A call to implement preclinical study registration in animal ethics review.

Protocol registration is required in clinical trials. Registration of animal studies could improve research transparency and reduce redundancy, yet uptake has been minimal. Integrating study registration into institutional approval of animal use protocols is a promising approach to increase uptake.

Self-reported sleep disturbances among people who have had a stroke: a cross-sectional analysis.

BACKGROUND: Sleep disturbances and their potential association with stroke remains understudied at a population level. We sought to determine the prevalence of sleep disturbances among people who have effects of stroke compared with the general population. METHODS: We used data from people aged 18 years or older who responded to the sleep and chronic disease modules of the 2017-2018 cycle of the Canadian Community Health Survey (CCHS). We measured sleep disturbances by self-reports of having trouble staying awake most or all of the time; either short (< 5 h) or long (> 9 h) nightly sleep duration; having trouble going to or staying asleep most or all of the time; and never, rarely or sometimes having refreshing sleep. We used log-binomial and multinomial regression to investigate prevalence of sleep disturbances among respondents who reported effects of stroke compared with others, adjusting for confounding factors. RESULTS: We included 46 404 CCHS respondents, 682 of whom reported effects of stroke. The prevalence of sleep disturbances for those with effects of stroke was higher than among others in the sample with regard to trouble staying awake (13.0% v. 6.1%; adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.59-2.94), short or long duration sleep (28.9% v. 10.0%; adjusted RR 1.93, 95% CI 1.57-2.38), trouble going to or staying asleep, (28.1% v. 17.6%; adjusted RR 1.53, 95% CI 1.28-1.83) and lack of refreshing sleep (41.1% v. 37.1%; adjusted RR 1.30, 95% CI 1.14-1.49). The prevalence of at least 1 reported measure of sleep disturbance was 61.6% among those with effects of stroke, compared with 48.2% among others (adjusted RR 1.28, 95% CI 1.18-1.40). INTERPRETATION: Self-report of having effects of stroke was associated with increased prevalence of sleep disturbances compared with the general population. Sleep disturbances were reported by a high proportion of respondents with effects of stroke, indicating the importance of screening for related disorders.

Identifying barriers and enablers to rigorous conduct and reporting of preclinical laboratory studies.

Use of rigorous study design methods and transparent reporting in publications are 2 key strategies proposed to improve the reproducibility of preclinical research. Despite promotion of these practices by funders and journals, assessments suggest uptake is low in preclinical research. Thirty preclinical scientists were interviewed to better understand barriers and enablers to rigorous design and reporting. The interview guide was informed by the Theoretical Domains Framework, which is a framework used to understand determinants of current and desired behavior. Four global themes were identified; 2 reflecting enablers and 2 reflecting barriers. We found that basic scientists are highly motivated to apply the methods of rigorous design and reporting and perceive a number of benefits to their adoption (e.g., improved quality and reliability). However, there was varied awareness of the guidelines and in implementation of these practices. Researchers also noted that these guidelines can result in disadvantages, such as increased sample sizes, expenses, time, and can require several personnel to operationalize. Most researchers expressed additional resources such as personnel and education/training would better enable the application of some methods. Using existing guidance (Behaviour Change Wheel (BCW); Expert Recommendations for Implementing Change (ERIC) project implementation strategies), we mapped and coded our interview findings to identify potential interventions, policies, and implementation strategies to improve routine use of the guidelines by preclinical scientists. These findings will help inform specific strategies that may guide the development of programs and resources to improve experimental design and transparent reporting in preclinical research.

Localizing Microemboli within the Rodent Brain through Block-Face Imaging and Atlas Registration.

Brain microinfarcts are prevalent in humans, however because of the inherent difficulty of identifying and localizing individual microinfarcts, brain-wide quantification is impractical. In mice, microinfarcts have been created by surgically introducing microemboli into the brain, but a major limitation of this model is the absence of automated methods to identify and localize individual occlusions. We present a novel and semi-automated workflow to identify the anatomic location of fluorescent emboli (microspheres) within the mouse brain through histologic processing and atlas registration. By incorporating vibratome block-face imaging with the QuickNII brain registration tool, we show that the anatomic location of microspheres can be accurately registered to brain structures within the Allen mouse brain (AMB) atlas (e.g, somatomotor areas, hippocampal region, visual areas, etc.). Compared with registering images of slide mounted sections to the AMB atlas, microsphere location was more accurately determined when block-face images were used. As a proof of principle, using this workflow we compared the distribution of microspheres within the brains of mice that were either perfused or immersion fixed. No significant effect of perfusion on total microsphere number or location was detected. In general, microspheres were distributed brain-wide, with the largest density found in the thalamus. In sum, our block-face imaging workflow enables efficient characterization of the widespread distribution of fluorescent microemboli, facilitating future investigation into the impact of microinfarct load and location on brain health.

Developmental and interventional plasticity of motor maps after perinatal stroke.

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: 1) Correlation to chronic impairment on a behavioral test battery; 2) Amenability to change using a skilled motor training paradigm; 3) Ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59-70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres was positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlated with performance in skilled reaching. Map size and movement latency did not show groupwise changes with training; however, mice with the smallest pre-training map sizes and worst impairments demonstrated the greatest expansion of map size in response to skilled forelimb training. Overall, motor map size showed utility as a potential biomarker for impairment and training-induced modulation in specific individuals. Future assessment of the predictive capacity of post-stroke motor representations for behavioral outcome in animal models opens the possibility of dissecting how plasticity mechanisms contribute to recovery following perinatal stroke.SIGNIFICANCE STATEMENTWe investigated the utility of two cortical motor representation measures (motor map size and movement onset latency) as potential biomarkers for post-stroke motor recovery in a mouse model of perinatal stroke. Both motor map size and movement latency were associated with functional recovery after perinatal stroke, with map size showing an additional association between training responsiveness and severity of impairment. Overall, both motor map size and movement onset latency show potential as neurophysiological correlates of recovery. As such, future studies of perinatal stroke rehabilitation and neuromodulation should include these measures in order to help explain neurophysiological changes that might be occurring in response to treatment.

Remote Ischemic Conditioning and Stroke Recovery.

Remote ischemic conditioning (RIC) is a noninvasive procedure whereby several periods of ischemia are induced in a limb. Although there is growing interest in using RIC to improve stroke recovery, preclinical RIC research has focused exclusively on neuroprotection, using male animals and the intraluminal suture stroke model, and delivered RIC at times not relevant to either brain repair or behavioral recovery. In alignment with the Stroke Recovery and Rehabilitation Roundtable, we address these shortcomings. First, a standardized session (5-minute inflation/deflation, 4 repetitions) of RIC was delivered using a cuff on the contralesional hindlimb in both male and female Sprague-Dawley rats. Using the endothelin-1 stroke model, RIC was delivered once either prestroke (18 hours before, pre-RIC) or poststroke (4 hours after, post-RIC), and infarct volume was assessed at 24 hours poststroke using magnetic resonance imaging. RIC was delivered at these times to mimic the day before a surgery where clots are possible or as a treatment similar to tissue plasminogen activator, respectively. Pre-RIC reduced infarct volume by 41% compared with 29% with post-RIC. RIC was neuroprotective in both sexes, but males had a 46% reduction of infarct volume compared with 23% in females. After confirming the acute efficacy of RIC, we applied it chronically for 4 weeks, beginning 5 days poststroke. This delayed RIC failed to enhance poststroke behavioral recovery. Based on these findings, the most promising application of RIC is during the hyperacute and early acute phases of stroke, a time when other interventions such as exercise may be contraindicated.

An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery.

Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.

Neuroprotection by Remote Ischemic Conditioning in Rodent Models of Focal Ischemia: a Systematic Review and Meta-Analysis.

Remote ischemic conditioning (RIC) is a promising neuroprotective therapy for ischemic stroke. Preclinical studies investigating RIC have shown RIC reduced infarct volume, but clinical trials have been equivocal. Therefore, the efficacy of RIC in reducing infarct volume and quality of current literature needs to be evaluated to identify knowledge gaps to support future clinical trials. We performed a systematic review and meta-analysis of preclinical literature involving RIC in rodent models of focal ischemia. This review was registered with PROSPERO (CRD42019145441). Eligibility criteria included rat or mice models of focal ischemia that received RIC to a limb either before, during, or after stroke. MEDLINE and Embase databases were searched from 1946 to August 2019. Risk of bias was assessed using the SYRCLE risk of bias tool along with construct validity. Seventy-two studies were included in the systematic review. RIC was shown to reduce infarct volume (SMD - 2.19; CI - 2.48 to - 1.91) when compared to stroke-only controls and no adverse events were reported with regard to RIC. Remote ischemic conditioning was shown to be most efficacious in males (SMD - 2.26; CI - 2.58 to - 1.94) and when delivered poststroke (SMD - 1.34; CI - 1.95 to - 0.73). A high risk of bias was present; thus, measures of efficacy may be exaggerated. A limitation is the poor methodological reporting of many studies, resulting in unclear construct validity. We identified several important, but under investigated topics including the efficacy of RIC in different stroke models, varied infarct sizes and location, and potential sex differences.

The Home-Cage Automated Skilled Reaching Apparatus (HASRA): Individualized Training of Group-Housed Mice in a Single Pellet Reaching Task.

The single pellet reaching task is commonly used in rodents to assess the acquisition of fine motor skill and recovery of function following nervous system injury. Although this task is useful for gauging skilled forelimb use in rodents, the process of training animals is labor intensive and variable across studies and labs. To address these limitations, we developed a single pellet reaching paradigm for training and testing group housed mice within their home cage. Mice enter a training compartment attached to the outside of the cage and retrieve millet seeds presented on a motorized pedestal that can be individually positioned to present seeds to either forelimb. To identify optimal training parameters, we compared task participation and success rates between groups of animals that were presented seeds at two different heights (floor vs mouth height) and at different intervals (fixed-time vs trial-based). The mouth height/fixed interval presentation style was most effective at promoting reaching behavior as all mice reached for seeds within 5 d. Using this paradigm, we assessed stroke-induced deficits in home-cage reaching. Following three weeks of baseline training, reaching success rate was ∼40%, with most trials performed during the dark cycle. A forelimb motor cortex stroke significantly decreased interaction with presented seeds within the first 2 d and impaired reaching success rates for the first 7 d. Our data demonstrate that group-housed mice can be efficiently trained on a single pellet reaching task in the home cage and that this assay is sensitive to stroke induced motor impairments.

Poststroke Impairment and Recovery Are Predicted by Task-Specific Regionalization of Injury.

Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats (N = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation.SIGNIFICANCE STATEMENT By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.

Influence of metabolic syndrome on cerebral perfusion and cognition.

Vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH) and memory deficits, and often occurs concurrently with metabolic syndrome (MetS). Despite their common occurrence, it is unknown whether CCH and MetS act synergistically to exacerbate VCI-associated pathology. Here, using male Sprague-Dawley rats, we examined the effects of a clinically relevant model of adolescent-onset MetS and adult-onset CCH on neuro-vascular outcomes, combining a cafeteria diet with a 2-vessel occlusion (2VO) model. Using longitudinal imaging, histology, and behavioural assessments, we identified several features of MetS and CCH including reduced cerebral blood volume, white matter atrophy, alterations in hippocampal cell density, and memory impairment. Furthermore, we identified a number of significant associations, potentially predictive of MetS and pathophysiological outcomes. White matter volume was positively correlated to HDL cholesterol; hippocampal cell density was negatively correlated to fasted blood glucose; cerebral blood flow and volume was negatively predicted by the combination of 2VO surgery and increased fasted blood glucose. These results emphasize the importance of including comorbid conditions when modeling VCI, and they outline a highly translational preclinical model that could be used to investigate potential interventions to mitigate VCI-associated pathology and cognitive decline.

Cognition in Stroke Rehabilitation and Recovery Research: Consensus-Based Core Recommendations From the Second Stroke Recovery and Rehabilitation Roundtable.

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway.

Cognition in stroke rehabilitation and recovery research: Consensus-based core recommendations from the second Stroke Recovery and Rehabilitation Roundtable.

Cognitive impairment is an important target for rehabilitation as it is common following stroke, is associated with reduced quality of life and interferes with motor and other types of recovery interventions. Cognitive function following stroke was identified as an important, but relatively neglected area during the first Stroke Recovery and Rehabilitation Roundtable (SRRR I), leading to a Cognition Working Group being convened as part of SRRR II. There is currently insufficient evidence to build consensus on specific approaches to cognitive rehabilitation. However, we present recommendations on the integration of cognitive assessments into stroke recovery studies generally and define priorities for ongoing and future research for stroke recovery and rehabilitation. A number of promising interventions are ready to be taken forward to trials to tackle the gap in evidence for cognitive rehabilitation. However, to accelerate progress requires that we coordinate efforts to tackle multiple gaps along the whole translational pathway.

An RFID-based activity tracking system to monitor individual rodent behavior in environmental enrichment: Implications for post-stroke cognitive recovery.

BACKGROUND: Diminished cognitive flexibility is a common form of executive dysfunction that results from stroke in the prefrontal cortex. Potential therapies targeting this type of cognitive deficit following stroke are lacking. NEW METHOD: Here, we used environmental enrichment (EE) as a rehabilitation approach, integrated with a radio frequency identification (RFID)-based activity tracking system to evaluate the contribution of individual EE elements to promote cognitive recovery. Male and female Sprague-Dawley rats received either sham surgery or endothelin-1 (ET-1) induced focal ischemia targeting the medial prefrontal cortex (mPFC). Cognitive flexibility was assessed through an egocentric-spatial version of the Morris Water Maze (MWM) task. RESULTS: Prefrontal cortex damage resulted in impaired reversal learning using the egocentric MWM and reduced physical activity in the running wheel, while social interaction was not affected. EE exposure (2 h/day, 5 days/week, for 5 weeks) improved cognitive flexibility in reversal learning of egocentric MWM for both stroke and sham rats. COMPARISON WITH EXISTING METHOD: As changes in cognition post-stroke can be subtle and difficult to detect using conventional behavioural assessment, we suggest that the implementation of individualized automated animal tracking as used herein will ultimately help decipher whether individual components of EE are important for promoting cognitive recovery post-stroke. CONCLUSION: This study represents an attempt to better align preclinical and clinical implementations of EE and facilitate the uptake of this intervention in the clinical setting.

Is Environmental Enrichment Ready for Clinical Application in Human Post-stroke Rehabilitation?

Environmental enrichment (EE) has been widely used as a means to enhance brain plasticity mechanisms (e.g., increased dendritic branching, synaptogenesis, etc.) and improve behavioral function in both normal and brain-damaged animals. In spite of the demonstrated efficacy of EE for enhancing brain plasticity, it has largely remained a laboratory phenomenon with little translation to the clinical setting. Impediments to the implementation of enrichment as an intervention for human stroke rehabilitation and a lack of clinical translation can be attributed to a number of factors not limited to: (i) concerns that EE is actually the "normal state" for animals, whereas standard housing is a form of impoverishment; (ii) difficulty in standardizing EE conditions across clinical sites; (iii) the exact mechanisms underlying the beneficial actions of enrichment are largely correlative in nature; (iv) a lack of knowledge concerning what aspects of enrichment (e.g., exercise, socialization, cognitive stimulation) represent the critical or active ingredients for enhancing brain plasticity; and (v) the required "dose" of enrichment is unknown, since most laboratory studies employ continuous periods of enrichment, a condition that most clinicians view as impractical. In this review article, we summarize preclinical stroke recovery studies that have successfully utilized EE to promote functional recovery and highlight the potential underlying mechanisms. Subsequently, we discuss how EE is being applied in a clinical setting and address differences in preclinical and clinical EE work to date. It is argued that the best way forward is through the careful alignment of preclinical and clinical rehabilitation research. A combination of both approaches will allow research to fully address gaps in knowledge and facilitate the implementation of EE to the clinical setting.

Metformin Preconditioning of Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells Promotes Their Engraftment and Improves Post-Stroke Regeneration and Recovery.

While transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) shows therapeutic potential in animal stroke models, major concerns for translating hiPSC therapy to the clinic are efficacy and safety. Therefore, there is a demand to develop an optimal strategy to enhance the engraftment and regenerative capacity of transplanted hiPSC-NSCs to produce fully differentiated neural cells to replace lost brain tissues. Metformin, an FDA-approved drug, is an optimal neuroregenerative agent that not only promotes NSC proliferation but also drives NSCs toward differentiation. In this regard, we hypothesize that preconditioning of hiPSC-NSCs with metformin before transplantation into the stroke-damaged brain will improve engraftment and regenerative capabilities of hiPSC-NSCs, ultimately enhancing functional recovery. In this study, we show that pretreatment of hiPSC-NSCs with metformin enhances the proliferation and differentiation of hiPSC-NSCs in culture. Furthermore, metformin-preconditioned hiPSC-NSCs show increased engraftment 1 week post-transplantation in a rat endothelin-1 focal ischemic stroke model. In addition, metformin-preconditioned cell grafts exhibit increased survival compared to naive cell grafts at 7 weeks post-transplantation. Analysis of the grafts demonstrates that metformin preconditioning enhances the differentiation of hiPSC-NSCs at the expense of their proliferation. As an outcome, rats receiving metformin-preconditioned cells display accelerated gross motor recovery and reduced infarct volume. These studies represent a vital step forward in the optimization of hiPSC-NSC-based transplantation to promote post-stroke recovery.

Post-stroke kinematic analysis in rats reveals similar reaching abnormalities as humans.

A coordinated pattern of multi-muscle activation is essential to produce efficient reaching trajectories. Disruption of these coordinated activation patterns, termed synergies, is evident following stroke and results in reaching deficits; however, preclinical investigation of this phenomenon has been largely ignored. Furthermore, traditional outcome measures of post-stroke performance seldom distinguish between impairment restitution and compensatory movement strategies. We sought to address this by using kinematic analysis to characterize reaching movements and kinematic synergies of rats performing the Montoya staircase task, before and after ischemic stroke. Synergy was defined as the simultaneous movement of the wrist and other proximal forelimb joints (i.e. shoulder, elbow) during reaching. Following stroke, rats exhibited less individuation between joints, moving the affected limb more as a unit. Moreover, abnormal flexor synergy characterized by concurrent elbow flexion, shoulder adduction, and external rotation was evident. These abnormalities ultimately led to inefficient and unstable reaching trajectories, and decreased reaching performance (pellets retrieved). The observed reaching abnormalities in this preclinical stroke model are similar to those classically observed in humans. This highlights the potential of kinematic analysis to better align preclinical and clinical outcome measures, which is essential for developing future rehabilitation strategies following stroke.

Short- and Long-term Exposure to Low and High Dose Running Produce Differential Effects on Hippocampal Neurogenesis.

Continuous running wheel (RW) exercise increases adult hippocampal neurogenesis in the dentate gyrus (DG) of rodents. Evidence suggests that greater amounts of RW exercise does not always equate to more adult-generated neurons in hippocampus. It can also be argued that continuous access to a RW results in exercise levels not representative of human exercise patterns. This study tested if RW paradigms that more closely represent human exercise patterns (e.g. shorter bouts, alternating daily exercise) alter neurogenesis. Neurogenesis was measured by examining the survival and fate of bromodeoxyuridine (BrdU)-labeled proliferating cells in the DG of male Sprague-Dawley rats after acute (14 days) or chronic (30 days) RW access. Rats were assigned to experimental groups based on the number of hours that they had access to a RW over two days: 0 h, 4 h, 8 h, 24 h, and 48 h. After acute RW access, rats that had unlimited access to the RW on alternating days (24 h) had a stronger neurogenic response compared to those rats that ran modest distances (4 h, 8 h) or not at all (0 h). In contrast, following chronic RW access, rats that ran a moderate amount (4 h, 8 h) had significantly more surviving cells compared to 0 h, 24 h, and 48 h. Linear regression analysis established a negative relationship between running distance and surviving BrdU+ cells in the chronic RW access cohort (R2 = 0.40). These data demonstrate that in rats moderate amounts of RW exercise are superior to continuous daily RW exercise paradigms at promoting hippocampal neurogenesis in the long-term.

Reduced Cerebrovascular Reactivity and Increased Resting Cerebral Perfusion in Rats Exposed to a Cafeteria Diet.

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology.