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Naturalistic observations show that animals pre-empt danger by moving to locations that increase their success in avoiding future threats. To test this in humans, we created a spatial margin of safety (MOS) decision task that quantifies pre-emptive avoidance by measuring the distance subjects place themselves to safety when facing different threats whose attack locations vary in predictability. Behavioral results show that human participants place themselves closer to safe locations when facing threats that attack in spatial locations with more outliers. Using both univariate and multivariate pattern analysis (MVPA) on fMRI data collected during a 2 h session on participants of both sexes, we demonstrate a dissociable role for the vmPFC in MOS-related decision-making. MVPA results revealed that the posterior vmPFC encoded for more unpredictable threats with univariate analyses showing a functional coupling with the amygdala and hippocampus. Conversely, the anterior vmPFC was more active for the more predictable attacks and showed coupling with the striatum. Our findings converge in showing that during pre-emptive danger, the anterior vmPFC may provide a safety signal, possibly via foreseeable outcomes, while the posterior vmPFC drives unpredictable danger signals. [ABSTRACT FROM AUTHOR]

To better understand neural processing during adaptive learning of stimulus‐response‐reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y‐maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule‐change responsive neurons (70%), but other neurons that were correlated with strategy‐change, strategy value and reward‐rate were not. However, hippocampal sharp wave‐ripples modulated significantly higher proportions of rule‐change, strategy‐change and reward‐rate responsive cells during post‐session sleep but not pre‐session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged. [ABSTRACT FROM AUTHOR]

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging. [ABSTRACT FROM AUTHOR]

Background and objectives: Cognitive reserve (CR) is a property of the brain that allows for better-than-expected cognitive performance relative to the degree of brain change over the course of life. However, neurophysiological markers of CR remain under-investigated. Electroencephalography (EEG) features may function as suitable neurophysiological markers of CR. To assess this, we investigated whether the dorsal attention network (DAN) and ventral attention network (VAN) activities, as measured during resting-state EEG, moderate the relationship between hippocampal volume and episodic memory. Methods: Participants were recruited as part of the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes. Hippocampal volume was determined using magnetic MRI, and episodic memory was measured using word lists. After testing the effect of hippocampal volume on memory performance using multiple regression analysis, we evaluated the interactions between hippocampal volume and DAN and VAN network activities. We further used the Johnson-Neyman technique to quantify the moderating effects of DAN and VAN network activities on the relationship between hippocampal volume and word list memory, as well as to identify specific ranges of DAN and VAN network activity with significant hippocampal-memory association. Results: A total of 449 participants were included in this study. Our analysis revealed significant moderation of DAN with a slope of β = -0.00012 (95% CI: -0.00024; -0.00001, p = 0.040), and VAN with a slope of β = 0.00014 (95% CI: 0.00001; 0.00026, p = 0.031). Further, we found that a larger hippocampal volume was associated with improved memory performance, and that this association became stronger as the DAN activity decreased until a limit of DAN activity of 944.9, after which the hippocampal volume was no longer significantly related to word-list memory performance. For the VAN, we found that a higher hippocampal volume was more strongly associated with better memory performance when VAN activity was higher. However, when VAN activity extended beyond -914.6, the hippocampal volume was no longer significantly associated with word-list memory. Discussion: Our results suggest that attentional networks help to maintain memory performance in the face of age-related structural decline, meeting the criteria for the neural implementation of cognitive reserve. [ABSTRACT FROM AUTHOR]

Background: Insomnia disorder (ID) is one of the most common sleep problems, usually accompanied by anxiety and depression symptoms. Functional magnetic resonance imaging (fMRI) study suggests that both poor sleep quality and negative emotion are linked to the dysregulation of brain network related to emotion processing in ID patients. Acupuncture therapy has been proven effective in improving sleep quality and mood of ID patients, but the involved neurobiological mechanism remains unclear. We aimed to investigate the modulation effect of acupuncture on resting-state functional connectivity (rsFC) of the emotional network (EN) in patients experiencing insomnia. Methods: A total of 30 healthy controls (HCs) and 60 ID patients were enrolled in this study. Sixty ID patients were randomly assigned to real and sham acupuncture groups and attended resting-state fMRI scans before and after 4 weeks of acupuncture treatment. HCs completed an MRI/fMRI scan at baseline. The rsFC values within EN were calculated, and Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), Hyperarousal Scale (HAS), and actigraphy data were collected for clinical efficacy evaluation. Results: Resting-state FC analysis showed abnormalities in rsFC centered on the thalamus and dorsolateral prefrontal cortex within EN of ID patients compared to HCs. After real acupuncture treatment, rsFC of the anterior cingulate cortex, hippocampus, and amygdala were increased compared with the sham acupuncture group (p < 0.05, FDR corrected). In real acupuncture group, the rsFC value was decreased between left amygdala and left thalamus after 4 weeks of treatment compared with baseline. A trend of correlation was found that the increased rsFC value between the right amygdala and left hippocampus was positively correlated with the decreased HAMA scores across all ID patients, and the decreased left amygdala rsFC value with the left thalamus was negatively correlated with the increased sleep efficiency in the real acupuncture group. Conclusion: Our findings showed that real acupuncture could produce a positive effect on modulating rsFC within network related to emotion processing in ID patients, which may illustrate the central mechanism underlying acupuncture for insomnia in improving sleep quality and emotion regulation. Trial registration: http://www.chictr.org.cn., ChiCTR1800015282, 20/03/2018. [ABSTRACT FROM AUTHOR]

Ageing is characterized by a gradual decline in the efficiency of physiological functions and increased vulnerability to diseases. Ageing affects the entire body, including physical, mental, and social well-being, but its impact on the brain and cognition can have a particularly significant effect on an individual's overall quality of life. Therefore, enhancing lifespan and physical health in longevity studies will be incomplete if cognitive ageing is over looked. Promoting successful cognitive ageing encompasses the objectives of mitigating cognitive decline, as well as simultaneously enhancing brain function and cognitive reserve. Studies in both humans and animal models indicate that cognitive decline related to normal ageing and age-associated brain disorders are more likely linked to changes in synaptic connections that form the basis of learning and memory. This activitydependent synaptic plasticity reorganises the structure and function of neurons not only to adapt to new environments, but also to remain robust and stable over time. Therefore, understanding the neural mechanisms that are responsible for age-related cognitive decline becomes increasingly important. In this review, we explore the multifaceted aspects of healthy brain ageing with emphasis on synaptic plasticity, its adaptive mechanisms and the various factors affecting the decline in cognitive functions during ageing. We will also explore the dynamic brain and neuroplasticity, and the role of lifestyle in shaping neuronal plasticity. [ABSTRACT FROM AUTHOR]

The entorhinal cortex represents allocentric spatial geometry and egocentric speed and heading information required for spatial navigation. However, it remains unclear whether it contributes to the prediction of an animalÕs future location. We discovered grid cells in the medial entorhinal cortex (MEC) that have grid fields representing future locations during goal-directed behavior. These predictive grid cells represented prospective spatial information by shifting their grid fields against the direction of travel. Predictive grid cells discharged at the trough phases of the hippocampal CA1 theta oscillation and, together with other types of grid cells, organized sequences of the trajectory from the current to future positions across each theta cycle. Our results suggest that the MEC provides a predictive map that supports forward planning in spatial navigation. [ABSTRACT FROM AUTHOR]

Memory consolidation involves the synchronous reactivation of hippocampal cells active during recent experience in sleep sharp-wave ripples (SWRs). How this increase in firing rates and synchrony after learning is counterbalanced to preserve network stability is not understood. We discovered a network event generated by an intrahippocampal circuit formed by a subset of CA2 pyramidal cells to cholecystokinin-expressing (CCK+) basket cells, which fire a barrage of action potentials (“BARR”) during non–rapid eye movement sleep. CA1 neurons and assemblies that increased their activity during learning were reactivated during SWRs but inhibited during BARRs. The initial increase in reactivation during SWRs returned to baseline through sleep. This trend was abolished by silencing CCK+ basket cells during BARRs, resulting in higher synchrony of CA1 assemblies and impaired memory consolidation. [ABSTRACT FROM AUTHOR]

The hippocampal CA3 region plays an important role in learning and memory. CA3 pyramidal neurons (PNs) receive two prominent excitatory inputs-mossy fibers (MFs) from dentate gyrus (DG) and recurrent collaterals (RCs) from CA3 PNs-that play opposing roles in pattern separation and pattern completion, respectively. Although the dorsoventral heterogeneity of the hippocampal anatomy, physiology, and behavior has been well established, nothing is known about the dorsoventral heterogeneity of synaptic connectivity in CA3 PNs. In this study, we performed Timm’s sulfide silver staining, dendritic and spine morphological analyses, and ex vivo electrophysiology in mice of both sexes to investigate the heterogeneity of MF and RC pathways along the CA3 dorsoventral axis. Our morphological analyses demonstrate that ventral CA3 (vCA3) PNs possess greater dendritic lengths and more complex dendritic arborization, compared with dorsal CA3 (dCA3) PNs. Moreover, using ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording, we found that the ratio of the RC-to-MF excitatory drive onto CA3 PNs increases substantially from dCA3 to vCA3, with vCA3 PNs receiving significantly weaker MFs, but stronger RCs, excitation than dCA3 PNs. Given the distinct roles of MF versus RC inputs in pattern separation versus completion, our findings of the significant dorsoventral variations of MF and RC excitation in CA3 PNs may have important functional implications for the contribution of CA3 circuit to the dorsoventral difference in hippocampal function [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common neurogenerative disorder without effective treatments. Defects in mitochondrial complex I are thought to contribute to AD pathogenesis. The aim of this study is to explore whether a novel gene therapy transducing yeast complex I gene NDI1 can be used to treat AD with severely reduced complex I function in cell and animal models. Methods: The differentiated human neural cells were induced by Aβ1–42 to establish the AD cell model, and adeno-associated virus serotype 9 (AAV9) was used to transduce yeast NDI1 into the cell model. Aβ1–42 was injected into the hippocampus area of the brain to establish the AD mouse model. AAV9-NDI1 was injected stereotaxically into the hippocampus area to test the therapeutic effect. Results: The expressed yeast complex I had an ameliorating effect on the defective function of human complex I and cellular pathological characteristics in the AD cell model. Furthermore, AAV9-NDI1 gene therapy in the hippocampus had a therapeutic effect on various aspects of mitochondrial function, histopathological characteristics and neurological defects in the AD mouse model. In addition, AAV9-NDI1 injection into the hippocampus of normal mice did not cause any adverse effect. Conclusions: Compensating mitochondrial complex I function with yeast NDI1 is effective for gene therapy in Aβ-induced AD cell and mouse models. The results of this study offer a novel strategy and approach for treating AD types characterized by complex I abnormalities. [ABSTRACT FROM AUTHOR]

Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor β-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM [ABSTRACT FROM AUTHOR]

Reactivating place cells during sharp-wave ripples in the hippocampus is important for memory consolidation. However, whether hippocampal reactivation is affected by the values of events experienced by the animal is largely unknown. Here, we investigated whether place cells in the dorsal (dHP) and intermediate hippocampus (iHP) of rats are differentially reactivated depending on the value associated with a place during the learning of places associated with higher-value rewards in a T-maze. Place cells in the iHP representing the high-value location were reactivated significantly more frequently than those representing the low-value location, characteristics not observed in the dHP. In contrast, the activities of place cells in the dHP coding the routes leading to high-value locations were replayed more than those in the iHP. Our findings suggest that value-based differential reactivation patterns along the septotemporal axis of the hippocampus may play essential roles in optimizing goal-directed spatial learning for maximal reward. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Photopharmacology is a new technique for modulating biological phenomena through the photoconversion of substances in a specific target region at precise times. Caged compounds are thought to be compatible with photopharmacology as uncaged ligands are released and function in a light irradiation‐dependent manner. Here, we investigated whether a microscale light‐emitting diode (MicroLED) probe is applicable for the photoconversion of caged‐glutamate (caged‐Glu) in vivo.A needle‐shaped MicroLED probe was fabricated and inserted into the mouse hippocampal dentate gyrus (DG) with a cannula for drug injection and a recording electrode for measuring the local field potential (LFP). Artificial cerebrospinal fluid (ACSF) or caged‐Glu was infused into the DG and illuminated with light from a MicroLED probe.In the caged‐Glu‐injected DG, the LFP changed in the 10–20 Hz frequency ranges after light illumination, whereas there was no change in the ACSF control condition.The MicroLED probe is applicable for photopharmacological experiments to modulate LFP with caged‐Glu in vivo. [ABSTRACT FROM AUTHOR]

Hippocampal CA1 neurons show intense firing at specific spatial locations, modulated by isolated landmarks. However, the impact of real‐world scene transitions on neuronal activity remains unclear. Moreover, long‐term neural recording during movement challenges device stability. Conventional rigid‐based electrodes cause inflammatory responses, restricting recording durations. Inspired by the jellyfish tentacles, the multi‐conductive layer ultra‐flexible microelectrode arrays (MEAs) are developed. The tentacle MEAs ensure stable recordings during movement, thereby enabling the discovery of soft boundary neurons. The soft boundary neurons demonstrate high‐frequency firing that aligns with the boundaries of scene transitions. Furthermore, the localization ability of soft boundary neurons improves with more scene transition boundaries, and their activity decreases when these boundaries are removed. The innovation of ultra‐flexible, high‐biocompatible tentacle MEAs improves the understanding of neural encoding in spatial cognition. They offer the potential for long‐term in vivo recording of neural information, facilitating breakthroughs in the understanding and application of brain spatial navigation mehanisms. [ABSTRACT FROM AUTHOR]

• vSub Microinfusion 5-HT1aR antagonist WAY100635 ameliorates MK-801-induced hyperactivity and PPI disruption. • Microinfusion of WAY100635 activated most of the excitatory neurons in the vSub. • WAY100635 reduced the MK-801-induced upregulation of 5-HT1aR in the vSub. Recent studies have shown that the 5-HT1a receptor (5-HT1aR) in the central 5-HT (Serotonergic) system is involved in the pathophysiology of schizophrenia through its various receptors, and the dysfunction of the ventral hippocampus may be a key causative factor in schizophrenia. To date, whether the 5-HT1a receptor is involved in ventral hippocampal dysfunction and its internal mechanism remain unclear. In this study, schizophrenia-like animal model was induced by intraperitoneal injection of aspartate receptor antagonist MK-801 in male Sprague Dawley rats, and the role of 5-HT1aR in this animal model was investigated by bilaterally micro-infusing the 5-HT1aR antagonist WAY100635 into the ventral subiculum (vSub) of the hippocampus of rats. Behavioral experiments such as open field test (OFT) and prepulse inhibition (PPI) were performed. The results showed that MK-801 induced hyperactivity and impaired prepulse inhibition in rats, whereas, micro-infusion of 5-HT1aR antagonist WAY100635 into the vSub ameliorated these phenomena. Immunofluorescence analysis revealed that WAY100635 significantly increased the c-Fos expression in vSub. Western blot and immunohistochemical analysis showed that MK-801 induced up-regulation of 5-HT1aR and phospho-extracellular regulated protein kinase (p-ERK) pathway, while micro-infusion of the WAY100635 down-regulated 5-HT1aR and p-ERK in the vSub. Therefore, the results of the present study suggested that in vSub, the 5-HT1aR antagonist WAY100635 may attenuate MK-801-induced schizophrenia-like activity by modulating excitatory neurons and downregulating p-ERK. [ABSTRACT FROM AUTHOR]

The dorsal region of the hippocampus (dHC) mediates many of the mnemonic functions traditionally associated with the hippocampus proper, such as spatial and episodic memory, whereas ventral hippocampus (vHC) has been extensively implicated in emotional memory and motivational processes. By contrast, the functions of the intermediate hippocampus (iHC) are far less understood. In this study, we aimed to investigate the mnemonic functions of iHC by reversibly inactivating iHC prior to testing memory in behavioral tasks dependent on the integrity of dHC, iHC, or vHC, namely, rapid place water maze, inhibitory avoidance, spontaneous alternation, and temporal ordering of odors. Given our previous findings showing that dHC and vHC are involved in mnemonic control of ingestive behavior, we also assessed the effects of iHC inactivation on sucrose intake. The results showed that pharmacological inhibition of iHC impairs rapid place water maze memory, which has been previously shown to be dependent on iHC but not dHC or vHC. iHC inactivation does not impact memory dependent on dHC (spontaneous alternation), vHC (temporal odor memory), or either dHC or vHC (inhibitory avoidance), and only modestly affects sucrose intake. These findings provide support for the involvement of iHC in mnemonic functions that are distinct from dHC and vHC and highlight the need to further advance our understanding of the functions of this hippocampal region that has been relatively understudied. [ABSTRACT FROM AUTHOR]

Although the hippocampus has been implicated in both the temporal organization of memories and association of scene elements, some theoretical accounts posit that the role of the hippocampus in episodic memory is largely atemporal. In this study, we set out to explore this discrepancy by identifying hippocampal activity patterns related to scene construction while participants performed a temporal order memory task. Participants in the fMRI scanner were shown a sequence of photographs, each consisting of a central object and a contextual background scene. On each retrieval trial, participants were shown a pair of the original photographs (FULL), objects from the scenes without the background (OBJ), or background contexts without the main foreground object (BACK). In the temporal order judgment (TOJ) task, participants judged the temporal order of the pair of scenes; in the Viewing trials, two identical scenes were shown without any task. First, we found that the anterior hippocampus—particularly the CA1 and subiculum—showed similar patterns of activation between the BACK and OBJ conditions, suggesting that scene construction occurred spontaneously during both TOJ and Viewing. Furthermore, neural markers of scene construction in the anterior hippocampus did not apply to incorrect trials, showing that successful temporal memory retrieval was functionally linked to scene construction. In the cortex, time‐processing areas, such as the supplementary motor area and the precuneus, and scene‐processing areas, such as the parahippocampal cortex, were activated and functionally connected with the hippocampus. Together, these results support the view that the hippocampus is concurrently involved in scene construction and temporal organization of memory and propose a model of hippocampal episodic memory that takes both processes into account. [ABSTRACT FROM AUTHOR]

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alphasynuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases. [ABSTRACT FROM AUTHOR]

It is well documented that older adults, compared to younger adults, produce fewer episodic details and more semantic details when recalling autobiographical memories. However, group comparisons have provided limited insight into the trajectories of detail generation across the lifespan. Utilising an open source dataset [Clark, I. A., & Maguire, E. A. (2023). Release of cognitive and multimodal MRI data including real-world tasks and hippocampal subfield segmentations. Scientific Data, 10(1), 1–29. https://doi.org/10.1038/s41597-022-01899-x], we examined how episodic and semantic detail generation varied with age among 194 younger adults, ages 20-41. We tested whether age differences were mediated by hippocampal subfield volumes and MTL resting-state functional connectivity. Results indicated that semantic details increased with age, while episodic details remained stable. We observed age differences in hippocampal subfield volumes and MTL connectivity, but these measures did not mediate age effects on semantic detail. Based on these and prior findings [Matijevic, S., Andrews-Hanna, J. R., Wank, A. A., Ryan, L., & Grilli, M. D. (2022). Individual differences in the relationship between episodic detail generation and resting state functional connectivity vary with age. Neuropsychologia, 166, 108138. https://doi.org/10.1016/j.neuropsychologia.2021.108138], we suggest a model of diverging episodic and semantic detail generation trajectories across the adult lifespan. [ABSTRACT FROM AUTHOR]

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O2) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s−1 and 15 cm·s−1. In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation. NEW & NOTEWORTHY: Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration. [ABSTRACT FROM AUTHOR]

Background: Consistent evidence shows that magnesium (Mg) intake is associated with lower blood pressure (BP), and that lower BP is associated with improved cerebral health. However, recent findings indicate that the positive effect of dietary Mg intake on cerebral health is not mediated by a decrease in BP. As Mg's anti-inflammatory action is a plausible alternative mechanism, the objective of this study was to investigate the associations between Mg intake and inflammation to determine whether it mediates any neuroprotective effect. Methods: Participants from the UK Biobank (n = 5775, aged 40–73 years, 54.7% female) were assessed for dietary magnesium using an online food questionnaire, brain and white matter lesion (WML) volumes were segmented with FreeSurfer software, and inflammation markers including high-sensitivity C-reactive protein (hs-CRP), leukocyte, erythrocyte count, and Glycoprotein acetylation (GlycA) were measured using specific laboratory techniques such as immunoturbidimetry, automated cell counting, and nuclear magnetic resonance. Hierarchical linear regression models were performed to investigate the association between dietary Mg, and inflammatory markers and between dietary Mg, brain and WMLs volumes. Mediation analysis was performed to test a possible mediation role of inflammation on the association between dietary Mg and brain and WMLs volumes. Results: Higher dietary Mg intake was associated with lower inflammation: hs-CRP level (− 0.0497%; 95% confidence interval [CI] − 0.0497%, − 0.0199%) leukocytes count (− 0.0015%; 95%CI − 0.00151%, − 0.0011%), and GlycA (− 0.0519%; 95%CI − 0.1298%, − 0.0129%). Moreover, higher dietary Mg intake was associated with larger grey matter volume (0.010%; 95%CI 0.004%, 0.017%), white matter volume (0.012%; 95%CI 0.003, 0.022) and right hippocampal volume (0.002%; 95%CI 0.0007, –0.0025%). Lower hs-CRP levels mediated the positive association between higher dietary Mg intake and larger grey matter volume. Conclusions: The anti-inflammatory effects of dietary Mg intake in the general population, appears to mediate its neuroprotective effect. [ABSTRACT FROM AUTHOR]

The hippocampus is a brain area linked to cognition. The mechanisms that maintain cognitive activity in humans are poorly understood. Centenarians display extreme longevity which is generally accompanied by better quality of life, lower cognitive impairment, and reduced incidence of pathologies including neurodegenerative diseases. We performed transcriptomic studies in hippocampus samples from individuals of different ages (centenarians [≥97 years], old, and young) and identified a differential gene expression pattern in centenarians compared to the other two groups. In particular, several isoforms of metallothioneins (MTs) were highly expressed in centenarians. Moreover, we identified that MTs were mainly expressed in astrocytes. Functional studies in human primary astrocytes revealed that MT1 and MT3 are necessary for their homeostasis maintenance. Overall, these results indicate that the expression of MTs specifically in astrocytes is a mechanism for protection during aging. [ABSTRACT FROM AUTHOR]

A topic of recent debate is the hypothesis that deficits associated with developmental disorders of language, such as reading disability, can be explained by a selective weakness in procedural memory. Adults with (n = 29; RD) and without (n = 29; TD) reading disability completed a weather prediction task under immediate and delayed feedback conditions, that rely on the striatal (procedural) and hippocampal (declarative) circuits, respectively. We examined trial‐by‐trial accuracy by feedback condition (immediate vs. delayed) and group (RD vs. TD). In the immediate feedback condition, we found the TD group to have a higher learning rate than the RD group. In the delayed feedback condition, we found the TD group reach a high level of accuracy early, and outperform the RD group for the duration of the task. The TD group also made gains in reaction time under both conditions, while the RD group slowed in their responses. Taken together, it appears that while procedural memory is indeed impaired in adults with reading disability, to a lesser extent, declarative memory is also affected. This lends partial support to the PDH, and more broadly to the position that reading disability is associated with general (non‐linguistic) difficulties in learning. [ABSTRACT FROM AUTHOR]

Background: The amygdala has an important role in cognitive and affective functions. The involvement of amygdala and related limbic structures is implicated in many aspects of memory and emotion in mild cognitive impairment (MCI). In the present study, we aimed to compare the volumetric measurements of amygdala and its subfields as well as their association with cognitive functions in stable MCI (sMCI). Methods: We performed Addenbrooke's cognitive examination III (ACE-III) test, as well as high-resolution T1-weighted images from 31 participants with sMCI and 31 age-matched healthy controls. The amygdala subfield volumes were extracted using Freesurfer software, and group differences were assessed using general linear model (GLM) with age, gender, education and estimated intracranial volume (ICV) as covariates. Partial correlation was also calculated between cognitive scores and volumes of amygdala subfields in healthy controls and sMCI participants controlling for estimated ICV. Results: sMCI participants exhibited significantly reduced volumes in most of the right amygdala subfields, including basal nucleus, accessory basal nucleus, central nucleus, medial nucleus, corticoamygdaloid transition area, and whole amygdala, as well as significantly reduced right amygdala/hippocampus ratio compared to healthy controls. In addition, our results revealed statistically significant positive correlations between ACE memory scores and the volumes of right central nucleus, right medial nucleus, right cortical nucleus, and the right whole amygdala, in sMCI. Conclusions: Our findings revealed volumetric reductions in most of the right amygdala subfields along with its association with the memory functions in sMCI. These findings provide valuable insights into the underlying anatomical factors contributing to neurocognitive symptoms in MCI. [ABSTRACT FROM AUTHOR]

Background: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. Methods: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. Results: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23–0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. Conclusion: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorder (FASD) is one of the leading causes of neurodevelopmental disorder for which there is a pressing need for an effective treatment. Recent studies have investigated the essential nutrient choline as a postnatal treatment option. Supplementation with choline has produced improvements in behavioral tasks related to learning and memory and reverted changes in methylation signature following third‐trimester equivalent ethanol exposure. We examined whether there are related improvements in hippocampal synaptic plasticity in vivo. Methods: Sprague–Dawley offspring were administered binge‐levels of ethanol from postnatal day (PND) 4 to 9, then treated with choline chloride (100 mg/kg/day) from PND 10 to 30. In vivo electrophysiology was performed on male and female offspring from PND 55 to 70. Long‐term potentiation (LTP) was induced in the medial perforant pathway of the dentate gyrus using a theta‐burst stimulation (TBS) protocol, and field‐evoked postsynaptic potentials (EPSPs) were evoked for 60 min following the conditioning stimulus. Results: Developmental ethanol exposure caused long‐lasting deficits in LTP of the slope of the evoked responses and in the amplitude of the population spike potentiation. Neither deficit was rescued by postnatal choline supplementation. Conclusions: In contrast to our prior findings that choline can improve hippocampal plasticity (Nutrients, 2022, 14, 2004), here we found that deficits in hippocampal synaptic plasticity due to developmental ethanol exposure persisted into adulthood despite adolescent choline supplementation. Future research should examine more subtle changes in synaptic plasticity to identify synaptic changes that mirror behavioral improvements. [ABSTRACT FROM AUTHOR]

Forgetting is often viewed as a human frailty. However, over the years, it has been considered an adaptive process that allows people to avoid retrieval of undesirable memories, preventing them from suffering and discomfort. Evidence shows that the ability to suppress memories is affected by several psychopathological conditions characterized by persistent unwanted thoughts, including anxiety and posttraumatic stress disorders. Nevertheless, memory suppression (MS) mechanisms in addiction—a clinical condition characterized by recurrent drug‐related thoughts that contribute to repeated drug use—have received little attention so far. Addiction theories reveal that drugs change behavior by working on memory systems, particularly on declarative memory, which is related to the retrieval and encoding of drug‐related memories. In this review, the main behavioral and neurofunctional findings concerning the Think/No‐Think task—an adaptation of the classical Go/No‐Go tasks typically used to evaluate the suppression of motor response—are presented. We then show how the memory system can be involved in the craving or anticipation/preoccupation stage of the addiction cycle. Subsequently, the study of MS in the context of addictive behaviors is highlighted as a promising approach for gaining knowledge about the mechanisms contributing to the continuation of addiction. Finally, we discuss how interventions aiming to strengthen this ability could impact the anticipation/preoccupation stage by (i) reducing the accessibility of drug‐related memories, (ii) decreasing craving and attention toward drug‐related stimuli, and (iii) improving overall inhibition abilities. In conclusion, this review aims to illustrate how the study of MS may be a valuable approach to enhance our understanding of substance use disorders by unveiling the underlying cognitive and neural mechanisms involved, which could have important implications for addiction treatment. [ABSTRACT FROM AUTHOR]

Fascinating phenomena such as landmark vector cells and splitter cells are frequently discovered in the hippocampus. Without a unifying principle, each experiment seemingly uncovers new anomalies or coding types. Here, we provide a unifying principle that the mental representation of space is an emergent property of latent higher-order sequence learning. Treating space as a sequence resolves numerous phenomena and suggests that the place field mapping methodology that interprets sequential neuronal responses in Euclidean terms might itself be a source of anomalies. Our model, clone-structured causal graph (CSCG), employs higher-order graph scaffolding to learn latent representations by mapping aliased egocentric sensory inputs to unique contexts. Learning to compress sequential and episodic experiences using CSCGs yields allocentric cognitive maps that are suitable for planning, introspection, consolidation, and abstraction. By explicating the role of Euclidean place field mapping and demonstrating how latent sequential representations unify myriad observed phenomena, our work positions the hippocampus in a sequence-centric paradigm, challenging the prevailing space-centric view. [ABSTRACT FROM AUTHOR]

Objectives The objectives of this project were to: (1) examine the relationship between the number of biological children and hippocampal-dependent cognitive performance among older African American women and (2) determine the influence of socioeconomic status (i.e. age, education, marital status, median household income), if any, on this relationship. Methods A total of 146 cognitively unimpaired African American women aged 60 and older were recruited from the greater Newark area and reported their number of biological children, marital status, educational level, and age. We retrieved median household income from census tract data based on the participants' addresses. Participants' cognitive performance was assessed using the Rey Auditory Verbal Learning Test (RAVLT) long delay recall and a Rutgers generalization task (Concurrent Discrimination and Transfer Task). Results As the number of biological children a woman has had increases, the number of generalization errors also increased, indicating poorer hippocampal-dependent cognitive performance when controlling for age, education, marital status, and median household income. There was no significant relationship between the number of children and performance on a standardized neuropsychological measure of episodic memory (RAVLT), although education was a significant covariate. Discussion Generalization tasks may better capture early changes in cognitive performance in older African American women who have had children than standardized neuropsychological assessments. This finding may be explained by the fluctuations in estrogen associated with having children. Future studies should explore how these findings can be applied to protecting cognitive function and preventing Alzheimer's disease in older African American women who have had children. [ABSTRACT FROM AUTHOR]

The goal of this research was to study the effect of different doses of resveratrol (RS) and RS with donepezil (DPZ) on the deposition of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) in colchicine-induced Alzheimer's disease (AD) brain. The study included three months old male Albino Wistar rats and consisted of six animal groups: AD model (group 1), treatment groups, RS 10 mg/kg body weight (group 2), RS 20 mg/kg body weight (group 3), RS 10 mg/kg body weight along with DPZ 1 mg/kg body weight (group 6), prophylaxis groups, RS 10 mg/kg body weight (group 4) and RS 20 mg/kg body weight (group 5). In the treatment groups, RS was given for 7 consecutive days from the day of induction of AD, and in the prophylaxis groups, we started RS 7 days even before the induction of AD and continued for seven days after the induction. The number of Aβs and NFTs at the frontal region, cornu ammonis (CA) 1,2,3,4 and dentate gyrus regions of hippocampus were evaluated. The immunohistochemical analysis was performed by using mouse anti-β-amyloid antibody for the Aβ plaques and polyclonal rabbit anti-human tau for the tau-positive neurons. The present study observed the accumulation of Aβ plaques and tau-positive neurons in the AD model. However, their numbers were significantly decreased in the treatment groups (p < 0.001). The best results were observed when RS 10 mg was given prophylactically (p < 0.01) and RS along with DPZ (p < 0.001), suggesting the neuroprotective effect of RS and its synergistic effect with the DPZ. [ABSTRACT FROM AUTHOR]

Epilepsy, affecting 0.5%‐1% of the global population, presents a significant challenge with 30% of patients resistant to medical treatment. Temporal lobe epilepsy, a common cause of medically refractory epilepsy, is often caused by hippocampal sclerosis (HS). HS can be divided further by subtype, as defined by the International League Against Epilepsy (ILAE). Type 1 HS, the most prevalent form (60%‐80% of all cases), is characterized by cell loss and gliosis predominantly in the subfields cornu ammonis (CA1) and CA4. Type 2 HS features cell loss and gliosis primarily in the CA1 sector, and type 3 HS features cell loss and gliosis predominantly in the CA4 subfield. This literature review evaluates studies on hippocampal subfields, exploring whether observable atrophy patterns from in vivo and ex vivo magnetic resonance imaging (MRI) scans correlate with histopathological examinations with manual or automated segmentation techniques. Our findings suggest only ex vivo 1.5 Tesla (T) or 3T MRI with manual segmentation or in vivo 7T MRI with manual or automated segmentations can consistently correlate subfield patterns with histopathologically derived ILAE‐HS subtypes. In conclusion, manual and automated segmentation methods offer advantages and limitations in diagnosing ILAE‐HS subtypes, with ongoing research crucial for refining hippocampal subfield segmentation techniques and enhancing clinical applicability. [ABSTRACT FROM AUTHOR]

• GDF11 treatment is shown to enhance hippocampal neurogenesis and ameliorate learning and memory deficits in a diabetic murine model. • Targeted microglial depletion in diabetic mice via CSF1R inhibitor PLX5622 reduces neuroinflammation and improves cognitive function. • The study delineates the neurogenic underpinnings critical for cognitive restoration, providing a potential therapeutic strategy for diabetes-associated cognitive decline. The cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. We utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. These findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Dimension reduction on neural activity paves a way for unsupervised neural decoding by dissociating the measurement of internal neural pattern reactivation from the measurement of external variable tuning. With assumptions only on the smoothness of latent dynamics and of internal tuning curves, the Poisson gaussian-process latent variable model (P-GPLVM; Wu et al., 2017) is a powerful tool to discover the low-dimensional latent structure for high-dimensional spike trains. However, when given novel neural data, the original model lacks a method to infer their latent trajectories in the learned latent space, limiting its ability for estimating the neural reactivation. Here, we extend the P-GPLVM to enable the latent variable inference of new data constrained by previously learned smoothness and mapping information. We also describe a principled approach for the constrained latent variable inference for temporally compressed patterns of activity, such as those found in population burst events during hippocampal sharp-wave ripples, as well as metrics for assessing the validity of neural pattern reactivation and inferring the encoded experience. Applying these approaches to hippocampal ensemble recordings during active maze exploration, we replicate the result that P-GPLVM learns a latent space encoding the animal's position. We further demonstrate that this latent space can differentiate one maze context from another. By inferring the latent variables of new neural data during running, certain neural patterns are observed to reactivate, in accordance with the similarity of experiences encoded by its nearby neural trajectories in the training data manifold. Finally, reactivation of neural patterns can be estimated for neural activity during population burst events as well, allowing the identification for replay events of versatile behaviors and more general experiences. Thus, our extension of the P-GPLVM framework for unsupervised analysis of neural activity can be used to answer critical questions related to scientific discovery. [ABSTRACT FROM AUTHOR]

Studies of the impact of brain injury on memory processes often focus on the quantity and episodic richness of those recollections. Here, we argue that the organization of one's recollections offers critical insights into the impact of brain injury on functional memory. It is well‐established in studies of word list memory that free recall of unrelated words exhibits a clear temporal organization. This temporal contiguity effect refers to the fact that the order in which word lists are recalled reflects the original presentation order. Little is known, however, about the organization of recall for semantically rich materials, nor how recall organization is impacted by hippocampal damage and memory impairment. The present research is the first study, to our knowledge, of temporal organization in semantically rich narratives in three groups: (1) Adults with bilateral hippocampal damage and severe declarative memory impairment, (2) adults with bilateral ventromedial prefrontal cortex (vmPFC) damage and no memory impairment, and (3) demographically matched non‐brain‐injured comparison participants. We find that although the narrative recall of adults with bilateral hippocampal damage reflected the temporal order in which those narratives were experienced above chance levels, their temporal contiguity effect was significantly attenuated relative to comparison groups. In contrast, individuals with vmPFC damage did not differ from non‐brain‐injured comparison participants in temporal contiguity. This pattern of group differences yields insights into the cognitive and neural systems that support the use of temporal organization in recall. These data provide evidence that the retrieval of temporal context in narrative recall is hippocampal‐dependent, whereas damage to the vmPFC does not impair the temporal organization of narrative recall. This evidence of limited but demonstrable organization of memory in participants with hippocampal damage and amnesia speaks to the power of narrative structures in supporting meaningfully organized recall despite memory impairment. [ABSTRACT FROM AUTHOR]

Remembering what just happened is a crucial prerequisite to form long‐term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short‐term memory. Using a classifier‐based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low‐rate predictive patterns are present in both working memory and non‐working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory‐motor context. [ABSTRACT FROM AUTHOR]

Synaptic excitation and inhibition are essential for neuronal communication. However, the variables that regulate synaptic excitation and inhibition in the intact brain remain largely unknown. Here, we examined how spike transmission and suppression between principal cells (PCs) and interneurons (INTs) are modulated by activity history, brain state, cell type, and somatic distance between presynaptic and postsynaptic neurons by applying cross‐correlogram analyses to datasets recorded from the dorsal hippocampus and medial entorhinal cortex (MEC) of 11 male behaving and sleeping Long Evans rats. The strength, temporal delay, and brain‐state dependency of the spike transmission and suppression depended on the subregions/layers. The spike transmission probability of PC–INT excitatory pairs that showed short‐term depression versus short‐term facilitation was higher in CA1 and lower in CA3. Likewise, the intersomatic distance affected the proportion of PC–INT excitatory pairs that showed short‐term depression and facilitation in the opposite manner in CA1 compared with CA3. The time constant of depression was longer, while that of facilitation was shorter in MEC than in CA1 and CA3. During sharp‐wave ripples, spike transmission showed a larger gain in the MEC than in CA1 and CA3. The intersomatic distance affected the spike transmission gain during sharp‐wave ripples differently in CA1 versus CA3. A subgroup of MEC layer 3 (EC3) INTs preferentially received excitatory inputs from and inhibited MEC layer 2 (EC2) PCs. The EC2 PC–EC3 INT excitatory pairs, most of which showed short‐term depression, exhibited higher spike transmission probabilities than the EC2 PC–EC2 INT and EC3 PC–EC3 INT excitatory pairs. EC2 putative stellate cells exhibited stronger spike transmission to and received weaker spike suppression from EC3 INTs than EC2 putative pyramidal cells. This study provides detailed comparisons of monosynaptic interaction dynamics in the hippocampal–entorhinal loop, which may help to elucidate circuit operations. [ABSTRACT FROM AUTHOR]

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long‐term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra‐hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression. [ABSTRACT FROM AUTHOR]

This study aimed to compare the effects of High-Intensity Interval Training (HIIT) performed in a single session(1xHIIT) versus three daily sessions (3xHIIT) on fitness level and behavior of aged rats. Eighteen-month-old Wistar rats were assigned to Untrained (UN), 1xHIIT, or 3xHIIT (n = 12/group). Both groups, 1xHIIT and 3xHIIT, performed 15 min of a treadmill running HIIT protocol during 8 weeks. 1xHIIT protocol consisted of a single daily session of 15 min, while the 3xHIIT performed three daily sessions of 5 min with a 4 h interval between the sessions. Morris Water Maze (MWM) task was used to evaluate spatial learning and memory. Splash test, Forced Swim test, and Elevated Plus Maze task (EPM) were used to evaluate anhedonic, depressive-like, and anxious behaviors, respectively. Rats were euthanized, and the hippocampus was harvested for western blot analyses (CaMKII and BDNF). Both HIIT protocols improved VO2max and spatial memory. Notably, only the 3xHIIT protocol attenuated anxious and depressive-like behaviors. Western blot analyses of the hippocampus revealed that both HIIT protocols increased BDNF levels. BDNF levels were higher in the 3xHIIT when compared with 1xHIIT group, and we observed increasement of the CamKII levels just in the 3x HIIT group. Therefore, this study provides evidence indicating that accumulated HIIT sessions is more effective than traditional daily HIIT sessions in improving fitness level, cognitive function, memory, inhibiting the development of mood disorders, and enhancing BDNF and CaMKII levels in the hippocampus of aged rats. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate histone deacetylase 6 (HDAC6) modifies the heat shock protein 90 (HSP90) and heat shock transcription factor 1 (HSF1) affect the levels of pathological markers such as Aβ oligomers (Aβo) and Tau phosphorylation (p-Tau) in APP/PS1 double transgenic mice hippocampal tissues or HT22 neurons as well as the changes in cognitive behavioral functions of mice. (1) APP/PS1 transgenic mice (6 months old, 25 ~ 30 g) were randomly assigned to 5 experimental groups, C57BL/6J mice (6 months old, 25 ~ 30 g) were used as 4 control groups, with 8 mice in each group. All mice underwent intracerebroventricular (i.c.v.) cannulation, and the experimental groups were administered with normal saline (APP + NS group), HDAC6 agonist tubastatin A hydrochloride (TSA) (APP + TSA group) or HDAC6 agonist theophylline (Theo) (APP + Theo group), HSP90 inhibitor Ganetespib (Gane) (APP + Gane group), or a combination of pre-injected Gane by TSA (APP + Gane + TSA group); the control group received i.c.v. injections of Gane (Gane group), TSA (TSA group), Theo (Theo group) or NS (NS group), respectively. (2) Mouse hippocampal neurons HT22 were randomly divided into a control group (Control) and an Aβ1−42 intervention group (Aβ). Within the Aβ group, further divisions were made for knockdown HSP90 (Aβ + siHSP90 group), overexpression HSP90 (Aβ + OE-HSP90 group), knockdown HSF1(Aβ + siHSF1 group) and knockdown HSF1 followed by overexpression HSP90 (Aβ + siHSF1 + OE-HSP90 group), resulting in a total of 6 groups. Morris water maze test was used to evaluate the cognitive behavior of the mice. Western blot and immunohistochemistry or immunofluorescence were performed to detect the levels of HDAC6, HSP90, HSF1, Aβ1−42, Tau protein, and p-Tau in the hippocampal tissue or HT22 cells. qRT-PCR was used to measure the levels of hdac6, hsp90, and hsf1 mRNA in the hippocampus or nerve cells. (1) The levels of HDAC6, Aβ1−42 and p-Tau were elevated, while HSP90 and HSF1 were decreased in the hippocampal tissue of APP/PS1 transgenic mice (all P < 0.01). Inhibiting HDAC6 upregulated the expressions of HSP90 and HSF1 in the hippocampal tissue of APP/PS1 mice, while decreasing the levels of Aβ1−42 and p-Tau as well as improving the spatial cognitive behavior in mice (P < 0.05 or P < 0.01). The opposite effects were observed upon HDAC6 activation. However, inhibiting HSP90 reduced the expression of HSF1 (P < 0.01) and increased the levels of Aβ1−42 and p-Tau (P < 0.05 or P < 0.01) but did not significantly affect the expression of HDAC6 (P > 0.05). No significant changes were observed in the aforementioned indicators in the 4 control groups (P > 0.05). (2) In the Aβ1−42 intervention group, HDAC6 and Aβ1−42, p-Tau expression levels were elevated, while HSP90 and HSF1 expressions were all decreased, and cell viability was reduced (P < 0.05 or P < 0.01). Overexpression of HSP90 upregulated HSF1 expression, decreased the levels of Aβ1−42 and p-Tau, and increased cell viability (P < 0.05 or P < 0.01). Knocking down HSP90 had the opposite effect; and knocking down HSF1 increased the levels of Aβ1−42 and p-Tau and decreased cells viability (all P < 0.01), but did not result in significant changes in the expression levels of HSP90 (P > 0.05). Inhibiting HDAC6 can upregulate the expressions of HSP90 and HSF1 but reduce the levels of Aβ1−42 and p-Tau in the hippocampus of APP/PS1 mice and improvement of cognitive behavioral function in mice; Overexpression of HSP90 can increase HSF1 but decrease Aβ1−42 and p-Tau levels in the hippocampal neurons and increase cell activity. It is suggested that HDAC6 may affect the formation of Aβ oligomers and the changes in Tau protein phosphorylation levels in the hippocampus of AD transgenic mouse as well as the alterations in cognitive behavioral functions by regulating the HSP90-HSF1 pathway. [ABSTRACT FROM AUTHOR]

Summary: Hippocampal atrophy is a prominent neurodegenerative feature of Alzheimer's disease and related dementias. Alterations in circadian rhythms can exacerbate cognitive aging and neurodegeneration. This study aimed to examine how dim light melatonin onset and melatonin levels are associated with hippocampal volume in cognitively healthy individuals. We studied data from 52 later‐life adults (mean age ± SD = 70.0 ± 6.3 years). T1‐weighted anatomical images from 3.0 T magnetic resonance imaging data were collected and processed using the BRAINSTools toolbox. Dim light melatonin onset was used to assess circadian timing. The area under the curve was calculated to quantify melatonin concentration levels 6 hr before bedtime, and 14‐day wrist actigraphy data were used to assess habitual bedtime. Multiple linear regression modelling with hippocampal volume as the dependent variable was used to analyse the data adjusting for age and sex. The average dim light melatonin onset was 19:45 hours (SD = 84 min), and area under the curve of melatonin levels 6 hr before habitual bedtime was 38.4 pg ml−1 × hr (SD = 29.3). We found that later dim light melatonin onset time (b = 0.16, p = 0.005) and greater area under the curve of melatonin levels 6 hr before habitual bedtime (b = 0.05, p = 0.046) were associated with greater adjusted hippocampal volume. The time between dim light melatonin onset and the midpoint of sleep timing was not associated with hippocampal volume. The findings suggest that earlier circadian timing (dim light melatonin onset) and reduced melatonin may be associated with reduced hippocampal volume in older adults. Future research will help researchers utilize circadian rhythm information to delay brain aging. [ABSTRACT FROM AUTHOR]

Aim: Understanding the physiological role of ATP6V1A, a component of the cytosolic V1 domain of the proton pump vacuolar ATPase, in regulating neuronal development and function. Methods: Modeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy. Results: Atp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V1 subunits, that leads to impairment of lysosomal pH‐regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons. Conclusions: These data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties. [ABSTRACT FROM AUTHOR]

Patients suffering from hepatic ischemia–reperfusion injury (HIRI) frequently exhibit postoperative cognitive deficits. Our previous observations have emphasized the diurnal variation in hepatic ischemia–reperfusion injury-induced cognitive impairment, in which gut microbiota-associated hippocampal lipid metabolism plays an important role. Herein, we further investigated the molecular mechanisms involved in the process. Hepatic ischemia–reperfusion surgery was performed under morning (ZT0, 08:00) and evening (ZT12, 20:00). Fecal microbiota transplantation was used to associate HIRI model with pseudo-germ-free mice. The novel object recognition test and Y-maze test were used to assess cognitive function. 16S rRNA gene sequencing and analysis were used for microbial analysis. Western blotting was used for hippocampal protein analysis. Compared with the ZT0-HIRI group, ZT12-HIRI mice showed learning and short term memory impairment, accompanied by down-regulated expression of hippocampal CB1R, but not CB2R. Both gut microbiota composition and microbiota metabolites were significantly different in ZT12-HIRI mice compared with ZT0-HIRI. Fecal microbiota transplantation from the ZT12-HIRI was demonstrated to induce cognitive impairment behavior and down-regulated hippocampal CB1R and β-arrestin1. Intraperitoneal administration of CB1R inhibitor AM251 (1 mg/kg) down-regulated hippocampal CB1R and caused cognitive impairment in ZT0-HIRI mice. And intraperitoneal administration of CB1R agonist WIN 55,212-2 (1 mg/kg) up-regulated hippocampal CB1R and improved cognitive impairment in ZT12-HIRI mice. In summary, the results suggest that gut microbiota may regulate the diurnal variation of HIRI-induced cognitive function by interfering with hippocampal CB1R. [ABSTRACT FROM AUTHOR]

Elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases, including Down syndrome (DS), which is the most common chromosomal condition causing intellectual disability globally. Previous research by our group has revealed that treatment with lamivudine, a reverse transcriptase inhibitor, improved neurobehavioral phenotypes and completely rescued hippocampaldependent recognition memory in a DS mouse model, Ts65Dn. We hypothesized that retrotransposition rates would increase in the Ts65Dn mouse model, and lamivudine could block retrotransposons. We analyzed the differentially expressed long interspersed element-1 (LINE-1 or L1) mapping on MMU16 and 17, and showed for the first time that retrotransposition could be associated with Ts65Dn's pathology, as misregulation of L1 was found in brain tissues associated with trisomy. In the cerebral cortex, 6 out of 26 upregulated L1s in trisomic treated mice were located in the telomeric region of MMU16 near Ttc3, Kcnj6, and Dscam genes. In the hippocampus, one upregulated L1 element in trisomic treated mice was located near the Fgd4 gene on MMU16. Moreover, two downregulated L1s rescued after treatment with lamivudine were located in the intronic region of Nrxn1 (MMU17) and Snhg14 (MMU7), implicated in a variety of neurodegenerative disorders. To gain further insight into the mechanism of this improvement, we here analyzed the gene expression profile in the hippocampus and cerebral cortex of trisomic mice treated and no-treated with lamivudine compared to their wild-type littermates. We found that treatment with lamivudine rescued the expression of 24% of trisomic genes in the cortex (located on mouse chromosome (MMU) 16 and 17) and 15% in the hippocampus (located in the human chromosome 21 orthologous regions), with important DS candidate genes such as App and Ets2, rescued in both regions. [ABSTRACT FROM AUTHOR]

The hippocampus is one of the most commonly studied brain regions in the context of depression. The volume of the hippocampus is significantly reduced in patients with depression, which severely disrupts hippocampal neuroplasticity. However, antidepressant therapies that target hippocampal neuroplasticity have not been identified as yet. Chinese medicine (CM) can slow the progression of depression, potentially by modulating hippocampal neuroplasticity. Xiaoyaosan (XYS) is a CM formula that has been clinically used for the treatment of depression. It is known to protect Gan (Liver) and Pi (Spleen) function, and may exert its antidepressant effects by regulating hippocampal neuroplasticity. In this review, we have summarized the association between depression and aberrant hippocampal neuroplasticity. Furthermore, we have discussed the researches published in the last 30 years on the effects of XYS on hippocampal neuroplasticity in order to elucidate the possible mechanisms underlying its therapeutic action against depression. The results of this review can aid future research on XYS for the treatment of depression. [ABSTRACT FROM AUTHOR]

Objective: To explore the rapid antidepressant potential and the underlying mechanism of Chaihu Shugan San (CSS) in female mice. Methods: Liquid chromatography mass spectrometry (LC-MS)/MS was used to determine the content of main components in CSS to determine its stability. Female C57BL/6J mice were randomly divided into 4 groups, including control (saline), vehicle (saline), CSS (4 g/kg) and ketamine (30 mg/kg) groups. Mice were subjected to irregular stress stimulation for 4 weeks to establish the chronic mild stress (CMS) model, then received a single administration of drugs. Two hours later, the behavioral tests were performed, including open field test, tail suspension test (TST), forced swimming test (FST), novelty suppression feeding test (NSF), and sucrose preference test (SPT). Western blot analysis was used to detect the expression levels of N-methyl-D-aspartate receptor (NMDA) subtypes [N-methyl-D-aspartate receptor 1 (NR1), NR2A, NR2B], synaptic proteins [synapsin1 and post synaptic density protein 95 (PSD95)], and brain-derived neurotrophic factor (BDNF). Moreover, the rapid antidepressant effect of CSS was tested by pharmacological technologies and optogenetic interventions that activated glutamate receptors, NMDA. Results: Compared with the vehicle group, a single administration of CSS (4 g/kg) reversed all behavioral defects in TST, FST, SPT and NSF caused by CMS (P<0.05 or P<0.01). CSS also significantly decreased the expressions of NMDA subtypes (NR1, NR2A, NR2B) at 2 h in hippocampus of mice (all P<0.01). In addition, similar to ketamine, CSS increased levels of synaptic proteins and BDNF (P<0.05 or P<0.01). Furthermore, the rapid antidepressant effects of CSS were blocked by transient activation of NMDA receptors in the hippocampus (all P<0.01). Conclusion: Rapid antidepressant effects of CSS by improving behavioral deficits in female CMS mice depended on rapid suppression of NMDA receptors and activation of synaptic proteins. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects and mechanisms of olfactory three-needle (OTN) electroacupuncture (EA) stimulation of the olfactory system on cognitive dysfunction, synaptic plasticity, and the gut microbiota in senescence-accelerated mouse prone 8 (SAMP8) mice. Methods: Thirty-six SAMP8 mice were randomly divided into the SAMP8 (P8), SAMP8+OTN (P8-OT), and SAMP8+nerve transection+OTN (P8-N-OT) groups according to a random number table (n=12 per group), and 12 accelerated senescence-resistant (SAMR1) mice were used as the control (R1) group. EA was performed at the Yintang (GV 29) and bilateral Yingxiang (LI 20) acupoints of SAMP8 mice for 4 weeks. The Morris water maze test, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, Nissl staining, Golgi staining, Western blot, and 16S rRNA sequencing were performed, respectively. Results: Compared with the P8 group, OTN improved the cognitive behavior of SAMP8 mice, inhibited neuronal apoptosis, increased neuronal activity, and attenuated hippocampal synaptic dysfunction (P<0.05 or P<0.01). Moreover, the expression levels of synaptic plasticity-related proteins N-methyl-D-aspartate receptor 1 (NMDAR1), NMDAR2B, synaptophysin (SYN), and postsynaptic density protein-95 (PSD95) in hippocampus were increased by OTN treatment (P<0.05 or P<0.01). Furthermore, OTN greatly enhanced the brain-derived neurotrophic factor (BDNF)/cAMP-response element binding (CREB) signaling and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling compared with the P8 group (P<0.05 or P<0.01). However, the neuroprotective effect of OTN was attenuated by olfactory nerve truncation. Compared with the P8 group, OTN had a very limited effect on the fecal microbial structure and composition of SAMP8 mice, while specifically increased the genera Oscillospira and Sutterella (P<0.05). Interestingly, the P8-N-OT group showed an abnormal fecal microbiota with higher microbial α-diversity, Firmicutes/Bacteroidetes ratio and pathogenic bacteria (P<0.05 or P<0.01). Conclusions: OTN improved cognitive deficits and hippocampal synaptic plasticity by stimulating the olfactory nerve and activating the BDNF/CREB and PI3K/AKT/mTOR signaling pathways. Although the gut microbiota was not the main therapeutic target of OTN for Alzheimer's disease, the olfactory nerve was essential to maintain the homeostasis of gut microbiota. [ABSTRACT FROM AUTHOR]

Voacangine, a naturally occurring alkaloid, has been testified to display beneficial effects on a variety of human diseases, but its role in ischemic stroke is unclear. The impacts of voacangine on oxygen–glucose deprivation/reoxygenation (OGD/R)‐tempted hippocampal neuronal cells are investigated. The bioinformatics analysis found that voacangine is a bioactive ingredient that may have good effects on ischemic stroke. KEGG pathways analysis found that voacangine may regulate ischemic stroke through modulating the PI3K‐Akt‐FoxO signaling pathway. Voacangine could mitigate OGD/R‐tempted cytotoxicity in HT22 cells. Voacangine mitigated OGD/R‐tempted oxidative stress in HT22 cells by diminishing reactive oxygen species level and enhancing superoxide dismutase level. Voacangine mitigated OGD/R‐tempted ferroptosis in HT22 cells. Voacangine promoted activation of the PI3K‐Akt‐FoxO signaling in OGD/R‐induced HT22 cells. Inactivation of the PI3K‐Akt‐FoxO signaling pathway reversed the protective effects of voacangine against OGD/R‐tempted oxidative stress, cytotoxicity, and ferroptosis in HT22 cells. In conclusion, voacangine protects hippocampal neuronal cells against OGD/R‐caused oxidative stress and ferroptosis by activating the PI3K‐Akt‐FoxO signaling. Voacangine has been shown to have beneficial effects on several human diseases, but its role in ischemic stroke has not been elucidated. In this study, we have identified the neuroprotective effects of voacangine against oxygen‐glucose deprivation/reoxygenation (OGD/R)‐induced damage through bioinformatics and in vitro cell experiments. Mechanistically, voacangine protected hippocampal neuronal cells against OGD/R‐caused oxidative stress and ferroptosis by activating the PI3K‐Akt‐FoxO signaling. [ABSTRACT FROM AUTHOR]

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs. [ABSTRACT FROM AUTHOR]

Introduction: The deregulation of lncRNAs expression has been associated with neuronal damage in Alzheimer's disease (AD), but how or whether they can influence its onset is still unknown. We investigated 2 RNA-seq datasets consisting, respectively, of the hippocampal and fusiform gyrus transcriptomic profile of AD patients, matched with non-demented controls. Methods: We performed a differential expression analysis, a gene correlation network analysis (WGCNA) and a pathway enrichment analysis of two RNA-seq datasets. Results: We found deregulated lncRNAs in common between hippocampus and fusiform gyrus and deregulated gene groups associated to functional pathways related to neurotransmission and memory consolidation. lncRNAs, co-expressed with known AD-related coding genes, were identified from the prioritized modules of both brain regions. Discussion: We found common deregulated lncRNAs in the AD hippocampus and fusiform gyrus, that could be considered common signatures of AD pathogenesis, providing an important source of information for understanding the molecular changes of AD. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]