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Nature Neuroscience Feb 2021Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To...
Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus-brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively-from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Astrocytes; Entorhinal Cortex; Female; Frontal Lobe; Humans; Male; Middle Aged; Neurofibrillary Tangles; Neurons; tau Proteins
PubMed: 33432193
DOI: 10.1038/s41593-020-00764-7 -
Trends in Neurosciences Feb 2023The entorhinal cortex (EC) is the brain region that often exhibits the earliest histological alterations in Alzheimer's disease (AD), including the formation of... (Review)
Review
The entorhinal cortex (EC) is the brain region that often exhibits the earliest histological alterations in Alzheimer's disease (AD), including the formation of neurofibrillary tangles and cell death. Recently, brain imaging studies from preclinical AD patients and electrophysiological recordings from AD animal models have shown that impaired neuronal activity in the EC precedes neurodegeneration. This implies that memory impairments and spatial navigation deficits at the initial stage of AD are likely caused by activity dysfunction rather than by cell death. This review focuses on recent findings on EC dysfunction in AD, and discusses the potential pathways for mitigating AD progression by protecting the EC.
Topics: Animals; Alzheimer Disease; Entorhinal Cortex; Neurofibrillary Tangles; Neurons; Brain; Hippocampus
PubMed: 36513524
DOI: 10.1016/j.tins.2022.11.006 -
Nature Reviews. Neuroscience Mar 2020The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions,... (Review)
Review
The dentate gyrus (DG) has a key role in hippocampal memory formation. Intriguingly, DG lesions impair many, but not all, hippocampus-dependent mnemonic functions, indicating that the rest of the hippocampus (CA1-CA3) can operate autonomously under certain conditions. An extensive body of theoretical work has proposed how the architectural elements and various cell types of the DG may underlie its function in cognition. Recent studies recorded and manipulated the activity of different neuron types in the DG during memory tasks and have provided exciting new insights into the mechanisms of DG computational processes, particularly for the encoding, retrieval and discrimination of similar memories. Here, we review these DG-dependent mnemonic functions in light of the new findings and explore mechanistic links between the cellular and network properties of, and the computations performed by, the DG.
Topics: Animals; Dentate Gyrus; Discrimination Learning; Entorhinal Cortex; Humans; Memory Consolidation; Memory, Episodic; Mental Recall; Models, Neurological; Neurons
PubMed: 32042144
DOI: 10.1038/s41583-019-0260-z -
Neurobiology of Learning and Memory Oct 2021Memories of emotionally arousing events tend to endure longer than other memories. This review compiles findings from several decades of research investigating the role... (Review)
Review
Memories of emotionally arousing events tend to endure longer than other memories. This review compiles findings from several decades of research investigating the role of the amygdala in modulating memories of emotional experiences. Episodic memory is a kind of declarative memory that depends upon the hippocampus, and studies suggest that the basolateral complex of the amygdala (BLA) modulates episodic memory consolidation through interactions with the hippocampus. Although many studies in rodents and imaging studies in humans indicate that the amygdala modulates memory consolidation and plasticity processes in the hippocampus, the anatomical pathways through which the amygdala affects hippocampal regions that are important for episodic memories were unresolved until recent optogenetic advances made it possible to visualize and manipulate specific BLA efferent pathways during memory consolidation. Findings indicate that the BLA influences hippocampal-dependent memories, as well as synaptic plasticity, histone modifications, gene expression, and translation of synaptic plasticity associated proteins in the hippocampus. More recent findings from optogenetic studies suggest that the BLA modulates spatial memory via projections to the medial entorhinal cortex, and that the frequency of activity in this pathway is a critical element of this modulation.
Topics: Amygdala; Animals; Entorhinal Cortex; Hippocampus; Humans; Memory Consolidation; Neural Pathways; Neuronal Plasticity
PubMed: 34302951
DOI: 10.1016/j.nlm.2021.107490 -
Cell Mar 2022We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice....
We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope weight below 3 g and a highly flexible connection cable, MINI2P allowed stable imaging with no impediment of behavior in a variety of assays compared to untethered, unimplanted animals. The improved cell yield was achieved through a optical system design featuring an enlarged field of view (FOV) and a microtunable lens with increased z-scanning range and speed that allows fast and stable imaging of multiple interleaved planes, as well as 3D functional imaging. Successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas.
Topics: Animals; Calcium; Entorhinal Cortex; Hippocampus; Mice; Microscopy; Neurons; Visual Cortex
PubMed: 35305313
DOI: 10.1016/j.cell.2022.02.017 -
Nature May 2020Vascular contributions to dementia and Alzheimer's disease are increasingly recognized. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is...
Vascular contributions to dementia and Alzheimer's disease are increasingly recognized. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction, including the early clinical stages of Alzheimer's disease. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes, which maintain BBB integrity. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
Topics: Alleles; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Blood-Brain Barrier; Capillaries; Cognitive Dysfunction; Cyclophilin A; Female; Heterozygote; Hippocampus; Humans; Male; Matrix Metalloproteinase 9; Parahippocampal Gyrus; Pericytes; Positron-Emission Tomography; Receptor, Platelet-Derived Growth Factor beta; Temporal Lobe; tau Proteins
PubMed: 32376954
DOI: 10.1038/s41586-020-2247-3 -
Neuron May 2022The hippocampus is essential for different forms of declarative memory, including social memory, the ability to recognize and remember a conspecific. Although recent...
The hippocampus is essential for different forms of declarative memory, including social memory, the ability to recognize and remember a conspecific. Although recent studies identify the importance of the dorsal CA2 region of the hippocampus in social memory storage, little is known about its sources of social information. Because CA2, like other hippocampal regions, receives its major source of spatial and non-spatial information from the medial and lateral subdivisions of entorhinal cortex (MEC and LEC), respectively, we investigated the importance of these inputs for social memory. Whereas MEC inputs to CA2 are dispensable, the direct inputs to CA2 from LEC are both selectively activated during social exploration and required for social memory. This selective behavioral role of LEC is reflected in the stronger excitatory drive it provides to CA2 compared with MEC. Thus, a direct LEC → CA2 circuit is tuned to convey social information that is critical for social memory.
Topics: Entorhinal Cortex; Hippocampus; Mental Recall
PubMed: 35180391
DOI: 10.1016/j.neuron.2022.01.028 -
Nature Oct 2021Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning. However, it remains unclear how dopamine reward...
Mounting evidence shows that dopamine in the striatum is critically involved in reward-based reinforcement learning. However, it remains unclear how dopamine reward signals influence the entorhinal-hippocampal circuit, another brain network that is crucial for learning and memory. Here, using cell-type-specific electrophysiological recording, we show that dopamine signals from the ventral tegmental area and substantia nigra control the encoding of cue-reward association rules in layer 2a fan cells of the lateral entorhinal cortex (LEC). When mice learned novel olfactory cue-reward associations using a pre-learned association rule, spike representations of LEC fan cells grouped newly learned rewarded cues with a pre-learned rewarded cue, but separated them from a pre-learned unrewarded cue. Optogenetic inhibition of fan cells impaired the learning of new associations while sparing the retrieval of pre-learned memory. Using fibre photometry, we found that dopamine sends novelty-induced reward expectation signals to the LEC. Inhibition of LEC dopamine signals disrupted the associative encoding of fan cells and impaired learning performance. These results suggest that LEC fan cells represent a cognitive map of abstract task rules, and that LEC dopamine facilitates the incorporation of new memories into this map.
Topics: Animals; Anticipation, Psychological; Cues; Dopamine; Entorhinal Cortex; Female; Male; Memory; Mice; Mice, Inbred C57BL; Pyramidal Cells; Reward
PubMed: 34552245
DOI: 10.1038/s41586-021-03948-8 -
Nature Reviews. Neuroscience Aug 2021An organism's survival can depend on its ability to recall and navigate to spatial locations associated with rewards, such as food or a home. Accumulating research has... (Review)
Review
An organism's survival can depend on its ability to recall and navigate to spatial locations associated with rewards, such as food or a home. Accumulating research has revealed that computations of reward and its prediction occur on multiple levels across a complex set of interacting brain regions, including those that support memory and navigation. However, how the brain coordinates the encoding, recall and use of reward information to guide navigation remains incompletely understood. In this Review, we propose that the brain's classical navigation centres - the hippocampus and the entorhinal cortex - are ideally suited to coordinate this larger network by representing both physical and mental space as a series of states. These states may be linked to reward via neuromodulatory inputs to the hippocampus-entorhinal cortex system. Hippocampal outputs can then broadcast sequences of states to the rest of the brain to store reward associations or to facilitate decision-making, potentially engaging additional value signals downstream. This proposal is supported by recent advances in both experimental and theoretical neuroscience. By discussing the neural systems traditionally tied to navigation and reward at their intersection, we aim to offer an integrated framework for understanding navigation to reward as a fundamental feature of many cognitive processes.
Topics: Animals; Entorhinal Cortex; Hippocampus; Humans; Neural Pathways; Reward; Spatial Memory; Spatial Navigation
PubMed: 34230644
DOI: 10.1038/s41583-021-00479-z