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Cell Reports Jul 2023Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We...
Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments.
Topics: Animals; Mice; Ankyrins; Calcium; Phenotype; Prosencephalon; Proteome; Proteomics; Seizures; Mice, Knockout
PubMed: 37428632
DOI: 10.1016/j.celrep.2023.112784 -
Reviews in the Neurosciences Oct 2023Since the 1950s study of Scoville and Milner on the case H.M., the hippocampus has attracted neuroscientists' attention. The hippocampus has been traditionally divided... (Review)
Review
Since the 1950s study of Scoville and Milner on the case H.M., the hippocampus has attracted neuroscientists' attention. The hippocampus has been traditionally divided into dorsal and ventral parts, each of which projects to different brain structures and mediates various functions. Despite a predominant interest in its dorsal part in animal models, especially regarding episodic-like and spatial cognition, recent data highlight the role of the ventral hippocampus (vHPC), as the main hippocampal output, in cognitive processes. Here, we review recent studies conducted in rodents that have used advanced functional techniques to specifically monitor and manipulate vHPC efferent pathways and delineate the roles of these specific projections in learning and memory processes. Results highlight that vHPC projections to basal amygdala are implicated in emotional memory, to nucleus accumbens in social memory and instrumental actions and to prefrontal cortex in all the above as well as in object-based memory. Some of these hippocampal projections also modulate feeding and anxiety-like behaviours providing further evidence that the "one pathway-one function" view is outdated and future directions are proposed to better understand the role of hippocampal pathways and shed further light on its connectivity and function.
Topics: Animals; Humans; Hippocampus; Nucleus Accumbens; Prefrontal Cortex; Learning; Cognition; Neural Pathways
PubMed: 37192533
DOI: 10.1515/revneuro-2023-0009 -
Molecular Psychiatry Dec 2023Deep brain regions such as hippocampus, insula, and amygdala are involved in neuropsychiatric disorders, including chronic insomnia and depression. Our recent reports...
Deep brain regions such as hippocampus, insula, and amygdala are involved in neuropsychiatric disorders, including chronic insomnia and depression. Our recent reports showed that transcranial alternating current stimulation (tACS) with a current of 15 mA and a frequency of 77.5 Hz, delivered through a montage of the forehead and both mastoids was safe and effective in intervening chronic insomnia and depression over 8 weeks. However, there is no physical evidence to support whether a large alternating current of 15 mA in tACS can send electrical currents to deep brain tissue in awake humans. Here, we directly recorded local field potentials (LFPs) in the hippocampus, insula and amygdala at different current strengths (1 to 15 mA) in 11 adult patients with drug-resistant epilepsy implanted with stereoelectroencephalography (SEEG) electrodes who received tACS at 77.5 Hz from 1 mA to 15 mA at 77.5 Hz for five minutes at each current for a total of 40 min. For the current of 15 mA at 77.5 Hz, additional 55 min were applied to add up a total of 60 min. Linear regression analysis revealed that the average LFPs for the remaining contacts on both sides of the hippocampus, insula, and amygdala of each patient were statistically associated with the given currents in each patient (p < 0.05-0.01), except for the left insula of one subject (p = 0.053). Alternating currents greater than 7 mA were required to produce significant differences in LFPs in the three brain regions compared to LFPs at 0 mA (p < 0.05). The differences remained significant after adjusting for multiple comparisons (p < 0.05). Our study provides direct evidence that the specific tACS procedures are capable of delivering electrical currents to deep brain tissues, opening a realistic avenue for modulating or treating neuropsychiatric disorders associated with hippocampus, insula, and amygdala.
Topics: Humans; Adult; Male; Female; Amygdala; Hippocampus; Transcranial Direct Current Stimulation; Drug Resistant Epilepsy; Middle Aged; Brain; Electroencephalography; Deep Brain Stimulation; Insular Cortex; Young Adult; Cerebral Cortex
PubMed: 37468529
DOI: 10.1038/s41380-023-02150-8 -
Neuron Oct 2023Neuronal activity during experience is thought to induce plastic changes within the hippocampal network that underlie memory formation, although the extent and details...
Neuronal activity during experience is thought to induce plastic changes within the hippocampal network that underlie memory formation, although the extent and details of such changes in vivo remain unclear. Here, we employed a temporally precise marker of neuronal activity, CaMPARI2, to label active CA1 hippocampal neurons in vivo, followed by immediate acute slice preparation and electrophysiological quantification of synaptic properties. Recently active neurons in the superficial sublayer of stratum pyramidale displayed larger post-synaptic responses at excitatory synapses from area CA3, with no change in pre-synaptic release probability. In contrast, in vivo activity correlated with weaker pre- and post-synaptic excitatory weights onto pyramidal cells in the deep sublayer. In vivo activity of deep and superficial neurons within sharp-wave/ripples was bidirectionally changed across experience, consistent with the observed changes in synaptic weights. These findings reveal novel, fundamental mechanisms through which the hippocampal network is modified by experience to store information.
Topics: CA3 Region, Hippocampal; Hippocampus; Neurons; Pyramidal Cells; Synapses; CA1 Region, Hippocampal
PubMed: 37689058
DOI: 10.1016/j.neuron.2023.08.014 -
Neuron Jul 2023The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We...
The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections' local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain.
Topics: Animals; Callithrix; Prefrontal Cortex; Brain; Cerebral Cortex; Corpus Striatum; Neural Pathways; Brain Mapping
PubMed: 37196659
DOI: 10.1016/j.neuron.2023.04.028 -
Anatomical Science International Sep 2023Recent evidence has shown that the precuneus plays a role in the pathogenesis of schizophrenia. The precuneus is a structure of the parietal lobe's medial and posterior... (Review)
Review
Recent evidence has shown that the precuneus plays a role in the pathogenesis of schizophrenia. The precuneus is a structure of the parietal lobe's medial and posterior cortex, representing a central hub involved in multimodal integration processes. Although neglected for several years, the precuneus is highly complex and crucial for multimodal integration. It has extensive connections with different cerebral areas and is an interface between external stimuli and internal representations. In human evolution, the precuneus has increased in size and complexity, allowing the development of higher cognitive functions, such as visual-spatial ability, mental imagery, episodic memory, and other tasks involved in emotional processing and mentalization. This paper reviews the functions of the precuneus and discusses them concerning the psychopathological aspects of schizophrenia. The different neuronal circuits, such as the default mode network (DMN), in which the precuneus is involved and its alterations in the structure (grey matter) and the disconnection of pathways (white matter) are described.
Topics: Humans; Magnetic Resonance Imaging; Brain Mapping; Schizophrenia; Parietal Lobe; Cerebral Cortex; Neural Pathways
PubMed: 37340095
DOI: 10.1007/s12565-023-00730-w -
Proceedings of the National Academy of... Jul 2023Understanding the claustrum's functions has recently progressed thanks to new anatomical and behavioral studies in rodents, which suggest that it plays an important role...
Understanding the claustrum's functions has recently progressed thanks to new anatomical and behavioral studies in rodents, which suggest that it plays an important role in attention, salience detection, slow-wave generation, and neocortical network synchronization. Nevertheless, knowledge about the origin and development of the claustrum, especially in primates, is still limited. Here, we show that neurons of rhesus macaque claustrum primordium are generated between embryonic day E48 and E55 and express some neocortical molecular markers, such as NR4A2, SATB2, and SOX5. However, in the early stages, it lacks TBR1 expression, which separates it from other surrounding telencephalic structures. We also found that two waves of neurogenesis (E48 and E55) in the claustrum, corresponding to the birthdates of layers 6 and 5 of the insular cortex, establish a "core" and "shell" cytoarchitecture, which is potentially a basis for differential circuit formation and could influence information processing underlying higher cognitive functions of the claustrum. In addition, parvalbumin-positive interneurons are the dominant interneuron type in the claustrum in fetal macaque, and their maturation is independent of that in the overlaying neocortex. Finally, our study reveals that the claustrum is likely not a continuance of subplate neurons of the insular cortex, but an independent pallial region, suggesting its potentially unique role in cognitive control.
Topics: Animals; Claustrum; Macaca mulatta; Neurons; Neocortex; Interneurons
PubMed: 37406098
DOI: 10.1073/pnas.2220918120 -
Progress in Neuro-psychopharmacology &... Aug 2023Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting... (Review)
Review
Memories of everyday experiences involve the encoding of a rich and dynamic representation of present objects and their contextual features. Traditionally, the resulting mnemonic trace is referred to as Episodic Memory, i.e. the "what", "where" and "when" of a lived episode. The journey for such memory trace encoding begins with the perceptual data of an experienced episode handled in sensory brain regions. The information is then streamed to cortical areas located in the ventral Medio Temporal Lobe, which produces multi-modal representations concerning either the objects (in the Perirhinal cortex) or the spatial and contextual features (in the parahippocampal region) of the episode. Then, this high-level data is gated through the Entorhinal Cortex and forwarded to the Hippocampal Formation, where all the pieces get bound together. Eventually, the resulting encoded neural pattern is relayed back to the Neocortex for a stable consolidation. This review will detail these different stages and provide a systematic overview of the major cortical streams toward the Hippocampus relevant for Episodic Memory encoding.
Topics: Memory, Episodic; Hippocampus; Entorhinal Cortex; Temporal Lobe; Neural Pathways
PubMed: 37086812
DOI: 10.1016/j.pnpbp.2023.110757 -
Science (New York, N.Y.) Oct 2023The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially distinct nuclei, but the molecular architecture of thalamic...
The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially distinct nuclei, but the molecular architecture of thalamic development is poorly understood, especially in humans. To begin to delineate the molecular trajectories of cell fate specification and organization in the developing human thalamus, we used single-cell and multiplexed spatial transcriptomics. We show that molecularly defined thalamic neurons differentiate in the second trimester of human development and that these neurons organize into spatially and molecularly distinct nuclei. We identified major subtypes of glutamatergic neuron subtypes that are differentially enriched in anatomically distinct nuclei and six subtypes of γ-aminobutyric acid-mediated (GABAergic) neurons that are shared and distinct across thalamic nuclei.
Topics: Humans; Thalamic Nuclei; Thalamus; GABAergic Neurons; Female; Pregnancy; Single-Cell Analysis; Neurogenesis; Pregnancy Trimester, Second
PubMed: 37824646
DOI: 10.1126/science.adf9941 -
Proceedings of the National Academy of... Jul 2023The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural...
The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations.
Topics: Cholinergic Agents; Acetylcholine; Prosencephalon; Cholinergic Neurons; gamma-Aminobutyric Acid; Logic
PubMed: 37399414
DOI: 10.1073/pnas.2218830120