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In the brains of Alzheimer's disease patients, the entorhinal cortex is known to show signs of early pathology. In this study, Khan et al . performed cerebral blood volume imaging of patients with preclinical Alzheimer's disease and mouse models of disease. Their results pinpoint the subregion in the entorhinal cortex most sensitive to the disease, and show how amyloid and tau interact in driving dysfunction and how dysfunction spreads to distal cortical regions. The entorhinal cortex has been implicated in the early stages of Alzheimer's disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer's disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.

Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell–like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell–like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell–like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-ε4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.

The tau protein aggregates in aging and Alzheimer disease and may lead to memory loss through disruption of medial temporal lobe (MTL)-dependent memory systems. Here, we investigated tau-mediated mechanisms of hippocampal dysfunction that underlie the expression of episodic memory decline using fMRI measures of hippocampal local coherence (regional homogeneity; ReHo), distant functional connectivity and tau-PET. We show that age and tau pathology are related to higher hippocampal ReHo. Functional disconnection between the hippocampus and other components of the MTL memory system, particularly an anterior-temporal network specialized for object memory, is also associated with higher hippocampal ReHo and greater tau burden in anterior-temporal regions. These associations are not observed in the posteromedial network, specialized for context/spatial information. Higher hippocampal ReHo predicts worse memory performance. These findings suggest that tau pathology plays a role in disconnecting the hippocampus from specific MTL memory systems leading to increased local coherence and memory decline. Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.

Depression is characterized by impairments in adult neurogenesis. Reduced hippocampal function, which is suggestive of neurogenesis impairments, is associated with depression-related phenotypes. As adult neurogenesis operates in an activity-dependent manner, disruption of hippocampal neurogenesis in depression may be a consequence of neural circuitry impairments. In particular, the entorhinal cortex is known to have a regulatory effect on the neural circuitry related to hippocampal function and adult neurogenesis. However, a comprehensive understanding of how disruption of the neural circuitry can lead to neurogenesis impairments in depression remains unclear with respect to the regulatory role of the entorhinal cortex. This review highlights recent findings suggesting neural circuitry-regulated neurogenesis, with a focus on the potential role of the entorhinal cortex in hippocampal neurogenesis in depression-related cognitive and emotional phenotypes. Taken together, these findings may provide a better understanding of the entorhinal cortex-regulated hippocampal neurogenesis model of depression.

Cognitive maps in the hippocampal-entorhinal system are central for the representation of both spatial and non-spatial relationships. Although this system, especially in humans, heavily relies on vision, the role of visual experience in shaping the development of cognitive maps remains largely unknown. Here, we test sighted and early blind individuals in both imagined navigation in fMRI and real-world navigation. During imagined navigation, the Human Navigation Network, constituted by frontal, medial temporal, and parietal cortices, is reliably activated in both groups, showing resilience to visual deprivation. However, neural geometry analyses highlight crucial differences between groups. A 60° rotational symmetry, characteristic of a hexagonal grid-like coding, emerges in the entorhinal cortex of sighted but not blind people, who instead show a 90° (4-fold) symmetry, indicative of a square grid. Moreover, higher parietal cortex activity during navigation in blind people correlates with the magnitude of 4-fold symmetry. In sum, early blindness can alter the geometry of entorhinal cognitive maps, possibly as a consequence of higher reliance on parietal egocentric coding during navigation. The contribution of visual experience to the formation of cognitive maps in humans is not well understood. Here, the authors show using fMRI and an imagined navigation paradigm, that sighted people display hexagonal grid-like neural coding, while blind people show neural representations consistent with a square grid.

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is attacked during the early stage of Alzheimer's disease (AD). Here, we report that the synaptic terminals of pyramidal neurons in the EC layer II (ECIIPN ) directly innervate CA1 parvalbumin (PV) neurons (CA1PV ) and are selectively degenerated in AD mice, which exhibit amyloid-β plaques similar to those observed in AD patients. A loss of ECIIPN -CA1PV synapses disables the excitatory and inhibitory balance in the CA1 circuit and impairs spatial learning and memory. Optogenetic activation of ECIIPN using a theta burst paradigm rescues ECIIPN -CA1PV synaptic defects and intercepts the decline in spatial learning and memory. These data reveal a novel mechanism of memory loss in AD mice via the selective degeneration of the ECIIPN -CA1PV pathway.

Specialized cell types in the medial entorhinal cortex (MEC), such as grid cells, are thought to provide spatial information to the hippocampus. Here the authors show that MEC lesions disrupt hippocampal theta phase precession, which suggests that the MEC is critical for cognitive functions that depend on precisely timed neuronal activity. The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC.

Understanding neural network behavior is essential to shed light on epileptogenesis and seizure propagation. The interconnectivity and plasticity of mammalian limbic and neocortical brain regions provide the substrate for the hypersynchrony and hyperexcitability associated with seizure activity. Recurrent unprovoked seizures are the hallmark of epilepsy, and limbic epilepsy is the most common type of medically-intractable focal epilepsy in adolescents and adults that necessitates surgical evaluation. In this review, we describe the role and relationships among the piriform (PIRC), perirhinal (PRC), and entorhinal cortex (ERC) in seizure-generation and epilepsy. The inherent function, anatomy, and histological composition of these cortical regions are discussed. In addition, the neurotransmitters, intrinsic and extrinsic connections, and the interaction of these regions are described. Furthermore, we provide evidence based on clinical research and animal models that suggest that these cortical regions may act as key seizure-trigger zones and, even, epileptogenesis.

Sex and apolipoprotein E (APOE) genotype have been shown to influence the risk and progression of Alzheimer’s disease (AD). However, the impact of these factors on the functional connectivity of the entorhinal cortex (ERC) in clinically unpaired older adults (CUOA) with amyloid-β (Aβ +) pathology remains unclear. A total of 1022 cognitively normal older adults with Aβ + (603 females and 586 APOE ε4 +) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study were included in this study. The 2 × 2 (gender, 2 APOE genotypes) analysis of covariance was performed to compare the demographic information, cognitive performance, and volumetric MRI data among these groups. Voxel-wise comparisons of bilateral ERC functional connectivity (FC) were conducted, and partial correlation analyses were used to explore the associations between cognitive performance and ERC-FC strength. We found that the APOE genotype influenced ERC functional connectivity mainly in the sensorimotor network (SMN). Males exhibited higher ERC-FC in the salience network (SN), while females displayed higher ERC-FC in the default mode network (DMN), executive control network (ECN), and reward network. The interplay of sex and APOE genotype on ERC-FC was observed in the SMN and cerebellar lobe. The ERC-FC was associated with executive function and memory performance in individuals with CUOA-Aβ + . Our findings provide evidence of sex-specific ERC functional connectivity compensation mechanism in cognitively normal older adults with Aβ + pathology. This study may contribute to a better understanding of the mechanisms underlying the early stages of AD and may help develop personalized interventions in preclinical AD.

To execute goal-directed behavior, retrieval of both context and object information is crucial. Despite the ubiquity of such contextual computations in daily navigation, the neural mechanisms underlying this process in humans and its connection to behavior remain largely elusive. Leveraging intracranial electroencephalography (iEEG) recorded from epilepsy patients ( N  = 31) engaged in a context-dependent spatial navigation task, we uncovered distinct oscillatory patterns in the hippocampus (HC) and entorhinal cortex (EC) that represented context and object information, respectively. Notably, the covariation of these neural representations predicted behavioral performance. Furthermore, both representations were primarily driven by low-frequency oscillations (2–8 Hz). The synchronization of low-frequency oscillations between HC and EC was associated with enhanced object representations in the EC. These findings highlight the importance of low-frequency neural dynamics in mediating both local representations and interregional interactions within the hippocampal–entorhinal circuit during context-dependent spatial navigation.