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1.
Sci Adv ; 7(7)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33568480

RESUMO

Evidence that offspring traits can be shaped by parental life experiences in an epigenetically inherited manner paves a way for understanding the etiology of depression. Here, we show that F1 offspring born to F0 males of depression-like model are susceptible to depression-like symptoms at the molecular, neuronal, and behavioral levels. Sperm small RNAs, and microRNAs (miRNAs) in particular, exhibit distinct expression profiles in F0 males of depression-like model and recapitulate paternal depressive-like phenotypes in F1 offspring. Neutralization of the abnormal miRNAs in zygotes by antisense strands rescues the acquired depressive-like phenotypes in F1 offspring born to F0 males of depression-like model. Mechanistically, sperm miRNAs reshape early embryonic transcriptional profiles in the core neuronal circuits toward depression-like phenotypes. Overall, the findings reveal a causal role of sperm miRNAs in the inheritance of depression and provide insight into the mechanism underlying susceptibility to depression.

2.
Neuropeptides ; 76: 101934, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31130301

RESUMO

Corticotropin-releasing factor (CRF) is a neuropeptide mainly synthesized in the hypothalamic paraventricular nucleus and has been traditionally implicated in stress and anxiety. Intriguingly, genetic or pharmacological manipulation of CRF receptors affects locomotor activity as well as motor coordination and balance in rodents, suggesting an active involvement of the central CRFergic system in motor control. Yet little is known about the exact role of CRF in central motor structures and the underlying mechanisms. Therefore, in the present study, we focused on the effect of CRF on the lateral vestibular nucleus (LVN) in the brainstem vestibular nuclear complex, an important center directly contributing to adjustment of muscle tone for both postural maintenance and the alternative change from the extensor to the flexor phase during locomotion. The results show that CRF depolarizes and increases the firing rate of neurons in the LVN. Tetrodotoxin does not block the CRF-induced depolarization and inward current on LVN neurons, suggesting a direct postsynaptic action of the neuropeptide. The CRF-induced depolarization on LVN neurons was partly blocked by antalarmin or antisauvagine-30, selective antagonists for CRF receptors 1 (CRFR1) and 2 (CRFR2), respectively. Furthermore, combined application of antalarmin and antisauvagine-30 totally abolished the CRF-induced depolarization. Immunofluorescence results show that CRFR1 and CRFR2 are co-localized in the rat LVN. These results demonstrate that CRF excites the LVN neurons by co-activation of both CRFR1 and CRFR2, suggesting that via the direct modulation on the LVN, the central CRFergic system may actively participate in the central vestibular-mediated postural and motor control.


Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Neurônios/fisiologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Núcleo Vestibular Lateral/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Hormônio Liberador da Corticotropina/administração & dosagem , Feminino , Masculino , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Núcleo Vestibular Lateral/efeitos dos fármacos
3.
J Neurosci ; 39(3): 420-433, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30413645

RESUMO

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.


Assuntos
Receptores Histamínicos H1/efeitos dos fármacos , Vestíbulo do Labirinto/fisiopatologia , Animais , beta-Histina/uso terapêutico , Orelha Interna , Lateralidade Funcional/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Neurônios/efeitos dos fármacos , Nistagmo Fisiológico/efeitos dos fármacos , Técnicas de Patch-Clamp , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Doenças Vestibulares/tratamento farmacológico , Núcleos Vestibulares/citologia , Núcleos Vestibulares/efeitos dos fármacos , Núcleos Vestibulares/fisiopatologia , Ácido gama-Aminobutírico
4.
Curr Biol ; 27(17): 2661-2669.e5, 2017 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-28844644

RESUMO

Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1-3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4-7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo-cerebellar system [10-14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia. Here we report that deficiency of CRF in the olivo-cerebellar system induces ataxia-like motor abnormalities. CRFergic neurons in the IO project directly to the cerebellar nuclei, the ultimate integration and output node of the cerebellum, and CRF selectively excites glutamatergic projection neurons rather than GABAergic neurons in the cerebellar interpositus nucleus (IN) via two CRF receptors, CRFR1 and CRFR2, and their downstream inward rectifier K+ channel and/or hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. Furthermore, CRF promotes cerebellar motor coordination and rescues ataxic motor deficits. The findings define a previously unknown role for CRF in the olivo-cerebellar system in the control of gait, posture, and motor coordination, and provide new insight into the etiology, pathophysiology, and treatment strategy of cerebellar ataxia.


Assuntos
Ataxia/fisiopatologia , Cerebelo/fisiologia , Hormônio Liberador da Corticotropina/deficiência , Atividade Motora/fisiologia , Animais , Masculino , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley
5.
Neurosci Bull ; 33(4): 365-372, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28389870

RESUMO

Orexin, released from the hypothalamus, has been implicated in various basic non-somatic functions including feeding, the sleep-wakefulness cycle, emotion, and cognition. However, the role of orexin in somatic motor control is still little known. Here, using whole-cell patch clamp recording and immunostaining, we investigated the effect and the underlying receptor mechanism of orexin-A on neurons in the globus pallidus internus (GPi), a critical structure in the basal ganglia and an effective target for deep brain stimulation therapy. Our results showed that orexin-A induced direct postsynaptic excitation of GPi neurons in a concentration-dependent manner. The orexin-A-induced excitation was mediated via co-activation of both OX1 and OX2 receptors. Furthermore, the immunostaining results showed that OX1 and OX2 receptors were co-localized in the same GPi neurons. These results suggest that the central orexinergic system actively modulates the motor functions of the basal ganglia via direct innervation on GPi neurons and presumably participates in somatic-non-somatic integration.


Assuntos
Globo Pálido/citologia , Interneurônios/efeitos dos fármacos , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Técnicas In Vitro , Isoquinolinas/farmacologia , Masculino , Receptores de Orexina/agonistas , Técnicas de Patch-Clamp , Piridazinas/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia
6.
Sci Rep ; 6: 20206, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26831220

RESUMO

Corticotropin releasing factor (CRF), a peptide hormone involved in the stress response, holds a key position in cardiovascular regulation. Here, we report that the central effect of CRF on cardiovascular activities is mediated by the posterior hypothalamic nucleus (PH), an important structure responsible for stress-induced cardiovascular changes. Our present results demonstrate that CRF directly excites PH neurons via two CRF receptors, CRFR1 and CRFR2, and consequently increases heart rate (HR) rather than the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). Bilateral vagotomy does not influence the tachycardia response to microinjection of CRF into the PH, while ß adrenergic receptor antagonist propranolol almost totally abolishes the tachycardia. Furthermore, microinjecting CRF into the PH primarily increases neuronal activity of the rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM), but does not influence that of the dorsal motor nucleus of the vagus nerve (DMNV). These findings suggest that the PH is a critical target for central CRF system in regulation of cardiac activity and the PH-RVLM/RVMM-cardiac sympathetic nerve pathways, rather than PH-DMNV-vagus pathway, may contribute to the CRF-induced tachycardia.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo Posterior/citologia , Hipotálamo Posterior/metabolismo , Neurônios/metabolismo , Taquicardia/etiologia , Taquicardia/metabolismo , Animais , Pressão Sanguínea , Hormônio Liberador da Corticotropina/farmacologia , Expressão Gênica , Frequência Cardíaca , Hipotálamo Posterior/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/inervação , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Microinjeções , Neurônios/efeitos dos fármacos , Ratos , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sistema Nervoso Simpático , Taquicardia/fisiopatologia , Vagotomia
7.
Front Cell Neurosci ; 10: 300, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28119568

RESUMO

Histamine and histamine receptors in the central nervous system actively participate in the modulation of motor control. In clinic, histamine-related agents have traditionally been used to treat vestibular disorders. Immunohistochemical studies have revealed a distribution of histaminergic afferents in the brainstem vestibular nuclei, including the lateral vestibular nucleus (LVN), which is critical for adjustment of muscle tone and vestibular reflexes. However, the mechanisms underlying the effect of histamine on LVN neurons and the role of histamine and histaminergic afferents in the LVN in motor control are still largely unknown. Here, we show that histamine, in cellular and molecular levels, elicits the LVN neurons of rats an excitatory response, which is co-mediated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and K+ channels linked to H2 receptors. Blockage of HCN channels coupled to H2 receptors decreases LVN neuronal sensitivity and changes their dynamic properties. Furthermore, in behavioral level, microinjection of histamine into bilateral LVNs significantly promotes motor performances of rats on both accelerating rota-rod and balance beam. This promotion is mimicked by selective H2 receptor agonist dimaprit, and blocked by selective H2 receptor antagonist ranitidine. More importantly, blockage of HCN channels to suppress endogenous histaminergic inputs in the LVN considerably attenuates motor balance and coordination, indicating a promotion role of hypothalamo-vestibular histaminergic circuit in motor control. All these results demonstrate that histamine H2 receptors and their coupled HCN channels mediate the histamine-induced increase in excitability and sensitivity of LVN neurons and contribute to the histaminergic improvement of the LVN-related motor behaviors. The findings suggest that histamine and the histaminergic afferents may directly modulate LVN neurons and play a critical role in the central vestibular-mediated motor reflexes and behaviors.

8.
J Neural Transm (Vienna) ; 122(6): 747-55, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25371350

RESUMO

Orexin deficiency results in cataplexy, a motor deficit characterized by sudden loss of muscle tone, strongly indicating an active role of central orexinergic system in motor control. However, effects of orexin on neurons in central motor structures are still largely unknown. Our previous studies have revealed that orexin excites neurons in the cerebellar nuclei and lateral vestibular nucleus, two important subcortical motor centers for control of muscle tone. Here, we report that both orexin-A and orexin-B depolarizes and increases the firing rate of neurons in the inferior vestibular nucleus (IVN), the largest nucleus in the vestibular nuclear complex and holding an important position in integration of information signals in the control of body posture. TTX does not block orexin-induced excitation on IVN neurons, suggesting a direct postsynaptic action of the neuropeptide. Furthermore, bath application of orexin induces an inward current on IVN neurons in a concentration-dependent manner. SB334867 and TCS-OX2-29, specific OX1 and OX2 receptor antagonists, blocked the excitatory effect of orexin, and [Ala(11), D-Leu(15)]-orexin B, a selective OX2 receptor agonist, mimics the orexin-induced inward current on IVN neurons. qPCR and immunofluorescence results show that both OX1 and OX2 receptor mRNAs and proteins are expressed and localized in the rat IVN. These results demonstrate that orexin excites the IVN neurons by co-activation of both OX1 and OX2 receptors, suggesting that via the direct modulation on the IVN, the central orexinergic system may actively participate in the central vestibular-mediated postural and motor control.


Assuntos
Neurônios/fisiologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Núcleos Vestibulares/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Benzoxazóis/farmacologia , Relação Dose-Resposta a Droga , Isoquinolinas/farmacologia , Naftiridinas , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/antagonistas & inibidores , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Técnicas de Cultura de Tecidos , Ureia/análogos & derivados , Ureia/farmacologia , Núcleos Vestibulares/efeitos dos fármacos
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