Science translational medicine
Huang, WC;Peng, Z;Murdock, MH;Liu, L;Mathys, H;Davila-Velderrain, J;Jiang, X;Chen, M;Ng, AP;Kim, T;Abdurrob, F;Gao, F;Bennett, DA;Kellis, M;Tsai, LH;
PMID: 37075128 | DOI: 10.1126/scitranslmed.abq1019
The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.
Roethler, O;Zohar, E;Cohen-Kashi Malina, K;Bitan, L;Gabel, HW;Spiegel, I;
PMID: 37354902 | DOI: 10.1016/j.neuron.2023.05.026
Experience-dependent plasticity of synapses modulates information processing in neural circuits and is essential for cognitive functions. The genome, via non-coding enhancers, was proposed to control information processing and circuit plasticity by regulating experience-induced transcription of genes that modulate specific sets of synapses. To test this idea, we analyze here the cellular and circuit functions of the genomic mechanisms that control the experience-induced transcription of Igf1 (insulin-like growth factor 1) in vasoactive intestinal peptide (VIP) interneurons (INs) in the visual cortex of adult mice. We find that two sensory-induced enhancers selectively and cooperatively drive the activity-induced transcription of Igf1 to thereby promote GABAergic inputs onto VIP INs and to homeostatically control the ratio between excitation and inhibition (E/I ratio)-in turn, this restricts neural activity in VIP INs and principal excitatory neurons and maintains spatial frequency tuning. Thus, enhancer-mediated activity-induced transcription maintains sensory processing in the adult cortex via homeostatic modulation of E/I ratio.
Liu, Y;Guerrero-Juarez, C;Xiao, F;Shettigar, N;Ramos, R;Kuan, C;Lin, Y;de Jesus Martinez Lomeli, L;Park, J;Oh, J;Liu, R;Lin, S;Tartaglia, M;Yang, R;Yu, Z;Nie, Q;Li, J;Plikus, M;
| DOI: 10.1016/j.devcel.2022.06.005
Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5ahigh states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-β ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-β inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-β mechanism.
Chen, P;Wang, W;Liu, R;Lyu, J;Zhang, L;Li, B;Qiu, B;Tian, A;Jiang, W;Ying, H;Jing, R;Wang, Q;Zhu, K;Bai, R;Zeng, L;Duan, S;Liu, C;
PMID: 35545672 | DOI: 10.1038/s41586-022-04719-9
Animals constantly receive various sensory stimuli, such as odours, sounds, light and touch, from the surrounding environment. These sensory inputs are essential for animals to search for food and avoid predators, but they also affect their physiological status, and may cause diseases such as cancer. Malignant gliomas-the most lethal form of brain tumour1-are known to intimately communicate with neurons at the cellular level2,3. However, it remains unclear whether external sensory stimuli can directly affect the development of malignant glioma under normal living conditions. Here we show that olfaction can directly regulate gliomagenesis. In an autochthonous mouse model that recapitulates adult gliomagenesis4-6 originating in oligodendrocyte precursor cells (OPCs), gliomas preferentially emerge in the olfactory bulb-the first relay of brain olfactory circuitry. Manipulating the activity of olfactory receptor neurons (ORNs) affects the development of glioma. Mechanistically, olfaction excites mitral and tufted (M/T) cells, which receive sensory information from ORNs and release insulin-like growth factor 1 (IGF1) in an activity-dependent manner. Specific knockout of Igf1 in M/T cells suppresses gliomagenesis. In addition, knocking out the IGF1 receptor in pre-cancerous mutant OPCs abolishes the ORN-activity-dependent mitogenic effects. Our findings establish a link between sensory experience and gliomagenesis through their corresponding sensory neuronal circuits.
Microglial transcriptome analysis in the rNLS8 mouse model of TDP-43 proteinopathy reveals discrete expression profiles associated with neurodegenerative progression and recovery
Acta neuropathologica communications
Hunter, M;Spiller, KJ;Dominique, MA;Xu, H;Hunter, FW;Fang, TC;Canter, RG;Roberts, CJ;Ransohoff, RM;Trojanowski, JQ;Lee, VM;
PMID: 34412701 | DOI: 10.1186/s40478-021-01239-x
The microglial reaction is a hallmark of neurodegenerative conditions, and elements thereof may exert differential effects on disease progression, either worsening or ameliorating severity. In amyotrophic lateral sclerosis (ALS), a syndrome characterized by cytoplasmic aggregation of TDP-43 protein and atrophy of motor neurons in the cortex and spinal cord, the transcriptomic signatures of microglia during disease progression are incompletely understood. Here, we performed longitudinal RNAseq analysis of cortical and spinal cord microglia from rNLS8 mice, in which doxycycline-regulatable expression of human TDP-43 (hTDP-43) in the cytoplasm of neurons recapitulates many features of ALS. Transgene suppression in rNLS8 mice leads to functional, anatomical and electrophysiological resolution that is dependent on a microglial reaction that is concurrent with recovery rather than disease onset. We identified basal differences between the gene expression profiles of microglia dependent on localization in spinal cord or cortex. Microglia subjected to chronic hTDP-43 overexpression demonstrated transcriptomic changes in both locations. We noted strong upregulation of Apoe, Axl, Cd63, Clec7a, Csf1, Cst7, Igf1, Itgax, Lgals3, Lilrb4, Lpl and Spp1 during late disease and recovery. Importantly, we identified a distinct suite of differentially expressed genes associated with each phase of disease progression and recovery. Differentially expressed genes were associated with chemotaxis, phagocytosis, inflammation, and production of neuroprotective factors. These data provide new insights into the microglial reaction in TDP-43 proteinopathy. Genes differentially expressed during progression and recovery may provide insight into a unique instance in which the microglial reaction promotes functional recovery after neuronal insult.
Zhao, ZD;Han, X;Chen, R;Liu, Y;Bhattacherjee, A;Chen, W;Zhang, Y;
PMID: 35960793 | DOI: 10.1126/sciadv.abn3552
The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2-expressing D1 MSN subtype (Tac2+), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2+ neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2+ neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.
Matson, KJE;Russ, DE;Kathe, C;Hua, I;Maric, D;Ding, Y;Krynitsky, J;Pursley, R;Sathyamurthy, A;Squair, JW;Levi, BP;Courtine, G;Levine, AJ;
PMID: 36163250 | DOI: 10.1038/s41467-022-33184-1
After spinal cord injury, tissue distal to the lesion contains undamaged cells that could support or augment recovery. Targeting these cells requires a clearer understanding of their injury responses and capacity for repair. Here, we use single nucleus RNA sequencing to profile how each cell type in the lumbar spinal cord changes after a thoracic injury in mice. We present an atlas of these dynamic responses across dozens of cell types in the acute, subacute, and chronically injured spinal cord. Using this resource, we find rare spinal neurons that express a signature of regeneration in response to injury, including a major population that represent spinocerebellar projection neurons. We characterize these cells anatomically and observed axonal sparing, outgrowth, and remodeling in the spinal cord and cerebellum. Together, this work provides a key resource for studying cellular responses to injury and uncovers the spontaneous plasticity of spinocerebellar neurons, uncovering a potential candidate for targeted therapy.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Lecordier, S;Menet, R;Allain, AS;ElAli, A;
PMID: 37340860 | DOI: 10.1177/0271678X231183742
Cerebral small vessel disease (cSVD) constitutes a major risk factor for dementia. Monocytes play important roles in cerebrovascular disorders. Herein, we aimed to investigate the contribution of non-classical C-X3-C motif chemokine receptor (CX3CR)1 monocytes to cSVD pathobiology and therapy. To this end, we generated chimeric mice in which CX3CR1 in non-classical monocytes was either functional (CX3CR1GFP/+) or dysfunctional (CX3CR1GFP/GFP). cSVD was induced in mice via the micro-occlusion of cerebral arterioles, and novel immunomodulatory approaches targeting CX3CR1 monocyte production were used. Our findings demonstrate that CX3CR1GFP/+ monocytes transiently infiltrated the ipsilateral hippocampus and were recruited to the microinfarcts 7 days after cSVD, inversely associated with neuronal degeneration and blood-brain barrier (BBB) disruption. Dysfunctional CX3CR1GFP/GFP monocytes failed to infiltrate the injured hippocampus and were associated with exacerbated microinfarctions and accelerated cognitive decline, accompanied with an impaired microvascular structure. Pharmacological stimulation of CX3CR1GFP/+ monocyte generation attenuated neuronal loss and improved cognitive functions by promoting microvascular function and preserving cerebral blood flow (CBF). These changes were associated with elevated levels of pro-angiogenic factors and matrix stabilizers in the blood circulation. The results indicate that non-classical CX3CR1 monocytes promote neurovascular repair after cSVD and constitute a promising target for the development of new therapies.
Hardaway JA, Halladay LR, Mazzone CM, Pati D, Bloodgood DW, Kim M, Jensen J, DiBerto JF, Boyt KM, Shiddapur A, Erfani A, Hon OJ, Neira S, Stanhope CM, Sugam JA, Saddoris MP, Tipton G, McElligott Z, Jhou TC, Stuber GD, Bruchas MR, Bulik CM, Holmes A, Kash TL.
PMID: 31029403 | DOI: 10.1016/j.neuron.2019.03.037
Food palatability is one of many factors that drives food consumption, and the hedonic drive to feed is a key contributor to obesity and binge eating. In this study, we identified a population of prepronociceptin-expressing cells in the central amygdala (PnocCeA) that are activated by palatable food consumption. Ablation or chemogenetic inhibition of these cells reduces palatable food consumption. Additionally, ablation of PnocCeA cells reduces high-fat-diet-driven increases in bodyweight and adiposity. PnocCeA neurons project to the ventral bed nucleus of the stria terminalis (vBNST), parabrachial nucleus (PBN), and nucleus of the solitary tract (NTS), and activation of cell bodies in the central amygdala (CeA) or axons in the vBNST, PBN, and NTS produces reward behavior but did not promote feeding of palatable food. These data suggest that the PnocCeA network is necessary for promoting the reinforcing and rewarding properties of palatable food, but activation of this network itself is not sufficient to promote feeding.
Human Adult Fibroblast-like Synoviocytes and Articular Chondrocytes Exhibit Prominent Overlap in Their Transcriptomic Signatures
Jones, K;Angelozzi, M;Gangishetti, U;Haseeb, A;de Charleroy, C;Lefebvre, V;Bhattaram, P;
PMID: 33931959 | DOI: 10.1002/acr2.11255
Fibroblast-like synoviocytes (FLS) and articular chondrocytes (AC) derive from a common pool of embryonic precursor cells. They are currently believed to engage in largely distinct differentiation programs to build synovium and articular cartilage and maintain healthy tissues throughout life. We tested this hypothesis by deeply characterizing and comparing their transcriptomic attributes. We profiled the transcriptomes of freshly isolated AC, synovium, primary FLS, and dermal fibroblasts from healthy adult humans using bulk RNA sequencing assays and downloaded published single-cell RNA sequencing data from freshly isolated human FLS. We integrated all data to define cell-specific signatures and validated findings with quantitative reverse transcription PCR of human samples and RNA hybridization of mouse joint sections. We identified 212 AC and 168 FLS markers on the basis of exclusive or enriched expression in either cell and 294 AC/FLS markers on the basis of similar expression in both cells. AC markers included joint-specific and pan-cartilaginous genes. FLS and AC/FLS markers featured 37 and 55 joint-specific genes, respectively, and 131 and 239 pan-fibroblastic genes, respectively. These signatures included many previously unrecognized markers with potentially important joint-specific roles. AC/FLS markers overlapped in their expression patterns among all FLS and AC subpopulations, suggesting that they fulfill joint-specific properties in all, rather than in discrete, AC and FLS subpopulations. This study broadens knowledge and identifies a prominent overlap of the human adult AC and FLS transcriptomic signatures. It also provides data resources to help further decipher mechanisms underlying joint homeostasis and degeneration and to improve the quality control of tissues engineered for regenerative treatments.
Lam, BYH;Williamson, A;Finer, S;Day, FR;Tadross, JA;Gonçalves Soares, A;Wade, K;Sweeney, P;Bedenbaugh, MN;Porter, DT;Melvin, A;Ellacott, KLJ;Lippert, RN;Buller, S;Rosmaninho-Salgado, J;Dowsett, GKC;Ridley, KE;Xu, Z;Cimino, I;Rimmington, D;Rainbow, K;Duckett, K;Holmqvist, S;Khan, A;Dai, X;Bochukova, EG;Genes & Health Research Team, ;Trembath, RC;Martin, HC;Coll, AP;Rowitch, DH;Wareham, NJ;van Heel, DA;Timpson, N;Simerly, RB;Ong, KK;Cone, RD;Langenberg, C;Perry, JRB;Yeo, GS;O'Rahilly, S;
PMID: 34732894 | DOI: 10.1038/s41586-021-04088-9
The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.
Kathe, C;Skinnider, MA;Hutson, TH;Regazzi, N;Gautier, M;Demesmaeker, R;Komi, S;Ceto, S;James, ND;Cho, N;Baud, L;Galan, K;Matson, KJE;Rowald, A;Kim, K;Wang, R;Minassian, K;Prior, JO;Asboth, L;Barraud, Q;Lacour, SP;Levine, AJ;Wagner, F;Bloch, J;Squair, JW;Courtine, G;
PMID: 36352232 | DOI: 10.1038/s41586-022-05385-7
A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord<sup>1-3</sup> applied during neurorehabilitation<sup>4,5</sup> (EES<sup>REHAB</sup>) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EES<sup>REHAB</sup> in mice. We applied single-nucleus RNA sequencing<sup>6-9</sup> and spatial transcriptomics<sup>10,11</sup> to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type<sup>12,13</sup> and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EES<sup>REHAB</sup>, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.
