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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 -
Molecular Psychiatry Sep 2022Major depressive disorder is viewed as a 'circuitopathy'. The hippocampal-entorhinal network plays a pivotal role in regulation of depression, and its main sensory...
Major depressive disorder is viewed as a 'circuitopathy'. The hippocampal-entorhinal network plays a pivotal role in regulation of depression, and its main sensory output, the visual cortex, is a promising target for stimulation therapy of depression. However, whether the entorhinal-visual cortical pathway mediates depression and the potential mechanism remains unknown. Here we report a cortical circuit linking entorhinal cortex layer Va neurons to the medial portion of secondary visual cortex (Ent→V2M) that bidirectionally regulates depression-like behaviors in mice. Analyses of brain-wide projections of Ent Va neurons and two-color retrograde tracing indicated that Ent Va→V2M projection neurons represented a unique population of neurons in Ent Va. Immunostaining of c-Fos revealed that activity in Ent Va neurons was decreased in mice under chronic social defeat stress (CSDS). Both chemogenetic inactivation of Ent→V2M projection neurons and optogenetic inactivation of the projection terminals induced social deficiency, anxiety- and despair-related behaviors in healthy mice. Chemogenetic inactivation of Ent→V2M projection neurons also aggravated these depression-like behaviors in CSDS-resilient mice. Optogenetic activation of Ent→V2M projection terminals rapidly ameliorated depression-like phenotypes. Optical recording using fiber photometry indicated that elevated neural activity in Ent→V2M projection terminals promoted antidepressant-like behaviors. Thus, the Ent→V2M circuit plays a crucial role in regulation of depression-like behaviors, and can function as a potential target for treating major depressive disorder.
Topics: Animals; Mice; Depression; Depressive Disorder, Major; Entorhinal Cortex; Neurons; Visual Cortex; Stress, Psychological; Mice, Inbred C57BL
PubMed: 35388184
DOI: 10.1038/s41380-022-01540-8 -
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 -
Annual Review of Neuroscience Jul 2020Although Lorente de No' recognized the anatomical distinction of the hippocampal Cornu Ammonis (CA) 2 region, it had, until recently, been assigned no unique function.... (Review)
Review
Although Lorente de No' recognized the anatomical distinction of the hippocampal Cornu Ammonis (CA) 2 region, it had, until recently, been assigned no unique function. Its location between the key players of the circuit, CA3 and CA1, which along with the entorhinal cortex and dentate gyrus compose the classic trisynaptic circuit, further distracted research interest. However, the connectivity of CA2 pyramidal cells, together with unique patterns of gene expression, hints at a much larger contribution to hippocampal information processing than has been ascribed. Here we review recent advances that have identified new roles for CA2 in hippocampal centric processing, together with specialized functions in social memory and, potentially, as a broadcaster of novelty. These new data, together with CA2's role in disease, justify a closer look at how this small region exerts its influence and how it might best be exploited to understand and treat disease-related circuit dysfunctions.
Topics: Animals; CA2 Region, Hippocampal; Entorhinal Cortex; Hippocampus; Humans; Memory; Nerve Net; Neural Pathways
PubMed: 31874067
DOI: 10.1146/annurev-neuro-080719-100343 -
World Neurosurgery Apr 2021The parahippocampal gyrus is understood to have a role in high cognitive functions including memory encoding and retrieval and visuospatial processing. A detailed...
BACKGROUND
The parahippocampal gyrus is understood to have a role in high cognitive functions including memory encoding and retrieval and visuospatial processing. A detailed understanding of the exact location and nature of associated white tracts could significantly improve postoperative morbidity related to declining capacity. Through diffusion tensor imaging-based fiber tracking validated by gross anatomic dissection as ground truth, we have characterized these connections based on relationships to other well-known structures.
METHODS
Diffusion imaging from the Human Connectome Project for 10 healthy adult controls was used for tractography analysis. We evaluated the parahippocampal gyrus as a whole based on connectivity with other regions. All parahippocampal gyrus tracts were mapped in both hemispheres, and a lateralization index was calculated with resultant tract volumes.
RESULTS
We identified 2 connections of the parahippocampal gyrus: inferior longitudinal fasciculus and cingulum. Lateralization of the cingulum was detected (P < 0.05).
CONCLUSIONS
The parahippocampal gyrus is an important center for memory processing. Subtle differences in executive functioning following surgery for limbic tumors may be better understood in the context of the fiber-bundle anatomy highlighted by this study.
Topics: Adult; Connectome; Diffusion Tensor Imaging; Female; Humans; Male; Middle Aged; Nerve Net; Parahippocampal Gyrus; White Matter
PubMed: 33412321
DOI: 10.1016/j.wneu.2020.12.136 -
ELife Jan 2023Blocking the activity of neurons in a region of the brain involved in memory leads to cell death, which could help explain the spatiotemporal disorientation observed in...
Blocking the activity of neurons in a region of the brain involved in memory leads to cell death, which could help explain the spatiotemporal disorientation observed in Alzheimer's disease.
Topics: Humans; Entorhinal Cortex; Alzheimer Disease; Neurons; Brain; Head
PubMed: 36692286
DOI: 10.7554/eLife.85437 -
Annual Review of Vision Science Sep 2019Humans are remarkably adept at perceiving and understanding complex real-world scenes. Uncovering the neural basis of this ability is an important goal of vision... (Review)
Review
Humans are remarkably adept at perceiving and understanding complex real-world scenes. Uncovering the neural basis of this ability is an important goal of vision science. Neuroimaging studies have identified three cortical regions that respond selectively to scenes: parahippocampal place area, retrosplenial complex/medial place area, and occipital place area. Here, we review what is known about the visual and functional properties of these brain areas. Scene-selective regions exhibit retinotopic properties and sensitivity to low-level visual features that are characteristic of scenes. They also mediate higher-level representations of layout, objects, and surface properties that allow individual scenes to be recognized and their spatial structure ascertained. Challenges for the future include developing computational models of information processing in scene regions, investigating how these regions support scene perception under ecologically realistic conditions, and understanding how they operate in the context of larger brain networks.
Topics: Animals; Brain; Brain Mapping; Humans; Magnetic Resonance Imaging; Occipital Lobe; Parahippocampal Gyrus; Spatial Navigation; Visual Cortex; Visual Perception
PubMed: 31226012
DOI: 10.1146/annurev-vision-091718-014809