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2.
CNS Neurosci Ther ; 30(6): e14808, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38887205

RESUMO

OBJECTIVE: Phenylethanolamine N-methyltransferase (PNMT)-expressing neurons in the nucleus tractus solitarii (NTS) contribute to the regulation of autonomic functions. However, the neural circuits linking these neurons to other brain regions remain unclear. This study aims to investigate the connectivity mechanisms of the PNMT-expressing neurons in the NTS (NTSPNMT neurons). METHODS: The methodologies employed in this study included a modified rabies virus-based retrograde neural tracing technique, conventional viral anterograde tracing, and immunohistochemical staining procedures. RESULTS: A total of 43 upstream nuclei projecting to NTSPNMT neurons were identified, spanning several key brain regions including the medulla oblongata, pons, midbrain, cerebellum, diencephalon, and telencephalon. Notably, dense projections to the NTSPNMT neurons were observed from the central amygdaloid nucleus, paraventricular nucleus of the hypothalamus, area postrema, and the gigantocellular reticular nucleus. In contrast, the ventrolateral medulla, lateral parabrachial nucleus, and lateral hypothalamic area were identified as the primary destinations for axon terminals originating from NTSPNMT neurons. Additionally, reciprocal projections were evident among 21 nuclei, primarily situated within the medulla oblongata. CONCLUSION: Our research findings demonstrate that NTSPNMT neurons form extensive connections with numerous nuclei, emphasizing their essential role in the homeostatic regulation of vital autonomic functions.


Assuntos
Neurônios , Feniletanolamina N-Metiltransferase , Núcleo Solitário , Animais , Feniletanolamina N-Metiltransferase/metabolismo , Feniletanolamina N-Metiltransferase/genética , Núcleo Solitário/enzimologia , Núcleo Solitário/metabolismo , Núcleo Solitário/citologia , Neurônios/metabolismo , Neurônios/enzimologia , Masculino , Vias Eferentes/enzimologia , Vias Aferentes/enzimologia , Ratos Sprague-Dawley , Mapeamento Encefálico/métodos , Ratos
3.
Acta Neuropathol Commun ; 11(1): 102, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37344916

RESUMO

Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer's disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-ß deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Animais , Camundongos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Colesterol/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Camundongos Transgênicos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
4.
J Neurochem ; 166(2): 233-247, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37353897

RESUMO

The cholinergic neurons in the nucleus basalis of Meynert (NBM) are a key structure in cognition, the dysfunction of which is associated with various neurological disorders, especially dementias. However, the whole-brain neural connectivity to cholinergic neurons in the NBM remains to be further and comprehensively researched. Using virus-based, specific, retrograde, and anterograde tracing, we illustrated the monosynaptic inputs and axon projections of NBM cholinergic neurons in choline acetyltransferase (ChAT)-Cre transgenic mice. Our results showed that NBM cholinergic neurons received mainly inputs from the caudate putamen and the posterior limb of the anterior commissure in the subcortex. Moreover, the majority of cholinergic terminals from the NBM were observed in the cortex mantle, including the motor cortex, sensory cortex, and visual cortex. Interestingly, although NBM cholinergic neurons received input projections from the caudate putamen, interstitial nucleus of the posterior limb of the anterior commissure, and central amygdaloid nucleus, NBM cholinergic neurons sparsely sent axon projection to innervate these areas. Furthermore, primary motor cortex, secondary motor cortex, and primary somatosensory cortex received abundant inputs from the NBM but sent few outputs to the NBM. Taken together, our results reveal the detailed and specific connectivity of cholinergic neurons of the NBM and provide a neuroanatomic foundation for further studies to explore the important physiological functions of NBM cholinergic neurons.


Assuntos
Núcleo Basal de Meynert , Substância Branca , Camundongos , Animais , Neurônios Colinérgicos , Córtex Cerebral , Axônios , Camundongos Transgênicos
5.
Physiol Rep ; 11(4): e15604, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36823776

RESUMO

It is well known that the main forms of innervation are synapses and free nerve endings, while other forms of innervation have not been reported. Here, we explore a new way of innervating lymphoid organs. Male Sprague-Dawley rats were used for studying the innervation of sympathetic nerve fibers in lymph nodes by means of anterograde tracking, immunoelectron microscopy, three-dimension reconstruction analysis, and immunofluorescence labeling. The results showed that the Fluoro-Ruby labeled nerve endings targeted only a group of cells in the lymph nodes and entered the cells through the plasma membrane. The electron microscopy showed that the biotinylated glucan amine reaction elements were distributed in the cytoplasm, and most of the biotinylated glucan amine active elements were concentrated on the microtubule and microfilament walls. Birbeck particles with rod-shaped and/or tennis racket like structures can be seen in the labeled cells at high magnification, and Birbeck particles contain biotinylated glucan amine-reactive elements. The immunofluoresence results showed that the Fluoro-Ruby-labeled nerve innervating cells expressed CD207 and CD1a protein. This result confirmed that the labeled cells were Langerhans cells. Our findings suggested that Langerhans cells might serve as a "bridge cell" for neuroimmune cross-talking in lymph organs, which play an important role in transmitting signals of the nervous system to immune system. This study also opened up a new way for further study of immune regulation mechanism.


Assuntos
Linfonodos , Sistema Linfático , Animais , Masculino , Ratos , Glucanos/metabolismo , Linfonodos/inervação , Sistema Linfático/inervação , Fibras Nervosas/metabolismo , Ratos Sprague-Dawley
6.
Cell Discov ; 8(1): 115, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36280664

RESUMO

Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep-wake cycles. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy.

7.
ACS Omega ; 7(14): 11839-11852, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35449961

RESUMO

Ubiquitination is a major posttranslational modification of proteins that affects their stability, and E3 ligases play a key role in ubiquitination by specifically recognizing their substrates. BTBD9, an adaptor of the Cullin-RING ligase complex, is responsible for substrate recognition and is associated with sleep homeostasis. However, the substrates of BTBD9-mediated ubiquitination remain unknown. Here, we generated an SH-SY5Y cell line stably expressing BTBD9 and performed proteomic analysis combined with ubiquitinome analysis to identify the downstream targets of BTBD9. Through this approach, we identified four potential BTBD9-mediated ubiquitination substrates that are targeted for degradation. Among these candidate substrates, inosine monophosphate dehydrogenase (IMPDH2), a novel target of BTBD9-mediated degradation, is a potential risk gene for sleep dysregulation. In conclusion, these findings not only demonstrate that proteomic analysis can be a useful general approach for the systematic identification of E3 ligase substrates but also identify novel substrates of BTBD9, providing a resource for future studies of sleep regulation mechanisms.

8.
Acta Neuropathol Commun ; 10(1): 35, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35296367

RESUMO

Previous studies show that 3ß-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in ß-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.


Assuntos
Colesterol , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Apoptose , Membrana Celular/metabolismo , Colesterol/metabolismo , Cognição , Humanos , Microdomínios da Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
9.
Curr Biol ; 32(3): 600-613.e4, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35021048

RESUMO

Patients with Parkinson's disease (PD) suffer from severe sleep disorders. Pathophysiology of the basal ganglia (BG) underlies PD, and the dorsal striatum represents the major input pathway of the BG. However, the roles and mechanisms of the dorsal striatum in controlling sleep-wake cycles remain unknown. To demonstrate the contribution of dopamine D1 receptor (D1R)-positive neurons within the dorsal striatum in promoting wakefulness, we combined optogenetic manipulations and fiber photometry with electroencephalography/electromyography recording in D1R-Cre mice. As a result, optogenetic activation of striatal D1R neurons induced immediate transitions from non-rapid eye movement (NREM) sleep to wakefulness, whereas inhibition of striatal D1R neurons attenuated wakefulness by chemogenetics. Multi-channel fiber photometry recordings revealed that the activity of striatal D1R neurons synchronized with that of BG upstreams, namely the prefrontal cortex and mediodorsal thalamus, in terms of immediate increase in activity during NREM-to-wake transitions and rapid decease during wake-to-NREM transitions. Further optogenetic manipulations revealed a prominent contribution of striatal D1R neurons in control of wakefulness by upstream, corticostriatal, thalamostriatal, and nigrostriatal projections and via downstream, striato-entopeduncular, or striatonigral pathways. Taken together, our findings revealed a circuit regulating wakefulness through striatal D1R neurons. Striatal D1R neurons play an important role in controlling wakefulness by integrating the corticostriatal, thalamostriatal, and nigrostriatal projections and innervation of striato-entopeduncular or striatonigral pathways.


Assuntos
Doença de Parkinson , Vigília , Animais , Corpo Estriado/fisiologia , Dopamina/metabolismo , Humanos , Camundongos , Neurônios/fisiologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Vigília/fisiologia
10.
Front Cell Dev Biol ; 9: 711792, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485298

RESUMO

Patients with monoallelic bromodomain and PHD finger-containing protein 1 (BRPF1) mutations showed intellectual disability. The hippocampus has essential roles in learning and memory. Our previous work indicated that Brpf1 was specifically and strongly expressed in the hippocampus from the perinatal period to adulthood. We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, and mRNA-Seq on shBrpf1-infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics, and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knock down Brpf1 in vivo and examined the learning and memory ability by Morris water maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that Brpf1 mild knockdown in the hippocampus showed a decreasing trend on the spatial learning and memory ability of mice. Finally, mRNA-Seq analyses showed that genes related to learning, memory, and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, and Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory synaptic transmission and reduced spatial learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.

11.
Exp Neurol ; 343: 113784, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139240

RESUMO

Arginine vasopressin (AVP) neurons in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) are involved in important physiological behaviors, such as controling osmotic stability and thermoregulation. However, the presynaptic input patterns governing AVP neurons have remained poorly understood due to their heterogeneity, as well as intermingling of AVP neurons with other neurons both in the SON and PVN. In the present study, we employed a retrograde modified rabies-virus system to reveal the brain areas that provide specific inputs to AVP neurons in the SON and PVN. We found that AVP neurons of the SON and PVN received similar input patterns from multiple areas of the brain, particularly massive afferent inputs from the diencephalon and other brain regions of the limbic system; however, PVNAVP neurons received relatively broader and denser inputs compared to SONAVP neurons. Additionally, SONAVP neurons received more projections from the median preoptic nucleus and organum vasculosum of the lamina terminalis (a circumventricular organ), compared to PVNAVP neurons, while PVNAVP neurons received more afferent inputs from the bed nucleus of stria terminalis and dorsomedial nucleus of the hypothalamus, both of which are thermoregulatory nuclei, compared to those of SONAVP neurons. In addition, both SONAVP and PVNAVP neurons received direct afferent projections from the bilateral suprachiasmatic nucleus, which is the master regulator of circadian rhythms and is concomitantly responsible for fluctuations in AVP levels. Taken together, our present results provide a comprehensive understanding of the specific afferent framework of AVP neurons both in the SON and PVN, and lay the foundation for further dissecting the diverse roles of SONAVP and PVNAVP neurons.


Assuntos
Arginina Vasopressina/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Terminações Pré-Sinápticas/metabolismo , Núcleo Supraóptico/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Neurônios/química , Núcleo Hipotalâmico Paraventricular/química , Terminações Pré-Sinápticas/química , Núcleo Supraóptico/química
12.
Neuropharmacology ; 181: 108249, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32931816

RESUMO

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABAA receptors (GABAA-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABAA-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABAA-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABAA-Rs and background potassium channels, which contributes to sevoflurane-induced hypnosis.


Assuntos
Anestésicos Inalatórios/farmacologia , Neurônios/efeitos dos fármacos , Núcleos Parabraquiais/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Sevoflurano/farmacologia , Animais , Fenômenos Eletrofisiológicos , Antagonistas GABAérgicos/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas/efeitos dos fármacos , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Sevoflurano/antagonistas & inibidores
13.
Neurosci Bull ; 36(6): 585-597, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32096114

RESUMO

Hypoglossal motor neurons (HMNs) innervate tongue muscles and play key roles in a variety of physiological functions, including swallowing, mastication, suckling, vocalization, and respiration. Dysfunction of HMNs is associated with several diseases, such as obstructive sleep apnea (OSA) and sudden infant death syndrome. OSA is a serious breathing disorder associated with the activity of HMNs during different sleep-wake states. Identifying the neural mechanisms by which the state-dependent activities of HMNs are controlled may be helpful in providing a theoretical basis for effective therapy for OSA. However, the presynaptic partners governing the activity of HMNs remain to be elucidated. In the present study, we used a cell-type-specific retrograde tracing system based on a modified rabies virus along with a Cre/loxP gene-expression strategy to map the whole-brain monosynaptic inputs to HMNs in mice. We identified 53 nuclei targeting HMNs from six brain regions: the amygdala, hypothalamus, midbrain, pons, medulla, and cerebellum. We discovered that GABAergic neurons in the central amygdaloid nucleus, as well as calretinin neurons in the parasubthalamic nucleus, sent monosynaptic projections to HMNs. In addition, HMNs received direct inputs from several regions associated with respiration, such as the pre-Botzinger complex, parabrachial nucleus, nucleus of the solitary tract, and hypothalamus. Some regions engaged in sleep-wake regulation (the parafacial zone, parabrachial nucleus, ventral medulla, sublaterodorsal tegmental nucleus, dorsal raphe nucleus, periaqueductal gray, and hypothalamus) also provided primary inputs to HMNs. These results contribute to further elucidating the neural circuits underlying disorders caused by the dysfunction of HMNs.


Assuntos
Encéfalo , Neurônios GABAérgicos/fisiologia , Neurônios Motores , Língua/inervação , Animais , Encéfalo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/fisiologia
14.
Front Neurosci ; 13: 375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068780

RESUMO

The GABAergic neurons in the lateral pontine tegmentum (LPT) play key roles in the regulation of sleep and locomotion. The dysfunction of the LPT is related to neurological disorders such as rapid eye movement sleep behavior disorder and ocular flutter. However, the whole-brain neural connectivity to LPT GABAergic neurons remains poorly understood. Using virus-based, cell-type-specific, retrograde and anterograde tracing systems, we mapped the monosynaptic inputs and axonal projections of LPT GABAergic neurons in mice. We found that LPT GABAergic neurons received inputs mainly from the superior colliculus, substantia nigra pars reticulata, dorsal raphe nucleus (DR), lateral hypothalamic area (LHA), parasubthalamic nucleus, and periaqueductal gray (PAG), as well as the limbic system (e.g., central nucleus of the amygdala). Further immunofluorescence assays revealed that the inputs to LPT GABAergic neurons were colocalized with several markers associated with important neural functions, especially the sleep-wake cycle. Moreover, numerous LPT GABAergic neuronal varicosities were observed in the medial and midline part of the thalamus, the LHA, PAG, DR, and parabrachial nuclei. Interestingly, LPT GABAergic neurons formed reciprocal connections with areas related to sleep-wake and motor control, including the LHA, PAG, DR, parabrachial nuclei, and superior colliculus, only the LPT-DR connections were in an equally bidirectional manner. These results provide a structural framework to understand the underlying neural mechanisms of rapid eye movement sleep behavior disorder and disorders of saccades.

15.
Front Neurosci ; 12: 807, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455627

RESUMO

The suprachiasmatic nucleus (SCN) is the principal pacemaker driving the circadian rhythms of physiological behaviors. The SCN consists of distinct neurons expressing neuropeptides, including arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and so on. AVP, VIP, and GRP neurons receive light stimulation from the retina to synchronize endogenous circadian clocks with the solar day, whereas CCK neurons are not directly innervated by retinal ganglion cells and may be involved in the non-photic regulation of the circadian clock. To better understand the function of CCK neurons in non-photic circadian rhythm, it is vital to clarify the direct afferent inputs to CCK neurons in the SCN. Here, we utilized a recently developed rabies virus- and Cre/loxP-based, cell type-specific, retrograde tracing system to map and quantitatively analyze the whole-brain monosynaptic inputs to SCN CCK neurons. We found that SCN CCK neurons received direct inputs from 29 brain nuclei. Among these nuclei, paraventricular nucleus of the hypothalamus (PVH), paraventricular nucleus of the thalamus (PVT), supraoptic nucleus (SON), ventromedial nucleus of the hypothalamus, and seven other nuclei sent numerous inputs to CCK neurons. Moderate inputs originated from the zona incerta, periventricular hypothalamic nucleus, and five other nuclei. A few inputs to CCK neurons originated from the orbital frontal cortex, prelimbic cortex, cingulate cortex, claustrum, and seven other nuclei. In addition, SCN CCK neurons were preferentially innervated by AVP neurons of the ipsilateral PVH and SON rather than their contralateral counterpart, whereas the contralateral PVT sent more projections to CCK neurons than to its ipsilateral counterpart. Taken together, these results expand our knowledge of the specific innervation to mouse SCN CCK neurons and provide an important indication for further investigations on the function of CCK neurons.

16.
Nat Commun ; 9(1): 1576, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29679009

RESUMO

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D1 receptor (D1R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D1R neurons. Optogenetic activation of NAc D1R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D1R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D1R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D1R neuron circuits are essential for the induction and maintenance of wakefulness.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Região Hipotalâmica Lateral/fisiologia , Mesencéfalo/fisiologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Vigília/fisiologia , Animais , Ritmo Circadiano/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Fotometria/métodos , Receptores de Dopamina D1/biossíntese , Sono/fisiologia
17.
PLoS Biol ; 16(4): e2002909, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652889

RESUMO

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.


Assuntos
Movimentos Oculares/fisiologia , Vias Neurais/fisiologia , Receptores Muscarínicos/genética , Sono/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Núcleo Dorsal da Rafe/anatomia & histologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/fisiologia , Eletrodos Implantados , Eletroencefalografia , Genes Reporter , Ácido Ibotênico/toxicidade , Locus Cerúleo/anatomia & histologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Mesencéfalo/anatomia & histologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/fisiologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Optogenética , Parte Compacta da Substância Negra/anatomia & histologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/metabolismo , Privação do Sono/fisiopatologia , Técnicas Estereotáxicas , Área Tegmentar Ventral/anatomia & histologia , Área Tegmentar Ventral/efeitos dos fármacos , Vigília/fisiologia , Ácido gama-Aminobutírico/metabolismo , Proteína Vermelha Fluorescente
18.
Sci Rep ; 7(1): 12678, 2017 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-28978989

RESUMO

Ethanol has extensive effects on sleep and daytime alertness, causing premature disability and death. Adenosine, as a potent sleep-promoting substance, is involved in many cellular and behavioral responses to ethanol. However, the mechanisms of hypnotic effects of ethanol remain unclear. In this study, we investigated the role of adenosine in ethanol-induced sleep using C57BL/6Slac mice, adenosine A2A receptor (A2AR) knockout mice, and their wild-type littermates. The results showed that intraperitoneal injection of ethanol (3.0 g/kg) at 21:00 decreased the latency to non-rapid eye movement (NREM) sleep and increased the duration of NREM sleep for 5 h. Ethanol dose-dependently increased NREM sleep, which was consistent with decreases in wakefulness in C57BL/6Slac mice compared with their own control. Caffeine (5, 10, or 15 mg/kg), a nonspecific adenosine receptor antagonist, dose-dependently and at high doses completely blocked ethanol-induced NREM sleep when administered 30 min prior to (but not after) ethanol injection. Moreover, ethanol-induced NREM sleep was completely abolished in A2AR knockout mice compared with wild-type mice. These findings strongly indicate that A2AR is a key receptor for the hypnotic effects of ethanol, and pretreatment of caffeine might be a strategy to counter the hypnotic effects of ethanol.


Assuntos
Etanol/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptor A2A de Adenosina/metabolismo , Animais , Cafeína/farmacologia , Eletroencefalografia , Etanol/administração & dosagem , Camundongos Endogâmicos C57BL , Latência do Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacos
19.
Elife ; 62017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-29022877

RESUMO

Dysfunction of the striatum is frequently associated with sleep disturbances. However, its role in sleep-wake regulation has been paid little attention even though the striatum densely expresses adenosine A2A receptors (A2ARs), which are essential for adenosine-induced sleep. Here we showed that chemogenetic activation of A2AR neurons in specific subregions of the striatum induced a remarkable increase in non-rapid eye movement (NREM) sleep. Anatomical mapping and immunoelectron microscopy revealed that striatal A2AR neurons innervated the external globus pallidus (GPe) in a topographically organized manner and preferentially formed inhibitory synapses with GPe parvalbumin (PV) neurons. Moreover, lesions of GPe PV neurons abolished the sleep-promoting effect of striatal A2AR neurons. In addition, chemogenetic inhibition of striatal A2AR neurons led to a significant decrease of NREM sleep at active period, but not inactive period of mice. These findings reveal a prominent contribution of striatal A2AR neuron/GPe PV neuron circuit in sleep control.


Assuntos
Globo Pálido/fisiologia , Neostriado/fisiologia , Neurônios/fisiologia , Parvalbuminas/análise , Receptor A2A de Adenosina/análise , Sono , Vigília , Adenosina/metabolismo , Animais , Mapeamento Encefálico , Masculino , Camundongos , Microscopia Imunoeletrônica , Neurônios/química
20.
CNS Neurol Disord Drug Targets ; 13(5): 765-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24365182

RESUMO

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.


Assuntos
Transtorno Autístico , Sistema Nervoso Central/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Transtorno Autístico/fisiopatologia , Humanos
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