Medial Entorhinal Cortex Research Articles

Medial temporal atrophy predicts the limbic comorbidities in lewy body disease.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

Synaptic interactions between stellate cells and parvalbumin interneurons in layer 2 of the medial entorhinal cortex are organized at the scale of grid cell clusters.

Interactions between excitatory and inhibitory neurons are critical to computations in cortical circuits but their organization is difficult to assess with standard electrophysiological approaches. Within the medial entorhinal cortex, representation of location by grid and other spatial cells involves circuits in layer 2 in which excitatory stellate cells interact with each other via inhibitory parvalbumin expressing interneurons. Whether this connectivity is structured to support local circuit computations is unclear. Here, we introduce strategies to address the functional organization of excitatory-inhibitory interactions using crossed Cre- and Flp-driver mouse lines to direct targeted presynaptic optogenetic activation and postsynaptic cell identification. We then use simultaneous patch-clamp recordings from postsynaptic neurons to assess their shared input from optically activated presynaptic populations. We find that extensive axonal projections support spatially organized connectivity between stellate cells and parvalbumin interneurons, such that direct connections are often, but not always, shared by nearby neurons, whereas multisynaptic interactions coordinate inputs to neurons with greater spatial separation. We suggest that direct excitatory-inhibitory synaptic interactions may operate at the scale of grid cell clusters, with local modules defined by excitatory-inhibitory connectivity, while indirect interactions may coordinate activity at the scale of grid cell modules.

Evidence for convergence of distributed cortical processing in band-like functional zones in human entorhinal cortex.

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing.

Isolated theta waves originating from the midline thalamus trigger memory reactivation during NREM sleep in mice

During non-rapid eye movement (NREM) sleep, neural ensembles in the entorhinal-hippocampal circuit responsible for encoding recent memories undergo reactivation to facilitate the process of memory consolidation. This reactivation is widely acknowledged as pivotal for the formation of stable memory and its impairment is closely associated with memory dysfunction. To date, the neural mechanisms driving the reactivation of neural ensembles during NREM sleep remain poorly understood. Here, we show that the neural ensembles in the medial entorhinal cortex (MEC) that encode spatial experiences exhibit reactivation during NREM sleep. Notably, this reactivation consistently coincides with isolated theta waves. In addition, we found that the nucleus reuniens (RE) in the midline thalamus exhibits typical theta waves during NREM sleep, which are highly synchronized with those occurring in the MEC in male mice. Closed-loop optogenetic inhibition of the RE-MEC pathway specifically suppressed these isolated theta waves, resulting in impaired reactivation and compromised memory consolidation following a spatial memory task in male mice. The findings suggest that theta waves originating from the ventral midline thalamus play a role in initiating memory reactivation and consolidation during sleep.

One-shot entorhinal maps enable flexible navigation in novel environments.

Animals must navigate changing environments to find food, shelter or mates. In mammals, grid cells in the medial entorhinal cortex construct a neural spatial map of the external environment1-5. However, how grid cell firing patterns rapidly adapt to novel or changing environmental features on a timescale relevant to behaviour remains unknown. Here, by recording over 15,000 grid cells in mice navigating virtual environments, we tracked the real-time state of the grid cell network. This allowed us to observe and predict how altering environmental features influenced grid cell firing patterns on a nearly instantaneous timescale. We found evidence that visual landmarks provide inputs to fixed points in the grid cell network. This resulted in stable grid cell firing patterns in novel and altered environments after a single exposure. Fixed visual landmark inputs also influenced the grid cell network such that altering landmarks induced distortions in grid cell firing patterns. Such distortions could be predicted by a computational model with a fixed landmark to grid cell network architecture. Finally, a medial entorhinal cortex-dependent task revealed that although grid cell firing patterns are distorted by landmark changes, behaviour can adapt via a downstream region implementing behavioural timescale synaptic plasticity6. Overall, our findings reveal how the navigational system of the brain constructs spatial maps that balance rapidity and accuracy. Fixed connections between landmarks and grid cells enable the brain to quickly generate stable spatial maps, essential for navigation in novel or changing environments. Conversely, plasticity in regions downstream from grid cells allows the spatial maps of the brain to more accurately mirror the external spatial environment. More generally, these findings raise the possibility of a broader neural principle: by allocating fixed and plastic connectivity across different networks, the brain can solve problems requiring both rapidity and representational accuracy.

Olfactory bulb stimulation mitigates Alzheimer's-like disease progression.

Deep brain stimulation (DBS) has demonstrated potential in mitigating Alzheimer's disease (AD). However, the invasive nature of DBS presents challenges for its application. The olfactory bulb (OB), showing early AD-related changes and extensive connections with memory regions, offers an attractive entry point for intervention, potentially restoring normal activity in deteriorating memory circuits. Our study examined the impact of electrically stimulating the OB on working memory as well as pathological and electrophysiological alterations in the OB, medial prefrontal cortex, hippocampus, and entorhinal cortex in amyloid beta (Aβ) AD model rats. Male Wistar rats underwent surgery for electrode implantation in brain regions, inducing Alzheimer's-like disease. Bilateral olfactory bulb (OB) electrical stimulation was performed for 1 hour daily to the OB of stimulation group animals for 18 consecutive days, followed by the evaluations of histological, behavioral, and local field potential signal processing. OB stimulation counteracted Aβ plaque accumulation and prevented AD-induced working memory impairments. Furthermore, it prompted an increase in power across diverse frequency bands and enhanced functional connectivity, particularly in the gamma band, within the investigated regions during a working memory task. This preclinical investigation highlights the potential of olfactory pathway-based brain stimulation to modulate the activity of deep-seated memory networks for AD treatment. Importantly, the accessibility of this pathway via the nasal cavity lays the groundwork for the development of minimally invasive approaches targeting the olfactory pathway for brain modulation.

Emerging signs of Alzheimer-like tau hyperphosphorylation and neuroinflammation in the brain post recovery from COVID-19.

Coronavirus disease 2019 (COVID-19) has been suggested to increase the risk of memory decline and Alzheimer's disease (AD), the main cause of dementia in the elderly. However, direct evidence about whether COVID-19 induces AD-like neuropathological changes in the brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation of hyperphosphorylated tau protein in the hippocampus and medial entorhinal cortex within 4-13 months post clinically recovery from acute COVID-19, together with prolonged activation of glia cells and increases in inflammatory factors, even though no SARS-COV-2 invasion was detected in these regions. By contrast, COVID-19 did not change beta-amyloid deposition and hippocampal neuron number, and had limited effects on AD-related pathological phenotypes in olfactory circuits including olfactory bulb, anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. These results provide neuropathological evidences linking COVID-19 with prognostic increase of risk for AD.

Path Integration Detects Prodromal Alzheimer's Disease and Predicts Cognitive Decline.

The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI-). Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI-. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12-15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD.

P219 ASSOCIATION OF 24-HOURS BLOOD PRESSURE VARIABILITY WITH BRAIN MRI REGIONS OF INTEREST FOR ALZHEIMER'S DISEASE

Introduction: Variability in blood pressure (BP) has been associated with Alzheimer's disease (AD). However, it is unclear whether high variability in BP over 24-hours (24-h) is associated with the pre-clinical stage of AD. By examining brain MRI regions that atrophy decades before AD develops, we investigated the association between 24-h BP variability and MRI regions of interest for AD. Methods: We included baseline information of 324 participants aged ≥40 years old from a population-based study who underwent 24-h ambulatory BP monitoring and brain MRI scans. 24-h systolic BP variability was quantified using the average real variability (ARV) index. Brain MRI regions of interest for AD included the superior and middle frontal gyrus, supramarginal, superior, and precuneus gyrus, temporal pole, medial and inferior gyrus, entorhinal cortex, and hippocampus. We performed adjusted linear regression models to evaluate the association between 24-h systolic BP variability and MRI regions of interest for AD. Results: The mean age was 58.8±12.5 and 75.3% (n=244) were women. The mean thickness of MRI regions of interest for AD ranged from 2.12 mm3 to 4.04 mm3. In linear regression models, every +1.85 mmHg increase in 24-h systolic ARV was associated with lower thickness of the superior (adjusted mean mm3, -0.10; 95% confidence interval [CI], -0.21 and -0.01) and middle (adjusted-mean, -0.12 mm3; 95% CI, -0.24 and -0.01) frontal gyrus, medial temporal gyrus (adjusted mean, -0.21 mm3; 95% CI, -0.32 and -0.10), entorhinal cortex (adjusted-mean, 0.11 mm3; 95% CI, -0.21 and -0.01), and hippocampus (adjusted-mean, -0.14 mm3; 95% CI, -0.25 and -0.03); analyses also accounted for the 24-h systolic BP level. High 24-h systolic BP level was associated with lower thickness in 3/10 regions of interest for AD (P≤0.029). Conclusions: Elevated 24-h systolic BP variability is associated with thinning of brain MRI regions of interest for AD. Prospective data are needed to examine whether 24-h BP variability associated with thinning in brain MRI regions will increase the risk of AD.

Intrinsic Bipolar Head-Direction Cells in the Medial Entorhinal Cortex.

Head-direction (HD) cells are a fundamental component in the hippocampal-entorhinal circuit for spatial navigation and help maintain an internal sense of direction to anchor the orientation in space. A classical HD cell robustly increases its firing rate when the head is oriented toward a specific direction, with each cell tuned to only one direction. Although unidirectional HD cells are reported broadly across multiple brain regions, computation modelling has predicted the existence of multiple equilibrium states of HD network, which has yet to be proven. In this study, a novel HD variant of bipolar HD cells in the medial entorhinal cortex (MEC) are identified that exhibit stable double-peaked directional tuning properties. The bipolar patterns remain stable in the darkness and across environments of distinct geometric shapes. Moreover, bipolar HD cells co-rotate coherently with unipolar HD cells to anchor the external visual cue. The discovery reveals a new spatial cell type of bipolar HD cells, whose unique activity patterns may comprise a potential building block for a sophisticated local neural circuit configuration for the internal representation of direction. These findings may contribute to the understanding of how the brain processes spatial information by shedding light on the role of bipolar HD cells in this process.

Non-spatial hippocampal behavioral timescale synaptic plasticity during working memory is gated by entorhinal inputs.

Behavioral timescale synaptic plasticity (BTSP) is a form of synaptic potentiation where the occurrence of a single large plateau potential in CA1 hippocampal neurons leads to the formation of reliable place fields during spatial learning tasks. We asked whether BTSP could also be a plasticity mechanism for generation of non-spatial responses in the hippocampus and what roles the medial and lateral entorhinal cortex (MEC and LEC) play in driving non-spatial BTSP. By performing simultaneous calcium imaging of dorsal CA1 neurons and chemogenetic inhibition of LEC or MEC while mice performed an olfactory working memory task, we discovered BTSP-like events which formed stable odor-specific fields. Critically, the success rate of calcium events generating a significant odor-field increased with event amplitude, and large events exhibited asymmetrical formation with the newly formed odor-fields preceding the timepoint of their induction event. We found that MEC and LEC play distinct roles in modulating BTSP: MEC inhibition reduced the frequency of large calcium events, while LEC inhibition reduced the success rate of odor-field generation. Using two-photon calcium imaging of LEC and MEC temporammonic axons projecting to CA1, we found that LEC projections to CA1 were strongly odor selective even early in task learning, while MEC projection odor-selectivity increased with task learning but remained weaker than LEC. Finally, we found that LEC and MEC inhibition both slowed representational drift of odor representations in CA1 across 48 hours. Altogether, odor-specific information from LEC and strong odor-timed activity from MEC are crucial for driving BTSP in CA1, which is a synaptic plasticity mechanism for generation of both spatial and non-spatial responses in the hippocampus that may play a role in explaining representational drift and one-shot learning of non-spatial information.

Predictive grid coding in the medial entorhinal cortex.

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

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep.

High-frequency oscillatory activity in cognition-related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

Associations of polygenic risk scores differentiating attention-deficit hyperactivity disorder from autism spectrum disorder with cognitive and cortical alterations in Schizophrenia patients.

Schizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. In this study, we investigated whether polygenic risk scores (PRSs) differentiating ASD from ADHD are associated with cognitive impairments and alterations in cortical structures in SCZ patients. Based on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n = 168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n = 145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n = 126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients. Among the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p = 0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta = 0.21, p = 8.29 × 10- 4), left entorhinal (beta = 0.21, p = 0.025), left postcentral (beta = 0.18, p = 7.52 × 10- 3), right fusiform (beta = 0.17, p = 6.64 × 10- 3), and left fusiform cortices (beta = 0.17, p = 7.77 × 10- 3) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p = 0.039; right, beta=-0.17, p = 0.045). Our study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.

Prenatal protein malnutrition decreases neuron numbers in the parahippocampal region but not prefrontal cortex in adult rats

ABSTRACT Objective Prenatal protein malnutrition produces anatomical and functional changes in the developing brain that persist despite immediate postnatal nutritional rehabilitation. Brain networks of prenatally malnourished animals show diminished activation of prefrontal areas and an increased activation of hippocampal regions during an attentional task [1]. While a reduction in cell number has been documented in hippocampal subfield CA1, nothing is known about changes in neuron numbers in the prefrontal or parahippocampal cortices. Methods In the present study, we used unbiased stereology to investigate the effect of prenatal protein malnutrition on the neuron numbers in the medial prefrontal cortex and the cortices of the parahippocampal region that comprise the larger functional network. Results Results show that prenatal protein malnutrition does not cause changes in the neuronal population in the medial prefrontal cortex of adult rats, indicating that the decrease in functional activation during attentional tasks is not due to a reduction in the number of neurons. Results also show that prenatal protein malnutrition is associated with a reduction in neuron numbers in specific parahippocampal subregions: the medial entorhinal cortex and presubiculum. Discussion The affected regions along with CA1 comprise a tightly interconnected circuit, suggesting that prenatal malnutrition confers a vulnerability to specific hippocampal circuits. These findings are consistent with the idea that prenatal protein malnutrition produces a reorganization of structural and functional networks, which may underlie observed alterations in attentional processes and capabilities.

Anatomical and electrophysiological analysis of the fasciola cinerea of the mouse hippocampus.

The hippocampus is considered essential for several forms of declarative memory, including spatial and social memory. Despite the extensive research of the classic subfields of the hippocampus, the fasciola cinerea (FC)-a medially located structure within the hippocampal formation-has remained largely unexplored. In the present study, we performed a morpho-functional characterization of principal neurons in the mouse FC. Using in vivo juxtacellular recording of single neurons, we found that FC neurons are distinct from neighboring CA1 pyramidal cells, both morphologically and electrophysiologically. Specifically, FC neurons displayed non-pyramidal morphology and granule cell-like apical dendrites. Compared to neighboring CA1 pyramidal neurons, FC neurons exhibited more regular in vivo firing patterns and a lower tendency to fire spikes at short interspike intervals. Furthermore, tracing experiments revealed that the FC receives inputs from the lateral but not the medial entorhinal cortex and CA3, and it provides a major intra-hippocampal projection to the septal CA2 and sparser inputs to the distal CA1. Overall, our results indicate that the FC is a morphologically and electrophysiologically distinct subfield of the hippocampal formation; given the established role of CA2 in social memory and seizure initiation, the unique efferent intra-hippocampal connectivity of the FC points to possible roles in social cognition and temporal lobe epilepsy.

Correlations of brain structure with the social behavior of 15q11-13 duplication mice, an animal model of autism

Duplication of chromosome 15q11–13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11–13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.

Environmental enrichment reduces restricted repetitive behavior by altering gray matter microstructure.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior.

Entorhinal cortex represents task-relevant remote locations independent of CA1.

Neurons can collectively represent the current sensory experience while an animal is exploring its environment or remote experiences while the animal is immobile. These remote representations can reflect learned associations and be required for learning. Neurons in the medial entorhinal cortex (MEC) reflect the animal's current location during movement, but little is known about what MEC neurons collectively represent during immobility. Here, we recorded thousands of neurons in superficial MEC and dorsal CA1 as mice learned to associate two pairs of rewarded locations. We found that during immobility, the MEC neural population frequently represented positions far from the animal's location, which we defined as 'non-local coding'. Cells with spatial firing fields at remote locations drove non-local coding, even as cells representing the current position remained active. While MEC non-local coding has been reported during sharp-wave ripples in downstream CA1, we observed non-local coding more often outside of ripples. In fact, CA1 activity was less coordinated with MEC during non-local coding. We further observed that non-local coding was pertinent to the task, as MEC preferentially represented remote task-relevant locations at appropriate times, while rarely representing task-irrelevant locations. Together, this work raises the possibility that MEC non-local coding could strengthen associations between locations independently from CA1.

Self-avoidance dominates the selection of hippocampal replay.

Spontaneous neural activity sequences are generated by the brain in the absence of external input 1-12 , yet how they are produced remains unknown. During immobility, hippocampal replay sequences depict spatial paths related to the animal's past experience or predicted future 13 . By recording from large ensembles of hippocampal place cells 14 in combination with optogenetic manipulation of cortical input in freely behaving rats, we show here that the selection of hippocampal replay is governed by a novel self-avoidance principle. Following movement cessation, replay of the animal's past path is strongly avoided, while replay of the future path predominates. Moreover, when the past and future paths overlap, early replays avoid both and depict entirely different trajectories. Further, replays avoid self-repetition, on a shorter timescale compared to the avoidance of previous behavioral trajectories. Eventually, several seconds into the stopping period, replay of the past trajectory dominates. This temporal organization contrasts with established and recent predictions 9,10,15,16 but is well-recapitulated by a symmetry-breaking attractor model of sequence generation in which individual neurons adapt their firing rates over time 26-35 . However, while the model is sufficient to produce avoidance of recently traversed or reactivated paths, it requires an additional excitatory input into recently activated cells to produce the later window of past-dominance. We performed optogenetic perturbations to demonstrate that this input is provided by medial entorhinal cortex, revealing its role in maintaining a memory of past experience that biases hippocampal replay. Together, these data provide specific evidence for how hippocampal replays are generated.