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1.
Nature ; 625(7996): 743-749, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38233522

RESUMO

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.


Assuntos
Aprendizagem da Esquiva , Núcleo Central da Amígdala , Vias Neurais , Neurônios , Aprendizagem da Esquiva/fisiologia , Núcleo Central da Amígdala/citologia , Núcleo Central da Amígdala/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Vias Neurais/fisiologia , Cálcio/análise , Eletrofisiologia , Ponte/citologia , Ponte/fisiologia
2.
Int J Legal Med ; 134(6): 2167-2176, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32719959

RESUMO

The aim of the present study was a refined analysis of neuroinflammation including TMEM119 as a useful microglia-specific marker in forensic assessments of traumatic causes of death, e.g., traumatic brain injury (TBI). Human brain tissue samples were obtained from autopsies and divided into cases with lethal TBI (n = 25) and subdivided into three groups according to their trauma survival time and compared with an age-, gender-, and postmortem interval-matched cohort of sudden cardiovascular fatalities as controls (n = 23). Brain tissue samples next to cortex contusions and surrounding white matter as well as samples of the ipsilateral uninjured brain stem and cerebellum were collected and stained immunohistochemically with antibodies against TMEM119, CD206, and CCR2. We could document the highest number of TMEM119-positive cells in acute TBI death with highly significant differences to the control numbers. CCR2-positive monocytes showed a significantly higher cell count in the cortex samples of TBI cases than in the controls with an increasing number of immunopositive cells over time. The number of CD206-positive M2 microglial cells increased survival time-dependent. After 3 days of survival, the cell number increased significantly in all four regions investigated compared with controls. In sum, we validate a specific and robustly expressed as well as fast reacting microglia marker, TMEM119, which distinguishes microglia from resident and infiltrating macrophages and thus offers a great potential for the estimation of the minimum survival time after TBI.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Glicoproteínas de Membrana , Proteínas de Membrana , Microglia/metabolismo , Receptores CCR2 , Receptores Imunológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Biomarcadores , Cerebelo/citologia , Criança , Pré-Escolar , Feminino , Patologia Legal , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Ponte/citologia , Substância Branca/citologia , Adulto Jovem
3.
J Neurosci ; 40(31): 5970-5989, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32576622

RESUMO

The cholinergic neurons in the pontomesencephalic tegmentum have been shown to discharge in association with and promote cortical activation during active or attentive waking and paradoxical or rapid eye movement sleep. However, GABA neurons lie intermingled with the cholinergic neurons and may contribute to or oppose this activity and role. Here we investigated in vitro and in vivo the properties, activities, and role of GABA neurons within the laterodorsal tegmental and sublaterodorsal tegmental nuclei (LDT/SubLDT) using male and female transgenic mice expressing channelrhodopsin-(ChR2)-EYFP in vesicular GABA transporter (VGAT)-expressing neurons. Presumed GABA (pGABA) neurons were identified by response to photostimulation and verified by immunohistochemical staining following juxtacellular labeling in vivo pGABA neurons were found to be fast-firing neurons with the capacity to burst when depolarized from a hyperpolarized membrane potential. When stimulated in vivo in urethane-anesthetized or unanesthetized mice, the pGABA neurons fired repetitively at relatively fast rates (∼40 Hz) during a continuous light pulse or phasically in bursts (>100 Hz) when driven by rhythmic light pulses at theta (4 or 8 Hz) frequencies. pNon-GABA, which likely included cholinergic, neurons were inhibited during each light pulse to discharge rhythmically in antiphase to the pGABA neurons. The reciprocal rhythmic bursting by the pGABA and pNon-GABA neurons drove rhythmic theta activity in the EEG. Such phasic bursting by GABA neurons also occurred in WT mice in association with theta activity during attentive waking and paradoxical sleep.SIGNIFICANCE STATEMENT Neurons in the pontomesencephalic tegmentum, particularly cholinergic neurons, play an important role in cortical activation, which occurs during active or attentive waking and paradoxical or rapid eye movement sleep. Yet the cholinergic neurons lie intermingled with GABA neurons, which could play a similar or opposing role. Optogenetic stimulation and recording of these GABA neurons in mice revealed that they can discharge in rhythmic bursts at theta frequencies and drive theta activity in limbic cortex. Such phasic burst firing also occurs during natural attentive waking and paradoxical sleep in association with theta activity and could serve to enhance sensory-motor processing and memory consolidation during these states.


Assuntos
Córtex Cerebral/fisiologia , Mesencéfalo/fisiologia , Ponte/fisiologia , Sono/fisiologia , Vigília/fisiologia , Ácido gama-Aminobutírico/fisiologia , Anestesia , Animais , Eletroencefalografia , Fenômenos Eletrofisiológicos , Feminino , Masculino , Mesencéfalo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética , Estimulação Luminosa , Ponte/citologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/fisiologia
4.
Elife ; 92020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32347794

RESUMO

Micturition requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. This involves a spino-bulbospinal control circuit incorporating Barrington's nucleus in the pons (Barr). Ponto-spinal glutamatergic neurons that express corticotrophin-releasing hormone (CRH) form one of the largest Barr cell populations. BarrCRH neurons can generate bladder contractions, but it is unknown whether they act as a simple switch or provide a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with multisite extracellular recordings in urethane anaesthetised CRHCre mice show that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. CRH itself provides negative feedback regulation of this process. These findings inform a new inferential model of autonomous micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.


Assuntos
Núcleo de Barrington/fisiopatologia , Neurônios/fisiologia , Ponte/fisiologia , Bexiga Urinária/fisiopatologia , Micção/fisiologia , Animais , Hormônio Liberador da Corticotropina/metabolismo , Camundongos , Vias Neurais/fisiologia , Ponte/citologia , Medula Espinal/fisiologia
5.
PLoS Biol ; 17(10): e3000480, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31613896

RESUMO

Many species execute ballistic escape reactions to avoid imminent danger. Despite fast reaction times, responses are often highly regulated, reflecting a trade-off between costly motor actions and perceived threat level. However, how sensory cues are integrated within premotor escape circuits remains poorly understood. Here, we show that in zebrafish, less precipitous threats elicit a delayed escape, characterized by flexible trajectories, which are driven by a cluster of 38 prepontine neurons that are completely separate from the fast escape pathway. Whereas neurons that initiate rapid escapes receive direct auditory input and drive motor neurons, input and output pathways for delayed escapes are indirect, facilitating integration of cross-modal sensory information. These results show that rapid decision-making in the escape system is enabled by parallel pathways for ballistic responses and flexible delayed actions and defines a neuronal substrate for hierarchical choice in the vertebrate nervous system.


Assuntos
Reação de Fuga/fisiologia , Córtex Motor/fisiologia , Neurônios Motores/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Ponte/fisiologia , Peixe-Zebra/fisiologia , Animais , Tomada de Decisões/fisiologia , Larva/fisiologia , Córtex Motor/citologia , Neurônios Motores/citologia , Ponte/citologia , Tempo de Reação/fisiologia
6.
Nat Commun ; 10(1): 3790, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439867

RESUMO

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Nicotinamida Fosforribosiltransferase/genética , Proteína Fosfatase 2C/genética , Animais , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Criança , Citocinas/antagonistas & inibidores , Metilação de DNA , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/patologia , Repressão Epigenética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Ponte/citologia , Ponte/patologia , Cultura Primária de Células , Proteína Fosfatase 2C/metabolismo , Mutações Sintéticas Letais , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Comp Neurol ; 527(12): 1966-1985, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737986

RESUMO

The basilar pontine nucleus (PN) is the key relay point for the cerebrocerebellar link. However, the projection pattern of pontocerebellar mossy fiber axons, which is essential in determining the functional organization of the cerebellar cortex, has not been fully clarified. We reconstructed the entire trajectory of 25 single pontocerebellar mossy fiber axons labeled by localized injection of biotinylated dextran amine into various locations in the PN and mapped all their terminals in an unfolded scheme of the cerebellum in 10 mice. The majority of axons (20/25 axons) entered the cerebellum through the middle cerebellar peduncle contralateral to the origin, while others entered through the ipsilateral pathway. A small number of axons (1/25 axons) had collaterals terminating in the cerebellar nuclei. Axons projected mostly to a combination of lobules, often bilaterally, and terminated in multiple zebrin (aldolase C) stripes, more frequently in zebrin-positive stripes (83.9%) than in zebrin-negative stripes, with 66.5 mossy fiber terminals on the average. Axons originating from the rostral (plus medial and lateral), central and caudal PN mainly terminated in the paraflocculus, crus I and lobule VIb-c, in the simplex lobule, crus II and paramedian lobule, and in lobules II-VIa, VIII and copula pyramidis, respectively. The results suggest that the interlobular branching pattern of pontocerebellar axons determines the group of cerebellar lobules that are involved in a related functional localization of the cerebellum. In the hemisphere, crus I may be functionally distinct from neighboring lobules (simple lobule and crus II) in the mouse cerebellum based on the pontocerebellar axonal projection pattern.


Assuntos
Axônios/ultraestrutura , Cerebelo/citologia , Vias Neurais/citologia , Ponte/citologia , Animais , Feminino , Masculino , Camundongos
8.
Anat Sci Int ; 94(2): 180-183, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30370477

RESUMO

The inner structure of the pons contains several layers of transverse and vertical fibers and many nuclei. The vertical bundles are described as fibers of the corticospinal tract, corticonuclear tract, frontopontine tract and parieto-temporopontine tract organized in three layers. The aim of this study was to investigate the structure of the vertical bundles in the ventral pons using the modified Klingler method. Ten brain stem specimens were investigated. Specimens were fixed in 10% formalin, frozen for 24 h to separate nerve fibers by ice crystals, and then unfrozen again in 10% formalin solution. Afterwards, the specimens were dissected using a sharpened spatula. Results point to the existence of three main layers of vertical bundles and a small, constant, and superficial fourth fascicle that is yet to be described in the literature. We propose the name fasciculus longitudinalis superficialis (superficial longitudinal fascicle) for this group of vertical fibers of the pons.


Assuntos
Anatomia/métodos , Fibras Nervosas , Ponte/anatomia & histologia , Ponte/citologia , Tratos Piramidais/anatomia & histologia , Substância Branca/anatomia & histologia , Substância Branca/citologia , Adulto , Idoso , Dissecação/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Comp Neurol ; 526(17): 2744-2775, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155886

RESUMO

The cerebellum is involved in the control of movement, emotional responses, and reward processing. The tree shrew is the closest living relative of primates. However, little is known not only about the systematic nomenclature for the tree shrew cerebellum but also about the detailed neurochemical characterization and afferent projections. In this study, Nissl staining and acetylcholinesterase histochemistry were used to reveal anatomical features of the cerebellum of tree shrews (Tupaia belangeri chinensis). The cerebellar cortex presented a laminar structure. The morphological characteristics of the cerebellum were comprehensively described in the coronal, sagittal, and horizontal sections. Moreover, distributive maps of calbindin-immunoreactive (-ir) cells in the Purkinje cell layer of the cerebellum of tree shrews were depicted using coronal, sagittal, and horizontal schematics. In addition, 5th cerebellar lobule (5Cb)-projecting neurons were present in the pontine nuclei, reticular nucleus, spinal vestibular nucleus, ventral spinocerebellar tract, and inferior olive of the tree shrew brain. The anterior part of the paramedian lobule of the cerebellum (PMa) received mainly strong innervation from the lateral reticular nucleus, inferior olive, pontine reticular nucleus, spinal trigeminal nucleus, pontine nuclei, and reticulotegmental nucleus of the pons. The present results provide the first systematic nomenclature, detailed atlas of the whole cerebellum, and whole-brain mapping of afferent projections to the 5Cb and PMa in tree shrews. Our findings provide morphological support for tree shrews as an alternative model for studies of human cerebellar pathologies.


Assuntos
Cerebelo/anatomia & histologia , Neuroquímica , Neurônios Aferentes/fisiologia , Tupaiidae/fisiologia , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Animais , Mapeamento Encefálico , Calbindinas/metabolismo , Córtex Cerebelar/anatomia & histologia , Córtex Cerebelar/química , Córtex Cerebelar/citologia , Cerebelo/química , Cerebelo/citologia , Imuno-Histoquímica , Masculino , Ponte/anatomia & histologia , Ponte/química , Ponte/citologia , Células de Purkinje/fisiologia , Terminologia como Assunto
10.
Brain Struct Funct ; 223(9): 4005-4022, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30116890

RESUMO

Sensory neurons of the jugular vagal ganglia innervate the respiratory tract and project to the poorly studied medullary paratrigeminal nucleus. In the present study, we used neuroanatomical tracing, pharmacology and physiology in guinea pig to investigate the paratrigeminal neural circuits mediating jugular ganglia-evoked respiratory reflexes. Retrogradely traced laryngeal jugular ganglia neurons were largely (> 60%) unmyelinated and expressed the neuropeptide substance P and calcitonin gene-related peptide, although a population (~ 30%) of larger diameter myelinated jugular neurons was defined by the expression of vGlut1. Within the brainstem, vagal afferent terminals were confined to the caudal two-thirds of the paratrigeminal nucleus. Electrical stimulation of the laryngeal mucosa evoked a vagally mediated respiratory slowing that was mimicked by laryngeal capsaicin application. These laryngeal reflexes were modestly reduced by neuropeptide receptor antagonist microinjections into the paratrigeminal nucleus, but abolished by ionotropic glutamate receptor antagonists. D,L-Homocysteic acid microinjections into the paratrigeminal nucleus mimicked the laryngeal-evoked respiratory slowing, whereas capsaicin microinjections evoked a persistent tachypnoea that was insensitive to glutamatergic inhibition but abolished by neuropeptide receptor antagonists. Extensive projections from paratrigeminal neurons were anterogradely traced throughout the pontomedullary respiratory column. Dual retrograde tracing from pontine and ventrolateral medullary termination sites, as well as immunohistochemical staining for calbindin and neurokinin 1 receptors, supported the existence of different subpopulations of paratrigeminal neurons. Collectively, these data provide anatomical and functional evidence for at least two types of post-synaptic paratrigeminal neurons involved in respiratory reflexes, highlighting an unrecognised complexity in sensory processing in this region of the brainstem.


Assuntos
Bulbo/fisiologia , Ponte/fisiologia , Respiração , Células Receptoras Sensoriais/fisiologia , Nervo Vago/fisiologia , Animais , Feminino , Cobaias , Masculino , Bulbo/citologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Ponte/citologia , Reflexo
11.
J Neurosci ; 38(33): 7351-7363, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29959235

RESUMO

Inputs from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) play a key role in working memory and emotional control. However, little is known about how excitatory inputs from the vHPC engage different populations of neurons in the PFC. Here we use optogenetics and whole-cell recordings to study the cell-type specificity of synaptic connections in acute slices from the mouse PFC. We first show that vHPC inputs target pyramidal neurons whose cell bodies are located in layer (L)2/3 and L5 of infralimbic (IL) PFC, but only in L5 of prelimbic (PL) PFC, and not L6 of either IL or PL. We then compare connections onto different classes of projection neurons located in these layers and subregions of PFC. We establish vHPC inputs similarly contact corticocortical (CC) and cortico-amygdala neurons in L2/3 of IL, but preferentially target CC neurons over cortico-pontine neurons in L5 of both IL and PL. Of all these neurons, we determine that vHPC inputs are most effective at driving action potential (AP) firing of CC neurons in L5 of IL. We also show this connection exhibits frequency-dependent facilitation, with repetitive activity enhancing AP firing of IL L5 CC neurons, even in the presence of feedforward inhibition. Our findings reveal how vHPC inputs engage defined populations of projection neurons in the PFC, allowing preferentially activation of the intratelencephalic network.SIGNIFICANCE STATEMENT We examined the impact of connections from the ventral hippocampus (vHPC) onto different projection neurons in the mouse prefrontal cortex (PFC). We found vHPC inputs were strongest at corticocortical neurons in layer 5 of infralimbic PFC, where they robustly evoked action potential firing, including during repetitive activity with intact feedforward inhibition.


Assuntos
Vias Aferentes/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Potenciais de Ação , Tonsila do Cerebelo/citologia , Animais , Transporte Axonal , Channelrhodopsins/biossíntese , Channelrhodopsins/genética , Channelrhodopsins/efeitos da radiação , Feminino , Genes Reporter , Hipocampo/citologia , Interneurônios/fisiologia , Masculino , Camundongos , Optogenética , Especificidade de Órgãos , Técnicas de Patch-Clamp , Ponte/citologia , Córtex Pré-Frontal/citologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Transmissão Sináptica
12.
Bull Exp Biol Med ; 165(2): 184-188, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29923008

RESUMO

Inhibitory afferent inputs to pontine A5 noradrenergic neurons (A5 NN) are not known, except partial baroreceptor input. In spontaneously breathing pentobarbital-anesthetized rats, we registered 35 A5 NN that were activated by hypoxia (100% N2, 10 sec) by more than 5 times in comparison with the background. Cooling of retrotrapezoid nucleus (15°C, 6 sec) completely blocked the motor inspiratory output and A5 NN discharge frequency increased (23/23) by more than 7 times in comparison with the background values. The beginning of A5 NN activation coincided with cessation of inspiratory activity. Short-term passive stretching of the shin muscles (1 sec, 100 g) caused BP drop and complete inhibition of A5 NN (12/12) activated by hypoxia. Inhibitory afferent inputs from proprioceptors and central inspiratory neurons that can limit A5 NN activity were demonstrated.


Assuntos
Neurônios Adrenérgicos/fisiologia , Neurônios Aferentes/fisiologia , Ponte/citologia , Propriocepção/fisiologia , Respiração , Sistema Nervoso Simpático/fisiologia , Animais , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Masculino , Pressorreceptores/fisiologia , Ratos , Ratos Wistar , Músculos Respiratórios/inervação , Córtex Somatossensorial/citologia , Córtex Somatossensorial/fisiologia
13.
Cell Rep ; 22(7): 1666-1680, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29444422

RESUMO

During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR), and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.


Assuntos
Netrina-1/metabolismo , Neurônios/metabolismo , Rombencéfalo/citologia , Animais , Membrana Basal/metabolismo , Movimento Celular , Nervos Cranianos/metabolismo , Receptor DCC/metabolismo , Cistos Glanglionares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Mutação/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Sistema Nervoso Periférico/citologia , Ponte/citologia , Rombencéfalo/embriologia , Rombencéfalo/metabolismo , Raízes Nervosas Espinhais/metabolismo
14.
J Physiol ; 596(9): 1659-1679, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29330867

RESUMO

KEY POINTS: Phasic activation of M1 muscarinic receptors generates transient inhibition followed by longer lasting excitation in neocortical pyramidal neurons. Corticopontine neurons in the mouse prefrontal cortex exhibit weaker cholinergic inhibition, but more robust and longer lasting excitation, than neighbouring callosal projection neurons. Optogenetic release of endogenous ACh in response to single flashes of light (5 ms) preferentially enhances the excitability of corticopontine neurons for many tens of seconds. Cholinergic excitation of corticopontine neurons involves at least three ionic mechanisms: suppression of KV 7 currents, activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Preferential cholinergic excitation of prefrontal corticopontine neurons may facilitate top-down attentional processes and behaviours. ABSTRACT: Pyramidal neurons in layer 5 of the neocortex comprise two broad classes of projection neurons: corticofugal neurons, including corticopontine (CPn) neurons, and intratelencephalic neurons, including commissural/callosal (COM) neurons. These non-overlapping neuron subpopulations represent discrete cortical output channels contributing to perception, decision making and behaviour. CPn and COM neurons have distinct morphological and physiological characteristics, and divergent responses to modulatory transmitters such as serotonin and acetylcholine (ACh). To better understand how ACh regulates cortical output, in slices of mouse prefrontal cortex (PFC) we compared the responsivity of CPn and COM neurons to transient exposure to exogenous or endogenous ACh. In both neuron subtypes, exogenous ACh generated qualitatively similar biphasic responses in which brief hyperpolarization was followed by longer lasting enhancement of excitability. However, cholinergic inhibition was more pronounced in COM neurons, while excitatory responses were larger and longer lasting in CPn neurons. Similarly, optically triggered release of endogenous ACh from cholinergic terminals preferentially and persistently (for ∼40 s) enhanced the excitability of CPn neurons, but had little impact on COM neurons. Cholinergic excitation of CPn neurons involved at least three distinct ionic mechanisms: suppression of KV 7 channels (the 'M-current'), activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Our findings demonstrate projection-specific selectivity in cholinergic signalling in the PFC, and suggest that transient release of ACh during behaviour will preferentially promote corticofugal output.


Assuntos
Acetilcolina/farmacologia , Neurônios/fisiologia , Ponte/fisiologia , Córtex Pré-Frontal/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação , Animais , Cálcio/metabolismo , Colinérgicos/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/efeitos dos fármacos , Optogenética , Ponte/citologia , Ponte/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Visual/citologia , Córtex Visual/efeitos dos fármacos
15.
Front Neural Circuits ; 11: 33, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28567005

RESUMO

The pontine nuclei (PN) are the largest of the precerebellar nuclei, neuronal assemblies in the hindbrain providing principal input to the cerebellum. The PN are predominantly innervated by the cerebral cortex and project as mossy fibers to the cerebellar hemispheres. Here, we comprehensively review the development of the PN from specification to migration, nucleogenesis and circuit formation. PN neurons originate at the posterior rhombic lip and migrate tangentially crossing several rhombomere derived territories to reach their final position in ventral part of the pons. The developing PN provide a classical example of tangential neuronal migration and a study system for understanding its molecular underpinnings. We anticipate that understanding the mechanisms of PN migration and assembly will also permit a deeper understanding of the molecular and cellular basis of cortico-cerebellar circuit formation and function.


Assuntos
Movimento Celular/fisiologia , Cerebelo/citologia , Córtex Cerebral/citologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Ponte/citologia , Animais , Cerebelo/embriologia , Córtex Cerebral/embriologia , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Humanos
16.
Endocr Regul ; 51(2): 73-83, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28609288

RESUMO

OBJECTIVE: Fos protein expression in catecholamine-synthesizing neurons of the substantia nigra (SN) pars compacta (SNC, A8), pars reticulata (SNR, A9), and pars lateralis (SNL), the ventral tegmental area (VTA, A10), the locus coeruleus (LC, A6) and subcoeruleus (sLC), the ventrolateral pons (PON-A5), the nucleus of the solitary tract (NTS-A2), the area postrema (AP), and the ventrolateral medulla (VLM-A1) was quantitatively evaluated aft er a single administration of asenapine (ASE) (designated for schizophrenia treatment) in male Wistar rats preconditioned with a chronic unpredictable variable mild stress (CMS) for 21 days. Th e aim of the present study was to reveal whether a single ASE treatment may 1) activate Fos expression in the brain areas selected; 2) activate tyrosine hydroxylase (TH)-synthesizing cells displaying Fos presence; and 3) be modulated by CMS preconditioning. METHODS: Control (CON), ASE, CMS, and CMS+ASE groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. Th e ASE and CMS+ASE groups received a single dose of ASE (0.3 mg/kg, s.c.) and CON and CMS saline (300 µl/rat, s.c.). The animals were sacrificed 90 min aft er the treatments. Fos protein and TH-labeled immunoreactive perikarya were analyzed on double labeled histological sections and enumerated on captured pictures using combined light and fluorescence microscope illumination. RESULTS: Saline or CMS alone did not promote Fos expression in any of the structures investigated. ASE alone or in combination with CMS elicited Fos expression in two parts of the SN (SNC, SNR) and the VTA. Aside from some cells in the central gray tegmental nuclei adjacent to LC, where a small number of Fos profiles occurred, none or negligible Fos occurrence was detected in the other structures investigated including the LC and sLC, PON-A5, NTS-A2, AP, and VLM-A1. CMS preconditioning did not infl uence the level of Fos induction in the SN and VTA elicited by ASE administration. Similarly, the ratio between the amount of free Fos and Fos colocalized with TH was not aff ected by stress preconditioning in the SNC, SNR, and the VTA. CONCLUSIONS: Th e present study provides an anatomical/functional knowledge about the nature of the acute ASE treatment on the catecholamine-synthesizing neurons activity in certain brain structures and their missing interplay with the CMS preconditioning.


Assuntos
Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Condicionamento Psicológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Estresse Psicológico/metabolismo , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Animais , Área Postrema/citologia , Área Postrema/efeitos dos fármacos , Área Postrema/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Catecolaminas/biossíntese , Dibenzocicloeptenos , Imuno-Histoquímica , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Microscopia de Fluorescência , Neurônios/metabolismo , Parte Compacta da Substância Negra/citologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/metabolismo , Parte Reticular da Substância Negra/citologia , Parte Reticular da Substância Negra/efeitos dos fármacos , Parte Reticular da Substância Negra/metabolismo , Ponte/citologia , Ponte/efeitos dos fármacos , Ponte/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Estresse Psicológico/psicologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
17.
Neuroscience ; 354: 146-157, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28461215

RESUMO

The A5 area at the ventrolateral pons contains noradrenergic neurons connected with other medullary areas involved in the cardiorespiratory control. Its contribution to the cardiorespiratory regulation was previously evidenced in anesthetized conditions. In the present study, we investigated the involvement of the A5 noradrenergic neurons to the basal and chemoreflex control of the sympathetic and respiratory activities in unanesthetized conditions. A5 noradrenergic neurons were lesioned using microinjections of anti-dopamine ß-hydroxylase saporin (anti-DßH-SAP). After 7-8days, we evaluated the arterial pressure levels, heart rate and minute ventilation in freely moving adult rats (280-350g) as well as recorded from thoracic sympathetic (tSN) and phrenic nerves (PN) using the arterially perfused in situ preparation of juvenile rats (80-90g). Baseline cardiovascular, sympathetic and respiratory parameters were similar between control (n=7-8) and A5-lesioned rats (n=5-6) in both experimental preparations. In adult rats, lesions of A5 noradrenergic neurons did not modify the reflex cardiorespiratory adjustments to hypoxia (7% O2) and hypercapnia (7% CO2). In the in situ preparations, the sympatho-excitation, but not the PN reflex response, elicited by either the stimulation of peripheral chemoreceptors (ΔtSN: 110±12% vs 58±8%, P<0.01) or hypercapnia (ΔtSN: 9.5±1.4% vs 3.9±1.7%, P<0.05) was attenuated in A5-lesioned rats compared to controls. Our data demonstrated that A5 noradrenergic neurons are part of the circuitry recruited for the processing of sympathetic response to hypoxia and hypercapnia in unanesthetized conditions.


Assuntos
Neurônios Adrenérgicos/fisiologia , Hipercapnia/fisiopatologia , Ponte/citologia , Sistema Nervoso Simpático/fisiologia , Vigília , Análise de Variância , Animais , Anticorpos Monoclonais/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipercapnia/induzido quimicamente , Masculino , Ponte/efeitos dos fármacos , Ponte/lesões , Ventilação Pulmonar/fisiologia , Ratos , Ratos Wistar , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saponinas/toxicidade , Saporinas , Sistema Nervoso Simpático/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Neurosci Lett ; 649: 14-19, 2017 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-28396281

RESUMO

OBJECTIVE: We investigated the neural pathway for tear secretion from the lacrimal gland of New Zealand White rabbits. METHODS: Nine healthy adult New Zealand White rabbits were randomly divided into three experimental groups, namely, an irritant-stimulated group, a non-stimulated group, and a saline-stimulated group. Sanitized dry cotton swabs with menthol were used to wipe both of the rabbits' eyelids in the irritant-stimulated group, and the non-stimulated group and saline- stimulated group were compared as controls. The animals in the three groups were killed 2h later and the expressions of c-Fos in the frontal cortex, hippocampus, hypothalamus, pons, and medulla oblongata of the rabbits were detected using immunofluorescence labeling. According to the distribution of c-Fos protein expression, 12 healthy adult New Zealand rabbits were similarly divided into three groups for retrograde tract tracing via pseudorabies virus (PRV) injection into the lacrimal gland. Immunofluorescence labeling was used to analyze PRV-infected neurons in the brains of rabbits after survival for 30h, 38h, and 46h. RESULTS: The most c-Fos-positive immunolabeled cells were observed in the menthol-stimulated group, whereas fewer c-Fos-positive immunolabeled cells were observed in the saline-stimulated group.The non-treated group showed the least c-Fos-positive immunolabeled cells. At 30h after PRV injection, PRV-positive neurons were found only in the superior salivary nucleus of the pons (SSN). At 38h, PRV-infected neurons were observed in the lateral nucleus of the superior olive (LSO) and the medial nucleus of the superior olive (MSO). At 46h, PRV-infected neurons were found in the nucleus of the trapezoid body (Tz) and the hypothalamic paraventricular nucleus (PVN), and their distributions were dense in the LSO and MSO. CONCLUSIONS: Menthol-induced c-Fos protein expression and PRV-mediated tract tracing suggest that in New Zealand White rabbits, the neural pathway that regulates tear secretion from the lacrimal gland proceeds from the PVN to the superior olivary complex of the pons to the SSN and finally to the lacrimal gland.


Assuntos
Encéfalo/citologia , Encéfalo/metabolismo , Aparelho Lacrimal/inervação , Aparelho Lacrimal/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Lobo Frontal/citologia , Lobo Frontal/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Bulbo/citologia , Bulbo/metabolismo , Mentol/administração & dosagem , Vias Neurais/citologia , Vias Neurais/metabolismo , Ponte/citologia , Ponte/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Coelhos
19.
Cell ; 167(1): 73-86.e12, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27662084

RESUMO

Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Contração Muscular/fisiologia , Neurônios/fisiologia , Ponte/fisiologia , Bexiga Urinária/fisiologia , Micção/fisiologia , Animais , Feminino , Ácido Glutâmico/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Ponte/citologia , Olfato , Medula Espinal/citologia , Medula Espinal/fisiologia , Bexiga Urinária/inervação
20.
Nat Commun ; 7: 11628, 2016 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-27188978

RESUMO

The pons controls crucial sensorimotor and autonomic functions. In humans, it grows sixfold postnatally and is a site of paediatric gliomas; however, the mechanisms of pontine growth remain poorly understood. We show that the murine pons quadruples in volume postnatally; growth is fastest during postnatal days 0-4 (P0-P4), preceding most myelination. We identify three postnatal proliferative compartments: ventricular, midline and parenchymal. We find no evidence of postnatal neurogenesis in the pons, but each progenitor compartment produces new astroglia and oligodendroglia; the latter expand 10- to 18-fold postnatally, and are derived mostly from the parenchyma. Nearly all parenchymal progenitors at P4 are Sox2(+)Olig2(+), but by P8 a Sox2(-) subpopulation emerges, suggesting a lineage progression from Sox2(+) 'early' to Sox2(-) 'late' oligodendrocyte progenitor. Fate mapping reveals that >90% of adult oligodendrocytes derive from P2-P3 Sox2(+) progenitors. These results demonstrate the importance of postnatal Sox2(+)Olig2(+) progenitors in pontine growth and oligodendrogenesis.


Assuntos
Células Precursoras de Oligodendrócitos/fisiologia , Ponte/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Proliferação de Células , Quarto Ventrículo/citologia , Camundongos , Neurogênese , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/fisiologia , Ponte/citologia , Fatores de Transcrição SOXB1/metabolismo
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