lesion group exhibited more missed string contacts with the (contralateral-to-lesion) hand and more grasps in which the string was hooked between the digits with both hands. In addition, an increase in mouth grasps was observed in the lesion group. Motion capture analyses revealed that the lesion group exhibited longer reach and withdraw movements and these movements were longer for the ipsilateral-to-lesion vs contralateral-to-lesion hand. Thus, although rhythmicity of string-pulling behavior recovers after sensorimotor cortex devascularization, the contralateral-to-lesion hand contributed less to string pulling and requires mouth grasps to stabilize the string for grasping. The results are discussed in relation to contemporary theories of the contributions of the forelimb motor cortex to skilled movement and the potential use of string-pulling as a therapy for brain injury.

High dose alcohol consumption predicts less reduction in post-traumatic stress symptoms after a campus mass shooting.

BACKGROUND: Recognizing that alcohol might affect subsequent processing of trauma-related information, this study examined whether high dose alcohol consumption (HDAC) following a campus mass shooting affected the relation between shooting exposure and post-traumatic stress symptoms (PTSS). METHODS: Female participants (N = 691) recorded levels of physical exposure to the shooting event, alcohol use, and PTSS 1 month following the shooting event and 8 months later. RESULTS: No evidence was found to suggest that pre-shooting HDAC moderated the relationship between trauma exposure and PTSS 1 month following the shooting. HDAC in the month following the shooting predicted less resolution of PTSS 8 months later. Specifically, at higher (but not lower) levels of HDAC, shooting exposure was associated with less reduction in PTSS from 1 to 8 months post-trauma. Several alternate explanations were ruled out. CONCLUSIONS: Less reduction in PTSS seems to occur at high levels of both shooting exposure and HDAC. Theoretical implications and directions for future research are discussed.