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1.
Nat Commun ; 10(1): 4093, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501438

RESUMO

ON and OFF selectivity in visual processing is encoded by parallel pathways that respond to either light increments or decrements. Despite lacking the anatomical features to support split channels, Drosophila larvae effectively perform visually-guided behaviors. To understand principles guiding visual computation in this simple circuit, we focus on investigating the physiological properties and behavioral relevance of larval visual interneurons. We find that the ON vs. OFF discrimination in the larval visual circuit emerges through light-elicited cholinergic signaling that depolarizes a cholinergic interneuron (cha-lOLP) and hyperpolarizes a glutamatergic interneuron (glu-lOLP). Genetic studies further indicate that muscarinic acetylcholine receptor (mAchR)/Gαo signaling produces the sign-inversion required for OFF detection in glu-lOLP, the disruption of which strongly impacts both physiological responses of downstream projection neurons and dark-induced pausing behavior. Together, our studies identify the molecular and circuit mechanisms underlying ON vs. OFF discrimination in the Drosophila larval visual system.


Assuntos
Drosophila melanogaster/fisiologia , Receptores Muscarínicos/metabolismo , Transdução de Sinais , Vias Visuais/metabolismo , Animais , Comportamento Animal/efeitos da radiação , Cálcio/metabolismo , Drosophila melanogaster/efeitos da radiação , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Ácido Glutâmico/metabolismo , Interneurônios/metabolismo , Interneurônios/efeitos da radiação , Larva/efeitos da radiação , Luz , Neurópilo/metabolismo , Neurópilo/efeitos da radiação , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/efeitos da radiação
2.
Nat Commun ; 10(1): 4249, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534164

RESUMO

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.


Assuntos
Apoptose/fisiologia , Interneurônios/metabolismo , Neurogênese/fisiologia , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Feminino , Neurônios GABAérgicos/citologia , Proteínas de Homeodomínio/metabolismo , Interneurônios/citologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/citologia
3.
Nat Commun ; 10(1): 4174, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519874

RESUMO

Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking interneurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ interneurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are used across the cortex as building blocks to assemble cortical circuits.


Assuntos
Neocórtex/citologia , Animais , Eletrofisiologia , Feminino , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Camundongos , Neocórtex/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Somatostatina/metabolismo
4.
Nat Commun ; 10(1): 4197, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519892

RESUMO

In all vertebrates, excitatory spinal interneurons execute dynamic adjustments in the timing and amplitude of locomotor movements. Currently, it is unclear whether interneurons responsible for timing control are distinct from those involved in amplitude control. Here, we show that in larval zebrafish, molecularly, morphologically and electrophysiologically distinct types of V2a neurons exhibit complementary patterns of connectivity. Stronger higher-order connections from type I neurons to other excitatory V2a and inhibitory V0d interneurons provide timing control, while stronger last-order connections from type II neurons to motor neurons provide amplitude control. Thus, timing and amplitude are coordinated by distinct interneurons distinguished not by their occupation of hierarchically-arranged anatomical layers, but rather by differences in the reliability and probability of higher-order and last-order connections that ultimately form a single anatomical layer. These findings contribute to our understanding of the origins of timing and amplitude control in the spinal cord.


Assuntos
Interneurônios/metabolismo , Locomoção/fisiologia , Animais , Interneurônios/citologia , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Medula Espinal/citologia , Medula Espinal/metabolismo , Peixe-Zebra
5.
Brain Struct Funct ; 224(8): 2703-2716, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31375982

RESUMO

The greater part of the striatum is composed of striosomes and matrix compartments, but we recently demonstrated the presence of a region that has a distinct structural organization in the ventral half of the mouse caudal striatum (Miyamoto et al. in Brain Struct Funct 223:4275-4291, 2018). This region, termed the tri-laminar part based upon its differential immunoreactivities for substance P and enkephalin, consists of medial, intermediate, and lateral divisions. In this study, we quantitatively analyzed the distributions of both projection neurons and interneurons in each division using immunohistochemistry. Two types of projection neurons expressing either the dopamine D1 receptor (D1R) or D2 receptor (D2R) showed complementary distributions throughout the tri-laminar part, but the proportions significantly differed among the three divisions. The proportion of D1R-expressing neurons in the medial, intermediate, and lateral divisions was 88.6 ± 8.2% (651 cells from 3 mice), 14.7 ± 3.8% (1025 cells), and 49.3 ± 4.5% (873 cells), respectively. The intermediate division was further characterized by poor innervation of tyrosine hydroxylase immunoreactive axons. The numerical density of choline acetyltransferase immunoreactive neurons differed among the three divisions following the order from the medial to lateral divisions. In contrast, PV-positive somata were distributed throughout all three divisions at a constant density. Two types of GABAergic interneurons labeled for nitric oxide synthase and calretinin showed the highest cell density in the medial division. The present results characterize the three divisions of the mouse caudal striatum as distinct structures, which will facilitate studies of novel functional loops in the basal ganglia.


Assuntos
Neurônios Colinérgicos/citologia , Corpo Estriado/citologia , Neurônios Dopaminérgicos/citologia , Neurônios GABAérgicos/citologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Axônios , Neurônios Colinérgicos/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
6.
Genetics ; 213(1): 267-279, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292211

RESUMO

Sleep is evolutionarily conserved, thus studying simple invertebrates such as Caenorhabditis elegans can provide mechanistic insight into sleep with single cell resolution. A conserved pathway regulating sleep across phylogeny involves cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger that functions in neurons by activating protein kinase A. C. elegans sleep in response to cellular stress caused by environmental insults [stress-induced sleep (SIS)], a model for studying sleep during sickness. SIS is controlled by simple neural circuitry, thus allowing for cellular dissection of cAMP signaling during sleep. We employed a red-light activated adenylyl cyclase, IlaC22, to identify cells involved in SIS regulation. We found that pan-neuronal activation of IlaC22 disrupts SIS through mechanisms independent of the cAMP response element binding protein. Activating IlaC22 in the single DVA interneuron, the paired RIF interneurons, and in the CEPsh glia identified these cells as wake-promoting. Using a cAMP biosensor, epac1-camps, we found that cAMP is decreased in the RIF and DVA interneurons by neuropeptidergic signaling from the ALA neuron. Ectopic overexpression of sleep-promoting neuropeptides coded by flp-13 and flp-24, released from the ALA, reduced cAMP in the DVA and RIFs, respectively. Overexpression of the wake-promoting neuropeptides coded by pdf-1 increased cAMP levels in the RIFs. Using a combination of optogenetic manipulation and in vivo imaging of cAMP we have identified wake-promoting neurons downstream of the neuropeptidergic output of the ALA. Our data suggest that sleep- and wake-promoting neuropeptides signal to reduce and heighten cAMP levels during sleep, respectively.


Assuntos
AMP Cíclico/metabolismo , Interneurônios/metabolismo , Locomoção , Transdução de Sinais , Sono , Estresse Fisiológico , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Animais , Técnicas Biossensoriais/métodos , Caenorhabditis elegans , Interneurônios/fisiologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Optogenética/métodos
7.
Elife ; 82019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31318331

RESUMO

Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.


Assuntos
Drosophila melanogaster/fisiologia , Retroalimentação Fisiológica , Ácido Glutâmico/toxicidade , Neurônios Motores/fisiologia , Neurotoxinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Estresse Oxidativo/efeitos dos fármacos
8.
Nat Commun ; 10(1): 3369, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358754

RESUMO

Inhibitory interneurons are integral to sensory processing, yet revealing their cell type-specific roles in sensory circuits remains an ongoing focus. To Investigate the mouse olfactory system, we selectively remove GABAergic transmission from a subset of olfactory bulb interneurons, EPL interneurons (EPL-INs), and assay odor responses from their downstream synaptic partners - tufted cells and mitral cells. Using a combination of in vivo electrophysiological and imaging analyses, we find that inactivating this single node of inhibition leads to differential effects in magnitude, reliability, tuning width, and temporal dynamics between the two principal neurons. Furthermore, tufted and not mitral cell responses to odor mixtures become more linearly predictable without EPL-IN inhibition. Our data suggest that olfactory bulb interneurons, through exerting distinct inhibitory functions onto their different synaptic partners, play a significant role in the processing of odor information.


Assuntos
Interneurônios/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/fisiologia , Condutos Olfatórios/fisiologia , Animais , Interneurônios/citologia , Interneurônios/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Inibição Neural/genética , Neurônios/citologia , Neurônios/metabolismo , Odorantes , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Olfato , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
9.
Int J Mol Sci ; 20(12)2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31212931

RESUMO

Inhibitory interneurons make up around 10-20% of the total neuron population in the cerebral cortex. A hallmark of inhibitory interneurons is their remarkable diversity in terms of morphology, synaptic connectivity, electrophysiological and neurochemical properties. It is generally understood that there are three distinct and non-overlapping interneuron classes in the mouse neocortex, namely, parvalbumin-expressing, 5-HT3A receptor-expressing and somatostatin-expressing interneuron classes. Each class is, in turn, composed of a multitude of subclasses, resulting in a growing number of interneuron classes and subclasses. In this review, I will focus on the diversity of somatostatin-expressing interneurons (SOM+ INs) in the cerebral cortex and elucidate their function in cortical circuits. I will then discuss pathological consequences of a malfunctioning of SOM+ INs in neurological disorders such as major depressive disorder, and present future avenues in SOM research and brain pathologies.


Assuntos
Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Regulação da Expressão Gênica , Interneurônios/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Animais , Fenômenos Eletrofisiológicos , Humanos , Aprendizagem , Memória , Transtornos do Humor/etiologia , Transtornos do Humor/metabolismo , Transtornos do Humor/psicologia , Sinapses , Transmissão Sináptica
10.
Cell Mol Life Sci ; 76(20): 3953-3967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250034

RESUMO

The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient's own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.


Assuntos
Lesões Encefálicas/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Interneurônios/citologia , Doenças Neurodegenerativas/terapia , Regeneração/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Transdiferenciação Celular , Reprogramação Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Injeções Intraventriculares , Interneurônios/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurogênese/genética , Transplante de Células-Tronco/métodos
11.
Brain Struct Funct ; 224(6): 2247-2267, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31190162

RESUMO

We describe a set of perivascular interneurons (PINs) with series of fibro-vesicular complexes (FVCs) throughout the gray matter of the adult rabbit and rat brains. PIN-FVCs are ubiquitous throughout the brain vasculature as detected in Golgi-impregnated specimens. Most PINs are small, aspiny cells with short or long (> 1 mm) axons that split and travel along arterial blood vessels. Upon ramification, axons form FVCs around the arising vascular branches; then, paired axons run parallel to the vessel wall until another ramification ensues, and a new FVC is formed. Cytologically, FVCs consist of clusters of perivascular bulbs (PVBs) encircling the precapillary and capillary wall surrounded by end-feet and the extracellular matrix of endothelial cells and pericytes. A PVB contains mitochondria, multivesicular bodies, and granules with a membranous core, similar to Meissner corpuscles and other mechanoreceptors. Some PVBs form asymmetrical, axo-spinous synapses with presumptive adjacent neurons. PINs appear to correspond to the type 1 nNOS-positive neurons whose FVCs co-label with markers of sensory fiber-terminals surrounded by astrocytic end-feet. The PIN is conserved in adult cats and rhesus monkey specimens. The location, ubiquity throughout the vasculature of the mammalian brain, and cytological organization of the PIN-FVCs suggests that it is a sensory receptor intrinsic to the mammalian neurovascular unit that corresponds to an afferent limb of the sensorimotor feed-back mechanism controlling local blood flow.


Assuntos
Axônios/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Mecanorreceptores/metabolismo , Sinapses/metabolismo , Animais , Gatos , Complexo de Golgi/metabolismo , Interneurônios/metabolismo , Mamíferos , Coelhos , Ratos , Células Receptoras Sensoriais/metabolismo
12.
Dev Cell ; 49(4): 632-642.e7, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31112699

RESUMO

While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. Here, we show that conditional deletion of Pnky from the developing cortex regulates the production of projection neurons from neural stem cells (NSCs) in a cell-autonomous manner, altering postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a BAC transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates development in trans.


Assuntos
Córtex Cerebral/embriologia , Células-Tronco Neurais/metabolismo , RNA Longo não Codificante/genética , Animais , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Neurogênese/genética , Neurônios/metabolismo , Fatores do Domínio POU/genética , RNA Longo não Codificante/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo
13.
Cell ; 177(5): 1346-1360.e24, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31080068

RESUMO

To decipher dynamic brain information processing, current genetically encoded calcium indicators (GECIs) are limited in single action potential (AP) detection speed, combinatorial spectral compatibility, and two-photon imaging depth. To address this, here, we rationally engineered a next-generation quadricolor GECI suite, XCaMPs. Single AP detection was achieved within 3-10 ms of spike onset, enabling measurements of fast-spike trains in parvalbumin (PV)-positive interneurons in the barrel cortex in vivo and recording three distinct (two inhibitory and one excitatory) ensembles during pre-motion activity in freely moving mice. In vivo paired recording of pre- and postsynaptic firing revealed spatiotemporal constraints of dendritic inhibition in layer 1 in vivo, between axons of somatostatin (SST)-positive interneurons and apical tufts dendrites of excitatory pyramidal neurons. Finally, non-invasive, subcortical imaging using red XCaMP-R uncovered somatosensation-evoked persistent activity in hippocampal CA1 neurons. Thus, the XCaMPs offer a critical enhancement of solution space in studies of complex neuronal circuit dynamics. VIDEO ABSTRACT.


Assuntos
Potenciais de Ação/fisiologia , Axônios/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Células Piramidais/metabolismo , Animais , Córtex Cerebral/citologia , Feminino , Hipocampo/citologia , Interneurônios/citologia , Camundongos , Camundongos Transgênicos , Células Piramidais/citologia , Ratos , Ratos Sprague-Dawley
14.
Brain Struct Funct ; 224(6): 2269-2280, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31098764

RESUMO

In cortical circuits, the vasoactive intestinal peptide (VIP+)-expressing GABAergic cells represent a heterogeneous but unique group of interneurons that is mainly specialized in network disinhibition. While the physiological properties and connectivity patterns have been elucidated in several types of VIP+ interneurons, little is known about the cell type-specific molecular repertoires important for selective targeting of VIP+ cell types and understanding their functions. Using patch-sequencing approach, we analyzed the transcriptomic profile of anatomically identified subiculum-projecting VIP+ GABAergic neurons that reside in the mouse hippocampal CA1 area, express muscarinic receptor 2 and coordinate the hippocampo-subicular interactions via selective innervation of interneurons in the CA1 area and of interneurons and pyramidal cells in subiculum. We explored the VIP+ cell gene expression within major gene families including ion channels, neurotransmitter receptors, neuromodulators, cell adhesion and myelination molecules. Among others, a large variety of genes involved in neuromodulatory signaling, including acetylcholine (Chrna4), norepinephrin (Adrb1), dopamine (Drd1), serotonin (Htr1d), cannabinoid (Cnr1), opioid (Oprd1, Oprl1) and neuropeptide Y (Npy1r) receptors was detected in these cells. Many genes that were enriched in other local VIP+ cell types, including the interneuron-selective interneurons and the cholecystokinin-coexpressing basket cells, were detected in VIP+ subiculum-projecting cells. In addition, the neuronatin (Nnat) and the Purkinje Cell Protein 4 (Pcp4) genes, which were detected previously in long-range projecting GABAergic neurons, were also common for the subiculum-projecting VIP+ cells. The expression of some genes was validated at the protein level, with proenkephalin being identified as an additional molecular marker of this VIP+ cell type. Together, our data indicate that the VIP+ subiculum-projecting cells share molecular identity with other VIP+ and long-range projecting GABAergic neurons, which can be important for specific function of these cells associated with their local and distant projection patterns.


Assuntos
Neurônios GABAérgicos/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Células Piramidais/metabolismo , Acetilcolina/metabolismo , Animais , Colecistocinina/metabolismo , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores Muscarínicos/metabolismo
15.
PLoS One ; 14(5): e0217094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125364

RESUMO

Local neocortical circuits play critical roles in information processing, including synaptic plasticity, circuit physiology, and learning, and GABAergic inhibitory interneurons have key roles in these circuits. Moreover, specific neurological disorders, including schizophrenia and autism, are associated with deficits in GABAergic transmission in these circuits. GABAergic synapses represent a small fraction of neocortical synapses, and are embedded in complex local circuits that contain many neuron and synapse types. Thus, it is challenging to study the physiological roles of GABAergic inhibitory interneurons and their synapses, and to develop treatments for the specific disorders caused by dysfunction at these GABAergic synapses. To these ends, we report a novel technology that can deliver different genes into pre- and post-synaptic neocortical interneurons connected by a GABAergic synapse: First, standard gene transfer into the presynaptic neurons delivers a synthetic peptide neurotransmitter, containing three domains, a dense core vesicle sorting domain, a GABAA receptor-binding domain, a single-chain variable fragment anti-GABAA ß2 or ß3, and the His tag. Second, upon release, this synthetic peptide neurotransmitter binds to GABAA receptors on the postsynaptic neurons. Third, as the synthetic peptide neurotransmitter contains the His tag, antibody-mediated, targeted gene transfer using anti-His tag antibodies is selective for these neurons. We established this technology by expressing the synthetic peptide neurotransmitter in GABAergic neurons in the middle layers of postrhinal cortex, and the delivering the postsynaptic vector into connected GABAergic neurons in the upper neocortical layers. Targeted gene transfer was 61% specific for the connected neurons, but untargeted gene transfer was only 21% specific for these neurons. This technology may support studies on the roles of GABAergic inhibitory interneurons in circuit physiology and learning, and support gene therapy treatments for specific disorders associated with deficits at GABAergic synapses.


Assuntos
Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Neocórtex/metabolismo , Neurotransmissores/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-B/genética , Sinapses/metabolismo , Animais , Técnicas de Transferência de Genes , Vetores Genéticos , Camundongos , Neurotransmissores/genética , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Receptores de GABA-A/imunologia , Receptores de GABA-A/metabolismo , Receptores de GABA-B/imunologia , Receptores de GABA-B/metabolismo , Anticorpos de Cadeia Única/imunologia
16.
Nat Commun ; 10(1): 1882, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015396

RESUMO

Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gαq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.


Assuntos
Comportamento Animal/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Ácido Glutâmico/metabolismo , Terminações Pré-Sinápticas/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Animais Geneticamente Modificados , Conjuntos de Dados como Assunto , Transportador 2 de Aminoácido Excitatório/metabolismo , Perfilação da Expressão Gênica , Interneurônios/metabolismo , Locomoção/fisiologia , Modelos Animais , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética
17.
Nat Commun ; 10(1): 1917, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015467

RESUMO

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.


Assuntos
Corpo Estriado/metabolismo , Proteínas Munc18/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neocórtex/metabolismo , Convulsões/genética , Transmissão Sináptica , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Dioxóis/farmacologia , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/metabolismo , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/farmacologia , Regulação da Expressão Gênica , Haploinsuficiência , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Interneurônios/patologia , Camundongos , Camundongos Knockout , Proteínas Munc18/deficiência , Canal de Sódio Disparado por Voltagem NAV1.2/deficiência , Neocórtex/efeitos dos fármacos , Neocórtex/patologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Piperidinas/farmacologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Transdução de Sinais , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
18.
Neuron ; 102(1): 60-74, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30946827

RESUMO

Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.


Assuntos
Encéfalo/fisiopatologia , Medo/fisiologia , Memória/fisiologia , Trauma Psicológico/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiopatologia , Hormônio Liberador da Corticotropina/metabolismo , Medo/psicologia , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Hipotálamo/fisiopatologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Trauma Psicológico/metabolismo , Trauma Psicológico/psicologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Tálamo/metabolismo , Tálamo/fisiologia , Tálamo/fisiopatologia
19.
Neuron ; 102(1): 75-90, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30946828

RESUMO

The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.


Assuntos
Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Ácido Glutâmico/metabolismo , Interneurônios/metabolismo , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Córtex Cerebral , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Ácido Glutâmico/efeitos dos fármacos , Hipocampo , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Neurônios/patologia , Fatores Sexuais , Transmissão Sináptica , Ácido gama-Aminobutírico/efeitos dos fármacos
20.
Transl Psychiatry ; 9(1): 132, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967545

RESUMO

Schizophrenia is a severe and highly heritable disorder. Dystrobrevin-binding protein 1 (DTNBP1), also known as dysbindin-1, has been implicated in the pathophysiology of schizophrenia. Specifically, dysbindin-1 mRNA and protein expression are decreased in the brains of subjects with this disorder. Mice lacking dysbinidn-1 also display behavioral phenotypes similar to those observed in schizophrenic patients. However, it remains unknown whether deletion of dysbindin-1 impacts functions of the amygdala, a brain region that is critical for emotional processing, which is disrupted in patients with schizophrenia. Here, we show that dysbindin-1 is expressed in both excitatory and inhibitory neurons of the basolateral amygdala (BLA). Deletion of dysbindin-1 in male mice (Dys-/-) impaired cued and context-dependent threat memory, without changes in measures of anxiety. The behavioral deficits observed in Dys-/- mice were associated with perturbations in the BLA, including the enhancement of GABAergic inhibition of pyramidal neurons, increased numbers of parvalbumin interneurons, and morphological abnormalities of dendritic spines on pyramidal neurons. Our findings highlight an important role for dysbindin-1 in the regulation of amygdalar function and indicate that enhanced inhibition of BLA pyramidal neuron activity may contribute to the weakened threat memory expression observed in Dys-/- mice.


Assuntos
Tonsila do Cerebelo/metabolismo , Disbindina/genética , Deleção de Genes , Consolidação da Memória , Esquizofrenia/genética , Tonsila do Cerebelo/fisiopatologia , Animais , Comportamento Animal , Sinais (Psicologia) , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Piramidais/metabolismo
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