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1.
Cell ; 185(18): 3284-3286, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055196

RESUMO

Nearly all neurons contain a primary cilium, but little is known about how this compartment contributes to neuromodulatory signaling. In a new study, Sheu et al. use cutting-edge electron microscopy and fluorescence imaging techniques to reveal a new type of synapse that enables chemical transmission between serotonergic axons and the primary cilia of hippocampal neurons.


Assuntos
Cílios , Neurônios/fisiologia , Sinapses , Hipocampo/citologia , Microscopia Eletrônica
2.
Cell ; 185(18): 3390-3407.e18, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055200

RESUMO

Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical Gαq/11-RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron's epigenetic state.


Assuntos
Axônios/fisiologia , Cromatina/química , Cílios , Sinapses , Núcleo Celular/metabolismo , Cromatina/metabolismo , Cílios/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Serotonina/metabolismo , Transdução de Sinais , Sinapses/fisiologia
3.
J Integr Neurosci ; 21(5): 133, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-36137969

RESUMO

BACKGROUND: Progressive axon degeneration is a common pathological feature of neurodegenerative diseases. Cdc42 is a member of the Rho GTPase family that participates in axonogenesis. GSK-3ß is a serine/threonine kinase highly implicated in neuronal development and neurodegeneration. This study aimed to examine whether cdc42 promotes axonogenesis by regulating GSK-3ß activity. METHODS: Hippocampal neurons were isolated from neonatal Sprague-Dawley rats and transfected with designated plasmid vectors to alter the activities of cdc42 and GSK-3ß. LiCl treatment was used to inhibit the GSK-3ß activity in primary neurons. GSK-3ß activity was determined by an enzyme activity assay kit. Immunofluorescence staining was used to detect axons stained with anti-Tau-1 antibody and dendrites stained with anti-MAP2 antibody. RESULTS: Transfection with an active cdc42 mutant (cdc42F28L) decreased the activity of GSK-3ß and induced axonogenesis in primary rat hippocampal neurons, while transfection with a negative cdc42 mutant (cdc42N17) resulted an opposite effect. Moreover, transfection with plasmid vectors carrying wild-type GSK-3ß or a constitutively active GSK3ß mutant (GSK-3ß S9A) increased the activity of GSK-3ß and attenuated axonogenesis of primary hippocampal neurons with excessive cdc42 activity, whereas inhibition of GSK-3ß by LiCl abolished the inhibitory effect of the negative cdc42 mutant on axonogenesis. CONCLUSIONS: This study suggests that cdc42 induces axonogenesis of primary rat hippocampal neurons via inhibiting GSK-3ß activity. These findings support further investigation into the mechanisms of cdc42/GSK-3ß-mediated axonogenesis.


Assuntos
Hipocampo , Neurônios , Proteína cdc42 de Ligação ao GTP , Animais , Glicogênio Sintase Quinase 3 beta , Hipocampo/citologia , Neurônios/fisiologia , Fosforilação , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Serina/farmacologia , Proteína cdc42 de Ligação ao GTP/fisiologia
4.
Nature ; 609(7925): 119-127, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002570

RESUMO

Throughout their daily lives, animals and humans often switch between different behaviours. However, neuroscience research typically studies the brain while the animal is performing one behavioural task at a time, and little is known about how brain circuits represent switches between different behaviours. Here we tested this question using an ethological setting: two bats flew together in a long 135 m tunnel, and switched between navigation when flying alone (solo) and collision avoidance as they flew past each other (cross-over). Bats increased their echolocation click rate before each cross-over, indicating attention to the other bat1-9. Hippocampal CA1 neurons represented the bat's own position when flying alone (place coding10-14). Notably, during cross-overs, neurons switched rapidly to jointly represent the interbat distance by self-position. This neuronal switch was very fast-as fast as 100 ms-which could be revealed owing to the very rapid natural behavioural switch. The neuronal switch correlated with the attention signal, as indexed by echolocation. Interestingly, the different place fields of the same neuron often exhibited very different tuning to interbat distance, creating a complex non-separable coding of position by distance. Theoretical analysis showed that this complex representation yields more efficient coding. Overall, our results suggest that during dynamic natural behaviour, hippocampal neurons can rapidly switch their core computation to represent the relevant behavioural variables, supporting behavioural flexibility.


Assuntos
Quirópteros , Ecolocação , Voo Animal , Hipocampo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Quirópteros/fisiologia , Ecolocação/fisiologia , Voo Animal/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/fisiologia , Orientação Espacial , Navegação Espacial , Processamento Espacial
5.
Nature ; 609(7926): 327-334, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36002569

RESUMO

In the hippocampus, spatial maps are formed by place cells while contextual memories are thought to be encoded as engrams1-6. Engrams are typically identified by expression of the immediate early gene Fos, but little is known about the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals7-10. Thus, it is unclear whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression correlates with and affects specific features of the place code11. Here we measured the activity of CA1 neurons with calcium imaging while monitoring Fos induction in mice performing a hippocampus-dependent spatial learning task in virtual reality. We find that neurons with high Fos induction form ensembles of cells with highly correlated activity, exhibit reliable place fields that evenly tile the environment and have more stable tuning across days than nearby non-Fos-induced cells. Comparing neighbouring cells with and without Fos function using a sparse genetic loss-of-function approach, we find that neurons with disrupted Fos function have less reliable activity, decreased spatial selectivity and lower across-day stability. Our results demonstrate that Fos-induced cells contribute to hippocampal place codes by encoding accurate, stable and spatially uniform maps and that Fos itself has a causal role in shaping these place codes. Fos ensembles may therefore link two key aspects of hippocampal function: engrams for contextual memories and place codes that underlie cognitive maps.


Assuntos
Hipocampo , Proteínas Proto-Oncogênicas c-fos , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Cálcio/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos , Neurônios/fisiologia , Células de Lugar/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo
6.
Nature ; 608(7921): 153-160, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35831504

RESUMO

Memory formation involves binding of contextual features into a unitary representation1-4, whereas memory recall can occur using partial combinations of these contextual features. The neural basis underlying the relationship between a contextual memory and its constituent features is not well understood; in particular, where features are represented in the brain and how they drive recall. Here, to gain insight into this question, we developed a behavioural task in which mice use features to recall an associated contextual memory. We performed longitudinal imaging in hippocampus as mice performed this task and identified robust representations of global context but not of individual features. To identify putative brain regions that provide feature inputs to hippocampus, we inhibited cortical afferents while imaging hippocampus during behaviour. We found that whereas inhibition of entorhinal cortex led to broad silencing of hippocampus, inhibition of prefrontal anterior cingulate led to a highly specific silencing of context neurons and deficits in feature-based recall. We next developed a preparation for simultaneous imaging of anterior cingulate and hippocampus during behaviour, which revealed robust population-level representation of features in anterior cingulate, that lag hippocampus context representations during training but dynamically reorganize to lead and target recruitment of context ensembles in hippocampus during recall. Together, we provide the first mechanistic insights into where contextual features are represented in the brain, how they emerge, and how they access long-range episodic representations to drive memory recall.


Assuntos
Giro do Cíngulo , Hipocampo , Rememoração Mental , Modelos Neurológicos , Animais , Mapeamento Encefálico , Córtex Entorrinal/citologia , Córtex Entorrinal/fisiologia , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Estudos Longitudinais , Rememoração Mental/fisiologia , Camundongos , Inibição Neural
7.
Nature ; 607(7919): 527-533, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35794479

RESUMO

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.


Assuntos
Envelhecimento , Hipocampo , Longevidade , Neurogênese , Neurônios , Adulto , Envelhecimento/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Proliferação de Células , Giro Denteado/citologia , Giro Denteado/patologia , Perfilação da Expressão Gênica , Hipocampo/citologia , Hipocampo/patologia , Humanos , Longevidade/genética , Aprendizado de Máquina , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Genética
8.
Aging Cell ; 21(7): e13661, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35717599

RESUMO

Neuronal hippocampal Ca2+ dysregulation is a critical component of cognitive decline in brain aging and Alzheimer's disease and is suggested to impact communication and excitability through the activation of a larger after hyperpolarization. However, few studies have tested for the presence of Ca2+ dysregulation in vivo, how it manifests, and whether it impacts network function across hundreds of neurons. Here, we tested for neuronal Ca2+ network dysregulation in vivo in the primary somatosensory cortex (S1) of anesthetized young and aged male Fisher 344 rats using single-cell resolution techniques. Because S1 is involved in sensory discrimination and proprioception, we tested for alterations in ambulatory performance in the aged animal and investigated two potential pathways underlying these central aging- and Ca2+ -dependent changes. Compared to young, aged animals displayed increased overall activity and connectivity of the network as well as decreased ambulatory speed. In aged animals, intranasal insulin (INI) increased network synchronicity and ambulatory speed. Importantly, in young animals, delivery of the L-type voltage-gated Ca2+ channel modifier Bay-K 8644 altered network properties, replicating some of the changes seen in the older animal. These results suggest that hippocampal Ca2+ dysregulation may be generalizable to other areas, such as S1, and might engage modalities that are associated with locomotor stability and motivation to ambulate. Further, given the safety profile of INI in the clinic and the evidence presented here showing that this central dysregulation is sensitive to insulin, we suggest that these processes can be targeted to potentially increase motivation and coordination while also reducing fall frequency with age.


Assuntos
Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacocinética , Envelhecimento/fisiologia , Agonistas dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Hipocampo/metabolismo , Insulina , Córtex Somatossensorial/metabolismo , Animais , Marcha/fisiologia , Hipocampo/citologia , Insulina/metabolismo , Masculino , Motivação , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Endogâmicos F344
9.
Proc Natl Acad Sci U S A ; 119(26): e2122141119, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35737843

RESUMO

The current dominant view of the hippocampus is that it is a navigation "device" guided by environmental inputs. Yet, a critical aspect of navigation is a sequence of planned, coordinated actions. We examined the role of action in the neuronal organization of the hippocampus by training rats to jump a gap on a linear track. Recording local field potentials and ensembles of single units in the hippocampus, we found that jumping produced a stereotypic behavior associated with consistent electrophysiological patterns, including phase reset of theta oscillations, predictable global firing-rate changes, and population vector shifts of hippocampal neurons. A subset of neurons ("jump cells") were systematically affected by the gap but only in one direction of travel. Novel place fields emerged and others were either boosted or attenuated by jumping, yet the theta spike phase versus animal position relationship remained unaltered. Thus, jumping involves an action plan for the animal to traverse the same route as without jumping, which is faithfully tracked by hippocampal neuronal activity.


Assuntos
Hipocampo , Atividade Motora , Animais , Eletrofisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Atividade Motora/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Ratos
10.
Sci Data ; 9(1): 365, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35752635

RESUMO

The human amygdala and hippocampus have long been associated with face perception. Here, we present a dataset of single-neuron activity in the human amygdala and hippocampus during face perception. We recorded 2082 neurons from the human amygdala and hippocampus when neurosurgical patients with intractable epilepsy performed a one-back task using natural face stimuli, which mimics natural face perception. Specifically, our data include (1) single-neuron activity from the amygdala (996 neurons) and hippocampus (1086 neurons), (2) eye movements (gaze position and pupil), (3) psychological assessment of the patients, and (4) social trait judgment ratings from a subset of patients and a large sample of participants from the general population. Together, our comprehensive dataset with a large population of neurons can facilitate multifaceted investigation of face perception with the highest spatial and temporal resolution currently available in humans.


Assuntos
Reconhecimento Facial , Neurônios , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Neurônios/fisiologia , Análise de Célula Única , Percepção Visual/fisiologia
11.
Proc Natl Acad Sci U S A ; 119(22): e2118240119, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35613055

RESUMO

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S. T. Schafer, F. H. Gage, Cell 167, 897­914 (2016)]. In previous studies, we observed that the delayed-rectifier voltage-gated potassium channel Kv1.1 controls the membrane potential of neural stem and progenitor cells and acts as a brake on neurogenesis during neonatal hippocampal development [S. M. Chou et al., eLife 10, e58779 (2021)]. To assess the role of Kv1.1 in adult hippocampal neurogenesis, we developed an inducible conditional knockout mouse to specifically remove Kv1.1 from adult neural stem cells via tamoxifen administration. We determined that Kv1.1 deletion in adult neural stem cells causes overproliferation and depletion of radial glia-like neural stem cells, prevents proper adult-born granule cell maturation and integration into the dentate gyrus, and moderately impairs hippocampus-dependent contextual fear learning and memory. Taken together, these findings support a critical role for this voltage-gated ion channel in adult neurogenesis.


Assuntos
Condicionamento Clássico , Hipocampo , Canal de Potássio Kv1.1 , Células-Tronco Neurais , Neurogênese , Neurônios , Animais , Medo , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Canal de Potássio Kv1.1/genética , Canal de Potássio Kv1.1/fisiologia , Camundongos , Camundongos Knockout , Neurogênese/genética , Neurogênese/fisiologia , Neurônios/citologia , Neurônios/fisiologia
12.
Bull Exp Biol Med ; 172(6): 785-788, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35503587

RESUMO

Mutations in the PSEN1 gene encoding presenilin-1 (PS1) protein are the most common cause of familial Alzheimer's disease. One of these, deletion of exon 9, results in the production of shortened PS1 protein (PS1ΔE9). Neuronal hyperexcitability and hyperactivation of L-type calcium channels were observed in cellular and animal models of familial Alzheimer's disease. However, the effect of PS1ΔE9 on L-type calcium channels has not been studied before. We demonstrate enhanced calcium entry through L-type calcium channels in hippocampal mouse neurons with exogenous expression of PS1ΔE9. Additionally, we show that the same effect of the exogenous PS1ΔE9 can be observed in cells with predominant expression of L-type calcium channels subunit Cav1.2. Further research is required to unravel molecular mechanisms underlying hyperactivation L-type calcium channels caused by PS1ΔE9 expression.


Assuntos
Doença de Alzheimer , Canais de Cálcio Tipo L , Cálcio , Hipocampo , Neurônios , Presenilina-1 , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Mutação , Neurônios/citologia , Neurônios/metabolismo , Presenilina-1/biossíntese , Presenilina-1/genética , Presenilina-1/metabolismo
13.
J Biol Chem ; 298(6): 102048, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35597282

RESUMO

The small GTPase Cdc42 exists in the form of two alternatively spliced variants that are modified by hydrophobic chains: the ubiquitously expressed Cdc42-prenyl and a brain-specific isoform that can be palmitoylated, Cdc42-palm. Our previous work demonstrated that Cdc42-palm can be palmitoylated at two cysteine residues, Cys188 and Cys189, while Cys188 can also be prenylated. We showed that palmitoylation of Cys188 is essential for the plasma membrane localization of Cdc42-palm and is critically involved in Cdc42-mediated regulation of gene transcription and neuronal morphology. However, the abundance and regulation of this modification was not investigated. In the present study, we found that only a minor fraction of Cdc42 undergoes monopalmitoylation in neuroblastoma cells and in hippocampal neurons. In addition, we identified DHHC5 as one of the major palmitoyl acyltransferases that could physically interact with Cdc42-palm. We demonstrate that overexpression of dominant negative DHHC5 mutant decreased palmitoylation and plasma membrane localization of Cdc42-palm. In addition, knockdown of DHHC5 significantly reduced Cdc42-palm palmitoylation, leading to a decrease of Cdc42-mediated gene transcription and spine formation in hippocampal neurons. We also found that the expression of DHHC5 in the brain is developmentally regulated. Taken together, these findings suggest that DHHC5-mediated palmitoylation of Cdc42 represents an important mechanism for the regulation of Cdc42 functions in hippocampus.


Assuntos
Aciltransferases , Lipoilação , Proteínas de Membrana , Proteínas Monoméricas de Ligação ao GTP , Neurônios , Coluna Vertebral , Proteína cdc42 de Ligação ao GTP , Aciltransferases/metabolismo , Animais , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Neurônios/citologia , Coluna Vertebral/crescimento & desenvolvimento , Transcrição Genética , Proteína cdc42 de Ligação ao GTP/metabolismo
14.
Cells ; 11(10)2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35626653

RESUMO

The interaction of Rabphilin-3A (Rph3A) with the NMDA receptor (NMDAR) in hippocampal neurons plays a pivotal role in the synaptic retention of this receptor. The formation of a Rph3A/NMDAR complex is needed for the induction of long-term potentiation and NMDAR-dependent hippocampal behaviors, such as spatial learning. Moreover, Rph3A can also interact with AMPA receptors (AMPARs) through the formation of a complex with myosin Va. Here, we used a confocal imaging approach to show that Rph3A overexpression in primary hippocampal neuronal cultures is sufficient to promote increased dendritic spine density. This morphological event is correlated with an increase in GluN2A-containing NMDARs at synaptic membranes and a decrease in the surface levels of GluA1-containing AMPARs. These molecular and morphological modifications of dendritic spines are sufficient to occlude the spine formation induced by long-term potentiation, but do not prevent the spine loss induced by long-term depression. Overall, our results demonstrate a key role for Rph3A in the modulation of structural synaptic plasticity at hippocampal synapses that correlates with its interactions with both NMDARs and AMPARs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Espinhas Dendríticas , Proteínas do Tecido Nervoso , Proteínas de Transporte Vesicular , Animais , Espinhas Dendríticas/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores de AMPA , Proteínas de Transporte Vesicular/metabolismo
15.
Nature ; 604(7907): 714-722, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35444284

RESUMO

Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Neurônios , Envelhecimento , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , DNA , Éxons , Genômica , Hipocampo/citologia , Humanos , Taxa de Mutação , Neurônios/patologia , Nucleotídeos , Córtex Pré-Frontal/citologia , Sequenciamento Completo do Genoma
16.
Science ; 376(6590): eabn8861, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35420933

RESUMO

Terreros-Roncal et al. investigated the impacts of human neurodegeneration on immunostainings assumed to be associated with neurogenesis. However, the study provides no evidence that putative proliferating cells are linked to neurogenesis, that multipolar nestin+ astrocytes are progenitors, or that mature-looking doublecortin+ neurons are adult-born. Their histology-marker expression differs from what is observed in species where adult hippocampal neurogenesis is well documented.


Assuntos
Hipocampo , Doenças Neurodegenerativas , Neurogênese , Adulto , Astrócitos , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Humanos , Doenças Neurodegenerativas/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia
17.
J Neurosci ; 42(22): 4415-4434, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35474277

RESUMO

In all cell types, endocytosed cargo is transported along a set of endosomal compartments, which are linked maturationally from early endosomes (EEs) via late endosomes (LEs) to lysosomes. Lysosomes are critical for degradation of proteins that enter through endocytic as well as autophagic pathways. Rab7 is the master regulator of early-to-late endosome maturation, motility, and fusion with lysosomes. We previously showed that most degradative lysosomes are localized in the soma and in the first 25 µm of the dendrite and that bulk degradation of dendritic membrane proteins occurs in/near the soma. Dendritic late endosomes therefore move retrogradely in a Rab7-dependent manner for fusion with somatic lysosomes. We now used cultured E18 rat hippocampal neurons of both sexes to determine which microtubule motor is responsible for degradative flux of late endosomes. Based on multiple approaches (inhibiting dynein/dynactin itself or inhibiting dynein recruitment to endosomes by expressing the C-terminus of the Rab7 effector, RILP), we now demonstrate that net retrograde flux of late endosomes in dendrites is supported by dynein. Inhibition of dynein also delays maturation of somatic endosomes, as evidenced by excessive accumulation of Rab7. In addition, degradation of dendritic cargos is inhibited. Our results also suggest that GDP-GTP cycling of Rab7 appears necessary not only for endosomal maturation but also for fusion with lysosomes subsequent to arrival in the soma. In conclusion, Rab7-dependent dynein/dynactin recruitment to dendritic endosomes plays multifaceted roles in dendritic endosome maturation as well as retrograde transport of late endosomes to sustain normal degradative flux.SIGNIFICANCE STATEMENT Lysosomes are critical for degradation of membrane and extracellular proteins that enter through endocytosis. Lysosomes are also the endpoint of autophagy and thus responsible for protein and organelle homeostasis. Endosomal-lysosomal dysfunction is linked to neurodegeneration and aging. We identify roles in dendrites for two proteins with links to human diseases, Rab7 and dynein. Our previous work identified a process that requires directional retrograde transport in dendrites, namely, efficient degradation of short-lived membrane proteins. Based on multiple approaches, we demonstrate that Rab7-dependent recruitment of dynein motors supports net retrograde transport to lysosomes and is needed for endosome maturation. Our data also suggest that GDP-GTP cycling of Rab7 is required for fusion with lysosomes and degradation, subsequent to arrival in the soma.


Assuntos
Dendritos , Dineínas , proteínas de unión al GTP Rab7 , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Dendritos/metabolismo , Dineínas/metabolismo , Endossomos/metabolismo , Feminino , Guanosina Trifosfato/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Lisossomos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Transporte Proteico/fisiologia , Ratos , proteínas de unión al GTP Rab7/metabolismo
18.
Proc Natl Acad Sci U S A ; 119(11): e2107337119, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35254897

RESUMO

SignificanceGoal-directed spatial navigation has been found to rely on hippocampal neurons that are spatially modulated. We show that "nonplace" cells without significant spatial modulation play a role in discriminating goals when environmental cues for goals are ambiguous. This nonplace cell activity is performance-dependent and is modulated by gamma oscillations. Finally, nonplace cell goal discrimination coding fails in a mouse model of Alzheimer's disease (AD). Together, these results show that nonplace cell firing can signal unique task-relevant information when spatial information is ambiguous; these signals depend on performance and are absent in a mouse model of AD.


Assuntos
Aprendizagem por Discriminação , Hipocampo/citologia , Hipocampo/fisiologia , Navegação Espacial , Potenciais de Ação , Animais , Ondas Encefálicas , Sinais (Psicologia) , Meio Ambiente , Camundongos , Células Piramidais/fisiologia
19.
Nature ; 603(7903): 885-892, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35165441

RESUMO

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.


Assuntos
Doença de Alzheimer , Encéfalo , Suscetibilidade a Doenças , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/metabolismo , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Estudo de Associação Genômica Ampla , Hipocampo/irrigação sanguínea , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Camundongos , Microglia/metabolismo , Pericitos/metabolismo , Transcriptoma
20.
Nat Commun ; 13(1): 680, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115539

RESUMO

The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.


Assuntos
Autofagia/fisiologia , Espinhas Dendríticas/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Proteoma/metabolismo , Proteômica/métodos , Potenciais Sinápticos/fisiologia , Animais , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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