RESUMO
BACKGROUND: Systemic administration of noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists such as MK-801 is widely used to model psychosis of schizophrenia (SZ). Acute systemic MK-801 in rodents caused an increase of the auditory steady-state responses (ASSRs), the oscillatory neural responses to periodic auditory stimulation, while most studies in patients with SZ reported a decrease of ASSRs. This inconsistency may be attributable to the comprehensive effects of systemic administration of MK-801. Here, we examined how the ASSR is affected by selectively blocking NMDAR in the thalamus. METHODS: We implanted multiple electrodes in the auditory cortex (AC) and prefrontal cortex to simultaneously record the local field potential and spike activity (SA) of multiple sites from awake mice. Click-trains at a 40-Hz repetition rate were used to evoke the ASSR. We compared the mean trial power and phase-locking factor and the firing rate of SA before and after microinjection of MK-801 (1.5 µg) into the medial geniculate body (MGB). RESULTS: We found that both the AC and prefrontal cortex showed a transient local field potential response at the onset of click-train stimulus, which was less affected by the application of MK-801 in the MGB. Following the onset response, the AC also showed a response continuing throughout the stimulus period, corresponding to the ASSR, which was suppressed by the application of MK-801. CONCLUSION: Our data suggest that the MGB is one of the generators of ASSR, and NMDAR hypofunction in the thalamocortical projection may account for the ASSR deficits in SZ.
Assuntos
Maleato de Dizocilpina/farmacologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Corpos Geniculados/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estimulação Acústica , Animais , Córtex Auditivo/efeitos dos fármacos , Maleato de Dizocilpina/administração & dosagem , Eletrodos Implantados , Eletroencefalografia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Córtex Pré-Frontal/efeitos dos fármacos , Tálamo/efeitos dos fármacos , VigíliaRESUMO
Experience-dependent plasticity in the mature visual system is widely considered to be cortical. Using chronic two-photon Ca2+ imaging of thalamic afferents in layer 1 of binocular visual cortex, we provide evidence against this tenet: the respective dorsal lateral geniculate nucleus (dLGN) cells showed pronounced ocular dominance (OD) shifts after monocular deprivation in adult mice. Most (86%), but not all, of dLGN cell boutons were monocular during normal visual experience. Following deprivation, initially deprived-eye-dominated boutons reduced or lost their visual responsiveness to that eye and frequently became responsive to the non-deprived eye. This cannot be explained by eye-specific cortical changes propagating to dLGN via cortico-thalamic feedback because the shift in dLGN responses was largely resistant to cortical inactivation using the GABAA receptor agonist muscimol. Our data suggest that OD shifts observed in the binocular visual cortex of adult mice may at least partially reflect plasticity of eye-specific inputs onto dLGN neurons.
Assuntos
Dominância Ocular/fisiologia , Corpos Geniculados/citologia , Corpos Geniculados/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Córtex Visual/citologia , Córtex Visual/fisiologia , Animais , Cegueira/patologia , Retroalimentação Sensorial/fisiologia , Agonistas GABAérgicos/farmacologia , Corpos Geniculados/efeitos dos fármacos , Masculino , Camundongos , Muscimol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Tálamo/citologia , Tálamo/fisiologia , Visão Binocular/fisiologia , Vias Visuais/citologia , Vias Visuais/fisiologiaRESUMO
Neural circuits formed during postnatal development have to be maintained stably thereafter, but their mechanisms remain largely unknown. Here we report that the metabotropic glutamate receptor subtype 1 (mGluR1) is essential for the maintenance of mature synaptic connectivity in the dorsal lateral geniculate nucleus (dLGN). In mGluR1 knockout (mGluR1-KO) mice, strengthening and elimination at retinogeniculate synapses occurred normally until around postnatal day 20 (P20). However, during the subsequent visual-experience-dependent maintenance phase, weak retinogeniculate synapses were newly recruited. These changes were similar to those of wild-type (WT) mice that underwent visual deprivation or inactivation of mGluR1 in the dLGN from P21. Importantly, visual deprivation was ineffective in mGluR1-KO mice, and the changes induced by visual deprivation in WT mice were rescued by pharmacological activation of mGluR1 in the dLGN. These results demonstrate that mGluR1 is crucial for the visual-experience-dependent maintenance of mature synaptic connectivity in the dLGN.
Assuntos
Corpos Geniculados/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Sinapses/fisiologia , Tálamo/fisiologia , Vias Visuais/fisiologia , Animais , Carbamatos/farmacologia , Corpos Geniculados/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Camundongos , Camundongos Knockout , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/genética , Resorcinóis/farmacologia , Retina/fisiologia , Privação Sensorial/fisiologia , Xantenos/farmacologiaRESUMO
The thalamic synapses relay peripheral sensory information to the cortex, and constitute an important part of the thalamocortical network that generates oscillatory activities responsible for different vigilance (sleep and wakefulness) states. However, the modulation of thalamic synaptic transmission by potential sleep regulators, especially by combination of regulators in physiological scenarios, is not fully characterized. We found that somnogen adenosine itself acts similar to wake-promoting serotonin, both decreasing synaptic strength as well as short-term depression, at the retinothalamic synapse. We then combined the two modulators considering the coexistence of them in the hypnagogic (sleep-onset) state. Adenosine plus serotonin results in robust synergistic inhibition of synaptic strength and dramatic transformation of short-term synaptic depression to facilitation. These synaptic effects are not achievable with a single modulator, and are consistent with a high signal-to-noise ratio but a low level of signal transmission through the thalamus appropriate for slow-wave sleep. This study for the first time demonstrates that the sleep-regulatory modulators may work differently when present in combination than present singly in terms of shaping information flow in the thalamocortical network. The major synaptic characters such as the strength and short-term plasticity can be profoundly altered by combination of modulators based on physiological considerations.
Assuntos
Adenosina/farmacologia , Vias Aferentes/efeitos dos fármacos , Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Adenosina/fisiologia , Vias Aferentes/citologia , Vias Aferentes/fisiologia , Animais , Sinergismo Farmacológico , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Corpos Geniculados/citologia , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurotransmissores/farmacologia , Técnicas de Cultura de Órgãos , Receptor A1 de Adenosina/fisiologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Sono/efeitos dos fármacos , Sono/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/citologia , Tálamo/fisiologiaRESUMO
Relay cells of dorsal lateral geniculate nucleus (LGN) receive a Class 1 glutamatergic input from the retina and a Class 2 input from cortical layer 6. Among the properties of Class 2 synapses is the ability to activate metabotropic glutamate receptors (mGluRs), and mGluR activation is known to affect thalamocortical transmission via regulating retinogeniculate and thalamocortical synapses. Using brain slices, we studied the effects of Group I (dihydroxyphenylglycine) and Group II ((2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine) mGluR agonists on retinogeniculate synapses. We showed that both agonists inhibit retinogeniculate excitatory postsynaptic currents (EPSCs) through presynaptic mechanisms, and their effects are additive and independent. We also found high-frequency stimulation of the layer 6 corticothalamic input produced a similar suppression of retinogeniculate EPSCs, suggesting layer 6 projection to LGN as a plausible source of activating these presynaptic mGluRs.
Assuntos
Corpos Geniculados/fisiologia , Inibição Neural/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Retina/fisiologia , Transmissão Sináptica/fisiologia , Animais , Córtex Cerebral/fisiologia , Ciclopropanos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Corpos Geniculados/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Camundongos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Estimulação Luminosa , Receptores de Glutamato Metabotrópico/agonistas , Resorcinóis/farmacologia , Retina/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tálamo/fisiologia , Vias Visuais/fisiologiaRESUMO
Sodium salicylate (NaSal), an aspirin metabolite, can cause tinnitus in animals and human subjects. To explore neural mechanisms underlying salicylate-induced tinnitus, we examined effects of NaSal on neural activities of the medial geniculate body (MGB), an auditory thalamic nucleus that provides the primary and immediate inputs to the auditory cortex, by using the whole-cell patch-clamp recording technique in MGB slices. Rats treated with NaSal (350 mg/kg) showed tinnitus-like behavior as revealed by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. NaSal (1.4 mM) decreased the membrane input resistance, hyperpolarized the resting membrane potential, suppressed current-evoked firing, changed the action potential, and depressed rebound depolarization in MGB neurons. NaSal also reduced the excitatory and inhibitory postsynaptic response in the MGB evoked by stimulating the brachium of the inferior colliculus. Our results demonstrate that NaSal alters neuronal intrinsic properties and reduces the synaptic transmission of the MGB, which may cause abnormal thalamic outputs to the auditory cortex and contribute to NaSal-induced tinnitus.
Assuntos
Corpos Geniculados/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Salicilato de Sódio/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Zumbido/fisiopatologia , Estimulação Acústica , Potenciais de Ação/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Corpos Geniculados/fisiopatologia , Colículos Inferiores/efeitos dos fármacos , Colículos Inferiores/fisiopatologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Zumbido/induzido quimicamenteRESUMO
We studied auditory thalamocortical interactions in vitro, using an auditory thalamocortical brain slice preparation. Cortical activity evoked by electrical stimulation of the medial geniculate nucleus (MGN) was investigated through field potential recordings and voltage sensitive dyes. Experiments were performed in slices obtained from adult mice (9-14 weeks). Stimulus evoked activity was detected in the granular and supragranular layers after a short latency (5-6 ms). In 9-14 weeks old mice infragranular activity was detected in 10 of 24 preparations and was found to be increased in younger mice (p 31-64). In 14 of 24 slices a prominent horizontal spread was observed, which extended into cortical areas lateral to A1. In these experiments, the shortest onset latencies and largest signal amplitudes were located in the supragranular layers of A1. In areas lateral to A1, shortest onset latencies were located in the granular layer, while largest signal amplitudes were found in the supragranular layers. Evoked cortical activity was sensitive to removal of extracellular Ca(2+) or application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). Short repetitive stimulation, resembling thalamic burst activity (three pulses at 100 Hz), resulted in an increase of signal amplitude and excited area by approximately 25%, without changing the overall spatiotemporal activity profile. Blockade of N-methyl-D-aspartate receptors by 2-amino-5-phosphonopentanoate (AP5, 50 microM) reduced amplitudes and excited area by approximately 15-30%, irrespective of stimulation frequency. Application of bicuculline (10 microM) greatly increased cortical responses to thalamic stimulation. Under these conditions, evoked activity displayed a pronounced horizontal spread in combination with a 2-3-fold increase in amplitude. In conclusion, afferent thalamic inputs primarily activate supragranular and granular layers in the auditory cortex of adult mice. This activation is predominantly mediated by non-NMDA receptors, while GABA(A) receptor-mediated inhibition limits the horizontal and vertical spread of activity.
Assuntos
Córtex Auditivo/fisiologia , Corpos Geniculados/fisiologia , Neurônios Aferentes/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Envelhecimento , Animais , Córtex Auditivo/efeitos dos fármacos , Bicuculina/farmacologia , Cálcio/metabolismo , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Corpos Geniculados/efeitos dos fármacos , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/fisiologia , Fatores de Tempo , Imagens com Corantes Sensíveis à VoltagemRESUMO
Compared with adults, immature metallothionein I and II knockout (MT(-/-)) mice incur greater neuronal loss and a more rapid rate of microglia accumulation after target deprivation-induced injury. Because minocycline has been proposed to inhibit microglial activation and associated production of neuroinflammatory factors, we investigated its ability to promote neuronal survival in the immature, metallothionein-deficient brain. After ablation of the visual cortex, 10-day-old MT(-/-) mice were treated with minocycline or saline and killed 24 or 48 hr after injury. By means of stereological methods, the number of microglia and neurons were estimated in the ipsilateral dorsal lateral geniculate nucleus (dLGN) by an investigator blinded to the treatment. No effect on neuronal survival was observed at 24 hr, but 48 hr after injury, an unanticipated but significant minocycline-mediated increase in neuronal loss was detected. Further, while failing to inhibit microglial accumulation, minocycline treatment increased the proportion of amoeboid microglia in the ipsilateral dLGN. To understand the molecular mechanisms underlying this neurotoxic response, we identified minocycline-mediated changes in the expression of three potentially proapoptotic/inflammatory genes: growth arrest- and DNA damage-inducible gene 45gamma (GADD45gamma); interferon-inducible protein 1 (IFI1), and cytokine-induced growth factor. We also observed increased mitogen-activated protein kinase p38 phosphorylation with minocycline treatment. Although minocycline inhibited calpain activity at 12 hr after injury, this effect was not sustained at 24 hr. Together, these results help to explain how minocycline has a deleterious effect on neuronal survival in this injury model.
Assuntos
Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Encéfalo/patologia , Metalotioneína/metabolismo , Minociclina/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Animais , Encéfalo/metabolismo , Calpaína/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica/efeitos dos fármacos , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metalotioneína/genética , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Vias Neurais/patologia , Fosforilação/efeitos dos fármacos , Tálamo/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas GADD45RESUMO
The auditory conditioned stimulus (CS) pathway that is necessary for delay eyeblink conditioning was investigated using reversible inactivation of the medial auditory thalamic nuclei (MATN) consisting of the medial division of the medial geniculate (MGm), suprageniculate (SG), and posterior intralaminar nucleus (PIN). Rats were given saline or muscimol infusions into the MATN contralateral to the trained eye before each of four conditioning sessions with an auditory CS. Rats were then given four additional sessions without infusions to assess savings from the initial training. All rats were then given a retention test with a muscimol infusion followed by a recovery session. Muscimol infusions through cannula placements within 0.5 mm of the MGm prevented acquisition of eyeblink conditioned responses (CRs) and also blocked CR retention. Cannula placements more than 0.5 mm from the MATN did not completely block CR acquisition and had a partial effect on CR retention. The primary and secondary effects of MATN inactivation were examined with 2-deoxy-glucose (2-DG) autoradiography. Differences in 2-DG uptake in the auditory thalamus were consistent with the cannula placements and behavioral results. Differences in 2-DG uptake were found between groups in the ipsilateral auditory cortex, basilar pontine nuclei, and inferior colliculus. Results from this experiment indicate that the MATN contralateral to the trained eye and its projection to the pontine nuclei are necessary for acquisition and retention of eyeblink CRs to an auditory CS.
Assuntos
Vias Auditivas/fisiologia , Piscadela/fisiologia , Condicionamento Palpebral/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Muscimol/farmacologia , Animais , Vias Auditivas/efeitos dos fármacos , Transporte Biológico , Piscadela/efeitos dos fármacos , Condicionamento Palpebral/efeitos dos fármacos , Desoxiglucose/metabolismo , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Ratos , Tálamo/efeitos dos fármacos , Tálamo/fisiologiaRESUMO
The mammalian thalamus is composed of two types of thalamocortical relay. First order relays receive information from subcortical sources and relay it to cortex, whereas higher order relays receive information from layer 5 of one cortical area and relay it to another. Recent reports suggest that modulatory inputs to first and higher order relays may differ. We used rat thalamic brain slices and whole cell recordings from relay cells in various first order (the lateral geniculate nucleus, the ventral posterior nucleus, and the ventral portion of the medial geniculate body) and higher order (the lateral posterior, the posterior medial nucleus, and the dorsal portion of the medial geniculate body) relays to explore their responses to activation of muscarinic receptors. We found that, whereas all first order relay cells show a depolarizing response to muscarinic activation, approximately 20% of higher order relay cells respond with hyperpolarization. The depolarization is accompanied by an overall increase in input resistance, whereas the hyperpolarization correlates with a decrease in resistance. Because activation of cholinergic brain stem afferents to thalamus increases with increasing behavioral vigilance, the findings suggest that increased vigilance will depolarize all first order and most higher order relay cells but will hyperpolarize a significant subset of higher order relay cells. Such hyperpolarization is expected to bias these relay cells to the burst firing mode, and so these results are consistent with evidence of more bursting among higher order than first order relay cells.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Receptores Muscarínicos/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Animais , Cálcio/fisiologia , Relação Dose-Resposta a Droga , Eletrofisiologia , Antagonistas de Receptores de GABA-A , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Rede Nervosa/citologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Sistema Nervoso Parassimpático/citologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/fisiologia , Tetrodotoxina/farmacologiaRESUMO
The medial geniculate nucleus of the thalamus responds to auditory information and is a critical part of the neural circuitry underlying aversive conditioning with auditory signals for shock. Prior work has shown that lesions of this brain area selectively disrupt conditioning with auditory stimuli and that neurons in the medial geniculate demonstrate plastic changes during fear conditioning. However, recent evidence is less clear as to whether or not this area plays a role in the storage of auditory fear memories. In the current set of experiments rats were given infusions of protein or messenger RNA (mRNA) synthesis inhibitors into the medial geniculate nucleus of the thalamus 30 min prior to auditory fear conditioning. The next day animals were tested to the auditory cue and conditioning context. Results showed that rats infused with either inhibitor demonstrated less freezing to the auditory cue 24 h after training, while freezing to the context was normal. Autoradiography confirmed that the doses used were effective in disrupting synthesis. Taken together with prior work, these data suggest that the formation of fear memory requires the synthesis of new protein and mRNA at multiple brain sites across the neural circuit that supports fear conditioning.
Assuntos
Condicionamento Clássico/fisiologia , Medo , Corpos Geniculados/metabolismo , Memória/fisiologia , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Estimulação Acústica , Animais , Anisomicina/farmacologia , Autorradiografia/métodos , Comportamento Animal , Condicionamento Clássico/efeitos dos fármacos , Diclororribofuranosilbenzimidazol/farmacologia , Eletrochoque/métodos , Medo/efeitos da radiação , Corpos Geniculados/efeitos dos fármacos , Masculino , Inibidores da Síntese de Ácido Nucleico/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
The amygdala mediates both emotional learning and fear potentiation of startle. The lateral amygdala nucleus (LA) receives auditory inputs from both the auditory thalamus (medial geniculate nucleus; MGN) and auditory association cortex (AAC), and is critical for auditory fear conditioning. The central amygdala nucleus, which has intra-amygdaloid connections with LA, enhances startle magnitude via midbrain connections to the startle circuits. Tetanic stimulation of either MGN or AAC in vitro or in vivo can induce long-term potentiation in LA. In the present study, behavioural consequences of tetanization of these auditory afferents were investigated in awake rats. The acoustic startle reflex of rats was enhanced by tetanic stimulation of MGN, but suppressed by that of AAC. All the tetanization-induced changes of startle diminished within 24 h. Blockade of GABAB receptors in the LA area reversed the suppressive effect of tetanic stimulation of AAC on startle but did not change the enhancing effect of tetanic stimulation of MGN. Moreover, transient electrical stimulation of MGN enhanced the acoustic startle reflex when it lagged behind acoustic stimulation, but inhibited the acoustic startle reflex when it preceded acoustic stimulation. The results of the present study indicate that MGN and AAC afferents to LA play different roles in emotional modulation of startle, and AAC afferents are more influenced by inhibitory GABAB transmission in LA.
Assuntos
Córtex Auditivo/efeitos da radiação , Baclofeno/análogos & derivados , Estimulação Elétrica , Corpos Geniculados/efeitos da radiação , Reflexo de Sobressalto/fisiologia , Vigília/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/fisiologia , Baclofeno/farmacologia , Comportamento Animal , Lateralidade Funcional , Antagonistas GABAérgicos/farmacologia , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Masculino , Modelos Biológicos , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Fatores de TempoRESUMO
The activity of the thalamus is state dependent. During slow-wave sleep, rhythmic burst firing is prominent, whereas during waking or rapid eye movement sleep, tonic, single-spike activity dominates. These state-dependent changes result from the actions of modulatory neurotransmitters. In the present study, we investigated the functional and cellular effects of the neuropeptide thyrotropin-releasing hormone (TRH) on the spontaneously active ferret geniculate slice. This peptide and its receptors are prominently expressed in the thalamic network, yet the role of thalamic TRH remains obscure. Bath application of TRH resulted in a transient cessation of both spindle waves and the epileptiform slow oscillation induced by application of bicuculline. With intracellular recordings, TRH application to the GABAergic neurons of the perigeniculate (PGN) or thalamocortical cells in the lateral geniculate nucleus resulted in depolarization and increased membrane resistance. In perigeniculate neurons, this effect reversed near the reversal potential for K+, suggesting that it is mediated by a decrease in K+ conductance. In thalamocortical cells, the TRH-induced depolarization was of sufficient amplitude to block the generation of rebound Ca2+ spikes, whereas the even larger direct depolarization of PGN neurons transformed these cells from the burst to tonic, single-spike mode of action potential generation. Furthermore, application of TRH prominently enhanced the afterdepolarization that follows rebound Ca2+ spikes, suggesting that this transmitter may also enhance Ca2+-activated nonspecific currents. These data suggest a novel role for TRH in the brain as an intrinsic regulator of thalamocortical network activity and provide a potential mechanism for the wake-promoting and anti-epileptic effects of this peptide.
Assuntos
Sinalização do Cálcio/fisiologia , Corpos Geniculados/fisiologia , Tálamo/fisiologia , Hormônio Liberador de Tireotropina/fisiologia , Vigília/fisiologia , Potenciais de Ação , Animais , Bicuculina/farmacologia , Epilepsia/fisiopatologia , Feminino , Furões , Antagonistas GABAérgicos/farmacologia , Corpos Geniculados/efeitos dos fármacos , Técnicas In Vitro , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Transporte de Íons/efeitos dos fármacos , Transporte de Íons/fisiologia , Masculino , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Técnicas de Patch-Clamp , Potássio/fisiologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Receptores de GABA-A/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Hormônio Liberador de Tireotropina/análise , Hormônio Liberador de Tireotropina/farmacologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Information gating through the thalamus is dependent on the output of thalamic relay neurons. These relay neurons receive convergent innervation from a number of sources, including GABA-containing interneurons that provide feed-forward inhibition. These interneurons are unique in that they have two distinct outputs: axonal and dendritic. In addition to conventional axonal outputs, these interneurons have presynaptic dendrites that may provide localized inhibitory influences. Our study indicates that synaptic activation of metabotropic glutamate receptors (mGluRs) increases inhibitory activity in relay neurons by increasing output of presynaptic dendrites of interneurons. Optic tract stimulation increases inhibitory activity in thalamic relay neurons in a frequency- and intensity-dependent manner and is attenuated by mGluR antagonists. Our data suggest that synaptic activation of mGluRs selectively alters dendritic output but not axonal output of thalamic interneurons. This mechanism could serve an important role in focal, feed-forward information processing in addition to dynamic information processing in thalamocortical circuits.
Assuntos
Dendritos/fisiologia , Interneurônios/fisiologia , Inibição Neural/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Vias Aferentes/citologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Dendritos/efeitos dos fármacos , Dendritos/ultraestrutura , Antagonistas de Aminoácidos Excitatórios/farmacologia , Corpos Geniculados/citologia , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Técnicas In Vitro , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Tálamo/citologia , Tálamo/efeitos dos fármacos , Vias Visuais/citologia , Vias Visuais/efeitos dos fármacos , Vias Visuais/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Mammalian thalamus is a critical site where early perception of sensorimotor signals is dynamically regulated by acetylcholine in a behavioral state-dependent manner. In this study, we examined how synaptic transmission is modulated by acetylcholine in auditory thalamus where sensory relay neurons form parallel lemniscal and nonlemniscal pathways. The former mediates tonotopic relay of acoustic signals, whereas the latter is involved in detecting and transmitting auditory cues of behavioral relevance. We report here that activation of cholinergic muscarinic receptors had opposite membrane effects on these parallel synaptic pathways. In lemniscal neurons, muscarine induced a sustained membrane depolarization and tonic firing by closing a linear K(+) conductance. In contrast, in nonlemniscal neurons, muscarine evoked a membrane hyperpolarization by opening a voltage-independent K(+) conductance. Depending on the level of membrane hyperpolarization and the strength of local synaptic input, nonlemniscal neurons were either suppressed or selectively engaged in detecting and transmitting synchronized synaptic input by firing a high-frequency spike burst. Immunohistochemical and Western blotting experiments showed that nonlemniscal neurons predominantly expressed M2 muscarinic receptors, whereas lemniscal cells had a significantly higher level of M1 receptors. Our data indicate that cholinergic modulation in the thalamus is pathway-specific. Enhanced cholinergic tone during behavioral arousal or attention may render synaptic transmission in nonlemniscal thalamus highly sensitive to the context of local synaptic activities.
Assuntos
Acetilcolina/fisiologia , Tálamo/fisiologia , Animais , Potenciais Evocados/efeitos dos fármacos , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana , Neurônios Aferentes/fisiologia , Potássio/metabolismo , Ratos , Ratos Long-Evans , Receptores Muscarínicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
The mechanisms of injury- and disease-associated apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex induces apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN), by 7 days post-lesion, that is p53 modulated and Bax dependent. We tested the hypothesis that this degenerative process is initiated by oxidative stress and early formation of DNA damage and is accompanied by changes in the levels of pro-apoptotic mediators of cell death. Immunoblotting revealed that the protein profiles of Bax, Bak and Bad were different during the progression of neuronal apoptosis in the LGN. Bax underwent a subcellular redistribution by 1 day post-lesion, while Bak increased later. Bad showed an early sustained increase. Cleaved caspase-3 was elevated maximally at 5 and 6 days. Active caspase-3 underwent a subcellular translocation to the nucleus. A dramatic phosphorylation of p53 was detected at 4 days post-lesion. DNA damage was assessed immunocytochemically as hydroxyl radical adducts (8-hydroxy-2-deoxyguanosine) and single-stranded DNA. Both forms of DNA damage accumulated early in target-deprived LGN neurons. Transgenic overexpression of superoxide dismutase-1 provided significant protection against the apoptosis but antioxidant pharmacotreatments with trolox and ascorbate were ineffective. We conclude that overlapping and sequential signaling pathways are involved in the apoptosis of adult brain neurons and that DNA damage generated by superoxide derivatives is an upstream mechanism for p53-regulated, Bax-dependent apoptosis of target-deprived neurons.
Assuntos
Apoptose/fisiologia , Lesões Encefálicas/fisiopatologia , Dano ao DNA/fisiologia , Neurônios/metabolismo , Estresse Oxidativo/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2 , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Axotomia , Lesões Encefálicas/patologia , Proteínas de Transporte/metabolismo , Caspase 3 , Caspases/metabolismo , Descorticação Cerebral , Modelos Animais de Doenças , Corpos Geniculados/química , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosforilação , Transporte Proteico/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/química , Tálamo/patologia , Tálamo/fisiopatologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2 , Proteína de Morte Celular Associada a bclRESUMO
Paired-pulse depression was studied at the glutamatergic synapse between retinal afferents and thalamocortical cells in the rat dorsal lateral geniculate nucleus. The main objective of this study was to examine the contributions of the pre- and postsynaptic sites to this depression by comparing AMPA- and NMDA-receptor-mediated responses. Equal depression of the two receptor components would indicate involvement of presynaptic mechanisms, while differences in depression would indicate involvement of postsynaptic mechanisms. Pharmacologically isolated AMPA- and NMDA-receptor-mediated currents were recorded using the whole-cell patch-clamp technique in acute thalamic slices. Both the AMPA and the NMDA components showed pronounced depression when retinal afferents were activated by paired pulses. The depression decayed within 5 s. The AMPA component was more strongly depressed than the NMDA component at paired-pulse intervals ranging from 20 to 200 ms, suggesting the involvement of postsynaptic mechanisms. For intervals of 500 ms and longer, the depression of the two components was identical, suggesting the involvement of purely presynaptic mechanisms. The degree of depression measured without the use of pharmacological tools produced similar results, thus excluding the involvement of presynaptic ionotropic glutamate receptors. Cyclothiazide, a blocker of AMPA-receptor desensitisation, reduced the difference in depression between the two components, suggesting that desensitisation of the AMPA receptors is a postsynaptic mechanism that contributes to the difference in depression between the AMPA and the NMDA components.
Assuntos
Corpos Geniculados/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Benzotiadiazinas/farmacologia , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Corpos Geniculados/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Cinética , Magnésio/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Ratos , Ratos Wistar , Receptores de AMPA/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores Pré-Sinápticos/efeitos dos fármacos , Receptores Pré-Sinápticos/metabolismo , Retina/citologia , Retina/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Tálamo/citologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologiaRESUMO
To facilitate an understanding of auditory thalamocortical mechanisms, we have developed a mouse brain-slice preparation with a functional connection between the ventral division of the medial geniculate (MGv) and the primary auditory cortex (ACx). Here we present the basic characteristics of the slice in terms of physiology (intracellular and extracellular recordings, including current source density analysis), pharmacology (including glutamate receptor involvement), and anatomy (gross anatomy, Nissl, parvalbumin immunocytochemistry, and tract tracing with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Thalamocortical transmission in this preparation (the "primary" slice) involves both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid/kainate and N-methyl-D-aspartate-type glutamate receptors that appear to mediate monosynaptic inputs to layers 3-4 of ACx. MGv stimulation also initiates disynaptic inhibitory postsynaptic potentials and longer-duration intracortical, polysynaptic activity. Important differences between responses elicited by MGv versus conventional columnar ("on-beam") stimulation emphasize the necessity of thalamic activation to infer thalamocortical mechanisms. We also introduce a second slice preparation, the "shell" slice, obtained from the brain region immediately ventral to the primary slice, that may contain a nonprimary thalamocortical pathway to temporal cortex. In the shell slice, stimulation of the thalamus or the region immediately ventral to it appears to produce fast activation of synapses in cortical layer 1 followed by robust intracortical polysynaptic activity. The layer 1 responses may result from orthodromic activation of nonprimary thalamocortical pathways; however, a plausible alternative could involve antidromic activation of corticotectal neurons and their layer 1 collaterals. The primary and shell slices will provide useful tools to investigate mechanisms of information processing in the ACx.
Assuntos
Córtex Auditivo/fisiologia , Vias Auditivas/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/fisiologia , Potenciais de Ação/fisiologia , Animais , Córtex Auditivo/anatomia & histologia , Córtex Auditivo/efeitos dos fármacos , Vias Auditivas/anatomia & histologia , Vias Auditivas/efeitos dos fármacos , Cálcio/metabolismo , Cálcio/farmacologia , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Corantes Fluorescentes , Corpos Geniculados/anatomia & histologia , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/fisiologia , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos , Inibição Neural/fisiologia , Tempo de Reação/fisiologia , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Tálamo/anatomia & histologia , Tálamo/efeitos dos fármacosRESUMO
Inhibition is crucial for sharpening the sensory information relayed through the thalamus. To understand how the interneuron-mediated inhibition in the thalamus is regulated, we studied the muscarinic effects on interneurons in the lateral posterior nucleus and lateral geniculate nucleus of the thalamus. Here, we report that activation of muscarinic receptors switched the firing pattern in thalamic interneurons from bursting to tonic. Although neuromodulators switch the firing mode in several other types of neurons by altering their membrane potential, we found that activation of muscarinic subtype 2 receptors switched the fire mode in thalamic interneurons by selectively decreasing their input resistance. This is attributable to the muscarinic enhancement of a hyperpolarizing potassium conductance and two depolarizing cation conductances. The decrease in input resistance appeared to electrotonically uncouple the distal dendrites of thalamic interneurons, which effectively changed the inhibition pattern in thalamocortical cells. These results suggest a novel cellular mechanism for the cholinergic transformation of long-range, slow dendrite- and axon-originated inhibition into short-range, fast dendrite-originated inhibition in the thalamus observed in vivo. It is concluded that the electrotonic properties of the dendritic compartments of thalamic interneurons can be dynamically regulated by muscarinic activity.
Assuntos
Axônios/metabolismo , Dendritos/metabolismo , Interneurônios/metabolismo , Receptores Muscarínicos/metabolismo , Tálamo/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Impedância Elétrica , Antagonistas GABAérgicos/farmacologia , Corpos Geniculados/citologia , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/metabolismo , Técnicas In Vitro , Interneurônios/efeitos dos fármacos , Núcleos Laterais do Tálamo/citologia , Núcleos Laterais do Tálamo/efeitos dos fármacos , Núcleos Laterais do Tálamo/metabolismo , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Inibição Neural/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Tempo de Reação/fisiologia , Tálamo/citologia , Tálamo/efeitos dos fármacosRESUMO
This study investigates the origins of tone-evoked oscillations (5-13 Hz) in the thalamo-cortical auditory system of anaesthetized rats. In three separate experiments, the auditory sector of the reticular nucleus (RE), the auditory cortex and the auditory thalamus were inactivated by local applications of muscimol (1 mg/mL). To assess the efficacy of this procedure, recordings were performed in the inactivated structure in each experiment; and to determine the extent of the drug diffusion autoradiographic experiments were carried out. The evolution of the strength of the oscillations was followed using power spectra during the whole recording session. In the first experiment, muscimol injection in the auditory RE totally suppressed the tone-evoked oscillations in the auditory thalamus and cortex. In the second experiment, inactivation of the auditory cortex did not interfere with the presence of tone-evoked oscillations in the auditory RE. In the third experiment, inactivation of the auditory thalamus impaired the oscillations produced by cortical stimulation in the auditory RE. From these results, it appears that both the auditory thalamus and the auditory sector of the RE, but not the auditory cortex, are involved in the generation of stimulus-evoked oscillations in the thalamo-cortical auditory system.