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Our ability to navigate in a new environment depends on learning new locations. Mental representations of locations are quickly accessible during navigation and allow us to know where we are regardless of our current viewpoint. Recent functional magnetic resonance imaging (fMRI) research using pattern classification has shown that these location‐based representations emerge in the retrosplenial cortex and parahippocampal gyrus, regions theorized to be critically involved in spatial navigation. However, little is currently known about the oscillatory dynamics that support the formation of location‐based representations. We used magnetoencephalogram (MEG) recordings to investigate region‐specific oscillatory activity in a task where participants could form location‐based representations. Participants viewed videos showing that two perceptually distinct scenes (180° apart) belonged to the same location. This "overlap" video allowed participants to bind the two distinct scenes together into a more coherent location‐based representation. Participants also viewed control "non‐overlap" videos where two distinct scenes from two different locations were shown, where no location‐based representation could be formed. In a post‐video behavioral task, participants successfully matched the two viewpoints shown in the overlap videos, but not the non‐overlap videos, indicating they successfully learned the locations in the overlap condition. Comparing oscillatory activity between the overlap and non‐overlap videos, we found greater theta and alpha/beta power during the overlap relative to non‐overlap videos, specifically at time‐points when we expected scene integration to occur. These oscillations localized to regions in the medial parietal cortex (precuneus and retrosplenial cortex) and the medial temporal lobe, including the hippocampus. Therefore, we find that theta and alpha/beta oscillations in the hippocampus and medial parietal cortex are likely involved in the formation of location‐based representations. [ABSTRACT FROM AUTHOR]

In a changing environment, animals must process spatial signals in a flexible manner. The rat hippocampal formation projects directly upon the retrosplenial cortex, with most inputs arising from the dorsal subiculum and terminating in the granular retrosplenial cortex (area 29). The present study examined whether these same projections are required for spatial working memory and what happens when available spatial cues are altered. Consequently, injections of iDREADDs were made into the dorsal subiculum of rats. In a separate control group, GFP‐expressing adeno‐associated virus was injected into the dorsal subiculum. Both groups received intracerebral infusions within the retrosplenial cortex of clozapine, which in the iDREADDs rats should selectively disrupt the subiculum to retrosplenial projections. When tested on reinforced T‐maze alternation, disruption of the subiculum to retrosplenial projections had no evident effect on the performance of those alternation trials when all spatial‐cue types remained present and unchanged. However, the same iDREADDs manipulation impaired performance on all three alternation conditions when there was a conflict or selective removal of spatial cues. These findings reveal how the direct projections from the dorsal subiculum to the retrosplenial cortex support the flexible integration of different spatial cue types, helping the animal to adopt the spatial strategy that best meets current environmental demands. [ABSTRACT FROM AUTHOR]

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non‐human primates, and humans. By contrast, damage to the hippocampus spares performance in most non‐navigational spatial memory tasks—which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self‐ordered non‐navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network‐based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non‐human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non‐navigational spatial memory, and help to reconcile the many null findings previously reported. [ABSTRACT FROM AUTHOR]

Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into the mouse's hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders. [ABSTRACT FROM AUTHOR]

High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected. Highlights: A two-hit protocol using HFD + L-NAME induces metabolic dysfunction in rats. Spatial memory is impacted in HFD + L-NAME rats. Hippocampal but not neocortex bioenergetics is affected in HFD + L-NAME rats. OPA-1 expression is upregulated in the hippocampus of HFD + L-NAME rats. Cortical calcium dynamics was not affected by HFD + L-NAME. [ABSTRACT FROM AUTHOR]

Physical exercise studies are generally underrepresented in young adulthood. Seventeen subjects were randomized into an intervention group (24.2 ± 3.9 years; 3 trainings/week) and 10 subjects into a passive control group (23.7 ± 4.2 years), over a duration of 6 months. Every two months, performance diagnostics, computerized spatial memory tests, and 3 Tesla magnetic resonance imaging were conducted. Here we find that the intervention group, compared to controls, showed increased cardiorespiratory fitness, spatial memory performance and subregional hippocampal volumes over time. Time-by-condition interactions occurred in right cornu ammonis 4 body and (trend only) dentate gyrus, left hippocampal tail and left subiculum. Increases in spatial memory performance correlated with hippocampal body volume changes and, subregionally, with left subicular volume changes. In conclusion, findings support earlier reports of exercise-induced subregional hippocampal volume changes. Such exercise-related plasticity may not only be of interest for young adults with clinical disorders of hippocampal function, but also for sedentary normal cohorts. A structural MRI study suggests that regular exercise training induces plasticity in hippocampal subregions also in young adults. Hippocampal plasticity correlates with changes in spatial memory precision. [ABSTRACT FROM AUTHOR]

The behavioral and neural mechanisms that support spatial cognition have been an enduring interest of psychologists, and much of that enduring interest is attributable to the groundbreaking research of Ken Cheng. One manifestation of this interest, inspired by the idea of studying spatial cognition under natural field conditions, has been research carried out to understand the role of the avian hippocampal formation (HF) in supporting homing pigeon navigation. Emerging from that research has been the conclusion that the role of HF in homing pigeon navigation aligns well with the canonical narrative of a hippocampus important for spatial memory and the implementation of such memories to support navigation. However, recently an accumulation of disparate observations has prompted a rethinking of the avian HF as a structure also important in shaping visual-spatial perception or attention antecedent to any memory processing. In this perspective paper, we summarize field observations contrasting the behavior of intact and HF-lesioned homing pigeons from several studies, based primarily on GPS-recorded flight paths, that support a recharacterization of HF's functional profile to include visual-spatial perception. Although admittedly still speculative, we hope the offered perspective will motivate controlled, experimental-laboratory studies to further test the hypothesis of a HF important for visual-perceptual integration, or scene construction, of landscape elements in support of navigation. [ABSTRACT FROM AUTHOR]

Aims: In this study, the anticonvulsant action of closed‐loop, low‐frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated. Methods: Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test. Results: Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre‐ictal, ictal, and post‐ictal periods. Meanwhile, DBS increased the post‐ictal‐to‐pre‐ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post‐ictal‐to‐pre‐ictal ratio of coherence. In addition, DBS increased the hippocampal‐mPFC coupling in pre‐ictal period and decreased the coupling in the ictal and post‐ictal periods. Conclusion: Applying closed‐loop, low‐frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low‐frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non‐seizure state in subjects that received DBS. [ABSTRACT FROM AUTHOR]

Brain rhythms of sleep reflect neuronal activity underlying sleep‐associated memory consolidation. The modulation of brain rhythms, such as the sleep slow oscillation (SO), is used both to investigate neurophysiological mechanisms as well as to measure the impact of sleep on presumed functional correlates. Previously, closed‐loop acoustic stimulation in humans targeted to the SO Up‐state successfully enhanced the slow oscillation rhythm and phase‐dependent spindle activity, although effects on memory retention have varied. Here, we aim to disclose relations between stimulation‐induced hippocampo‐thalamo‐cortical activity and retention performance on a hippocampus‐dependent object‐place recognition task in mice by applying acoustic stimulation at four estimated SO phases compared to sham condition. Across the 3‐h retention interval at the beginning of the light phase closed‐loop stimulation failed to improve retention significantly over sham. However, retention during SO Up‐state stimulation was significantly higher than for another SO phase. At all SO phases, acoustic stimulation was accompanied by a sharp increase in ripple activity followed by about a second‐long suppression of hippocampal sharp wave ripple and longer maintained suppression of thalamo‐cortical spindle activity. Importantly, dynamics of SO‐coupled hippocampal ripple activity distinguished SOUp‐state stimulation. Non‐rapid eye movement (NREM) sleep was not impacted by stimulation, yet preREM sleep duration was effected. Results reveal the complex effect of stimulation on the brain dynamics and support the use of closed‐loop acoustic stimulation in mice to investigate the inter‐regional mechanisms underlying memory consolidation. [ABSTRACT FROM AUTHOR]

Hippocampome. org is a mature open-access knowledge base of the rodent hippocampal formation focusing on neuron types and their properties. Previously, Hippocampome. org v1.0 established a foundational classification system identifying 122 hippocampal neuron types based on their axonal and dendritic morphologies, main neurotransmitter, membrane biophysics, and molecular expression (Wheeler et al., 2015). Releases v1.1 through v1.12 furthered the aggregation of literature-mined data, including among others neuron counts, spiking patterns, synaptic physiology, in vivo firing phases, and connection probabilities. Those additional properties increased the online information content of this public resource over 100-fold, enabling numerous independent discoveries by the scientific community. Hippocampome. org v2.0, introduced here, besides incorporating over 50 new neuron types, now recenters its focus on extending the functionality to build real-scale, biologically detailed, data-driven computational simulations. In all cases, the freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Possible research applications include quantitative, multiscale analyses of circuit connectivity and spiking neural network simulations of activity dynamics. These advances can help generate precise, experimentally testable hypotheses and shed light on the neural mechanisms underlying associative memory and spatial navigation. [ABSTRACT FROM AUTHOR]

Hippocampal synaptic plasticity, learning and memory formation, and memory consolidation require Ca2+ release from the endoplasmic reticulum mediated by ryanodine receptor (RyR) channels. Of the three brain RyR isoforms (RyR1–3), hippocampal RyR2 channels play a major role, via Ca2+-induced Ca2+ release, in activity-induced nuclear Ca2+ signal generation. Functional RyR channels are partially required for the neuronal activity-induced stimulation of CREB phosphorylation and the enhanced expression of the immediate early gene Npas4 and RyR2 channels, which are all required for hippocampal memory formation. The increased oxidative tone of aged neurons boosts redox-sensitive RyR-mediated Ca2+ release, leading to age-related synaptic plasticity and memory defects. Alterations in RyR channel expression and function contribute to AD-related memory loss. Hippocampal synaptic plasticity is widely considered the cellular basis of learning and spatial memory processes. This article highlights the central role of Ca2+ release from the endoplasmic reticulum (ER) in hippocampal synaptic plasticity and hippocampus-dependent memory in health and disease. The key participation of ryanodine receptor (RyR) channels, which are the principal Ca2+ release channels expressed in the hippocampus, in these processes is emphasized. It is proposed that the increased neuronal oxidative tone displayed by hippocampal neurons during aging or Alzheimer's disease (AD) leads to excessive activation of RyR-mediated Ca2+ release, a process that is highly redox-sensitive, and that this abnormal response contributes to and aggravates these deleterious conditions. Hippocampal synaptic plasticity is widely considered the cellular basis of learning and spatial memory processes. This article highlights the central role of Ca2+ release from the endoplasmic reticulum (ER) in hippocampal synaptic plasticity and hippocampus-dependent memory in health and disease. The key participation of ryanodine receptors (RyRs), which are the principal Ca2+ release channels expressed in the hippocampus, in these processes is emphasized. It is proposed that the increased neuronal oxidative tone displayed by hippocampal neurons during aging or Alzheimer's disease (AD) leads to excessive activation of RyR-mediated Ca2+ release, a process that is highly redox-sensitive, and that this abnormal response contributes to and aggravates these deleterious conditions. [ABSTRACT FROM AUTHOR]

• tDCS of the rTPJ improves spatial memory consolidation in AD and MCI. • we suggest a neuromodulatory effect of tDCS on the parietal-hippocampal navigation network. • tDCS may serve as a therapeutic strategy to foster spatial orientation of AD patients. Spatial memory deficits are an early symptom in Alzheimer's disease (AD), reflecting the neurodegenerative processes in the neuronal navigation network such as in hippocampal and parietal cortical areas. As no effective treatment options are available, neuromodulatory interventions are increasingly evaluated. Against this backdrop, we investigated the neuromodulatory effect of anodal transcranial direct current stimulation (tDCS) on hippocampal place learning in patients with AD or mild cognitive impairment (MCI). In this randomized, double-blind, sham-controlled study with a cross-over design anodal tDCS of the right temporoparietal junction (2 mA for 20 min) was applied to 20 patients diagnosed with AD or MCI and in 22 healthy controls while they performed a virtual navigation paradigm testing hippocampal place learning. We show an improved recall performance of hippocampal place learning after anodal tDCS in the patient group compared to sham stimulation but not in the control group. These results suggest that tDCS can facilitate spatial memory consolidation via stimulating the parietal-hippocampal navigation network in AD and MCI patients. Our findings suggest that tDCS of the temporoparietal junction may restore spatial navigation and memory deficits in patients with AD and MCI. [ABSTRACT FROM AUTHOR]

Olfactory bulbectomy (OBX) is an experimental strategy that is widely employed because it produces changes at different levels (from behavioral to molecular) that can be related to symptoms of depression in humans. This procedure has been widely studied in adult rats, but little information has been obtained of its effect in neonatal rats. The objective of the present study was to evaluate learning and memory capacity and dendritic spine density in dorsal hippocampal CA3 neurons. Seven-day-old male and female Wistar rats were subjected to nOBX by suction, we included an intact group as a control (CON) and a sham-operated group (SHAM), too. Spatial learning and memory were measured at 56 days of age using a Morris water maze. A different cohort of experimental groups was used to measure dendritic spine density by Golgi-Cox impregnation. Male rats with nOBX showed a pronounced spatial learning deficit than female rats. Also, there was a significant decrease in basilar dendritic spine density in female rats with nOBX compared to the CON group. No changes were observed in this variable in male rats with nOBX. Our results allow us to suggest that there is sexual dimorphism in the effect of nOBX on the dorsal hippocampus and its relationship with spatial learning and memory processes. [ABSTRACT FROM AUTHOR]

Thioacetamide (TAA)-induced hepatic encephalopathy (HE) has been reported in several studies. Sequel to acute or chronic liver failure, there is impairment in the hippocampal structure and hippocampal-mediated functions. The precise pathophysiological mechanism leading to neurological alterations remains elusive. The hippocampus also has rarely been examined in HE, hence this study. Vernonia amygdalina (VA) which possesses diverse biological activities has been studied and has promising therapeutic potential in several neurodegenerative diseases. Here, we investigated the neuroprotective activities of Vernonia amygdalina against thioacetamide-induced neuronal damage in the CA1 region of the hippocampus in the rat model. Thirty male Wistar rats were divided into five groups A-E (n=6). Group A (control) was the placebo and was administered 2mL/kg distilled water, group B was administered 100mg/kg thioacetamide only. Groups C-E were administered 100mg/kg of thioacetamide and were subsequently treated with 100mg/kg VA, 200mg/kg VA, and 3mg/kg vitamin C respectively. All administration was carried out for 14 days duration orally. Neurobehavioral tests were conducted. Required brain tissues for biochemical analyses were harvested following rat sacrifice. Glucose-6-phosphate dehydrogenase activity and hippocampal Glutamate levels were evaluated. Histological stains (H&E and cresyl violet) and immunohistochemical expression of Iba-1 protein (microglial marker) were used to assess neuroinflammation and neurodegeneration in the CA1 subfield. Statistical analyses were carried out using Graph pad prism 5 and all results were expressed as Mean±SEM. Means differences were identified by Tukey's post hoc test. Statistical significance was set at (p< 0.05). The neurobehavioral test results showed an observable increase in anxiety and impaired spatial working memory of the Wistar rats while glutamate (p = 0.6187; F =0.6844) and G6PDH activity (p = 0.6187; F= 0.9486) were not significantly different across groups. Thioacetamide treatment also resulted in neuroinflammation vis-à-vis microglial activation, causing neurodegeneration in the CA1 subfield. Vernonia amygdalina treatment ameliorated these neurotoxic changes. Altogether, Vernonia amygdalina treatment ameliorated thioacetamideinduced neurotoxicity in the CA1 region of the hippocampus via anti-neuroinflammatory and neuroprotective mechanisms. [ABSTRACT FROM AUTHOR]

Older adults show declines in spatial memory, although the extent of these alterations is not uniform across the healthy older population. Here, we investigate the stability of neural representations for the same and different spatial environments in a sample of younger and older adults using high-resolution functional MRI of the medial temporal lobes. Older adults showed, on average, lower neural pattern similarity for retrieving the same environment and more variable neural patterns compared to young adults. We also found a positive association between spatial distance discrimination and the distinctiveness of neural patterns between environments. Our analyses suggested that one source for this association was the extent of informational connectivity to CA1 from other subfields, which was dependent on age, while another source was the fidelity of signals within CA1 itself, which was independent of age. Together, our findings suggest both age-dependent and independent neural contributions to spatial memory performance. [ABSTRACT FROM AUTHOR]

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2a (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2a phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2a in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories. [ABSTRACT FROM AUTHOR]

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development. [ABSTRACT FROM AUTHOR]

Investigation of spatial memory entails studying the process for encoding and retrieving spatial information in working memory that is required for animal and human survival. Synaptic plasticity in the hippocampus is necessary for working memory. Physical activity stimulates the N-methyl-D-aspartate receptor (NMDAR) and subsequently increases NR2A or NR2B subunits of NMDAR-enabling synaptic plasticity in the hippocampus. Reduction of NMDAR and the postsynaptic density (PSD)-95 protein can be found in learning and memory impairment. An increasing amount of evidence has shown that peripheral physical activity has an enhancing effect on learning and memory and elevates the expression of brain-derived neurotrophic factor (BDNF). However, the mechanisms of physical activity that improve working memory have not been fully understood. In the current study, we study the potential effects of peripheral physical activity on spatial memory and synaptic plasticity-related proteins. Physical activity was performed by having the rats do voluntary wheel running throughout P25--P40. The Morris water maze task was performed on P40 for 6 days to study spatial memory. The hippocampal protein expression was ascertained by Western blot analysis. We found that physical activity enhanced spatial memory and BDNF, PSD-95, NR2A, and NR2B levels in the hippocampus. Physical activity can be effective in improving the central synaptic plasticity-related proteins that are essential for learning and memory. Peripheral physical activity is a promising candidate for further investigation as a potential treatment for learning and memory impairment. [ABSTRACT FROM AUTHOR]

Background: Caffeine (Cf) antagonizes the adenosine receptors and has neuroprotective properties. The effect of Cf has been seen on stress‐induced deficits of cognitive. In this study, we have investigated the effect of Cf on learning and memory functions induced by social isolation (SI) stress. Materials and methods: In the present study, 21‐day‐old Wistar albino male rats (n = 28) were divided into four groups: the control (C), the SI, the Cf, and the social isolation + caffeine (SICf). Cf (0.3 g/L) was added to the drinking water of the experimental animals for 4 weeks. The learning and memory functions were assessed using the Morris Water Maze Test (MWMT). Following, was performed histopathological evaluation and determined hippocampal gene expression levels by RT‐qPCR. Results: According to MWMT findings, the time spent in the quadrant where the platform removed was decreased in the SI group compared with the C (p < 0.05). Histological evaluation showed morphological changes in SI by irregular appearance, cellular edema, and dark pycnotic appearance of nuclei in some neurons. However, it was observed that the histological structure of most of the neurons in the SICf group was similar to the C and Cf groups. Hippocampal SNAP25 expression was decreased in the Cf and SICf groups than in the C group (p < 0.05). The GFAP expression was increased in the SICf group than in the C group (p < 0.05). NR2A increased in the SI and SICf groups compared with C and Cf groups (p < 0.05). NR2B expression decreased in the Cf group compared with C and SI groups (p < 0.05). Conclusions: SI impaired spatial memory and causes morphological changes in adolescent rats, but this effect of isolation was not seen in Cf‐treated animals. The effects of SI on NR2A, Cf on NR2B, and SNAP25 are remarkable. Here, we propose that the impaired effect of SI on spatial memory may be mediated by NR2A, but further studies are needed to explain this effect. [ABSTRACT FROM AUTHOR]

The rodent dorsal hippocampus (dHPC) displays spatial representations that can be biased by the positive or negative valence of the environment. The ventral hippocampus (vHPC) displays poorer spatial coding properties than the dHPC but stronger valence-related processing. The reactivation of spatial representations in the dHPC that sustain spatial memory consolidation can occur conjointly with valence-processing structures despite limited direct anatomical connections. The vHPC has reciprocal connections with key structures of the valence-processing network such as the basolateral amygdala or medial prefrontal cortex. The vHPC has the potential to serve as a central hub for the integration of contextual information from the dHPC and valence information from the rest of the network during sleep-dependent consolidation, through theta oscillations during rapid eye movement (REM) sleep and sharp-wave ripples during Non-REM sleep. Episodic memory relies on the hippocampus, a heterogeneous brain region with distinct functions. Spatial representations in the dorsal hippocampus (dHPC) are crucial for contextual memory, while the ventral hippocampus (vHPC) is more involved in emotional processing. Here, we review the literature in rodents highlighting the anatomical and functional properties of the hippocampus along its dorsoventral axis that underlie its role in contextual and emotional memory encoding, consolidation, and retrieval. We propose that the coordination between the dorsal and vHPC through theta oscillations during rapid eye movement (REM) sleep, and through sharp-wave ripples during non-REM (NREM) sleep, might facilitate the transfer of contextual information for integration with valence-related processing in other structures of the network. Further investigation into the physiology of the vHPC and its connections with other brain areas is needed to deepen the current understanding of emotional memory consolidation during sleep. [ABSTRACT FROM AUTHOR]

Targeting Aberrant Dendritic Integration to Treat Cognitive Comorbidities of Epilepsy Masala N, Pofahl M, Haubrich AN, Islam KUS, Nikbakht N, Pasdarnavab M, Bohmbach K, Araki K, Kamali F, Henneberger C, Golcuk K, Ewell LA, Blaess S, Kelly T, Beck H. Brain. 2023;146(6):2399-2417. doi:10.1093/brain/awac455 Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions. [ABSTRACT FROM AUTHOR]

The hippocampal formation and entorhinal cortex are crucially involved in learning and memory as well as in spatial navigation. The conservation of these structures across the entire mammalian lineage demonstrates their importance. Information on a diverse set of spatially tuned neurons has become available, but we only have a rudimentary understanding of how anatomical network structure affects functional tuning. Bats are the only order of mammals that have evolved true flight, and with this specialization comes the need to navigate and behave in a three dimensional (3D) environment. Spatial tuning of cells in the entorhinal‐hippocampal network of bats has been studied for some time, but whether the reported tuning in 3D is associated with changes in the entorhinal‐hippocampal network is not known. Here we investigated the entorhinal‐hippocampal projections in the Egyptian fruit bat (Rousettus aegyptiacus), by injecting chemical anterograde tracers in the entorhinal cortex. Detailed analyses of the terminations of these projections in the hippocampus showed that both the medial and lateral entorhinal cortex sent projections to the molecular layer of all subfields of the hippocampal formation. Our analyses showed that the terminal distributions of entorhinal fibers in the hippocampal formation of Egyptian fruit bats—including the proximo‐distal and longitudinal topography and the layer‐specificity—are similar to what has been described in other mammalian species such as rodents and primates. The major difference in entorhinal‐hippocampal projections that was described to date between rodents and primates is in the terminal distribution of the DG projection. We found that bats have entorhinal‐DG projections that seem more like those in primates than in rodents. It is likely that the latter projection in bats is specialized to the behavioral needs of this species, including 3D flight and long‐distance navigation. [ABSTRACT FROM AUTHOR]

Background: Hippocampal phase precession, which depends on the precise spike timing of place cells relative to local theta oscillations, has been proposed to underlie sequential memory. N-methyl-D-asparate (NMDA) receptor antagonists such as ketamine disrupt memory and also reproduce several schizophrenia-like symptoms, including spatial memory impairments and disorganized cognition. It is possible that these impairments result from disruptions to phase precession. Aims/methods: We used an ABA design to test whether an acute, subanesthetic dose (7.5 mg/kg) of ketamine disrupted phase precession in CA1 of male rats as they navigated around a rectangular track for a food reward. Results/outcomes: Ketamine did not affect the ability of CA1 place cells to precess despite changes to place cell firing rates, local field potential properties and locomotor speed. However, ketamine reduced the range of phase precession that occurred across a theta cycle. Conclusion: Phase precession is largely robust to acute NMDA receptor antagonism by ketamine, but the reduced range of precession could have important implications for learning and memory. [ABSTRACT FROM AUTHOR]

Memory consolidation involves interactions between the hippocampus and other cortical areas. A new study identifies neurons in the medial entorhinal cortex that over learning increase their coordination with hippocampal replay events, suggesting a route for consolidation of spatial memories. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR), which comprises three branches: PERK, ATF6α, and IRE1, is a major mechanism for maintaining cellular proteostasis. Many studies show that the UPR is a major player in regulating neuron viability and function in various neurodegenerative diseases; however, its role in neurodegeneration is highly controversial. Moreover, while evidence suggests activation of the UPR in neurons under normal conditions, deficiency of individual branches of the UPR has no major effect on brain neurons in animals. It remains unclear whether or how the UPR participates in regulating neuronal proteostasis under normal and disease conditions. To determine the physiological role of the UPR in neurons, we generated mice with double deletion of PERK and ATF6α in neurons. We found that inactivation of PERK and ATF6α in neurons caused lysosomal dysfunction (as evidenced by decreased expression of the V0a1 subunit of v-ATPase and decreased activation of cathepsin D), impairment of autophagic flux (as evidenced by increased ratio of LC3-II/LC3-I and increased p62 level), and accumulation of p-tau and Aβ42 in the hippocampus, and led to impairment of spatial memory, impairment of hippocampal LTP, and hippocampal degeneration in adult mice. These results suggest that the UPR is required for maintaining neuronal proteostasis (particularly tau and Aβ homeostasis) and the viability and function of neurons in the hippocampus of adult mice. [ABSTRACT FROM AUTHOR]

Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca2+ imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca2+ activity became increasingly related to reward during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, "reward off sustained", "reward off transient", "reward on sustained" and "reward on transient", and these responses showed reorganization after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent reward- related activity during learning. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location. [ABSTRACT FROM AUTHOR]

Circadian rhythms in behavior and physiology such as rest/activity and hormones are driven by an internal clock and persist in the absence of rhythmic environmental cues. However, the period and phase of the internal clock are entrained by the environmental light/dark cycle. Consequently, aberrant lighting conditions, which are increasing in modern society, have a strong impact on rhythmic body and brain functions. Mice were exposed to three different lighting conditions, 12 h light/12 h dark cycle (LD), constant darkness (DD), and constant light (LL), to study the effects of the light/dark cycle and aberrant lighting on the hippocampus, a critical structure for temporal and spatial memory formation and navigation. Locomotor activity and plasma corticosterone levels were analyzed as readouts for circadian rhythms. Spatial working memory via Y-maze, spine morphology of Golgi–Cox-stained hippocampi, and plasticity of excitatory synapses, measured by number and size of synaptopodin and GluR1-immunreactive clusters, were analyzed. Our results indicate that the light/dark cycle drives diurnal differences in synaptic plasticity in hippocampus. Moreover, spatial working memory, spine density, and size and number of synaptopodin and GluR1 clusters were reduced in LL, while corticosterone levels were increased. This indicates that acute constant light affects hippocampal function and synaptic plasticity. [ABSTRACT FROM AUTHOR]

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N‐de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA‐12 only partly prevented the NDPIH‐induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK‐293T cells, an effect that was not sensitive to ANA‐12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan‐neurotrophic signaling pathway, leading to improved cognitive performance. [ABSTRACT FROM AUTHOR]

The hippocampus is a critical component of a mammalian spatial navigation system, with the firing sequences of hippocampal place cells during sleep or immobility constituting a "replay" of an animal's past trajectories. A novel spatial navigation task recently revealed that such "replay" sequences of place fields can also prospectively map onto imminent new paths to a goal that occupies a stable location during each session. It was hypothesized that such "prospective replay" sequences may play a causal role in goal‐directed navigation. In the present study, we query this putative causal role in finding only minimal effects of muscimol‐induced inactivation of the dorsal and intermediate hippocampus on the same spatial navigation task. The concentration of muscimol used demonstrably inhibited hippocampal cell firing in vivo and caused a severe deficit in a hippocampal‐dependent "episodic‐like" spatial memory task in a watermaze. These findings call into question whether "prospective replay" of an imminent and direct path is actually necessary for its execution in certain navigational tasks. [ABSTRACT FROM AUTHOR]

The hippocampus is a center for spatial and episodic memory formation in rodents. Understanding the composition of subregions and circuitry maps of the hippocampus is essential for elucidating the mechanism of memory formation and recall. For decades, the trisynaptic circuit (entorhinal cortex layer II—dentate gyrus — CA3—CA1) has been considered the neural network substrate responsible for learning and memory. Recently, CA2 has emerged as an important area in the hippocampal circuitry, with distinct functions from those of CA3. In this article, we review the historical definition of the hippocampal area CA2 and the differential projection patterns between CA2 and CA3 pyramidal neurons. We provide a concise and comprehensive map of CA2 outputs by comparing (1) ipsi versus contra projections, (2) septal versus temporal projections, and (3) lamellar structures of CA2 and CA3 pyramidal neurons. [ABSTRACT FROM AUTHOR]

Development of the hippocampus is critical for its normal maturation. However, there is no systematic study on the effects of low‐dose (≤2 Gy) neonatal X‐ray exposure on different cells at different developmental stages of the mouse hippocampus. The present study demonstrated that irradiation with 2 Gy at postnatal day (PD) 3 in mice induced anxiety and impairment of spatial learning and memory in adult mice. Neuroinflammatory cells were observed in the dentate gyrus (DG) and CA3 areas of the hippocampus at PD3 + 1. X‐ray irradiation impaired neuronal complexity and neurogenesis. However, the number of astrocytes and microglia in the hippocampus was increased the first day after irradiation, and then decreased 21 days later. The protein expression levels of NF‐κB, C/EBP homologous protein (CHOP), and γH2A histone family member X (γH2AX) increased from 7 to 21 days after irradiation, or till 90 days after irradiation for IL‐1β, whereas those of hippocampal sirtuin1 (SIRT1) decreased after 21 days of irradiation at PD3. These results suggest that neonatal X‐ray irradiation‐induced neuroinflammation impaired neuroplasticity and neurogenesis in the hippocampus, leading to the anxiety and spatial memory disorder during adulthood. The mechanisms involved in the induction of developmental neurotoxicity following low‐dose irradiation may involve the inflammation‐mediated signaling pathway IL‐1β/ SIRT1/CHOP. [ABSTRACT FROM AUTHOR]

Entorhinal cortex is the major gateway between the neocortex and the hippocampus and thus plays an essential role in subserving episodic memory and spatial navigation. It can be divided into the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), which are commonly theorized to be critical for spatial (context) and non‐spatial (content) inputs, respectively. Consistent with this theory, LEC neurons are found to carry little information about allocentric self‐location, even in cue‐rich environments, but they exhibit egocentric spatial information about external items in the environment. The superficial and deep layers of LEC are believed to mediate the input to and output from the hippocampus, respectively. As earlier studies mainly examined the spatial firing properties of superficial‐layer LEC neurons, here we characterized the deep‐layer LEC neurons and made direct comparisons with their superficial counterparts in single unit recordings from behaving rats. Because deep‐layer LEC cells received inputs from hippocampal regions, which have strong selectivity for self‐location, we hypothesized that deep‐layer LEC neurons would be more informative about allocentric position than superficial‐layer LEC neurons. We found that deep‐layer LEC cells showed only slightly more allocentric spatial information and higher spatial consistency than superficial‐layer LEC cells. Egocentric coding properties were comparable between these two subregions. In addition, LEC neurons demonstrated preferential firing at lower speeds, as well as at the boundary or corners of the environment. These results suggest that allocentric spatial outputs from the hippocampus are transformed in deep‐layer LEC into the egocentric coding dimensions of LEC, rather than maintaining the allocentric spatial tuning of the CA1 place fields. [ABSTRACT FROM AUTHOR]

Background: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. Methods: To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. Results: In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. Conclusions: Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD. [ABSTRACT FROM AUTHOR]

Developmental morphine (MOR) exposure (DME) detrimentally affects the cognitive abilities of the next generation. It is shown that postnatal rearing environments and prenatal conditions effectively impact memory. The present study investigated the effects of DME, postweaning rearing, and sex on spatial learning and memory. At molecular level, we evaluated mRNA levels of brain‐derived neurotrophic factor, cyclic AMP response element‐binding protein (CREB), μ‐opioid receptor, and ΔFosB in the hippocampus of male offspring. Female Wistar rats were treated with escalating doses of MOR or saline before mating, gestation, and lactation. On Postnatal Day 22, the male and female pups were divided into 12 groups and raised for 2 months under different conditions: standard, isolated (ISO), or enriched environment. Afterward, the Morris water maze task measured spatial learning and reference memory; rats were then sacrificed to assess hippocampus gene expressions. Results indicated the DME and isolated rearing increased latency to find the hidden platform in male offspring. DME was insignificant in female offspring, whereas rearing environments significantly altered escape latency in both sexes. We also found that the enriched environment upregulated the brain‐derived neurotrophic factor mRNA in both saline and MOR groups, whereas it downregulated the mRNA levels of CREB1, μ‐opioid receptor, and ΔFosB in the MOR group. In addition, the DME enhanced CREB1, μ‐opioid receptor, and ΔFosB gene expression in the MOR + isolated group. Our findings signified the effects of DME, rearing environment, and sex on the spatial learning abilities of offspring. Also, we showed that DME and rearing conditions could manipulate hippocampal neurochemistry. [ABSTRACT FROM AUTHOR]

Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62–65% reduction in proliferating 5-bromo-2′deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus. [ABSTRACT FROM AUTHOR]

Acute and chronic corticosterone (CS) elevations after traumatic brain injury (TBI) may be involved in distant hippocampal damage and the development of late posttraumatic behavioral pathology. CS-dependent behavioral and morphological changes were studied 3 months after TBI induced by lateral fluid percussion in 51 male Sprague–Dawley rats. CS was measured in the background 3 and 7 days and 1, 2 and 3 months after TBI. Tests including open field, elevated plus maze, object location, new object recognition tests (NORT) and Barnes maze with reversal learning were used to assess behavioral changes in acute and late TBI periods. The elevation of CS on day 3 after TBI was accompanied by early CS-dependent objective memory impairments detected in NORT. Blood CS levels > 860 nmol/L predicted delayed mortality with an accuracy of 0.947. Ipsilateral neuronal loss in the hippocampal dentate gyrus, microgliosis in the contralateral dentate gyrus and bilateral thinning of hippocampal cell layers as well as delayed spatial memory deficits in the Barnes maze were revealed 3 months after TBI. Because only animals with moderate but not severe posttraumatic CS elevation survived, we suggest that moderate late posttraumatic morphological and behavioral deficits may be at least partially masked by CS-dependent survivorship bias. [ABSTRACT FROM AUTHOR]

Our minds are constantly in transit, from the present to the past to the future, across places we have and have not directly experienced. Nevertheless, memories of our mental time travel are not organized continuously and are adaptively chunked into contexts and episodes. In this paper, I will review evidence that suggests that spatial boundary representations play a critical role in providing structure to both our spatial and temporal memories. I will illustrate the intimate connection between hippocampal spatial mapping and temporal sequencing of episodic memory to propose that high-level cognitive processes like mental time travel and conceptual mapping are rooted in basic navigational mechanisms that we humans and nonhuman animals share. Our neuroscientific understanding of hippocampal function across species may provide new insight into the origins of even the most uniquely human cognitive abilities. [ABSTRACT FROM AUTHOR]

Slow gamma oscillations (20–50 Hz) have been suggested to coordinate information transfer between brain structures involved in memory formation. Whereas the involvement of slow gamma in memory processing was studied by means of correlation between the gamma power and the occurrence of a given event (sharp wave ripples (SWRs), cortical transients), our approach consists of the analysis of the transmission of slow gamma itself. We use the method based on Granger causality principle—direct Directed Transfer Function, which allows to determine directed propagation of brain activity, including bidirectional flows. Four cortical sites along with CA1 ipsi- and contralateral were recorded in behaving wild-type and APP/PS1 mice before and after learning session of a spatial memory task. During slow wave sleep propagation of slow gamma was bidirectional, forming multiple loops of interaction which involved both CA1 and some of cortical sites. In episodes coincident with SWRs the number and strength of connectivity pathways increased in both groups compared to episodes without SWRs. The effect of learning was expressed only in APP/PS1 mice and consisted in strengthening of the slow gamma transmission from hippocampus to cortex as well as between both CA1 which may serve more efficient transmission of information from impaired CA1. [ABSTRACT FROM AUTHOR]

Imagination is a biological function that is vital to human experience and advanced cognition. Despite this importance, it remains unknown how imagination is realized in the brain. Substantial research focusing on the hippocampus, a brain structure traditionally linked to memory, indicates that firing patterns in spatially tuned neurons can represent previous and upcoming paths in space. This work has generally been interpreted under standard views that the hippocampus implements cognitive abilities primarily related to actual experience, whether in the past (e.g. recollection, consolidation), present (e.g. spatial mapping) or future (e.g. planning). However, relatively recent findings in rodents identify robust patterns of hippocampal firing corresponding to a variety of alternatives to actual experience, in many cases without overt reference to the past, present or future. Given these findings, and others on hippocampal contributions to human imagination, we suggest that a fundamental function of the hippocampus is to generate a wealth of hypothetical experiences and thoughts. Under this view, traditional accounts of hippocampal function in episodic memory and spatial navigation can be understood as particular applications of a more general system for imagination. This view also suggests that the hippocampus contributes to a wider range of cognitive abilities than previously thought. This article is part of the theme issue 'Thinking about possibilities: mechanisms, ontogeny, functions and phylogeny'. [ABSTRACT FROM AUTHOR]

The hippocampus plays a crucial role in the formation and retrieval of spatial memory across mammals and episodic memory in humans. Episodic and spatial memories can be retrieved irrespective of the subject's awake behavioral state and independently of its actual spatial context. However, the nature of hippocampal network activity during such out-context retrieval has not been described so far. Theoretically, context-independent spatial memory retrieval suggests a shift of the hippocampal spatial representations from coding the current spatial context to coding the remembered environment. In this study we show in rats that the CA3 neuronal population can switch spontaneously across representations and transiently activate another stored familiar spatial pattern without direct external sensory cuing. This phenomenon qualitatively differs from the well-described sharp wave-related pattern reactivations during immobility. Here, it occurs under the theta oscillatory state during active exploration and reflects the preceding experience of sudden environmental change. The respective out-context coding spikes appeared later in the theta cycle than the in-context ones. Finally, the experience also induced the emergence of population vectors with a co-expression of both codes segregated into different phases of the theta cycle. [ABSTRACT FROM AUTHOR]

Although the association of prolonged use of proton pump inhibitors, such as omeprazole, with memory impairment has been reported more than two decades ago, its underlying molecular mechanism is yet to be determined. Thus, in this study, we aimed to determine the mechanisms underlying the effect of prolonged omeprazole treatment on hippocampal synaptic function and spatial memory in male rats. Adult rats were subcutaneously administered with omeprazole for 12 or 24 weeks. Spatial memory was assessed using the Morris water maze (MWM) test. We examined the hippocampal protein expression of synaptic plasticity proteins, including the AMPA receptor subunit GluA1, postsynaptic density-95 (PSD-95), and activity-regulated cytoskeleton-associated protein (Arc), and the hippocampal expression and localization of androgen receptor (AR). In the MWM test, the escape latency was found to be significantly higher, and the number of platform crossings and the time spent in the target quadrant were significantly lower in the rats treated with omeprazole compared to the control rats. Hypomagnesemia and lower bone and brain Mg2+ content were also detected in the omeprazole-treated groups compared with the control group. The expression of GluA1, PSD-95, and Arc in the hippocampus and the expression of AR in the dentate gyrus and CA1 of the hippocampus were significantly lower in the omeprazole-treated groups than in the control group. These results suggest that prolonged omeprazole treatment might lead to memory deficit by impairing glutamate receptor trafficking or synaptic anchoring. Hypomagnesemia and brain Mg2+ deficiency may be, at least in part, involved in omeprazole-induced memory impairment. [ABSTRACT FROM AUTHOR]

In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6- and 26.6-month-old rats. Spatial memory performance was assessed with the Barnes maze test. To evaluate learning ability and spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNAm data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpG proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant. These results suggest that age-related hypermethylation of transcription factors related to certain gene families, such as Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats. [ABSTRACT FROM AUTHOR]

The mammalian hippocampus (Hp) can be functionally segregated along its septotemporal axis, with involvement of dorsal hippocampus (dHp) in spatial memory and ventral hippocampus (vHp) in stress responses and emotional behaviour. In the present study, we investigate comparable functional segregation in proposed homologues within the avian brain. Using Japanese quail (Coturnix Japonica), we report that bilateral lesions of the rostral hippocampus (rHp) produce robust deficits in a spatial Y-maze discrimination (YMD) test while sparing performance during contextual fear conditioning (CFC), comparable to results from lesions to homologous regions in mammals. In contrast, caudal hippocampus (cHp) lesions failed to produce deficits in either CFC or YMD, suggesting that, unlike mammals, both cHp and rHp of birds can support emotional behavior. These observations demonstrate functional segregation along the rostrocaudal axis of the avian Hp that is comparable in part to distinctions seen along the mammalian hippocampal septotemporal axis. [ABSTRACT FROM AUTHOR]

The hippocampus is regarded as a cognition hub, particularly for learning and memory. Previously, neuronal mechanisms underlying various cognitive functions are delineated with the lamellar hippocampal circuitry, dentate gyrus—CA3 or CA2—CA1, within the transverse plane. More recently, interlamellar (often referred to as longitudinal) projections have received intensive attention to help understand signal convergence and divergence in cognition and behavior. Signal propagation along the longitudinal axis is evidenced by axonal arborization patterns and synaptic responses to electro‐ and photo‐stimulation, further demonstrating that information flow is more enriched in the longitudinal plane than the transverse plane. Here, we review the significance of longitudinal connections for cognition, discuss a putative circuit mechanism of place coding, and suggest the reconceptualization of the hippocampal circuitry. [ABSTRACT FROM AUTHOR]

Memory is vital to our daily existence. Although a large number of studies have suggested that the hippocampus is dedicated to long‐term memory, understanding how memory is anatomically encoded within the hippocampal neuronal network is still lacking. Previously our laboratory showed that hippocampal pyramidal cells are organized in cell clusters to encode both spatial and episodic memory. Based on these findings, we hypothesized that "cluster‐type" is a functional organization principal in the hippocampus to encode all types of memory. Here, we tested whether contextual fear, another hippocampus‐dependent memory, is also organized in cell clusters. We further investigated the possibility that post‐learning sleep may affect functional organization. Cluster formation was examined by assessing the topographic localization of active cells using immediate early gene (IEG, Zif268) imaging methods. The first experiment provides evidence of a cluster‐type organization in the hippocampus for fear memory by showing a spatial distribution of adjacent Zif268 positive cells. Exposure to the context itself, without electric shocks, induced a similar cellular formation; however, the degree of clustering was significantly lower. The second experiment provides evidence that sleep plays a role in the refinement and long‐term stability of the clusters. The present results confirm the existence of a cluster‐type topographic functional neuronal organization in the hippocampus for memory, and further suggest that post‐learning sleep enhances the cluster‐type organization. [ABSTRACT FROM AUTHOR]

Obesity is characterized by excessive fat accumulation. The Zucker rat displays genetic obesity due to a mutation in the leptin receptor gene; this model is of great interest because of its similarity to human obesity. Brain regions may be affected by obesity, but detailed information is lacking. In the present study, we analyzed the morphology of neurons in the hippocampal trisynaptic circuit as well as the spatial memory of obese Zucker rats. We performed two experiments. Each experiment contained two experimental groups: the control group (male Long Evans rats) and the study group (obese male Zucker rats). We monitored the body weights of all rats over 4 weeks. In the first experiment, we analyzed the morphology of hippocampal neurons. Under anesthesia, we measured the abdominal and hip circumferences and collected at least 1 ml of blood to assess serum glucose (GLU), triglyceride (TGC), and cholesterol (COL) concentrations. We perfused the brains of these rats with 0.9% saline solution, incubated the brains in Golgi‐Cox solution, and subsequently evaluated the morphology of pyramidal neurons in the hippocampus (the CA1‐CA3 regions) and the entorhinal cortex as well as the morphology of granule neurons in the dentate gyrus. In the second experiment, we assessed the spatial memory of animals with the Morris water maze. The Zucker rats had an obese phenotype, as indicated by their elevated body weight and increased abdominal and hip circumferences as well as elevated GLU, COL, and TGC concentrations. Analysis of neurons from the specified regions in obese male Zucker rats indicated reduced dendritic arborization and reduced dendritic spine density. In terms of spatial learning and memory, the obese Zucker rats exhibited intact spatial learning (i.e., of platform location) but deficits in spatial memory. These data provide evidence that obesity alters the morphology and function of hippocampal neurons. [ABSTRACT FROM AUTHOR]