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1.
Neuron ; 109(20): 3312-3322.e5, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34672984

RESUMO

Concurrent genetic neuromodulation and functional magnetic resonance imaging (fMRI) in primates has provided a valuable opportunity to assess the modified brain-wide operation in the resting state. However, its application to link the network operation with behavior still remains challenging. Here, we combined chemogenetic silencing of the primary somatosensory cortex (SI) with tactile fMRI and related behaviors in macaques. Focal chemogenetic silencing of functionally identified SI hand region impaired grasping behavior. The same silencing also attenuated hand stimulation-evoked fMRI signal at both the local silencing site and the anatomically and/or functionally connected downstream grasping network, suggesting altered network operation underlying the induced behavioral impairment. Furthermore, the hand region silencing unexpectedly disinhibited foot representation with accompanying behavioral hypersensitization. These results demonstrate that focal chemogenetic silencing with sensory fMRI in macaques unveils bidirectional network changes to generate multifaceted behavioral impairments, thereby opening a pivotal window toward elucidating the causal network operation underpinning higher brain functions in primates.


Assuntos
Técnicas Genéticas , Força da Mão , Córtex Somatossensorial/diagnóstico por imagem , Tato , Animais , , Neuroimagem Funcional , Mãos , Macaca fuscata , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Primatas , Córtex Somatossensorial/metabolismo , Córtex Somatossensorial/fisiologia
2.
Sci Rep ; 11(1): 17656, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480033

RESUMO

Several scientific, engineering, and medical advancements are based on breakthroughs made by people who excel in mathematics. Our current understanding of the underlying brain networks stems primarily from anatomical and functional investigations, but our knowledge of how neurotransmitters subserve numerical skills, the building block of mathematics, is scarce. Using 1H magnetic resonance spectroscopy (N = 54, 3T, semi-LASER sequence, TE = 32 ms, TR = 3.5 s), the study examined the relation between numerical skills and the brain's major inhibitory (GABA) and excitatory (glutamate) neurotransmitters. A negative association was found between the performance in a number sequences task and the resting concentration of GABA within the left intraparietal sulcus (IPS), a key region supporting numeracy. The relation between GABA in the IPS and number sequences was specific to (1) parietal but not frontal regions and to (2) GABA but not glutamate. It was additionally found that the resting functional connectivity of the left IPS and the left superior frontal gyrus was positively associated with number sequences performance. However, resting GABA concentration within the IPS explained number sequences performance above and beyond the resting frontoparietal connectivity measure. Our findings further motivate the study of inhibition mechanisms in the human brain and significantly contribute to our current understanding of numerical cognition's biological bases.


Assuntos
Matemática , Lobo Parietal/metabolismo , Resolução de Problemas/fisiologia , Ácido gama-Aminobutírico/metabolismo , Adolescente , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Lobo Parietal/diagnóstico por imagem , Adulto Jovem
3.
Elife ; 102021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34423776

RESUMO

While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting, the regulation of infant-directed aggression and how it relates to adult-adult aggression is poorly understood. Here we show that urocortin-3 (Ucn3)-expressing neurons in the hypothalamic perifornical area (PeFAUcn3) are activated during infant-directed attacks in males and females, but not other behaviors. Functional manipulations of PeFAUcn3 neurons demonstrate the role of this population in the negative control of parenting in both sexes. PeFAUcn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send projections to hypothalamic and limbic areas. Optogenetic activation of PeFAUcn3 axon terminals in these regions triggers various aspects of infant-directed agonistic responses, such as neglect, repulsion, and aggression. Thus, PeFAUcn3 neurons emerge as a dedicated circuit component controlling infant-directed neglect and aggression, providing a new framework to understand the positive and negative regulation of parenting in health and disease.


Assuntos
Agressão , Comportamento Animal , Hipotálamo/metabolismo , Comportamento Materno , Neurônios/metabolismo , Comportamento Paterno , Urocortinas/metabolismo , Animais , Feminino , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/metabolismo , Optogenética , Fatores Sexuais , Urocortinas/genética
4.
Elife ; 102021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34372969

RESUMO

Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones ß-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.


Assuntos
Lesões Encefálicas/fisiopatologia , Vias Neurais/fisiologia , Reflexo , Córtex Sensório-Motor/fisiologia , Animais , Lesões Encefálicas/metabolismo , Masculino , Vias Neurais/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
5.
J Neurosci ; 41(39): 8181-8196, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34380766

RESUMO

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network.SIGNIFICANCE STATEMENT The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.


Assuntos
Giro Denteado/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Neurônios/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Vias Neurais/metabolismo , Sinapses/fisiologia
6.
J Neurosci ; 41(31): 6699-6713, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34226275

RESUMO

Paternal care plays a critical role in the development of brain and behaviors in offspring in monogamous species. However, the neurobiological mechanisms, especially the neuronal circuity, underlying paternal care is largely unknown. Using socially monogamous male mandarin voles (Microtus mandarinus) with high levels of paternal care, we found that paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) or nucleus accumbens (NAc) oxytocin (OT) neurons are activated during paternal care. Chemogenetic activation/inhibition of the PVN OT projection to VTA promoted/decreased paternal care, respectively. Chemogenetic inhibition of the PVN to VTA OT pathway reduced dopamine (DA) release in the NAc of male mandarin voles during licking and grooming of pups as revealed by in vivo fiber photometry. Optogenetic activation/inhibition of the VTA to NAc DA pathway possibly enhanced/suppressed paternal behaviors, respectively. Furthermore, chemogenetic activation/inhibition of PVN to NAc OT circuit enhanced/inhibited paternal care. This finding is a first step toward delineating the neuronal circuity underlying paternal care and may have implications for treating abnormalities in paternal care associated with paternal postpartum depression or paternal abuse.SIGNIFICANCE STATEMENT Paternal behavior is essential for offspring survival and development in some mammalian species. However, the circuit mechanisms underlying the paternal brain are poorly understood. We show that manipulation of paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) oxytocin (OT) projections as well as VTA to nucleus accumbens (NAc) DA projections promote paternal behaviors. Inhibition the PVN to VTA OT pathway reduces DA release in the NAc during pup licking and grooming. PVN to NAc OT circuit is also essential for paternal behaviors. Our findings identify two new neural circuits that modulate paternal behaviors.


Assuntos
Comportamento Animal/fisiologia , Vias Neurais/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Comportamento Paterno/fisiologia , Animais , Arvicolinae , Masculino
7.
Neuron ; 109(13): 2106-2115.e4, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077742

RESUMO

The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.


Assuntos
Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Sistema Nervoso Entérico/metabolismo , Mucosa Gástrica/metabolismo , Neurônios Motores/metabolismo , Estômago/inervação , Nervo Vago/metabolismo , Animais , Perfilação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/metabolismo
8.
Elife ; 102021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061025

RESUMO

Neurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors - typically activated by neurotransmitters and modulated by neuromodulators - provide a powerful way of fine-tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at mossy fiber boutons in the rodent hippocampus can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor release and contribute to presynaptic calcium rise. Taken together, our results indicate that by increasing presynaptic calcium, preNMDARs fine-tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occur in vivo.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Plasticidade Neuronal , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica , Animais , Região CA3 Hipocampal/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musgosas Hipocampais/ultraestrutura , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/metabolismo , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/ultraestrutura , Fatores de Tempo
9.
Elife ; 102021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34080539

RESUMO

Consolation is a common response to the distress of others in humans and some social animals, but the neural mechanisms underlying this behavior are not well characterized. By using socially monogamous mandarin voles, we found that optogenetic or chemogenetic inhibition of 5-HTergic neurons in the dorsal raphe nucleus (DR) or optogenetic inhibition of serotonin (5-HT) terminals in the anterior cingulate cortex (ACC) significantly decreased allogrooming time in the consolation test and reduced sociability in the three-chamber test. The release of 5-HT within the ACC and the activity of DR neurons were significantly increased during allogrooming, sniffing, and social approaching. Finally, we found that the activation of 5-HT1A receptors in the ACC was sufficient to reverse consolation and sociability deficits induced by the chemogenetic inhibition of 5-HTergic neurons in the DR. Our study provided the first direct evidence that DR-ACC 5-HTergic neural circuit is implicated in consolation-like behaviors and sociability.


Assuntos
Comportamento Animal , Núcleo Dorsal da Rafe/fisiologia , Giro do Cíngulo/fisiologia , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Comportamento Social , Animais , Arvicolinae , Núcleo Dorsal da Rafe/metabolismo , Feminino , Asseio Animal , Giro do Cíngulo/metabolismo , Masculino , Atividade Motora , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Optogenética , Receptor 5-HT1A de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Fatores de Tempo
10.
Endocrinology ; 162(9)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34161572

RESUMO

Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 hour induced messenger RNA (mRNA) expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 hour significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine ß-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.


Assuntos
Glucose/metabolismo , Vias Neurais/metabolismo , Rombencéfalo/metabolismo , Animais , Glicemia/metabolismo , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Privação de Alimentos/fisiologia , Glucose/deficiência , Glucose/farmacologia , Hipotálamo/anatomia & histologia , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Wistar , Rombencéfalo/anatomia & histologia , Rombencéfalo/citologia , Rombencéfalo/efeitos dos fármacos
12.
Elife ; 102021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34042586

RESUMO

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.


Assuntos
Comportamento Animal , Região Hipotalâmica Lateral/fisiopatologia , Nociceptividade , Dor/fisiopatologia , Dor/psicologia , Analgésicos Opioides/uso terapêutico , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Sinalização do Cálcio , Modelos Animais de Doenças , Tolerância a Medicamentos , Feminino , Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Morfina/farmacologia , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Técnicas de Rastreamento Neuroanatômico , Nociceptividade/efeitos dos fármacos , Optogenética , Dor/metabolismo , Dor/prevenção & controle , Parvalbuminas/genética , Parvalbuminas/metabolismo
13.
Exp Neurol ; 342: 113744, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33965409

RESUMO

The dysregulation of neuronal networks may contribute to the etiology of major depressive disorder (MDD). However, the neural connections underlying the symptoms of MDD have yet to be elucidated. Here, we observed that glutamatergic neurons in the paraventricular thalamus (PVT) were activated by chronic unpredictable stress (CUS) with higher expression numbers of ΔFosB-labeled neurons and protein expression levels, activation of PVT neurons caused depressive-like phenotypes, whereas suppression of PVT neuronal activity induced an antidepressant effect in male, but not female mice, which were achieved by using a chemogenetic approach. Moreover, we found that PVT glutamatergic neurons showed strong neuronal projections to the central amygdala (CeA), activation of the CeA-projecting neurons in PVT or the neuronal terminals of PVT-CeA projection neurons induced depression-related behaviors or showed enhanced stress-induced susceptibility. These results suggest that PVT is a key depression-controlling nucleus, and PVT-CeA projection regulates depression-related behaviors in a sex-dependent manner, which could be served as an essential pathway for morbidity and treatment of depression.


Assuntos
Núcleo Central da Amígdala/metabolismo , Depressão/metabolismo , Núcleos da Linha Média do Tálamo/metabolismo , Animais , Núcleo Central da Amígdala/química , Depressão/genética , Depressão/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleos da Linha Média do Tálamo/química , Vias Neurais/metabolismo , Vias Neurais/patologia
14.
Food Funct ; 12(13): 5703-5718, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34048514

RESUMO

Osteoporosis (OP) is a kind of systemic metabolic disease characterized by decreased bone mass and destruction of the bone microstructure. In recent years, it has become an expected research trend to explore the cross-linking relationship in the pathogenesis process of OP so as to develop reasonable and effective intervention strategies. With the further development of intestinal microbiology and the profound exploration of the gut microbiota (GM), it has been further revealed that the "brain-gut" axis may be a potential target for the bone, thereby affecting the occurrence and progression of OP. Hence, based on the concept of "brain-gut-bone" axis, we look forward to deeply discussing and summarizing the cross-linking relationship of OP in the next three parts, including the "brain-bone" connection, "gut-bone" connection, and "brain-gut" connection, so as to provide an emerging thought for the prevention strategies and mechanism researches of OP.


Assuntos
Microbioma Gastrointestinal , Osteoporose/prevenção & controle , Animais , Osso e Ossos/metabolismo , Encéfalo/metabolismo , Feminino , Trato Gastrointestinal/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Imunitário/metabolismo , Masculino , Camundongos , Vias Neurais/metabolismo , Osteoporose/patologia , Osteoporose/terapia , Transdução de Sinais
15.
Nat Neurosci ; 24(6): 873-885, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33972801

RESUMO

Functional circuits consist of neurons with diverse axonal projections and gene expression. Understanding the molecular signature of projections requires high-throughput interrogation of both gene expression and projections to multiple targets in the same cells at cellular resolution, which is difficult to achieve using current technology. Here, we introduce BARseq2, a technique that simultaneously maps projections and detects multiplexed gene expression by in situ sequencing. We determined the expression of cadherins and cell-type markers in 29,933 cells and the projections of 3,164 cells in both the mouse motor cortex and auditory cortex. Associating gene expression and projections in 1,349 neurons revealed shared cadherin signatures of homologous projections across the two cortical areas. These cadherins were enriched across multiple branches of the transcriptomic taxonomy. By correlating multigene expression and projections to many targets in single neurons with high throughput, BARseq2 provides a potential path to uncovering the molecular logic underlying neuronal circuits.


Assuntos
Córtex Auditivo/metabolismo , Mapeamento Encefálico/métodos , Processamento Eletrônico de Dados/métodos , Redes Reguladoras de Genes/genética , Córtex Motor/metabolismo , Animais , Córtex Auditivo/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Motor/química , Vias Neurais/química , Vias Neurais/metabolismo
16.
J Neurosci ; 41(22): 4795-4808, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33906900

RESUMO

Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7-positive frontal and occipital cortical areas extend their axon collaterals into the EfnA5-negative rostral part of the basilar pons, whereas EfnA5-positive parietal cortical areas extend their collaterals into the EphA7-negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets.SIGNIFICANCE STATEMENT Our findings put forward a model in which region-to-region connections between cortex and subcortical areas are shaped by mutually exclusive molecules to ensure the fidelity of regionally restricted circuitry. This model is distinct from earlier work showing that neuronal circuits within individual cortical modalities form in a topographical manner controlled by a gradient of axon guidance molecules. The principle that a shared molecular program of mutually repulsive signaling instructs regional organization-both within each brain region and between connected brain regions-may well be applicable to other contexts in which information is sorted by converging and diverging neuronal circuits.


Assuntos
Orientação de Axônios/fisiologia , Efrina-A5/metabolismo , Neocórtex/embriologia , Vias Neurais/embriologia , Ponte/embriologia , Receptor EphA7/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/metabolismo , Vias Neurais/metabolismo , Ponte/patologia
17.
Eur J Pharmacol ; 899: 174033, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33727058

RESUMO

The dorsomedial hypothalamus (DMH) receives dense orexinergic innervation. Intra-DMH application of orexins increases arterial pressure and heart rate in rats. We studied the effects of orexin-A on DMH neurons, including those innervating the medullary cardiovascular center, the rostral ventrolateral medulla (RVLM), by using whole-cell recordings in brain slices. In the presence of tetrodotoxin, orexin-A (30-1000 nM) depolarized 56% of DMH neurons (EC50 82.4 ± 4.4 nM). Under voltage-clamp recording, orexin-A (300 nM) induced three types of responses characterized by different current-voltage relationships, namely unchanged, increased, and decreased slope conductance in 68%, 14%, and 18% of orexin-A-responsive neurons, respectively. The reversal potential of the decreased-conductance response was near the equilibrium potential of K+ and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is the underlying mechanism. In a low-Na+ solution, unchanged-, increased-, and decreased-conductance responses were observed in 56%, 11%, and 33% of orexin-A-responsive neurons, respectively, implying that a non-selective cation current (NSCC) underlies orexin-A-induced responses in a small population of DMH neurons. KBR-7943 (70 µM), an inhibitor of Na+-Ca2+ exchanger (NCX), suppressed orexin-A-induced depolarization in 7 of 10 neurons. In the presence of KBR-7943, the majority of orexin-A-responsive neurons exhibited decreased-conductance responses. These findings suggest that NCX activation may underlie orexin-A-induced depolarization in the majority of orexin-responsive DMH neurons. Of 19 RVLM-projecting DMH neurons identified by retrograde labeling, 17 (90%) were orexin-A responsive. In conclusion, orexin-A directly excited over half of DMH neurons, including those innervating the RVLM, through decreasing K+ conductance, activating NCX, and/or increasing NSCC.


Assuntos
Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Bulbo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Orexinas/farmacologia , Animais , Núcleo Hipotalâmico Dorsomedial/citologia , Núcleo Hipotalâmico Dorsomedial/metabolismo , Feminino , Técnicas In Vitro , Masculino , Bulbo/citologia , Bulbo/metabolismo , Potenciais da Membrana , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Técnicas de Rastreamento Neuroanatômico , Neurônios/metabolismo , Potássio/metabolismo , Ratos Sprague-Dawley , Trocador de Sódio e Cálcio/metabolismo
18.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668086

RESUMO

The present study investigated the effect of unilateral axotomy of urinary bladder trigone (UBT)-projecting nerve fibers from the right anterior pelvic ganglion (APG) on changes in the chemical coding of their neuronal bodies. The study was performed using male pigs with immunohistochemistry and quantitative real-time PCR (qPCR). The animals were divided into a control (C), a morphological (MG) or a molecular biology group (MBG). APG neurons supplying UBT were revealed using the retrograde tracing technique with Fast Blue (FB). Unilateral axotomy resulted in an over 50% decrease in the number of FB+ neurons in both APG ganglia. Immunohistochemistry revealed significant changes in the chemical coding of FB+ cells only in the right ganglion: decreased expression of dopamine-B-hydroxylase (DBH)/tyrosine hydroxylase (TH) and up-regulation of the vesicular acetylcholine transporter (VAChT)/choline acetyltransferase (ChAT), galanin (GAL), vasoactive intestinal polypeptide (VIP) and brain nitric oxide synthase (bNOS). The qPCR results partly corresponded with immunofluorescence findings. In the APGs, genes for VAChT and ChAT, TH and DBH, VIP, and NOS were distinctly down-regulated, while the expression of GAL was up-regulated. Such data may be the basis for further studies concerning the plasticity of these ganglia under experimental or pathological conditions.


Assuntos
Gânglios Simpáticos/fisiologia , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Pelve/fisiologia , Bexiga Urinária/fisiologia , Animais , Axotomia , Catecolaminas/metabolismo , Colina O-Acetiltransferase/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Masculino , Vias Neurais/metabolismo , Neuropeptídeos/metabolismo , Pelve/inervação , Suínos , Tirosina 3-Mono-Oxigenase/metabolismo , Bexiga Urinária/inervação
19.
Neurosci Lett ; 751: 135827, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33727128

RESUMO

The role of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented individually. The present study aimed to investigate the role of dopamine receptors of the VTA in the modulation of the LH stimulation-induced antinociception during both phases of the formalin test as an animal model of tonic pain. In this study, male Wistar rats were unilaterally implanted with two guide cannulae in the VTA and LH. In two separate groups, animals received different doses (0.25, 1, and 4 µg/rat) of D1- or D2-like dopamine receptor antagonists (SCH-23,390 or Sulpiride, respectively) into the VTA before intra-LH injection of carbachol (22.83 ng/rat) following formalin injection (50 µL; s.c.) into their contralateral hind paws. The blockade of these two receptors reduced intra-LH carbachol-induced antinociception during both phases of the formalin test. This reduction during the late phase of the formalin test was more than that of the early phase. The results indicated that LH stimulation-induced antinociception was mediated by D1- and D2-like dopamine receptors in the VTA, and so, the neural pathway projecting from the LH to the VTA contributes to the modulation of formalin-induced nociception in the rats.


Assuntos
Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Nociceptividade , Sulpirida/farmacologia , Área Tegmentar Ventral/metabolismo , Analgésicos não Narcóticos/farmacologia , Animais , Carbacol/farmacologia , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Ratos , Ratos Wistar , Receptores Dopaminérgicos/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia
20.
Elife ; 102021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33787489

RESUMO

Adolescence is a critical time for the continued maturation of brain networks. Here, we assessed structural connectome development in a large longitudinal sample ranging from childhood to young adulthood. By projecting high-dimensional connectomes into compact manifold spaces, we identified a marked expansion of structural connectomes, with strongest effects in transmodal regions during adolescence. Findings reflected increased within-module connectivity together with increased segregation, indicating increasing differentiation of higher-order association networks from the rest of the brain. Projection of subcortico-cortical connectivity patterns into these manifolds showed parallel alterations in pathways centered on the caudate and thalamus. Connectome findings were contextualized via spatial transcriptome association analysis, highlighting genes enriched in cortex, thalamus, and striatum. Statistical learning of cortical and subcortical manifold features at baseline and their maturational change predicted measures of intelligence at follow-up. Our findings demonstrate that connectome manifold learning can bridge the conceptual and empirical gaps between macroscale network reconfigurations, microscale processes, and cognitive outcomes in adolescent development.


Assuntos
Comportamento do Adolescente , Desenvolvimento do Adolescente , Encéfalo/crescimento & desenvolvimento , Conectoma , Vias Neurais/crescimento & desenvolvimento , Neurogênese , Adolescente , Adulto , Fatores Etários , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cognição , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Transcriptoma , Adulto Jovem
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