Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.482
Filtrar
1.
Mol Brain ; 12(1): 29, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935412

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Recognição (Psicologia)/efeitos dos fármacos , Inibidores de Captação de Serotonina/efeitos adversos , Comportamento Social , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Fluoxetina/efeitos adversos , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sinapses/efeitos dos fármacos
2.
Pain ; 160(4): 805-823, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681984

RESUMO

Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.


Assuntos
Glutamatos/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/terapia , Neuralgia/complicações , Optogenética/métodos , Córtex Pré-Frontal/citologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Memória de Curto Prazo/fisiologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Transdução Genética
3.
Pain ; 160(4): 824-832, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30681985

RESUMO

Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.


Assuntos
Núcleo Central da Amígdala/metabolismo , Inibição Neural/efeitos dos fármacos , Neuralgia/prevenção & controle , Neuralgia/terapia , Receptores Opioides kappa/metabolismo , Transdução de Sinais/fisiologia , Animais , Núcleo Central da Amígdala/patologia , Dor Crônica/terapia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Naltrexona/análogos & derivados , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Limiar da Dor/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
4.
Neuroreport ; 30(1): 19-25, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30371538

RESUMO

BACKGROUND: Baclofen is a lipophilic γ-aminobutyric acid (GABA) derivative that exhibits strong intrinsic activity and a high affinity for GABAB receptors. Intrathecal baclofen therapy has been used as an antispasticity and muscle relaxant drug in the clinical treatment of patients with severe spasticity. However, the cellular mechanisms of the antispasticity effects of baclofen on the ventral horn neurons of the spinal cord are unknown. OBJECTIVE: We examined the action of baclofen on excitatory synaptic transmission in ventral horn neurons in the rat spinal cord by whole-cell patch-clamp recordings. RESULTS: Baclofen significantly reduced the frequency and amplitude of miniature excitatory postsynaptic currents. The reduction in miniature excitatory postsynaptic current frequency was particularly strong, indicating presynaptic inhibition by baclofen. Moreover, baclofen-induced outward currents in all neurons tested. The baclofen-induced outward currents persisted in the presence of tetrodotoxin and glutamate receptor antagonists and were diminished in the presence of the postsynaptic intracellular K channel blocker cesium sulfate and the G-protein inhibitor guanosine 5'-(ß-thio)diphosphate trilithium salt. These results indicate direct postsynaptic depression mediated by G-protein-activated K channels by GABAB receptors on ventral horn neurons. The baclofen-induced outward currents and the inhibitory effects on spontaneous excitatory postsynaptic currents were blocked by the selective GABAB receptor antagonist CGP35348. CONCLUSION: Baclofen may have both presynaptic and postsynaptic capacity to inhibit synaptic transmission in ventral horn neurons by GABAB receptors. These cellular mechanisms may induce the antispasticity effects of intrathecal baclofen therapy in the spinal cord.


Assuntos
Células do Corno Anterior/efeitos dos fármacos , Baclofeno/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Agonistas dos Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/farmacologia , Inibição Neural/efeitos dos fármacos , Animais , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
5.
Neuropharmacology ; 144: 1-8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30321611

RESUMO

Decades of work in Aplysia californica established the general rule that principles of synaptic plasticity and their molecular mechanisms are evolutionarily conserved from mollusks to mammals. However, an exquisitely sensitive, activity-dependent homosynaptic mechanism that protects against the depression of neurotransmitter release in Aplysia sensory neuron terminals has, to date, not been uncovered in other animals, including mammals. Here, we discover that depression at a mammalian synapse that is implicated in habit formation and habit learning acceleration by ethanol, the fast-spiking interneuron (FSI) to medium spiny principal projection neuron (MSN) synapse of the dorsolateral striatum, is subject to this type of synaptic protection. We show that this protection against synaptic depression is calcium- and PDZ domain interaction-dependent. These findings support activity dependent protection against synaptic depression as an Aplysia-like synaptic switch in mammals that may represent a leveraging point for treating alcohol use disorders.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Corpo Estriado/fisiologia , Etanol/farmacologia , Hábitos , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Aplysia/fisiologia , Cálcio/metabolismo , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Feminino , Masculino , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Domínios PDZ , Proteína Quinase C/metabolismo , Sinapses/efeitos dos fármacos , Técnicas de Cultura de Tecidos
6.
Exp Neurol ; 311: 57-66, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30257183

RESUMO

The central serotonin2B receptor (5-HT2BR) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT2BR antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 µM) administration of the selective 5-HT2BR antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABAA antagonist bicuculline (100 µM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 µM) administration of the selective 5-HT1AR antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 µM) was potentiated by the intra-DRN administration (0.5 µM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT2BR mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT2BRs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC.


Assuntos
Núcleo Dorsal da Rafe/metabolismo , Neurônios GABAérgicos/metabolismo , Inibição Neural/fisiologia , Receptor 5-HT2B de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Inibição Neural/efeitos dos fármacos , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Ácido gama-Aminobutírico/metabolismo
7.
Biomed Pharmacother ; 102: 362-368, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29571021

RESUMO

Olmesartan-associated enteropathy (OAE) is a life-threatening pathological condition, but its underlying mechanisms have not been elucidated. Although intestinal hypermotility is frequently accompanied by chronic diarrhea, there have been no studies of olmesartan-induced hypermotility. Intestinal motility should be well regulated by the enteric nervous system, but degeneration of enteric neurons has been reported in patients with chronic diarrheal diseases, such as irritable bowel syndrome, suggesting a connection between OAE and intestinal hypermotility. In this study, interference with this inhibitory pathway was analyzed in a model of olmesartan-induced intestinal hypermotility (OIH) in rats with nicotine-induced hypertension exposed to chronic immobilizing stress. The effects of the potent inhibitory neurotransmitters norepinephrine (NE) and sodium nitroprusside (SNP), which act via different pathways, were assessed ex vivo, with only NE-modulated frequency and amplitude of spontaneous contractions found to be elevated in OIH rat jejunum. Clinical symptoms frequent in OAE, including atrophy of the intestinal epithelium and weight loss, were observed in these rats. Interestingly, olmesartan significantly elevated heart rate while lowering blood pressure in OIH rats. These abnormal conditions were prevented by adding linalyl acetate (LA), while the blood pressure-lowering effects of olmesartan were maintained. These findings suggest that olmesartan induces intestinal hypermotility by interfering with the sympathetic inhibitory pathway, and reduces epithelial cell size or body weight in hypertensive rats. As LA prevented these effects, combination treatment with olmesartan plus LA may provide better antihypertensive efficacy without inducing OAE.


Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Monoterpenos/farmacologia , Inibição Neural/efeitos dos fármacos , Sistema Nervoso Simpático/patologia , Tetrazóis/efeitos adversos , Tetrazóis/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/fisiopatologia , Masculino , Monoterpenos/uso terapêutico , Óxido Nítrico/sangue , Nitritos/metabolismo , Nitroprussiato/farmacologia , Norepinefrina , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação/efeitos dos fármacos
8.
Vitam Horm ; 107: 177-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29544630

RESUMO

Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus. Recently, a consensus neurosteroid pharmacophore model has been proposed at extrasynaptic δGABA-A receptors based on structure-activity relationship for functional activation of tonic currents and seizure protection. Aside from anticonvulsant actions, neurosteroids have been found to be powerful anxiolytic and anesthetic agents. Neurosteroids and Zn2+ have preferential affinity for δ-containing receptors. Thus, Zn2+ can prevent neurosteroid activation of extrasynaptic δGABA-A receptor-mediated tonic inhibition. Recently, we demonstrated that Zn2+ selectively inhibits extrasynaptic δGABA-A receptors and thereby fully prevents AP activation of tonic inhibition and seizure protection. We confirmed that neurosteroids exhibit greater sensitivity at extrasynaptic δGABA-A receptors. Overall, extrasynaptic GABA-A receptors are primary mediators of tonic inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurological disorders.


Assuntos
Encéfalo/metabolismo , Modelos Neurológicos , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural , Neurônios/metabolismo , Neurotransmissores/metabolismo , Receptores de GABA-A/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Humanos , Ciclo Menstrual/sangue , Ciclo Menstrual/efeitos dos fármacos , Ciclo Menstrual/metabolismo , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/enzimologia , Fibras Musgosas Hipocampais/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibição Neural/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurotransmissores/sangue , Neurotransmissores/farmacologia , Receptores de GABA-A/química , Zinco/metabolismo
9.
J Ethnopharmacol ; 219: 117-125, 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29550579

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pien-Tze-Huang (PZH) is a famous formula of traditional Chinese medicine used to treating stroke. However, the protective effect of PZH and its mechanisms in acute ischemic stroke remain to be explored. AIM OF THE STUDY: To investigate the protective effect of PZH on neuronal apoptosis in acute cerebral ischemic injury rats and explore its underlying mechanisms. MATERIALS AND METHODS: The effects of PZH were studied in acute ischemic stroke rats induced by transient middle cerebral artery occlusion, and the mitochondria-mediated apoptotic proteins including cytochrome C (Cyt C), Bax, Bcl-xl, P53, caspase-3, and caspase-9 as well as AKT and glycogen synthase kinase-3 beta (GSK-3ß) were assessed. RESULTS: Four days of PZH treatment (180 mg/kg) could significantly reduce cerebral infarct volume, improve neurological deficit, attenuate inflammatory response, and inhibit neuronal apoptosis in acute ischemic stroke rats. Moreover, PZH treatment significantly decreased cytosolic Cyt C, Bax, P53, cleaved caspase-3, and cleaved caspase-9 levels, but elevated mitochondrial Cyt C and Bcl-xl levels. PZH treatment also increased phosphorylation of AKT and GSK-3ß. CONCLUSION: PZH potently protects the brain from cerebral ischemia/reperfusion injury in vivo, and inhibiting mitochondria-mediated neuronal apoptosis as well as attenuating inflammatory responses may be involved in this effect. This study provides experimental basis of PZH in treating acute cerebral ischemic stroke, which would provide some novel insights for its prevention and treatment of ischemic stroke.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Inibição Neural/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Apoptose/fisiologia , Isquemia Encefálica/patologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Inibição Neural/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia
10.
J Neurol ; 265(Suppl 1): 18-25, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29556714

RESUMO

Vestibulo-ocular reflexes (VOR) are mediated by three-neuronal brainstem pathways that transform semicircular canal and otolith sensory signals into motor commands for the contraction of spatially specific sets of eye muscles. The vestibular excitation and inhibition of extraocular motoneurons underlying this reflex is reciprocally organized and allows coordinated activation of particular eye muscles and concurrent relaxation of their antagonistic counterparts. Here, we demonstrate in isolated preparations of Xenopus laevis tadpoles that the discharge modulation of superior oblique motoneurons during cyclic head motion derives from an alternating excitation and inhibition. The latter component is mediated exclusively by GABA, at variance with the glycinergic inhibitory component in lateral rectus motoneurons. The different pharmacological profile of the inhibition correlates with rhombomere-specific origins of vestibulo-ocular projection neurons and the complementary segmental abundance of GABAergic and glycinergic vestibular neurons. The evolutionary conserved rhombomeric topography of vestibulo-ocular projections makes it likely that a similar pharmacological organization of inhibitory VOR neurons as reported here for anurans is also implemented in mammalian species including humans.


Assuntos
Neurônios Motores/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Neurotransmissores/farmacologia , Músculos Oculomotores/inervação , Reflexo Vestíbulo-Ocular/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Glicina/metabolismo , Movimentos da Cabeça/efeitos dos fármacos , Movimentos da Cabeça/fisiologia , Larva , Percepção de Movimento/efeitos dos fármacos , Percepção de Movimento/fisiologia , Neurônios Motores/fisiologia , Inibição Neural/fisiologia , Piridazinas/farmacologia , Reflexo Vestíbulo-Ocular/fisiologia , Canais Semicirculares/efeitos dos fármacos , Canais Semicirculares/fisiologia , Estricnina/farmacologia , Tegmento Mesencefálico/efeitos dos fármacos , Tegmento Mesencefálico/fisiologia , Xenopus laevis , Ácido gama-Aminobutírico/metabolismo
11.
Nat Commun ; 9(1): 843, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483589

RESUMO

The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons.


Assuntos
Interneurônios/fisiologia , Bulbo/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Periodicidade , Respiração , Animais , Retroalimentação Fisiológica , Feminino , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Masculino , Bulbo/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Optogenética , Piridazinas/farmacologia , Estricnina/farmacologia , Vagotomia
12.
Behav Brain Res ; 344: 1-8, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29408282

RESUMO

Figure-ground segregation is a fundamental visual ability that allows an organism to separate an object from its background. Our earlier research has shown that nucleus rotundus (Rt), a thalamic nucleus processing visual information in pigeons, together with its inhibitory complex, nucleus subpretectalis/interstitio-pretecto-subpretectalis (SP/IPS), are critically involved in figure-ground discrimination (Acerbo et al., 2012; Scully et al., 2014). Here, we further investigated the role of SP/IPS by conducting bilateral microinjections of GABAergic receptor antagonist and agonists (bicuculline and muscimol, respectively) and non-NMDA glutamate receptor antagonist (CNQX) after the pigeons mastered figure-ground discrimination task. We used two doses of each drug (bicuculline: 0.1 mM and 0.05 mM; muscimol: 4.4 mM and 8.8 mM; CNQX: 2.15 mM and 4.6 mM) in a within-subject design, and alternated drug injections with baseline (ACSF). The order of injections was randomized across birds to reduce potential carryover effects. We found that a low dose of bicuculline produced a decrement on figure trials but not on background trials, whereas a high dose impaired performance on background trials but not on figure trials. Muscimol produced an equivalent, dose-dependent impairment on both types of trials. Finally, CNQX had no consistent effect at either dose. Together, these results further confirm our earlier hypothesis that inhibitory projections from SP to Rt modulate figure-ground discrimination, and suggest that the Rt and the SP/IPS provide a plausible substrate that could perform figure-ground segregation in avian brain.


Assuntos
Encéfalo/metabolismo , Columbidae/metabolismo , Discriminação (Psicologia)/fisiologia , Receptores de GABA-A/metabolismo , Percepção Visual/fisiologia , Ácido gama-Aminobutírico/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Bicuculina/farmacologia , Encéfalo/efeitos dos fármacos , Discriminação (Psicologia)/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Muscimol/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Receptores de Glutamato/metabolismo , Vias Visuais/efeitos dos fármacos , Vias Visuais/metabolismo , Percepção Visual/efeitos dos fármacos
13.
Synapse ; 72(5): e22028, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29360185

RESUMO

Inhibition mediated by horizontal and amacrine cells in the outer and inner retina, respectively, are fundamental components of visual processing. Here, our purpose was to determine how these different inhibitory processes affect glutamate release from ON bipolar cells when the retina is stimulated with full-field light of various intensities. Light-evoked membrane potential changes (ΔVm ) were recorded directly from axon terminals of intact bipolar cells receiving mixed rod and cone inputs (Mbs) in slices of dark-adapted goldfish retina. Inner and outer retinal inhibition to Mbs was blocked with bath applied picrotoxin (PTX) and NBQX, respectively. Then, control and pharmacologically modified light responses were injected into axotomized Mb terminals as command potentials to induce voltage-gated Ca2+ influx (QCa ) and consequent glutamate release. Stimulus-evoked glutamate release was quantified by the increase in membrane capacitance (ΔCm ). Increasing depolarization of Mb terminals upon removal of inner and outer retinal inhibition enhanced the ΔVm /QCa ratio equally at a given light intensity and inhibition did not alter the overall relation between QCa and ΔCm . However, relative to control, light responses recorded in the presence of PTX and PTX + NBQX increased ΔCm unevenly across different stimulus intensities: at dim stimulus intensities predominantly the inner retinal GABAergic inhibition controlled release from Mbs, whereas the inner and outer retinal inhibition affected release equally in response to bright stimuli. Furthermore, our results suggest that non-linear relationship between QCa and glutamate release can influence the efficacy of inner and outer retinal inhibitory pathways to mediate Mb output at different light intensities.


Assuntos
Ácido Glutâmico/metabolismo , Luz , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Rede Nervosa/fisiologia , Inibição Neural/fisiologia , Células Bipolares da Retina/fisiologia , Células Bipolares da Retina/efeitos da radiação , Animais , Biofísica , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Antagonistas GABAérgicos/farmacologia , Carpa Dourada , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/efeitos da radiação , Inibição Neural/efeitos dos fármacos , Inibição Neural/efeitos da radiação , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Quinoxalinas/farmacologia , Retina/citologia , Células Bipolares da Retina/efeitos dos fármacos
14.
Brain Res Bull ; 137: 294-300, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29330035

RESUMO

Emerging evidence indicates that loss of inhibitory tone in amygdala with its subsequent overactivation contributes to the development of multiple mental disorders such as anxiety disorders and post-traumatic stress disorder (PTSD). Harmine is a member of natural ß-carboline alkaloids which can readily cross the blood brain barrier and displays significant antidepressant and anxiolytic effects in rodents. However, the underlying neurobiological mechanisms are largely unknown. Here, by using whole-cell patch clamp recordings in in vitro amygdala slices, we examined the effect of harmine on glutamatergic and GABAergic transmission onto basal amygdala (BA) projection neurons (PNs). Our results showed that harmine affected neither the amplitude nor the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) of PNs. By contrast, it markedly increased both the amplitude and frequency of the spontaneous inhibitory postsynaptic currents (sIPSCs). For mIPSCs, only an increase of their frequency but not amplitude was observed following harmine perfusion, suggesting that harmine might act through presynaptic mechanism. In parallel, a reduction of paired-pulse ratio of evoked IPSCs emerged in the presence of harmine. Furthermore, the intrinsic excitability of PNs was dramatically decreased upon harmine treatment. Together, our study suggests that harmine selectively potentiates the inhibitory but not excitatory transmission onto BA PNs, which may contribute to its antidepressant and anxiolytic influence.


Assuntos
Ansiolíticos/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Harmina/farmacologia , Células Piramidais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Células Piramidais/metabolismo , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
15.
Brain Res Bull ; 137: 178-186, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29246865

RESUMO

Accumulating evidence support the growing non-medical use of morphine during adolescence. Despite this concern which has recently been addressed in some studies, cellular mechanisms underlying the long-term neurobiological and behavioral effects of opiate exposure during this critical period have still remained largely unexplored. Several reports have proposed that subtle long-lasting neurobiological alterations might be triggered by exposure to opiate derivatives or drugs of abuse particularly when this occurs during a critical phase of brain maturation such as adolescence. The present study was designed to investigate how chronic adolescent morphine exposure could affect the responsiveness of lateral paragigantocellular (LPGi) neurons to acute morphine administration in adult rats. Male Wistar rats received chronic escalating morphine or saline during adolescence (30-39d) for 10 days. During adulthood (65d), the extracellular unit activities of LPGi neurons were recorded in urethane-anesthetized animals. Results indicated that adolescent morphine treatment enhances the baseline activity of LPGi neurons. In addition, morphine-induced inhibition of spontaneous discharge rate was potentiated in adult rats received morphine during adolescence. However, this pretreatment did not affect the extent of morphine excitatory effect, onset or peak of cellular response and regularity of unit discharge in LPGi neurons. Our study supports the hypothesis that adolescent morphine exposure induces long-lasting neurophysiological alterations in brain regions known to play a role in mediating opiate effects. This finding sheds light on the possible effect of opiate pre-exposure on addiction susceptibility in future.


Assuntos
Morfina/toxicidade , Entorpecentes/toxicidade , Neurônios/efeitos dos fármacos , Formação Reticular/efeitos dos fármacos , Formação Reticular/crescimento & desenvolvimento , Potenciais de Ação/efeitos dos fármacos , Animais , Esquema de Medicação , Injeções Intraperitoneais , Masculino , Microeletrodos , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Inibição Neural/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar
16.
Cereb Cortex ; 28(1): 1-8, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29253248

RESUMO

The amygdala receives cortical inputs from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) that are believed to affect emotional control and cue-outcome contingencies, respectively. Although mPFC impact on the amygdala has been studied, how the OFC modulates mPFC-amygdala information flow, specifically the infralimbic (IL) division of mPFC, is largely unknown. In this study, combined in vivo extracellular single-unit recordings and pharmacological manipulations were used in anesthetized rats to examine how OFC modulates amygdala neurons responsive to mPFC activation. Compared with basal condition, pharmacological (N-Methyl-D-aspartate) or electrical activation of the OFC exerted an inhibitory modulation of the mPFC-amygdala pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, potentiation of the OFC-related pathways resulted in a loss of OFC control over the mPFC-amygdala pathway. These results show that the OFC potently inhibits mPFC drive of the amygdala in a GABA-dependent manner; but with extended OFC pathway activation this modulation is lost. Our results provide a circuit-level basis for this interaction at the level of the amygdala, which would be critical in understanding the normal and pathophysiological control of emotion and contingency associations regulating behavior.


Assuntos
Tonsila do Cerebelo/fisiologia , Lobo Frontal/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Anestesia , Animais , Baclofeno/análogos & derivados , Baclofeno/farmacologia , Bicuculina/farmacologia , Estimulação Elétrica , Emoções/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Lobo Frontal/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Masculino , Microeletrodos , N-Metilaspartato/farmacologia , Inibição Neural/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Neuropsychopharmacology ; 43(2): 354-361, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28553835

RESUMO

Cortical inhibition (CI) occurs largely through GABA receptor-mediated inhibitory neurotransmission, which can be modulated by cholinergic, dopaminergic, and glutamatergic inputs. Transcranial magnetic stimulation (TMS) can be used to index CI through a paradigm known as long-interval CI (LICI). When TMS is combined with electroencephalography (EEG), LICI can index GABA receptor-mediated inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). We conducted a hypothesis-driven pharmacological study to assess the role of cholinergic, dopaminergic, GABAergic, and glutamatergic neurotransmission on LICI from the DLPFC using TMS-EEG. In this randomized controlled, double-blind crossover within-subject study, 12 healthy participants received five sessions of LICI to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. LICI was assessed after each drug administration and compared to LICI after placebo. Relative to placebo, baclofen resulted in a significant increase in LICI, while rivastigmine resulted in a significant decrease in LICI. Dextromethorphan and L-DOPA did not result in a significant change in LICI relative to placebo. Our study confirms that LICI in the DLPFC is largely mediated by GABAB receptor-mediated inhibitory neurotransmission and also suggests that cholinergic modulation decreases LICI in the DLPFC. Such findings may help guide future work examining the neurophysiological impact of these neurotransmitters in healthy and diseased states.


Assuntos
Inibidores da Colinesterase/farmacologia , Dopaminérgicos/farmacologia , Eletroencefalografia/métodos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Inibição Neural/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Estimulação Magnética Transcraniana/métodos , Adulto , Baclofeno/farmacologia , Inibidores da Colinesterase/administração & dosagem , Estudos Cross-Over , Dextrometorfano/administração & dosagem , Dextrometorfano/farmacologia , Dopaminérgicos/administração & dosagem , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Humanos , Levodopa/administração & dosagem , Levodopa/farmacologia , Masculino , Rivastigmina , Adulto Jovem
18.
Sci Transl Med ; 9(421)2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-29263233

RESUMO

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.


Assuntos
Disfunção Cognitiva/patologia , Depressão/patologia , Matriz Extracelular/metabolismo , Hipocampo/patologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Condroitina ABC Liase/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Doença Crônica , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imipramina/farmacologia , Imipramina/uso terapêutico , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Masculino , Memória/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Ratos Wistar , Comportamento Social , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
19.
eNeuro ; 4(5)2017 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29085896

RESUMO

Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Giro Denteado/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sirolimo/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Técnicas de Cultura de Tecidos
20.
J Comput Neurosci ; 43(3): 173-187, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29047010

RESUMO

The pathophysiology of auditory hallucination, a common symptom of schizophrenia, has yet been understood, but during auditory hallucination, primary auditory cortex (A1) shows paradoxical responses. When auditory stimuli are absent, A1 becomes hyperactive, while A1 responses to auditory stimuli are reduced. Such activation pattern of A1 responses during auditory hallucination is consistent with aberrant gamma rhythms in schizophrenia observed during auditory tasks, raising the possibility that the pathology underlying abnormal gamma rhythms can account for auditory hallucination. Moreover, A1 receives top-down signals in the gamma frequency band from an adjacent association area (Par2), and cholinergic modulation regulates interactions between A1 and Par2. In this study, we utilized a computational model of A1 to ask if disrupted cholinergic modulation could underlie abnormal gamma rhythms in schizophrenia. Furthermore, based on our simulation results, we propose potential pathology by which A1 can directly contribute to auditory hallucination.


Assuntos
Córtex Auditivo/fisiopatologia , Colinérgicos/farmacologia , Ritmo Gama/efeitos dos fármacos , Alucinações/fisiopatologia , Esquizofrenia/fisiopatologia , Estimulação Acústica , Córtex Auditivo/efeitos dos fármacos , Simulação por Computador , Eletroencefalografia , Feminino , Ritmo Gama/fisiologia , Alucinações/patologia , Humanos , Masculino , Modelos Neurológicos , Inibição Neural/efeitos dos fármacos , Esquizofrenia/patologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA