Behavioral Analysis of NMDAR Function in Rodents: Tests of Long-Term Spatial Memory.

NMDAR-dependent forms of synaptic plasticity in brain regions like the hippocampus are widely believed to provide the neural substrate for long-term associative memory formation. However, the experimental data are equivocal at best and may suggest a more nuanced role for NMDARs and synaptic plasticity in memory. Much of the experimental data available comes from studies in genetically modified mice in which NMDAR subunits have been deleted or mutated in order to disrupt NMDAR function. Behavioral assessment of long-term memory in these mice has involved tests like the Morris watermaze and the radial arm maze. Here we describe these behavioral tests and some of the different testing protocols that can be used to assess memory performance. We discuss the importance of distinguishing selective effects on learning and memory processes from nonspecific effects on sensorimotor or motivational aspects of performance.

Location analysis of presynaptically active and silent synapses in single-cultured hippocampal neurons.

A morphologically present but non-functioning synapse is termed a silent synapse. Silent synapses are categorized into "postsynaptically silent synapses," where AMPA receptors are either absent or non-functional, and "presynaptically silent synapses," where neurotransmitters cannot be released from nerve terminals. The presence of presynaptically silent synapses remains enigmatic, and their physiological significance is highly intriguing. In this study, we examined the distribution and developmental changes of presynaptically active and silent synapses in individual neurons. Our findings show a gradual increase in the number of excitatory synapses, along with a corresponding decrease in the percentage of presynaptically silent synapses during neuronal development. To pinpoint the distribution of presynaptically active and silent synapses, i.e., their positional information, we employed Sholl analysis. Our results indicate that the distribution of presynaptically silent synapses within a single neuron does not exhibit a distinct pattern during synapse development in different distance from the cell body. However, irrespective of neuronal development, the proportion of presynaptically silent synapses tends to rise as the projection site moves farther from the cell body, suggesting that synapses near the cell body may exhibit higher synaptic transmission efficiency. This study represents the first observation of changes in the distribution of presynaptically active and silent synapses within a single neuron.

Study on Improving the Modulatory Effect of Rhythmic Oscillations by Transcranial Magneto-Acoustic Stimulation.

In hippocampus, synaptic plasticity and rhythmic oscillations reflect the cytological basis and the intermediate level of cognition, respectively. Transcranial ultrasound stimulation (TUS) has demonstrated the ability to elicit changes in neural response. However, the modulatory effect of TUS on synaptic plasticity and rhythmic oscillations was insufficient in the present studies, which may be attributed to the fact that TUS acts mainly through mechanical forces. To enhance the modulatory effect on synaptic plasticity and rhythmic oscillations, transcranial magneto-acoustic stimulation (TMAS) which induced a coupled electric field together with TUS's ultrasound field was applied. The modulatory effect of TMAS and TUS with a pulse repetition frequency of 100 Hz were compared. TMAS/TUS were performed on C57 mice for 7 days at two different ultrasound intensities (3 W/cm2 and 5 W/cm [Formula: see text]. Behavioral tests, long-term potential (LTP) and local field potentials in vivo were performed to evaluate TUS/TMAS modulatory effect on cognition, synaptic plasticity and rhythmic oscillations. Protein expression based on western blotting were used to investigate the under- lying mechanisms of these beneficial effects. At 5 W/cm2, TMAS-induced LTP were 113.4% compared to the sham group and 110.5% compared to TUS. Moreover, the relative power of high gamma oscillations (50-100Hz) in the TMAS group ( 1.060±0.155 %) was markedly higher than that in the TUS group ( 0.560±0.114 %) and sham group ( 0.570±0.088 %). TMAS significantly enhanced the synchronization of theta and gamma oscillations as well as theta-gamma cross-frequency coupling. Whereas, TUS did not show relative enhancements. TMAS provides enhanced effect for modulating the synaptic plasticity and rhythmic oscillations in hippocampus.

A Bionic Localization Memristive Circuit Based on Spatial Cognitive Mechanisms of Hippocampus and Entorhinal Cortex.

In this article, a bionic localization memristive circuit is proposed, which mainly consists of head direction cell module, grid cell module, place cell module and decoding module. This work modifies the two-dimensional Continuous Attractor Network (CAN) model of grid cells into two one-dimensional models in X and Y directions. The head direction cell module utilizes memristors to integrate angular velocity and represents the real orientation of an agent. The grid cell module uses memristors to sense linear velocity and orientation signals, which are both self-motion cues, and encodes the position in space by firing in a periodic mode. The place cell module receives the grid cell module's output and fires in a specific position. The decoding module decodes the angle or place information and transfers the neuron state to a 'one-hot' code. This proposed circuit completes the localizing task in space and realizes in-memory computing due to the use of memristors, which can shorten the execution time. The functions mentioned above are implemented in LTSPICE. The simulation results show that the proposed circuit can realize path integration and localization. Moreover, it is shown that the proposed circuit has good robustness and low area overhead. This work provides a possible application idea in a prospective robot platform to help the robot localize and build maps.

Short-Term Preexposure to Novel Enriched Environment Augments Hippocampal Ripples in Urethane-Anesthetized Mice.

Learning and memory are affected by novel enriched environment, a condition where animals play and interact with a variety of toys and conspecifics. Exposure of animals to the novel enriched environments improves memory by altering neural plasticity during natural sleep, a process called memory consolidation. The hippocampus, a pivotal brain region for learning and memory, generates high-frequency oscillations called ripples during sleep, which is required for memory consolidation. Naturally occurring sleep shares characteristics in common with general anesthesia in terms of extracellular oscillations, guaranteeing anesthetized animals suitable to examine neural activity in a sleep-like state. However, it is poorly understood whether the preexposure of animals to the novel enriched environment modulates neural activity in the hippocampus under subsequent anesthesia. To ask this question, we allowed mice to freely explore the novel enriched environment or their standard environment, anesthetized them, and recorded local field potentials in the hippocampal CA1 area. We then compared the characteristics of hippocampal ripples between the two groups and found that the amplitude of ripples and the number of successive ripples were larger in the novel enriched environment group than in the standard environment group, suggesting that the afferent synaptic input from the CA3 area to the CA1 area was higher when the animals underwent the novel enriched environment. These results underscore the importance of prior experience that surpasses subsequent physical states from the neurophysiological point of view.

Recognizing ideas generated in a creative task: the roles of the hippocampus and medial prefrontal cortex in facilitating self-generated learning.

Creative idea generation plays an important role in promoting successful memory formation. Yet, its underlying neural correlates remain unclear. We investigated the self-generated learning of creative ideas motivated by the schema-linked interactions between medial prefrontal and medial temporal regions framework. This was achieved by having participants generate ideas in the alternative uses task, self-evaluating their ideas based on novelty and source (i.e. new or old), and then later being tested on the recognition performance of the generated ideas. At the behavioral level, our results indicated superior performances in discriminating novel ideas, highlighting the novelty effect on memory. At the neural level, the regions-of-interest analyses revealed that successful recognition of novel ideas was associated with greater activations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) during ideation. However, only activation in the right HPC was positively related to the successful recognition of novel ideas. Importantly, the weaker the connection between the right HPC and left mPFC, the higher the recognition accuracy of novel ideas. Moreover, activations in the right HPC and left mPFC were both effective predictors of successful recognition of novel ideas. These findings uniquely highlight the role of novelty in promoting self-generated learning of creative ideas.

Continuous decision to wait for a future reward is guided by fronto-hippocampal anticipatory dynamics.

Deciding whether to wait for a future reward is crucial for surviving in an uncertain world. While seeking rewards, agents anticipate a reward in the present environment and constantly face a trade-off between staying in their environment or leaving it. It remains unclear, however, how humans make continuous decisions in such situations. Here, we show that anticipatory activity in the anterior prefrontal cortex, ventrolateral prefrontal cortex, and hippocampus underpins continuous stay-leave decision-making. Participants awaited real liquid rewards available after tens of seconds, and their continuous decision was tracked by dynamic brain activity associated with the anticipation of a reward. Participants stopped waiting more frequently and sooner after they experienced longer delays and received smaller rewards. When the dynamic anticipatory brain activity was enhanced in the anterior prefrontal cortex, participants remained in their current environment, but when this activity diminished, they left the environment. Moreover, while experiencing a delayed reward in a novel environment, the ventrolateral prefrontal cortex and hippocampus showed anticipatory activity. Finally, the activity in the anterior prefrontal cortex and ventrolateral prefrontal cortex was enhanced in participants adopting a leave strategy, whereas those remaining stationary showed enhanced hippocampal activity. Our results suggest that fronto-hippocampal anticipatory dynamics underlie continuous decision-making while anticipating a future reward.

Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning.

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it. Thus, activation of midbrain dopamine can operate as a teaching signal that triggers NeoHebbian LTP and promotes supervised learning.

Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding.

Our brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we describe the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results show feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observe backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintain the same hierarchical level, except for the final tone, where the cingulate gyrus assumes the top position within the hierarchy. The evoked responses of memorised sequences and variations engage the same hierarchical brain network but systematically differ in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis shows that alpha and beta power is stronger for the variations, while gamma power is enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.

Hippocampal sharp-wave ripples correlate with periods of naturally occurring self-generated thoughts in humans.

Core features of human cognition highlight the importance of the capacity to focus on information distinct from events in the here and now, such as mind wandering. However, the brain mechanisms that underpin these self-generated states remain unclear. An emerging hypothesis is that self-generated states depend on the process of memory replay, which is linked to sharp-wave ripples (SWRs), which are transient high-frequency oscillations originating in the hippocampus. Local field potentials were recorded from the hippocampus of 10 patients with epilepsy for up to 15 days, and experience sampling was used to describe their association with ongoing thought patterns. The SWR rates were higher during extended periods of time when participants' ongoing thoughts were more vivid, less desirable, had more imaginable properties, and exhibited fewer correlations with an external task. These data suggest a role for SWR in the patterns of ongoing thoughts that humans experience in daily life.

Visual boundary cues suffice to anchor place and grid cells in virtual reality.

The hippocampal formation contains neurons responsive to an animal's current location and orientation, which together provide the organism with a neural map of space.1,2,3 Spatially tuned neurons rely on external landmark cues and internally generated movement information to estimate position.4,5 An important class of landmark cue are the boundaries delimiting an environment, which can define place cell field position6,7 and stabilize grid cell firing.8 However, the precise nature of the sensory information used to detect boundaries remains unknown. We used 2-dimensional virtual reality (VR)9 to show that visual cues from elevated walls surrounding the environment are both sufficient and necessary to stabilize place and grid cell responses in VR, when only visual and self-motion cues are available. By contrast, flat boundaries formed by the edges of a textured floor did not stabilize place and grid cells, indicating only specific forms of visual boundary stabilize hippocampal spatial firing. Unstable grid cells retain internally coherent, hexagonally arranged firing fields, but these fields "drift" with respect to the virtual environment over periods >5 s. Optic flow from a virtual floor does not slow drift dynamics, emphasizing the importance of boundary-related visual information. Surprisingly, place fields are more stable close to boundaries even with floor and wall cues removed, suggesting invisible boundaries are inferred using the motion of a discrete, separate cue (a beacon signaling reward location). Subsets of place cells show allocentric directional tuning toward the beacon, with strength of tuning correlating with place field stability when boundaries are removed.

Remapping revisited: how the hippocampus represents different spaces.

The representation of distinct spaces by hippocampal place cells has been linked to changes in their place fields (the locations in the environment where the place cells discharge strongly), a phenomenon that has been termed 'remapping'. Remapping has been assumed to be accompanied by the reorganization of subsecond cofiring relationships among the place cells, potentially maximizing hippocampal information coding capacity. However, several observations challenge this standard view. For example, place cells exhibit mixed selectivity, encode non-positional variables, can have multiple place fields and exhibit unreliable discharge in fixed environments. Furthermore, recent evidence suggests that, when measured at subsecond timescales, the moment-to-moment cofiring of a pair of cells in one environment is remarkably similar in another environment, despite remapping. Here, I propose that remapping is a misnomer for the changes in place fields across environments and suggest instead that internally organized manifold representations of hippocampal activity are actively registered to different environments to enable navigation, promote memory and organize knowledge.

Retuning of hippocampal representations during sleep.

Hippocampal representations that underlie spatial memory undergo continuous refinement following formation1. Here, to track the spatial tuning of neurons dynamically during offline states, we used a new Bayesian learning approach based on the spike-triggered average decoded position in ensemble recordings from freely moving rats. Measuring these tunings, we found spatial representations within hippocampal sharp-wave ripples that were stable for hours during sleep and were strongly aligned with place fields initially observed during maze exploration. These representations were explained by a combination of factors that included preconfigured structure before maze exposure and representations that emerged during θ-oscillations and awake sharp-wave ripples while on the maze, revealing the contribution of these events in forming ensembles. Strikingly, the ripple representations during sleep predicted the future place fields of neurons during re-exposure to the maze, even when those fields deviated from previous place preferences. By contrast, we observed tunings with poor alignment to maze place fields during sleep and rest before maze exposure and in the later stages of sleep. In sum, the new decoding approach allowed us to infer and characterize the stability and retuning of place fields during offline periods, revealing the rapid emergence of representations following new exploration and the role of sleep in the representational dynamics of the hippocampus.

Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activation.

Serotonin is a neuromodulator that affects multiple behavioral and cognitive functions. Nonetheless, how serotonin causes such a variety of effects via brain-wide projections and various receptors remains unclear. Here we measured brain-wide responses to optogenetic stimulation of serotonin neurons in the dorsal raphe nucleus (DRN) of the male mouse brain using functional MRI with an 11.7 T scanner and a cryoprobe. Transient activation of DRN serotonin neurons caused brain-wide activation, including the medial prefrontal cortex, the striatum, and the ventral tegmental area. The same stimulation under anesthesia with isoflurane decreased brain-wide activation, including the hippocampal complex. These brain-wide response patterns can be explained by DRN serotonergic projection topography and serotonin receptor expression profiles, with enhanced weights on 5-HT1 receptors. Together, these results provide insight into the DR serotonergic system, which is consistent with recent discoveries of its functions in adaptive behaviors.

Parallel processing of quickly and slowly mobilized reserve vesicles in hippocampal synapses.

Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are often assumed to feed pools that are mobilized more quickly, in a series. However, electrophysiological studies of synaptic transmission have suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool. Here, we use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses and a parallel organization that prevents intermixing between the pools, even when stimulation is intense enough to drive exocytosis at the maximum rate. The experiments additionally demonstrate extensive heterogeneity among synapses in the relative sizes of the slowly and quickly mobilized reserve pools, which suggests equivalent heterogeneity in the numbers of reluctant and fast-releasing readily releasable vesicles that may be relevant for understanding information processing and storage.

Neurogenesis and pesticides: news of no new neurons.

New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.

Novos neurônios hipocampais são gerados continuamente no cérebro humano adulto. Vários estudos têm demonstrado que a proliferação de células do hipocampo é influenciada por uma variedade de estímulos, incluindo a exposição a pesticidas. Estes efeitos são particularmente importantes porque a desregulação da neurogênese pode estar associada ao declínio das funções neuronais e cognitivas e ao possível desenvolvimento de doenças neuropsiquiátricas.

5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.

Forming cognitive maps for abstract spaces: the roles of the human hippocampus and orbitofrontal cortex.

How does the human brain construct cognitive maps for decision-making and inference? Here, we conduct an fMRI study on a navigation task in multidimensional abstract spaces. Using a deep neural network model, we assess learning levels and categorized paths into exploration and exploitation stages. Univariate analyses show higher activation in the bilateral hippocampus and lateral prefrontal cortex during exploration, positively associated with learning level and response accuracy. Conversely, the bilateral orbitofrontal cortex (OFC) and retrosplenial cortex show higher activation during exploitation, negatively associated with learning level and response accuracy. Representational similarity analysis show that the hippocampus, entorhinal cortex, and OFC more accurately represent destinations in exploitation than exploration stages. These findings highlight the collaboration between the medial temporal lobe and prefrontal cortex in learning abstract space structures. The hippocampus may be involved in spatial memory formation and representation, while the OFC integrates sensory information for decision-making in multidimensional abstract spaces.

Orienteering combines vigorous-intensity exercise with navigation to improve human cognition and increase brain-derived neurotrophic factor.

Exercise enhances aspects of human cognition, but its intensity may matter. Recent animal research suggests that vigorous exercise, which releases greater amounts of lactate, activates more brain-derived neurotrophic factor (BDNF) in the hippocampus and, thus, may be optimal for supporting cognitive function. The cognitive benefits of exercise may be further augmented when combined with cognitive training. The sport of orienteering simultaneously combines exercise with spatial navigation and, therefore, may result in greater cognitive benefits than exercising only, especially at vigorous intensities. The present study aimed to examine the effects of an acute bout of orienteering at different intensities on cognition and BDNF compared to exercising only. We hypothesized that vigorous-intensity orienteering would increase lactate and BDNF and improve cognition more than moderate-intensity orienteering or vigorous exercise alone. Sixty-three recreationally active, healthy young adults (Mage = 21.10±2.75 years) with no orienteering experience completed a 1.3 km intervention course by navigating and exercising at a vigorous (80-85% of heart rate reserve) or moderate (40-50% of heart rate reserve) intensity or exercising vigorously without navigation. Exercise intensity was monitored using peak lactate, heart rate and rating of perceived exertion. Serum BDNF was extracted immediately before and after the intervention. Memory was assessed using the Mnemonic Similarity Task (high-interference memory) and the Groton Maze Learning Test (spatial memory). Both exercising and orienteering at a vigorous intensity elicited greater peak lactate and increases in BDNF than moderate-intensity orienteering, and individuals with higher peak lactate also had greater increases in BDNF. High-interference memory improved after both vigorous-intensity interventions but did not improve after the moderate-intensity intervention. Spatial memory only increased after vigorous-intensity orienteering, suggesting that orienteering at a vigorous intensity may particularly benefit spatial cognition. Overall, the results demonstrate the benefits of vigorous exercise on human cognition and BDNF.

PyHFO: lightweight deep learning-powered end-to-end high-frequency oscillations analysis application.

Objective. This study aims to develop and validate an end-to-end software platform, PyHFO, that streamlines the application of deep learning (DL) methodologies in detecting neurophysiological biomarkers for epileptogenic zones from EEG recordings.Approach. We introduced PyHFO, which enables time-efficient high-frequency oscillation (HFO) detection algorithms like short-term energy and Montreal Neurological Institute and Hospital detectors. It incorporates DL models for artifact and HFO with spike classification, designed to operate efficiently on standard computer hardware.Main results. The validation of PyHFO was conducted on three separate datasets: the first comprised solely of grid/strip electrodes, the second a combination of grid/strip and depth electrodes, and the third derived from rodent studies, which sampled the neocortex and hippocampus using depth electrodes. PyHFO demonstrated an ability to handle datasets efficiently, with optimization techniques enabling it to achieve speeds up to 50 times faster than traditional HFO detection applications. Users have the flexibility to employ our pre-trained DL model or use their EEG data for custom model training.Significance. PyHFO successfully bridges the computational challenge faced in applying DL techniques to EEG data analysis in epilepsy studies, presenting a feasible solution for both clinical and research settings. By offering a user-friendly and computationally efficient platform, PyHFO paves the way for broader adoption of advanced EEG data analysis tools in clinical practice and fosters potential for large-scale research collaborations.