Spatial Memory Performance Research Articles

IGF1 enhances memory function in obese mice and stabilizes the neural structure under insulin resistance via AKT-GSK3β-BDNF signaling.

Obesity is a prevalent metabolic disorder linked to insulin resistance, hyperglycemia, increased adiposity, chronic inflammation, and cognitive dysfunction. Recent research has focused on developing therapeutic strategies to mitigate cognitive impairment associated with obesity. Insulin growth factor-1 (IGF1) deficiency is linked to insulin resistance, glucose intolerance, and the progression of obesity-related central nervous system (CNS) disorders. In this study, we investigated the neuroprotective effects of IGF1 in two obesity models: diet-induced obesity (high-fat diet mice) and genetic obesity (ob/ob mice which is genetically deficient in leptin), and in vitro Neuro2A neuronal cells and primary cortical neurons under insulin resistance conditions. We performed RNA sequencing analysis using the cortex of high-fat diet mice injected with IGF1. Also, we detected cytokine levels in blood of high-fat diet mice injected with IGF1. In addition, we conducted the Barnes maze test as a spatial memory function test and open field test as an anxiety behavior test in ob/ob mice. We measured the levels of proteins and mRNAs related to insulin signaling, including synaptic density proteins in brain cortex of ob/ob mice. Our results showed that IGF1 injection enhanced spatial memory function and synaptic plasticity in obese mice. Furthermore, in vitro data demonstrated that IGF1 treated neurons revealed enhanced neural complexity and improved neurite outgrowth under insulin resistance condition through the AKT-GSK3β-BDNF pathway related to antidepressant, cognitive function and anti-apoptotic mechanisms. Therefore, our results provided that IGF1 have potential to alleviate cognitive impairment by promoting synaptic plasticity and neural complexity in the obese brain.

Photobiomodulation using an 830-nm laser alleviates hippocampal reactive gliosis and cognitive dysfunction in a mouse model of adolescent chronic alcohol exposure.

Chronic alcoholism is known to have detrimental effects on the brain, including cognitive impairment, neurotransmitter imbalances, and brain atrophy. The hippocampus, crucial for spatial memory and cognitive functions, is particularly susceptible to alcohol-induced changes. Photobiomodulation (PBM), a non-invasive therapeutic method that utilizes red or near-infrared light, has shown promising applications in the central and peripheral nervous systems. Near-infrared (NIR) light, in particular, has been shown to prevent apoptosis, and neuroinflammation, as well as to improve cognitive functions. In this study, we aimed to investigate whether 830-nm laser irradiation could mitigate cognitive deficits in a chronic alcohol mouse model. Chronic alcoholism was induced in C57BL/6 mice through continuous ethanol gavage for 4 weeks at a dosage of 5 g/kg/day. Gavaging was performed 3 times per week for 4 weeks. Mice were transcranial irradiated by 830-nm laser, following making a chronic alcohol mouse model. Laser irradiation (50 mW/cm2) was performed 5 times per week for 3 weeks. To verify memory and cognitive defeats of a chronic alcohol mouse model, we performed animal behavior tasks such as Morris water maze, Y maze, and novel objective recognition. Our results confirmed the cognitive impairment in the chronic alcohol mouse model compared to the control group in conducted tasks. However, cognitive and spatial memory significantly improved following 830-nm laser irradiation. Additionally, we confirmed whether the behavior tasks result from histological changes. We performed immunofluorescence staining in the hippocampus region (CA3, CA1 and hilus) using astrocyte (GFAP) and microglia (Iba1) markers. As a result, reactive astrocyte was significantly increased in the chronic alcohol mouse model compared to control mice, whereas the number of GFAP-positive cells was significantly reduced by 830-nm laser irradiation. These findings indicate that chronic alcohol exposure induces spatial memory and cognitive impairment, which can be effectively rescued through near-infrared laser irradiation.

Relationship between cognitive impairment and hippocampal iron overload: A quantitative susceptibility mapping study of a rat model.

The aim of this study was to establish an iron overload rat model to simulate the elevated iron levels in patients with thalassemia and to investigate the potential association between hippocampal iron deposition and cognition. Two groups of iron overloaded rats and one group of control rats were used for this study. The Morris water maze (MWM) was used to test spatial reference memory indicated by escape latency time and number of MWM platform crossings. The magnetic susceptibility value of the hippocampal tissue, a measure of iron deposition, was assessed by quantitative susceptibility mapping (QSM) and was correlated with spatial reference memory performance. The iron content in hippocampal tissue sections of the rats were assessed using diaminobenzidine (DAB)-enhanced Perl's Prussian blue (PPB) staining. The rat groups with iron overload including the Group H and Group L had higher hippocampal magnetic susceptibility values than the control rat group, i.e., Group D. In addition, the iron overloaded groups had longer MWM escape latency than the control group, and reduced number of MWM platform crossings. There was a positive correlation between the mean escape latency and the mean hippocampal magnetic susceptibility value, a negative correlation between the number of platform crossings and the mean hippocampal magnetic susceptibility value, and a negative correlation between the number of platform crossings and the latent escape time in Group H and Group L. This rat model simulating iron overload in thalassemia showed hippocampal iron overload being associated with impairment of spatial reference memory. QSM could be used to quantify brain iron overload in vivo, highlighting its potential clinical application for assessing cognitive impairment in patients with thalassemia.

Diethyl nitrosamine-induces neurobehavioral deficit, oxido-nitrosative stress in rats' brain: a neuroprotective role of diphenyl diselenide.

Diethylnitrosamine (DEN), a common dietary carcinogen, is associated with neurotoxicity in humans and animals. This study investigated the neuroprotective effects of diphenyl diselenide (DPDS) against DEN-induced neurotoxicity in male Albino Wistar rats (n = 40). Rats were randomly distributed into cohorts and treated as follows: vehicle control (corn oil 2mL/kg; gavage), DPDS-only (5mg/kg; gavage) and DEN-only (200mg/kg; single dose i.p.). Also, two other rat cohorts were pre-treated with DPDS (3 or 5mg/kg) for 15days (day: 0-15), subsequently administered with DEN (200mg/kg) and continuously treated with DPDS for another 7days, (days:15-21). Behavioural tests (OFT- using the open field test; NORT- novel object recognition test; FST- forced swimming test and Y-maze) were conducted from days 19-21, followed by biochemical analysis of the hippocampus and prefrontal cortex for oxidative stress, inflammation, neurotransmitter metabolic enzyme, and histopathology. DEN-treated rats exhibited decreased locomotor activity, spatial memory function and antioxidant activity, increased oxidative and nitration stress, anxiety, and depressive-like behaviour, causing histoarchitectural damage in prefrontal and hippocampal cortices. DPDS treatment (pre- and post-DEN exposure) significantly alleviated these neurotoxic, oxidative, and nitration effects, reversed DEN-induced histopathological alterations, and improved locomotive and cognitive functions. In conclusion, DPDS demonstrates potent neuroprotective effects against DEN-induced toxicity, likely through enhanced endogenous antioxidant capacity that mitigates oxido-nitrative damage. These findings suggest that the organo-selenium -DPDS- is a promising chemotherapeutic agent potent in alleviating DEN-mediated neurotoxicity and maintaining brain health.

Episodic Aspects of a Path Navigated Through Hippocampal Neurobiology

ABSTRACTAs requested by the editors of this special issue of Hippocampus on Scientific Histories of Hippocampal Research, this review provides a detailed personal perspective and historical background on the research involved in a number of findings. The review includes description of the development of the water maze and its use in providing evidence to support the role of the hippocampus in spatial memory function. The review also describes how the water maze was then used in further work to support the proposal that NMDA‐dependent synaptic modification in the hippocampus mediates the encoding of new spatial memories. This personal history gives a perspective on the convergence of different streams of physiological, biochemical, theoretical and behavioral research that resulted in these findings on hippocampal function.

Connectome-based prediction of functional impairment in experimental stroke models.

Experimental rat models of stroke and hemorrhage are important tools to investigate cerebrovascular disease pathophysiology mechanisms, yet how significant patterns of functional impairment induced in various models of stroke are related to changes in connectivity at the level of neuronal populations and mesoscopic parcellations of rat brains remain unresolved. To address this gap in knowledge, we employed two middle cerebral artery occlusion models and one intracerebral hemorrhage model with variant extent and location of neuronal dysfunction. Motor and spatial memory function was assessed and the level of hippocampal activation via Fos immunohistochemistry. Contribution of connectivity change to functional impairment was analyzed for connection similarities, graph distances and spatial distances as well as the importance of regions in terms of network architecture based on the neuroVIISAS rat connectome. We found that functional impairment correlated with not only the extent but also the locations of the injury among the models. In addition, via coactivation analysis in dynamic rat brain models, we found that lesioned regions led to stronger coactivations with motor function and spatial learning regions than with other unaffected regions of the connectome. Dynamic modeling with the weighted bilateral connectome detected changes in signal propagation in the remote hippocampus in all 3 stroke types, predicting the extent of hippocampal hypoactivation and impairment in spatial learning and memory function. Our study provides a comprehensive analytical framework in predictive identification of remote regions not directly altered by stroke events and their functional implication.

Acute Treatment with Fucoidan Ameliorates Traumatic Brain Injury-Induced Neurological Damages and Memory Deficits in Rats: Role of BBB Integrity, Microglial Activity, Neuroinflammation, and Oxidative Stress.

There is no acquiesced remedy for the treatment of traumatic brain injury (TBI)-associated impairment, especially cognitive decline. The first 24h after TBI is a golden time for preventing the progress of the impairments. The present study aimed to examine the acute effects of fucoidan on neurological outcomes and memory performance and investigate its potential mechanisms in rats with TBI. Fucoidan (25, 50, and 100mg/kg, i.p.) was injected immediately after TBI induction. Veterinary coma scale (VCS), brain edema, blood-brain barrier (BBB) integrity, passive avoidance memory and spatial memory, neuroplasticity, myeloperoxidase (MPO) activity, oxidative stress, and histological alteration were evaluated after TBI induction and fucoidan treatment. The findings revealed that TBI resulted in an enhancement in brain water content and BBB permeability and diminished the performance of passive avoidance memory and spatial memory. These were accompanied by long-term potentiation (LTP) suppression in the hippocampus and the prevention of activities of SOD, catalase, and GPx and enhancement of MPO activity, TNF-α, IL-6, and lipid peroxidation levels in the hippocampus as well as hippocampal neuronal loss. Fascinatingly, acute treatment of TBI rats with fucoidan especially in the higher doses (50 and 100mg/kg) significantly ameliorated (p < 0.05) neurological outcomes of VCS, cerebral edema, BBB integrity, passive avoidance memory, spatial memory, LTP impairment, and oxidative-antioxidative balance. Also, fucoidan significantly ameliorated hippocampal neuronal loss, TNF-α and IL-6 levels, and MPO activity as an indicator of microglial activation. These outcomes imply that fucoidan can be a hopeful remedy for TBI-associated neuronal impairments. However, further research is necessary to endorse this issue.

The effect of tactile stimulation on spatial memory and hippocampal neuronal density in male rats with sensory deprivation during a critical period.

It is well known that sensory information driven from whiskers serves as an example of tactile perception in rodents, and plays an important role in social behavior, environmental exploration, and decision-making processes, the influence of manipulations performed during the development of whiskers, on learning has been received little attention in the literature. This study aimed to evaluate the effect of tactile stimulation (TS) on spatial memory performance and neuronal density in the hippocampus during adulthood in early sensory-deprived rats. Wistar albino male rats were divided into four groups: control (CTL), bilateral whisker trimming (BWT), tactile stimulation (TS), and bilateral whisker trimming+tactile stimulation (BWT + TS). All whiskers were trimmed between P0-10, a critical period for whisker development. TS was applied from P3 to P21 using a soft brush. In this study, the 8-arm radial maze test was conducted from postnatal days 77 to 81 to assess spatial memory Animals sacrificed by intracardial perfusion and neuronal density in CA1, CA3, vDG, and dDG regions of the hippocampus were evaluated by Nissl staining. TS exposure negatively affected spatial memory performance and hippocampal neuronal density compared to BWT. We conclude that TS in healthy offspring can cause stress by interrupting maternal care, given the vulnerability of early development. On the contrary, the sensory deprivation protocol in this study was terminated at a time of high homeostatic plasticity and did not produce complete whisker deprivation, have triggered learning by inducing moderate stress early in development.

Exploring the molecular mechanisms of curcumin in modulating memory impairment in neurodegenerative disorders.

Memory impairment is a critical challenge in neurodegenerative disorders, particularly in Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. This research explores the molecular mechanisms by which curcumin, a polyphenolic compound derived from Curcuma longa, exerts neuroprotective effects that may ameliorate cognitive deficits associated with these conditions. Evidence from both preclinical studies and emerging clinical trials indicates that curcumin enhances neuronal signaling and synaptic plasticity, primarily through the modulation of pathways such as NF-κB and PI3K/Akt. Specifically, curcumin has been shown to reduce neuroinflammation and oxidative stress, thereby promoting synaptic integrity and function. For instance, studies demonstrate that curcumin treatment increases the density of dendritic spines in the hippocampus, which correlates with improved spatial learning and memory performance in animal models. Despite promising findings, significant gaps remain in our understanding of curcumin's efficacy in humans. Most existing research is derived from animal studies, with limited large-scale clinical trials to substantiate its therapeutic potential. Furthermore, challenges such as curcumin's low bioavailability and inconsistencies in dosing complicate its clinical application. This review underscores the need for future research focused on enhancing curcumin's bioavailability, establishing optimal dosages, and conducting comprehensive human trials to validate its effectiveness. By addressing these issues, we aim to clarify curcumin's role as a potential therapeutic agent for memory impairment in neurodegenerative disorders, paving the way for innovative treatment strategies.

The impact of a smartphone‐assisted real‐world wayfinding training on spatial memory performance as measured in VR in older adults

The impact of a smartphone‐assisted real‐world wayfinding training on spatial memory performance as measured in VR in older adults

Perceptual learning and neural correlates of virtual navigation in subjective cognitive decline: A pilot study.

Spatial navigation deficits in age-related diseases involve brain changes affecting spatial memory and verbal cognition. Studies in blind and blindfolded individuals show that multisensory training can induce neuroplasticity through visual cortex recruitment. This proof-of-concept study introduces a digital navigation training protocol, integrating egocentric and allocentric strategies with multisensory stimulation and visual masking to enhance spatial cognition and brain connectivity in 17 individuals (mean age 57.2 years) with subjective cognitive decline. Results indicate improved spatial memory performance correlated with recruitment of the visual area 6-thalamic pathway and enhanced connectivity between memory, executive frontal areas, and default mode network (DMN) regions. Additionally, increased connectivity between allocentric and egocentric navigation areas via the retrosplenial complex (RSC) hub was observed. These findings suggest that this training has the potential to induce perceptual learning and neuroplasticity through key functional connectivity hubs, offering potential widespread cognitive benefits by enhancing critical brain network functions.

Impact of masticatory activity and rehabilitation on astrocyte morphology across the molecular layer of the dentate gyrus: Insights from the outer, medial, and inner sublayers and their relationship with spatial learning and memory

The dentate gyrus plays a crucial role in learning and spatial memory, particularly in its middle third molecular layer, which receives the primary afferent input via the medial perforant path. Interestingly, changes in masticatory activity are described to affect this region with visible astrogliosis, release of pro-inflammatory cytokines and oxidative stress, affecting synaptic physiology, and cognition. This study aimed to investigate the impact of altered masticatory activity on spatial memory in young Swiss albino mice, correlating these effects with morphological changes in astrocytes. The mice were divided into three groups: Hard diet with pellets (HD), hard diet/soft diet (HD/SD, reduced masticatory activity), and HD/SD/HD (rehabilitated). The Morris water maze test was used to measure escape latency, while three-dimensional microscopic reconstruction methods provided morphometric data on the astrocytes. Hierarchical clustering analysis validated the existence of four morphological subtypes with decreasing complexity (AST1, AST2, AST3, and AST4), in the outer, middle, and inner thirds of the dentate gyrus molecular layer. Changes in masticatory activity affected the number and distribution of astrocytes subtypes excepting AST3 in the middle third layer. Canonical discriminant function analysis indicated that complexity was the variable most influencing cluster formation. Correlation tests between complexity and escape latency for each animal group showed a significant correlation with a large effect size of 60 % [Pearson’s R: 0.605, p < 0.001] in the HD group in the middle third, which was disrupted by altered masticatory activity. AST3 morphotype in the middle third showed a linear correlation with learning and spatial memory functions in the HD group [Pearson’s R: 0.624, p < 0.001] that disappeared with a reduction in masticatory activity, and nor restored by diet rehabilitation. This finding was not observed for inner and outer layers, supporting the contribution of middle third AST3 to learning and spatial memory. Group comparison tests also revealed that diet differentially impacts astrocyte subpopulations on each third of the dentate gyrus molecular layer. Data validate the influence of the masticatory activity on astrocyte complexity and suggest the existence of AST3 association with spatial memory and learning tasks in young female mice. Further research on the underlying mechanisms of these relationships is essential to identify potential therapeutic targets for cognitive disorders and to develop effective interventions to preserve cognitive function.

Nucleus accumbens shell electrical lesion attenuates seizures and gliosis in chronic temporal lobe epilepsy rats.

Temporal lobe epilepsy (TLE) is the most prevalent form of epilepsy. Prior research has indicated the involvement of the nucleus accumbens shell (NAcSh) in the process of epileptogenesis, thereby implying its potential as a therapeutic target for TLE. In the present study, we investigated the antiepileptic effect of the NAcSh electrical lesion. Chronic TLE was induced by stereotactic injection of kainic acid (KA) into the hippocampus 3 weeks after KA administration, and NAcSh electrical lesions were performed. Seizures in rats were monitored by video electroencephalogram (EEG) 1 week following the NAcSh electrical lesion. Besides, the spatial memory function assessment in rats was conducted using the Morris water maze (MWM) test in the final week of the experiment. Later, hippocampal glial cell activation and neuron loss in rats were evaluated through immunohistochemistry. TLE rats subjected to NAcSh electrical lesion exhibited a significant reduction in the frequency of seizures compared to untreated TLE rats. Furthermore, NAcSh electrical lesion led to less activation of hippocampal glial cells and fewer neuronal loss in TLE rats. It is worth noting that the NAcSh electrical lesion did not cause additional memory impairment. In the present study, the NAcSh electrical lesion exhibited a definitive therapeutic effect on the chronic TLE rat model, potentially due to decreased hippocampal TLE-induced activation of glial cells and neuron loss. In conclusion, our results indicated that the NAcSh is a promising therapeutic target for TLE and possesses high potential for clinical application.

Neuronal plasticity changes in the central amygdala and prelimbic cortex network in mice with chronic unpredictable mild stress-induced depression

To explore the relationship between alterations of neural network plasticity and spatial learning and memory functions in mouse models with depression-like behaviors. C57Thy1-YFP/GAD67-GFP mice were randomized into control group (with no treatment) and chronic unpredictable mild stress (CUMS) group (n=15) subjected to CUMS for 8 weeks. Depression-like behaviors of the mice were assessed using sucrose preference test, open field test, and forced swimming test, and their spatial learning and memory abilities were evaluated using Morris water maze test. The changes in the firing patterns of different neuronal subtypes were detected in the central nucleus of the amygdala (CeA) and the prelimbic cortex (PrL) using whole-cell patch-clamp technique. Compared with the control mice, CUMS mice showed significantly decreased sucrose preference, total distance moved, number of grid-crossings, entries into the central area, and time spent in the central area in the open field test (P < 0.01). In the forced swimming test, CUMS mice exhibited obviously shortened time of struggling, swimming, and climbing with increased immobility time. In Morris water maze test, CUMS mice showed significantly increased escape latency and path length, decreased percentage of distance and swimming time within the target quadrant, and increased first entry latency into the target zone and swimming time within the opposite quadrant. Exposure to CUMS resulted in significantly enhanced energy barrier and increased absolute refractory period and inter-spike interval of glutamatergic neurons in the CeA and GABAergic neurons in the PrL, while the opposite changes were observed in GABAergic neurons in the CeA and glutamatergic neurons in the PrL. CUMS-induced depression may lead to plastic changes in the excitatory and inhibitory neuronal networks within the CeA and PrL to cause impairment of spatial learning and memory abilities in mice.

Alterations in Circular RNAs circOprm1 and circSerpini in the Striatum are Associated with Changes in Spatial Working Memory Performance after Morphine Dependence and Withdrawal in Rats.

Modulating role of circRNAs and microRNAs in neurobiological changes induced by drug exposure remains unclear. We examined alterations in some circRNAs and microRNAs in the striatum after morphine dependence and withdrawal and their associations with the changes in spatial working memory performance. Male Wistar rats were used in which 10 days morphine exposure induced dependence. Withdrawal effects were assessed 30 days after stopping morphine exposure. Spatial working memory was assessed using a Y maze test on days 1 and 10 of the drug exposure and 30 days after withdrawal. The gene and protein expression were assessed after dependence and withdrawal. The results revealed that 10 days morphine exposure impaired working memory, which partially reinstated after withdrawal. After 10 days morphine exposure, significant increases in Oprm1 gene and OPRM1 protein levels were detected, which persisted even after withdrawal. The expression of circOprm1 and miR-339-3p decreased in the morphine-dependent group, but they returned to normal levels after withdrawal. The expression of Tlr4 gene and TLR4 protein levels decreased after dependence. While Tlr4 mRNA levels returned to normal after withdrawal, TLR4 protein levels remained lower than the control group. In the morphine-dependent group, both Serpini1 and circSerpini expression significantly increased, but they restored after withdrawal. Expression of miR-181b-3p, miR-181b-5p, miR-181c-3p, and miR-181c-5p decreased after dependence, but they reinstated after withdrawal. It can be concluded that circOprm1 and circSerpini via regulating the OPRM1 and TLR4 expression in the striatum are associated with the neuroadaptation underlying spatial working memory after both morphine dependence and withdrawal.

Hippocampal iron overload and spatial reference memory impairment: Insights from a rat model

BackgroundBrain iron overload may induce neuronal death and lead to cognitive impairment. The hippocampus is a critical limbic structure involved in memory. This study aimed to investigate iron overload and its role in hippocampal damage and memory impairment using a rat model. MethodsYoung rats (2 weeks old) received intraperitoneal injections of high-dose iron solution (Group H, n = 10), low-dose iron solution (Group L, n = 10) and normal saline as control (Group D, n = 5). The Morris water maze (MWM) test was performed on all rats to evaluate their spatial reference memory by assessing their escape latency time and number of platform crossing. The iron content and neuronal damage in hippocampal tissue sections of the rats were assessed semi-quantitatively using diaminobenzidine (DAB)-enhanced Perl’s Prussian blue (PPB) staining, and their correlation with spatial reference memory performance was evaluated. ResultsThe escape latency in Group H was significantly longer compared to Groups L and D (P < 0.05). The number of platform crossings was significantly lower in Group H than in Group L or D (P < 0.001). The neuronal cells in Group H had more brown iron deposits than those of Groups L and D. There were significant correlations between the severity of structural damage in the hippocampal tissue and the number of platform crossings (P1 = 0.001 for Group H; P2 = 0.043 for Group L). ConclusionThis study showed an association between hippocampal iron-induced structural damage and spatial reference memory impairment in a rat model. This work should advance our understanding of hippocampal iron overload on cognitive functioning.

Spatial memory in Alzheimer's disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330.

The proteostatic decline in Alzheimer's disease is well established and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that XPO1 inhibitor KPT-330 (Selinexor), an FDA approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells and improves spatial memory performance in a murine model of Alzheimer's disease (5XFAD). Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

Spatial mRNA expression patterns of orexin receptors in the dorsal hippocampus.

Orexins are wake-promoting neuropeptides that originate from hypothalamic neurons projecting to widespread brain areas throughout the central nervous system. They modulate various physiological functions via their orexin 1 (OXR1) and 2 (OXR2) receptors, including sleep-wake rhythm but also cognitive functions such as memory formation. Here, we provide a detailed analysis of OXR1 and OXR2 mRNA expression profiles in the dorsal hippocampus as a key region for memory formation, using RNAscope multiplex in situ hybridization. Interconnected subareas relevant for cognition and memory such as the medial prefrontal cortex and the nucleus reuniens of the thalamus were assessed as well. Both receptor types display distinct profiles, with the highest percentage of OXR1 mRNA-positive cells in the hilus of the dentate gyrus. Here, the content of OXR1 mRNA per cell was slightly modulated at selected time points over a 12h light/ 12 dark light phase. Using RNAScope and quantitative polymerase chain reaction approaches, we began to address a cell-type specific expression of OXR1 in hilar GABAergic interneurons. The distinct expression profiles of both receptor subtypes within hippocampal subareas and circuits provide an interesting basis for future interventional studies on orexin receptor function in spatial and contextual memory.

Assessing rapid spatial working memory in community-living older adults in a virtual adaptation of the rodent water maze paradigm

Aging often leads to a decline in various cognitive domains, potentially contributing to spatial navigation challenges among older individuals. While the Morris water maze is a common tool in rodents research for evaluating allocentric spatial memory function, its translation to studying aging in humans, particularly its association with hippocampal dysfunction, has predominantly focused on spatial reference memory assessments. This study expanded the adaptation of the Morris water maze for older adults to assess flexible, rapid, one-trial working memory. This adaptation involved a spatial search task guided by allocentric cues within a 3-D virtual reality (VR) environment. The sensitivity of this approach to aging was examined in 146 community-living adults from three Chinese cities, categorized into three age groups. Significant performance deficits were observed in participants over 60 years old compared to younger adults aged between 18 and 43. However, interpreting these findings was complicated by factors such as psychomotor slowness and potential variations in task engagement, except during the probe tests. Notably, the transition from the 60 s to the 70 s was not associated with a substantial deterioration of performance. A distinction only emerged when the pattern of spatial search over the entire maze was examined in the probe tests when the target location was never revealed. The VR task's sensitivity to overall cognitive function in older adults was reinforced by the correlation between Montreal Cognitive Assessment (MoCA) scores and probe test performance, demonstrating up to 17 % shared variance beyond that predicted by chronological age alone. In conclusion, while implementing a VR-based adaptation of rodent water maze paradigms in older adults was feasible, our experience highlighted specific interpretative challenges that must be addressed before such a test can effectively supplement traditional cognitive assessment tools in evaluating age-related cognitive decline.

Whole-Body Vibration Affects Hippocampal Choline Acetyltransferase and Synaptophysin Expression and Improves Spatial Memory in Young Adult Mice.

Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-μm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases.