A Blended Vitamin Supplement Improves Spatial Cognitive and Short-Term Memory in Aged Mice.

Although many types of antioxidant supplements are available, the effect is greater if multiple types are taken simultaneously rather than one type. However, it is difficult to know which type and how much to take, as it is possible to take too many of some vitamins. As it is difficult for general consumers to make this choice, it is important to provide information based on scientific evidence. This study investigated the various effects of continuous administration of a blended supplement to aging mice. In 18-month-old C57BL/6 mice given a blended supplement ad libitum for 1 month, spatial cognition and short-term memory in the Morris water maze and Y-maze improved compared with the normal aged mice (spontaneous alternative ratio, normal aged mice, 49.5%, supplement-treated mice, 68.67%, p < 0.01). No significant differences in brain levels of secreted neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, were observed between these two groups. In treadmill durability tests before and after administration, the rate of increase in running distance after administration was significantly higher than that of the untreated group (increase rate, normal aged mice, 91.17%, supplement-treated aged mice, 111.4%, p < 0.04). However, training had no reinforcing effect, and post-mortem serum tests showed a significant decrease in aspartate aminotransferase, alanine aminotransferase, and total cholesterol values. These results suggest continuous intake of a blended supplement may improve cognitive function and suppress age-related muscle decline.

Vestibular dysfunction leads to cognitive impairments: State of knowledge in the field and clinical perspectives (Review).

The vestibular system may have a critical role in the integration of sensory information and the maintenance of cognitive function. A dysfunction in the vestibular system has a significant impact on quality of life. Recent research has provided evidence of a connection between vestibular information and cognitive functions, such as spatial memory, navigation and attention. Although the exact mechanisms linking the vestibular system to cognition remain elusive, researchers have identified various pathways. Vestibular dysfunction may lead to the degeneration of cortical vestibular network regions and adversely affect synaptic plasticity and neurogenesis in the hippocampus, ultimately contributing to neuronal atrophy and cell death, resulting in memory and visuospatial deficits. Furthermore, the extent of cognitive impairment varies depending on the specific type of vestibular disease. In the present study, the current literature was reviewed, potential causal relationships between vestibular dysfunction and cognitive performance were discussed and directions for future research were proposed.

Converting an allocentric goal into an egocentric steering signal.

Neuronal signals that are relevant for spatial navigation have been described in many species1-10. However, a circuit-level understanding of how such signals interact to guide navigational behaviour is lacking. Here we characterize a neuronal circuit in the Drosophila central complex that compares internally generated estimates of the heading and goal angles of the fly-both of which are encoded in world-centred (allocentric) coordinates-to generate a body-centred (egocentric) steering signal. Past work has suggested that the activity of EPG neurons represents the fly's moment-to-moment angular orientation, or heading angle, during navigation2,11. An animal's moment-to-moment heading angle, however, is not always aligned with its goal angle-that is, the allocentric direction in which it wishes to progress forward. We describe FC2 cells12, a second set of neurons in the Drosophila brain with activity that correlates with the fly's goal angle. Focal optogenetic activation of FC2 neurons induces flies to orient along experimenter-defined directions as they walk forward. EPG and FC2 neurons connect monosynaptically to a third neuronal class, PFL3 cells12,13. We found that individual PFL3 cells show conjunctive, spike-rate tuning to both the heading angle and the goal angle during goal-directed navigation. Informed by the anatomy and physiology of these three cell classes, we develop a model that explains how this circuit compares allocentric heading and goal angles to build an egocentric steering signal in the PFL3 output terminals. Quantitative analyses and optogenetic manipulations of PFL3 activity support the model. Finally, using a new navigational memory task, we show that flies expressing disruptors of synaptic transmission in subsets of PFL3 cells have a reduced ability to orient along arbitrary goal directions, with an effect size in quantitative accordance with the prediction of our model. The biological circuit described here reveals how two population-level allocentric signals are compared in the brain to produce an egocentric output signal that is appropriate for motor control.

Muscarinic receptor activation promotes destabilization and updating of object location memories in mice.

The storage of long-term memories is a dynamic process. Reminder cues can destabilize previously consolidated memories, rendering them labile and modifiable. However, memories that are strongly encoded or relatively remote at the time of reactivation can resist destabilization only being rendered labile under conditions that favour memory updating. Using the object location recognition task, here we show in male C57BL/6 mice that novelty-induced destabilization of strongly-encoded memories requires muscarinic acetylcholine receptor (mAChR) activation. Furthermore, we use the objects-in-updated locations task to show that updating of object location memories is mAChR-dependent. Thus, mAChR stimulation appears to be critical for spatial memory destabilization and related memory updating. Enhancing our understanding of the role of ACh in memory updating should inform future research into the underlying causes of behavioural disorders that are characterized by persistent maladaptive memories, such as age-related cognitive inflexibility and post-traumatic stress disorder.

Arctigenin attenuated spatial memory impairment in pR5 mice by regulating mitochondrial energy metabolism.

OBJECTIVES: Arctigenin (ATG) is a natural product with a variety of biological activity, which can improve the pathological changes of Alzheimer's disease (AD) model mice through multiple mechanisms. This study aims to further elucidate the potential mechanism by which ATG improves memory impairment in AD mice. METHODS: Here, we used pR5 mice as an experimental model, and ATG was administered continuously for 90 days. Novel object recognition, Y-maze, and Morris water maze were used to evaluate the therapeutic effect of ATG on memory impairment in AD mice. Immunohistochemical and immunofluorescence analyses were used to evaluate the effects of ATG on tau hyperphosphorylation and neuroinflammation, respectively. Finally, proteomics techniques were used to explore the possible mechanism of ATG. KEY FINDINGS: ATG significantly improved memory impairment in pR5 mice and inhibited tau phosphorylation in the hippocampus and neuroinflammation in the cortex. According to the proteomic analysis, the altered cognitive function of ATG was associated with the proteins of the tricarboxylic acid cycle and the electron transport chain. CONCLUSION: These results suggest that ATG is a potential therapeutic agent for diseases related to aberrant energy metabolism that can treat AD by improving mitochondrial function.

Analysis of NAPA Gene Expression in Brain Structures of Wistar Rats during the Formation of Long-Term Spatial Memory and Physical Activity under Stress Situation.

In the cerebellum, hippocampus, and prefrontal cortex of mature male Wistar rats with trained spatial navigational skill in the Morris water maze, the transcriptional activity the NAPA gene that regulates the transport and secretion of synaptic vesicles, release of neurotransmitters, and protein degradation was determined by real-time PCR. Animals subjected to forced swimming in a time-matched regime (active control) and naïve rats were used as the comparison groups. Suppression of NAPA gene activity was found in the hippocampus and cerebellum of the active control group, while navigation skill training led to a significant increase in gene expression in all brain structures under study. The findings suggest the existence of specific mechanisms regulating NAPA gene activity during the formation of spatial memory and adaptive behavior under stress conditions.

Collective interactions, collaborative inhibition, and shared spatial knowledge.

Research on spatial mental representations focuses on individual mental maps and spatial knowledge. This exploratory study investigates instead collective interactions, collaborative memory, and the sharing of spatial knowledge. Based on the principle of collaborative inhibition (i.e., people recall information less effectively in groups), we posed the following research question: How do collective interactions, occurring during environmental exploration and group drawing sessions, affect collaborative inhibition, and the quality of sketch maps designed collectively? We conducted in situ explorations in Plaine St-Denis (France) with real-time tracking, followed by individual and group drawing sessions. This experiment involved 118 participants divided into three groups: (1) solo explorations without devices; (2) solo explorations with a mobile mapping application; (3) collective explorations using the same application enhanced with interaction features (viewing collective routes and photos of visited places). The comparison of the total number of entities found on individual mental maps with those included in collective sketch maps reveals that collaborative inhibition applies to spatial memory. Additional findings indicate that the use of a map, combined with collective interactions, mitigates collaborative inhibition and increases the accuracy of the sketch maps. However, the effect of such interactions on group dynamics remains unclear as of now.

Extended trajectory of spatial memory errors in typical and atypical development: The role of binding and precision.

Spatial reconstruction, a method for evaluating how individuals remember the placement of objects, has traditionally been evaluated through the aggregate estimation of placement errors. However, this approach may obscure the nature of task errors. Specifically, recent data has suggested the importance of examining the precision of responses, as well as absolute performance on item-context bindings. In contrast to traditional analysis approaches based on the distance between the target and the reconstructed item, in this study we further explored three types of errors (swap error, global error, and local distance) that may all contribute to the distance, with particular emphasis on swap errors and local distance due to their associations with item-context bindings and memory precision, respectively. We examined these errors in children aged 3-18 years, making comparisons between children with typical development (TD) and children with Down syndrome (DS), a population with known memory challenges. As expected, older children outperformed younger children in terms of overall memory accuracy. Of importance is that we measured uneven maturational trajectories of memory abilities across the various error types. Specifically, both remembered locations (irrespective of object identity) and swap errors (object-location binding errors) align with the overall memory accuracy. Memory precision, as measured by local distance in simpler set size 2 trials, mirrored overall memory accuracy. However, for more complex set size 3 trials, local distance remained stable before age 8 and showed age-related change thereafter. The group with DS showed reduced precision compared to a TD matched group, and measures of precision, and to a lesser extent binding errors, correlated with standard neuropsychological outcomes. Overall, our study contributed to a fine-grained understanding of developing spatial memory ability in a large sample of typical developing children and a memory impaired population. These findings contribute to a growing body of research examining precision as a key factor in memory performance.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

Delayed formation of neural representations of space in aged mice.

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan.

Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences. We show that adult and aged male wild-type mice that underwent a 10-week environmental enrichment protocol demonstrated improved performance in a variety of behavioural tasks, including those testing spatial working and spatial reference memory, and an enhancement in hippocampal LTP. Aged animals in particular benefitted from enrichment, performing spatial memory tasks at levels similar to healthy adult mice. Many of these benefits, including in gene expression, were absent in mice with a mutation in an enzyme, MSK1, which is activated by BDNF, a growth factor implicated in rodent and human cognition. We conclude that enrichment is beneficial across the lifespan and that MSK1 is required for the full extent of these experience-induced improvements of cognitive abilities, synaptic plasticity and gene expression.

Muscimol inactivation of dorsal striatum in young and aged male rats does not affect paired associates learning performance.

Improving cognitive health for older adults requires understanding the neurobiology of age-related cognitive decline and the mechanisms underlying preserved cognition in old age. During spatial learning tasks, aged humans and rodents shift navigation preferences in favor of a stimulus-response learning strategy. This has been hypothesized to result from competitive interactions of the caudate nucleus/dorsal striatum (DS) memory system with the hippocampus (HPC)-dependent spatial/allocentric memory system. In support of this hypothesis, a recent study reported that inactivation of the DS in aged rodents rescued HPC-dependent spatial learning on a T-maze (Gardner, Gold, & Korol, 2020). Currently, it is unclear whether a shift from HPC-dependent to DS-dependent behavior also contributes to age-related cognitive decline outside of spatial learning and memory. To test the hypothesis that inactivation of the DS can restore age-related cognitive function outside of spatial behavior, the present study bilaterally inactivated the DS of young (n = 8) and aged (n = 7) rats during visuospatial paired associates learning (PAL). This study found that inactivation of the DS did not alter PAL performance in young or aged rats, but did alter a positive control, DS-dependent spatial navigation task. This observation suggests that elevated DS activity does not play a role in the decline of HPC-dependent PAL performance in aged male rats. Given the persistent tendencies of aged rodents toward DS-dependent learning, it will be worthwhile to explore further the coordination dynamics between the HPC and DS that may contribute to age-related cognitive decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cognitive rescue in aging through prior training in rats.

Cognitive decline in spatial memory is seen in aging. Understanding affected processes in aging is vital for developing methods to improve wellbeing. Daily memory persistence can be influenced by events around the time of learning or by prior experiences in early life. Fading memories in young can last longer if a novel event is introduced around encoding, a process called behavioral tagging. Based on this principle, we asked what processes are affected in aging and if prior training can rescue them. Two groups of aged rats received training in an appetitive delayed matching-to-place task. One of the groups additionally received prior training of the same task in young and in mid-life, constituting a longitudinal study. The results showed long-term memory decline in late aging without prior training. This would reflect affected encoding and consolidation. On the other hand, short-term memory was preserved and novelty at memory reactivation and reconsolidation enabled memory maintenance in aging. Prior training improved cognition through facilitating task performance, strengthening short-term memory and intermediate memory, and enabling encoding-boosted long-term memory. Implication of these findings in understanding brain mechanisms in cognitive aging and in beneficial effects of prior training is discussed.

Nucleus incertus projections to rat medial septum and entorhinal cortex: rare collateralization and septal-gating of temporal lobe theta rhythm activity.

Nucleus incertus (NI) neurons in the pontine tegmentum give rise to ascending forebrain projections and express the neuropeptide relaxin-3 (RLN3) which acts via the relaxin-family peptide 3 receptor (RXFP3). Activity in the hippocampus and entorhinal cortex can be driven from the medial septum (MS), and the NI projects to all these centers, where a prominent pattern of activity is theta rhythm, which is related to spatial memory processing. Therefore, we examined the degree of collateralization of NI projections to the MS and the medial temporal lobe (MTL), comprising medial and lateral entorhinal cortex (MEnt, LEnt) and dentate gyrus (DG), and the ability of the MS to drive entorhinal theta in the adult rat. We injected fluorogold and cholera toxin-B into the MS septum and either MEnt, LEnt or DG, to determine the percentage of retrogradely labeled neurons in the NI projecting to both or single targets, and the relative proportion of these neurons that were RLN3-positive ( +). The projection to the MS was threefold stronger than that to the MTL. Moreover, a majority of NI neurons projected independently to either MS or the MTL. However, RLN3 + neurons collateralize significantly more than RLN3-negative (-) neurons. In in vivo studies, electrical stimulation of the NI induced theta activity in the MS and the entorhinal cortex, which was impaired by intraseptal infusion of an RXFP3 antagonist, R3(BΔ23-27)R/I5, particularly at ~ 20 min post-injection. These findings suggest that the MS plays an important relay function in the NI-induced generation of theta within the entorhinal cortex.

Running throughout Middle-Age Keeps Old Adult-Born Neurons Wired.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Dopamine differentially modulates medial temporal lobe activity and behavior during spatial navigation in young and older adults.

Aging is associated with changes in spatial navigation behavior. In addition to an overall performance decline, older adults tend to rely more on proximal location cue information than on environmental boundary information during spatial navigation compared to young adults. The fact that older adults are more susceptible to errors during spatial navigation might be partly attributed to deficient dopaminergic modulation of hippocampal and striatal functioning. Hence, elevating dopamine levels might differentially modulate spatial navigation and memory performance in young and older adults. In this work, we administered levodopa (L-DOPA) in a double-blind within-subject, placebo-controlled design and recorded functional neuroimaging while young and older adults performed a 3D spatial navigation task in which boundary geometry or the position of a location cue were systematically manipulated. An age by intervention interaction on the neural level revealed an upregulation of brain responses in older adults and a downregulation of responses in young adults within the medial temporal lobe (including hippocampus and parahippocampus) and brainstem, during memory retrieval. Behaviorally, L-DOPA had no effect on older adults' overall memory performance; however, older adults whose spatial memory improved under L-DOPA also showed a shift towards more boundary processing under L-DOPA. In young adults, L-DOPA induced a decline in spatial memory performance in task-naïve participants. These results are consistent with the inverted-U-shaped hypothesis of dopamine signaling and cognitive function and suggest that increasing dopamine availability improves hippocampus-dependent place learning in some older adults.

Persicaria minor ameliorates the cognitive function of chronic cerebral hypoperfusion rats: Metabolomic analysis and potential mechanisms.

Persicaria minor (P. minor) is a herbal plant with many uses in food, perfume, and the medical industry. P. minor extract contains flavonoids with antioxidant and anticholinesterase capacity, which could enhance cognitive functions. P. minor extract has been proven to enhance memory. However, its role in an animal model of chronic cerebral hypoperfusion (CCH), which resembles human vascular dementia, has yet to be explored. Therefore, the present study investigates the effects of chronic (14 days) administration of aqueous P. minor extract on different stages of learning and memory processes and the metabolic pathways involved in the chronic cerebral hypoperfused rats induced by the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery. Chronic treatment of P. minor extract at doses of 200 and 300 mg/kg, enhanced recognition memory of the PBOCCA rats. P. minor extract (200 mg/kg) was also found to restore the spatial memory impairment induced by CCH. A high dose (300 mg/kg) of the P. minor extract significantly increased the expression of both ACh and GABA neurotransmitters in the hippocampus. Further, distinctive metabolite profiles were observed in rats with different treatments. Three major pathways involved in the cognitive enhancement mechanism of P. minor were identified. The present findings demonstrated an improving effect of P. minor extract on memory in the CCH rat model, suggesting that P. minor extract could be a potential treatment for vascular dementia and Alzheimer's patients. P. minor is believed to improve cognitive deficits by regulating pathways involved in retinol, histidine, pentose, glucuronate, and CoA metabolism.

Hippocampal inactivation during rearing on hind legs impairs spatial memory.

Spatial memory requires an intact hippocampus. Hippocampal function during epochs of locomotion and quiet rest (e.g., grooming and reward consumption) has been the target of extensive study. However, during navigation rats frequently rear up onto their hind legs, and the importance of hippocampal activity during these periods of attentive sampling for spatial memory is unknown. To address this, we tested the necessity of dorsal hippocampal activity during rearing epochs in the study phase of a delayed win-shift task for memory performance in the subsequent test phase. Hippocampal activity was manipulated with closed-loop, bilateral, optogenetic inactivation. Spatial memory accuracy was significantly and selectively reduced when the dorsal hippocampus was inactivated during rearing epochs at encoding. These data show that hippocampal activity during periods of rearing can be important for spatial memory, revealing a novel link between hippocampal function during epochs of rearing and spatial memory.

Limbic progesterone receptors regulate spatial memory.

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory is not understood. Male mice expressed PRs, predominately in excitatory neurons, in brain regions that support spatial memory, such as the hippocampus and entorhinal cortex (EC). Furthermore, segesterone, a specific PR agonist, activates neurons in both the EC and hippocampus. We assessed the contribution of PRs in promoting spatial and non-spatial cognitive learning in male mice by examining the performance of mice lacking this receptor (PRKO), in novel object recognition, object placement, Y-maze alternation, and Morris-Water Maze (MWM) tasks. In the recognition test, the PRKO mice preferred the familiar object over the novel object. A similar preference for the familiar object was also seen following the EC-specific deletion of PRs. PRKO mice were also unable to recognize the change in object position. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation and MWM tasks; PR deletion affected animal's performance in both these tasks. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. These studies provide novel insights into the role of PRs in facilitating spatial, declarative memory in males, which may help with finding reproductive partners.

Chronic stress beginning in adolescence decreases spatial memory following an acute inflammatory challenge in adulthood.

Prolonged stress beginning in adolescence can contribute to the dysregulation of the neuroendocrine system in adulthood. As the neuroendocrine and neuroimmune systems participate in bi-directional regulatory control, adolescent stress can prime the neuroimmune system to future inflammatory insults. Previous work from our group demonstrates that stress exaggerates the hippocampal response to inflammation, which can lead to deficits in learning and memory. In the current study, we sought to interrogate the interaction between an acute peripheral challenge of lipopolysaccharide (LPS) in male and female Wistar rats with a history of stress beginning in adolescence (CAS). Males from the CAS group were more vulnerable to the peripheral effects of LPS compared to non-stressed males including porphyrin staining and ruffled fur. In contrast, LPS generated similar peripheral effects in females regardless of adolescent stress history. Learning and memory were differentially impacted by LPS as a function of stress history and effects manifested differently when stratified by sex. Males with a history of adolescent stress exhibited deficits in initial learning. Females from the CAS group performed similar to controls during acquisition but exhibited a slight impairment during reversal learning. Males and females with a history of stress displayed memory impairment during the probe assessments as compared to their same-sex control group. We conclude that while stress beginning in adolescence enhanced the vulnerability of learning and memory to an inflammatory challenge, the phenotype of this effect manifested differently in males and females. These data demonstrate a sustained impact of adolescent stress on the neuroimmune system which is sufficient to influence cognitive performance in both sexes.