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Cell Sep 2023Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus...
Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
Topics: Humans; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Microglia; Neurons; Pyramidal Cells; Biopsy; Frontal Lobe; Single-Cell Gene Expression Analysis; Cell Nucleus
PubMed: 37774681
DOI: 10.1016/j.cell.2023.08.005 -
Neuron Sep 2023The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit...
The cardinal classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings gloss over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. Although there is evidence that this diversity is functionally relevant, the circuit implications of this diversity are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes and found that each subtype possesses a unique laminar organization and stereotyped axonal projection pattern. Using these strategies, we examined the afferent and efferent connectivity of three subtypes (two Martinotti and one non-Martinotti) and demonstrated that they possess selective connectivity with intratelecephalic or pyramidal tract neurons. Even when two subtypes targeted the same pyramidal cell type, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin interneurons form cell-type-specific cortical circuits.
Topics: Interneurons; Neurons; Pyramidal Cells; Axons; Somatostatin; Parvalbumins
PubMed: 37390821
DOI: 10.1016/j.neuron.2023.05.032 -
A corticoamygdalar pathway controls reward devaluation and depression using dynamic inhibition code.Neuron Dec 2023Reward devaluation adaptively controls reward intake. It remains unclear how cortical circuits causally encode reward devaluation in healthy and depressed states. Here,...
Reward devaluation adaptively controls reward intake. It remains unclear how cortical circuits causally encode reward devaluation in healthy and depressed states. Here, we show that the neural pathway from the anterior cingulate cortex (ACC) to the basolateral amygdala (BLA) employs a dynamic inhibition code to control reward devaluation and depression. Fiber photometry and imaging of ACC pyramidal neurons reveal reward-induced inhibition, which weakens during satiation and becomes further attenuated in depression mouse models. Ablating or inhibiting these neurons desensitizes reward devaluation, causes reward intake increase and ultimate obesity, and ameliorates depression, whereas activating the cells sensitizes reward devaluation, suppresses reward consumption, and produces depression-like behaviors. Among various ACC neuron subpopulations, the BLA-projecting subset bidirectionally regulates reward devaluation and depression-like behaviors. Our study thus uncovers a corticoamygdalar circuit that encodes reward devaluation via blunted inhibition and suggests that enhancing inhibition within this circuit may offer a therapeutic approach for treating depression.
Topics: Animals; Mice; Conditioning, Operant; Depression; Reward; Basolateral Nuclear Complex; Satiation
PubMed: 37734380
DOI: 10.1016/j.neuron.2023.08.022 -
Neuron Jul 2023Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates...
Traditionally considered a homogeneous cell type, hippocampal pyramidal cells have been recently shown to be highly diverse. However, how this cellular diversity relates to the different hippocampal network computations that support memory-guided behavior is not yet known. We show that the anatomical identity of pyramidal cells is a major organizing principle of CA1 assembly dynamics, the emergence of memory replay, and cortical projection patterns in rats. Segregated pyramidal cell subpopulations encoded trajectory and choice-specific information or tracked changes in reward configuration respectively, and their activity was selectively read out by different cortical targets. Furthermore, distinct hippocampo-cortical assemblies coordinated the reactivation of complementary memory representations. These findings reveal the existence of specialized hippocampo-cortical subcircuits and provide a cellular mechanism that supports the computational flexibility and memory capacities of these structures.
Topics: Rats; Animals; Hippocampus; Pyramidal Cells
PubMed: 37196658
DOI: 10.1016/j.neuron.2023.04.015 -
Cell Dec 2023The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific...
The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) β-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.
Topics: Animals; Humans; Mice; Action Potentials; Axons; Neurons; Pyramidal Cells; Voltage-Gated Sodium Channels
PubMed: 38134874
DOI: 10.1016/j.cell.2023.11.028 -
Immunity Jan 2024Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with...
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
Topics: Alzheimer Disease; Brain; Energy Metabolism; Microglia; Neurons; Animals; Mice
PubMed: 38159572
DOI: 10.1016/j.immuni.2023.12.002