RESUMO
We have found that daily subcutaneous injection with a maximum tolerated dose of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks of age dramatically improves the motor, neuronal and neurochemical phenotype in R6/2 mice, a rapidly progressing transgenic model of Huntington's disease (HD). We also previously showed that the benefit of daily LY379268 in R6/2 mice was associated with increases in corticostriatal brain-derived neurotrophic factor (BDNF), and in particular was associated with a reduction in enkephalinergic striatal projection neuron loss. In the present study, we show that daily LY379268 also rescues expression of BDNF by neurons of the thalamic parafascicular nucleus in R6/2 mice, which projects prominently to the striatum, and this increase too is linked to the rescue of enkephalinergic striatal neurons. Thus, LY379268 may protect enkephalinergic striatal projection neurons from loss by boosting BDNF production and delivery via both the corticostriatal and thalamostriatal projection systems. These results suggest that chronic treatment with mGluR2/3 agonists may represent an approach for slowing enkephalinergic neuron loss in HD, and perhaps progression in general.
Assuntos
Aminoácidos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Doença de Huntington/tratamento farmacológico , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Aminoácidos/uso terapêutico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Corpo Estriado/citologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Feminino , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Injeções Subcutâneas , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/patologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
Propofol is the most commonly used intravenous anesthetic worldwide. It can induce loss of consciousness prior to the occurrence of severe respiratory suppression, which is also a pharmacodynamic feature of all general anesthetics. However, the neural mechanisms underlying this natural phenomenon are controversial and highly related to patient safety. In the present study, we demonstrated that the pharmacodynamic effects of propofol (50 and 100 µM) on suppression of consciousness-related excitatory postsynaptic currents in the medial prefrontal cortex (mPFC) and centromedian nucleus of the thalamus (CMT) were lower than those in the kernel respiratory rhythmogenesis nucleus pre-Bötzinger complex (PrBo). Furthermore, we unexpectedly found that the GABAA receptor ß3 subunit is the key target for propofol's action and that it is mutually and exclusively expressed in GABAergic neurons. It is also more abundant in the mPFC and CMT, but mainly co-localized with GABAergic neurons in the PrBo. As a result, the differentiated expression pattern should mediate more neuron suppression through the activation of GABAergic neurons in the mPFC and CMT at low doses of propofol (50 µM). However, PrBo GABAergic neurons were only activated by propofol at a high dose (100 µM). These results highlight the detailed pharmacodynamic effects of propofol on consciousness-related and respiration-related nuclei and provide the distinct interaction mechanism between the ß3 subunit and GABAergic neurons in mediating the suppression of consciousness compared to the inhibition of respiration.
Assuntos
Neurônios GABAérgicos/metabolismo , Núcleos Intralaminares do Tálamo , Córtex Pré-Frontal , Propofol/farmacologia , Receptores de GABA-A/metabolismo , Mecânica Respiratória/efeitos dos fármacos , Inconsciência , Animais , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/fisiopatologia , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Ratos Sprague-Dawley , Inconsciência/induzido quimicamente , Inconsciência/metabolismo , Inconsciência/fisiopatologiaRESUMO
Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.
Assuntos
Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/metabolismo , Epilepsias Mioclônicas/metabolismo , Hidrogênio/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Pulmão/inervação , Respiração , Somatostatina/metabolismo , Animais , Modelos Animais de Doenças , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Feminino , Ácido Glutâmico/metabolismo , Núcleos Intralaminares do Tálamo/fisiopatologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Inibição Neural , Somatostatina/genética , Transmissão SinápticaRESUMO
Parvalbumin-immunoreactive (Parv+) interneurons is an important component of striatal GABAergic microcircuits, which receive excitatory inputs from the cortex and thalamus, and then target striatal projection neurons. The present study aimed to examine ultrastructural synaptic connection features of Parv+ neruons with cortical and thalamic input, and striatal projection neurons by using immuno-electron microscopy (immuno-EM) and immunofluorescence techniques. Our results showed that both Parv+ somas and dendrites received numerous asymmetric synaptic inputs, and Parv+ terminals formed symmetric synapses with Parv- somas, dendrites and spine bases. Most interestingly, spine bases targeted by Parv+ terminals simultaneously received excitatory inputs at their heads. Electrical stimulation of the motor cortex (M1) induced higher proportion of striatal Parv+ neurons express c-Jun than stimulation of the parafascicular nucleus (PFN), and indicated that cortical- and thalamic-inputs differentially modulate Parv+ neurons. Consistent with that, both Parv + soma and dendrites received more VGlut1+ than VGlut2+ terminals. However, the proportion of VGlut1+ terminal targeting onto Parv+ proximal and distal dendrites was not different, but VGlut2+ terminals tended to target Parv+ somas and proximal dendrites than distal dendrites. These functional and morphological results suggested excitatory cortical and thalamic glutamatergic inputs differently modulate Parv+ interneurons, which provided inhibition inputs onto striatal projection neurons. To maintain the balance between the cortex and thalamus onto Parv+ interneurons may be an important therapeutic target for neurological disorders.
Assuntos
Córtex Cerebral/ultraestrutura , Dendritos/ultraestrutura , Interneurônios/ultraestrutura , Núcleos Intralaminares do Tálamo/ultraestrutura , Parvalbuminas/metabolismo , Sinapses/ultraestrutura , Animais , Córtex Cerebral/metabolismo , Dendritos/metabolismo , Interneurônios/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Masculino , Ratos Sprague-Dawley , Sinapses/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Methamphetamine (Meth) seeking progressively increases after cessation from drug self-administration (incubation of Meth craving). We have previously shown that both dorsomedial and dorsolateral striatum (DMS and DLS) play critical roles in this incubation in male rats. Moreover, our recent anatomical tracing study examined afferent projections into DMS and demonstrated a novel role of projections from anterior intralaminar nucleus of thalamus (AIT) to DMS in incubation of Meth craving in male rats. Here we investigated projection-specific activation of afferent glutamate projections into DLS associated with incubated Meth seeking in female rats. We trained female rats to self-administer Meth (6-h/d for 10 d). On abstinence day 12, we injected cholera toxin subunit B (CTb, a retrograde tracer) unilaterally into DLS. On abstinence day 26, we tested rats for relapse to Meth seeking and measured Fos (a neuronal activity marker), and double-labeling of CTb and Fos in anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, basolateral amygdala, AIT, and parafascicular nuclei of thalamus. We observed neuronal activation in both cortical and thalamic regions associated with incubated Meth seeking. At the circuit level, AITâDLS projections were strongly activated, followed by other corticostriatal projections. Overall our results suggest that AIT to DLS may play a role in Meth seeking after prolonged abstinence in female rats.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/metabolismo , Metanfetamina/farmacologia , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Fissura/efeitos dos fármacos , Feminino , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração/métodos , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
Number of ligations made in the chronic constriction injury (CCI) neuropathic pain model has raised serious concerns. We compared behavioural responses, nerve morphology and expression of pain marker, c-fos among CCI models developed with one, two, three and four ligations. The numbers of ligation(s) on sciatic nerve shows no significant difference in displaying mechanical and cold allodynia, and mechanical and thermal hyperalgesia throughout 84 days. All groups underwent similar levels of nerve degeneration post-surgery. Similar c-fos level in brain cingulate cortex, parafascicular nuclei and amygdala were observed in all CCI models compared to sham-operated group. Therefore, number of ligations does not impact intensity of pain symptoms, pathogenesis and neuronal activation. A single ligation is sufficient to develop neuropathic pain, in contrast to the established model of four ligations. This study dissects and characterises the CCI model, ascertaining a more uniform animal model to surrogate actual neuropathic pain condition.
Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos ICR , Neuralgia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Constrição Patológica/complicações , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/patologia , Ligadura , Masculino , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Medição da Dor , Proteínas Proto-Oncogênicas c-fos/metabolismo , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Neuropatia Ciática/etiologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologiaRESUMO
Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24â¯h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Ketamina/farmacologia , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Fenciclidina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Neurônios GABAérgicos/metabolismo , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/metabolismo , Núcleo Mediodorsal do Tálamo/citologia , Núcleo Mediodorsal do Tálamo/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tálamo , VigíliaRESUMO
Locomotion relies on the activity of basal ganglia networks, where, as the output, the substantia nigra pars reticulata (SNr) integrates incoming signals and relays them to downstream areas. The cellular and circuit substrates of such a complex function remain unclear. We hypothesized that the SNr controls different aspects of locomotion through coordinated cell-type-specific sub-circuits. Using anatomical mapping, single-cell qPCR, and electrophysiological techniques, we identified two SNr sub-populations: the centromedial-thalamo projectors (CMps) and the SN compacta projectors (SNcps), which are genetically targeted based on vesicular transporter for gamma-aminobutyric acid (VGAT) or parvalbumin (PV) expression, respectively. Optogenetic manipulation of these two sub-types across a series of motor tests provided evidence that they govern different aspects of motor behavior. While CMp activity supports the continuity of motor patterns, SNcp modulates the immediate motor drive behind them. Collectively, our data suggest that at least two different sub-circuits arise from the SNr, engage different behavioral motor components, and collaborate to produce correct locomotion.
Assuntos
Locomoção/fisiologia , Neurônios/fisiologia , Substância Negra/citologia , Potenciais de Ação/fisiologia , Animais , Feminino , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/metabolismo , Locomoção/genética , Masculino , Camundongos , Inibição Neural/fisiologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Optogenética , Parvalbuminas/metabolismo , Substância Negra/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
The selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine have been considered to involve activation of postsynaptic α2A adrenoceptor in frontal pyramidal neurons. However, the effects of chronic guanfacine administration on catecholaminergic transmissions associated with the orbitofrontal cortex (OFC) remain unclear. To explore the mechanisms of action of guanfacine on catecholaminergic transmission, the effects of its acute local or sub-chronic systemic administration on catecholamine release within pathways from locus coeruleus (LC) to OFC and reticular thalamic nucleus (RTN), from RTN to mediodorsal thalamic nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Acute OFC local administration of guanfacine did not affect catecholamine release in OFC. Acute LC local and sub-chronic systemic administrations of guanfacine reduced norepinephrine release in LC, OFC and RTN, and also reduced GABA release in MDTN, whereas AMPA-induced (perfusion with AMPA into NDTN) releases of l-glutamate, norepinephrine and dopamine in OFC were enhanced by sub-chronic systemic guanfacine administration. This study identified that catecholaminergic transmission is composed of three pathways: direct noradrenergic and co-releasing catecholaminergic LC-OFC pathways and intermediate LC-OFC (LC-RTN-MDTN-OFC) pathway. We demonstrated the dual actions of guanfacine on catecholaminergic transmission: attenuation of direct noradrenergic LC-OFC transmission at the resting stage and enhancement of direct co-releasing catecholaminergic LC-OFC transmission via GABAergic disinhibition in the intermediate LC-OFC pathway. These dual actions of guanfacine probably contribute to clinical actions of guanfacine against ADHD and its comorbid symptoms. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Dopamina/metabolismo , Guanfacina/administração & dosagem , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica , Animais , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Núcleo Mediodorsal do Tálamo/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacosRESUMO
Follicular development and ovulation are profoundly suppressed during lactation in mammals. This suppression is suggested to be mainly due to the suckling-induced inhibition of kisspeptin gene (Kiss1) expression in the arcuate nucleus (ARC) and consequent inhibition of pulsatile GnRH/LH release. We examined whether central somatostatin (SST) signaling mediates the suckling-induced suppression of pulsatile LH secretion. SST has been reported to be expressed in the posterior intralaminar thalamic nucleus (PIL), where the suckling stimulus is postulated to be relayed to the hypothalamus during lactation. SST inhibitory receptors (SSTRs) are abundantly expressed in the ARC, where kisspeptin/neurokinin B/dynorphin A (KNDy) neurons are located. Histological and quantitative studies revealed that the suckling stimulus increased the number of SST-expressing cells in the PIL, and Sstr2 expression in the ARC. Furthermore, a central injection of an SSTR2 antagonist caused a significant increase in pulsatile LH release in lactating rats. Double labeling of Sstr2 and the neurokinin B gene, as a marker for ARC KNDy neurons, showed Sstr2 expression was abundantly detected in the ARC, but few KNDy neurons coexpressed Sstr2 in lactating rats. Taken together, these findings suggest the suckling-induced activation of SST-SSTR2 signaling mediates, at least in part, the suppression of pulsatile LH secretion during lactation in rats, probably via the indirect effects of SST on KNDy neurons. These results provide a new aspect on the role of central SST-SSTR signaling in understanding the mechanism underlying lactational anestrus.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Lactação , Hormônio Luteinizante/metabolismo , Receptores de Somatostatina/metabolismo , Animais , Animais Lactentes , Feminino , Núcleos Intralaminares do Tálamo/metabolismo , Neuropeptídeos/metabolismo , Ratos , Receptores de Somatostatina/antagonistas & inibidores , Somatostatina/metabolismoRESUMO
The widely held view that the pathophysiology of Parkinson's disease arises from an under-activation of the direct pathway striatal spiny neurons (dSPNs) has gained support from a recently described weakening of the glutamatergic projection from the parafascicular nucleus (PfN) to dSPNs in experimental parkinsonism. However, the impact of the remodeling of the thalamostriatal projection cannot be fully appreciated without considering its impact on cholinergic interneurons (ChIs) that themselves preferentially activate indirect pathway spiny neurons (iSPNs). To study this thalamostriatal projection, we virally transfected with Cre-dependent channelrhodopsin-2 (ChR2) the PfN of Vglut2-Cre mice that were dopamine-depleted with 6-hydroxydopamine (6-OHDA). In parallel, we studied the corticostriatal projection to ChIs in 6-OHDA-treated transgenic mice expressing ChR2 under the Thy1 promoter. We found the 6-OHDA lesions failed to affect short-term synaptic plasticity or the size of unitary responses evoked optogenetically in either of these projections. However, we found that NMDA-to-AMPA ratios at PfN synapses-that were significantly larger than NMDA-to-AMPA ratios at cortical synapses-were reduced by 6-OHDA treatment, thereby impairing synaptic integration at PfN synapses onto ChIs. Finally, we found that application of an agonist of the D5 dopamine receptors on ChIs potentiated NMDA currents without affecting AMPA currents or short-term plasticity selectively at PfN synapses. We propose that dopamine depletion leads to an effective de-potentiation of NMDA currents at PfN synapses onto ChIs which degrades synaptic integration. This selective remodeling of NMDA currents at PfN synapses may counter the selective weakening of PfN synapses onto dSPNs in parkinsonism.
Assuntos
Neurônios Colinérgicos/metabolismo , Dopamina/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Corpo Estriado/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Masculino , Camundongos Transgênicos , Vias Neurais/fisiologia , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/fisiopatologiaRESUMO
KEY POINTS: Electrical synapses are modified by various forms of activity, including paired activity in coupled neurons and tetanization of the input to coupled neurons. We show that plasticity of electrical synapses that results from paired spiking activity in coupled neurons depends on calcium influx and calcium-initiated signalling pathways. Plasticity that results from tetanization of input fibres does not depend on calcium influx or dynamics. These results imply that electrically coupled neurons have distinct sets of mechanisms for adjusting coupling according to the specific type of activity they experience. ABSTRACT: Recent results have demonstrated modification of electrical synapse strength by varied forms of neuronal activity. However, the mechanisms underlying plasticity induction in central mammalian neurons are unclear. Here we show that the two established inductors of plasticity at electrical synapses in the thalamic reticular nucleus - paired burst spiking in coupled neurons, and mGluR-dependent tetanization of synaptic input - are separate pathways that converge at a common downstream endpoint. Using occlusion experiments and pharmacology in patched pairs of coupled neurons in vitro, we show that burst-induced depression depends on calcium entry via voltage-gated channels, is blocked by BAPTA chelation, and recruits intracellular calcium release on its way to activation of phosphatase activity. In contrast, mGluR-dependent plasticity is independent of calcium entry or calcium dynamics. Together, these results show that the spiking-initiated mechanisms underlying electrical synapse plasticity are similar to those that induce plasticity at chemical synapses, and offer the possibility that calcium-regulated mechanisms may also lead to alternate outcomes, such as potentiation. Because these mechanistic elements are widely found in mature neurons, we expect them to apply broadly to electrical synapses across the brain, acting as the crucial link between neuronal activity and electrical synapse strength.
Assuntos
Sinalização do Cálcio , Sinapses Elétricas/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Plasticidade Neuronal , Potenciais de Ação , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Sinapses Elétricas/fisiologia , Feminino , Núcleos Intralaminares do Tálamo/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.
Assuntos
Comportamento Animal , Núcleos Intralaminares do Tálamo/metabolismo , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Animais , Nível de Alerta , Atenção , Modelos Animais de Doenças , Eletroencefalografia , Terapia Genética , Comportamento Impulsivo , Locomoção , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Camundongos , Camundongos Transgênicos , Mutação , Fenótipo , Inibição Pré-Pulso , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Memória EspacialRESUMO
The thalamic reticular nucleus (TRN), a cluster of GABAergic cells, is thought to regulate bottom-up and top-down streams of sensory processing in the loop circuitry between the thalamus and cortex. Provided that sensory inputs of different modalities interact in the TRN, the TRN could contribute to fast and flexible cross-modal modulation of attention and perception that incessantly takes place in our everyday life. Indeed, diverse subthreshold interactions of auditory and visual inputs have been revealed in TRN cells (Kimura, 2014). To determine whether such sensory interaction could extend across modalities as a universal neural mechanism, the present study examined TRN cell activities elicited by auditory and cutaneous electrical stimulations in anesthetized rats. Juxta-cellular recording and labeling techniques were used. Recordings were obtained from 129 cells. Auditory or somatosensory responses were modulated by subthreshold electrical stimulation or sound (noise burst) in the majority of recordings (77 of 85 auditory and 13 of 15 somatosensory cells). Additionally, 22 bimodal cells and seven cells that responded only to combined stimulation were recognized. Suppression was predominant in modulation that was observed in both early and repeatedly evoked late responses. Combined stimulation also induced de novo cell activities. Further, response latency and burst spiking were modulated. Axonal projections of cells showing modulation terminated in first- or higher-order thalamic nuclei. Nine auditory cells projected to somatosensory thalamic nuclei. These results suggest that the TRN could regulate sensory processing in the loop circuitry between the thalamus and cortex through the sensory interaction pervasive across modalities.
Assuntos
Vias Auditivas/fisiologia , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/fisiologia , Estimulação Acústica , Animais , Atenção/fisiologia , Percepção Auditiva/fisiologia , Axônios/fisiologia , Córtex Cerebral/fisiologia , Estimulação Elétrica , Corpos Geniculados/fisiologia , Masculino , Neurônios/fisiologia , Ratos , Ratos Wistar , Pele , Núcleos Talâmicos/fisiologia , Tálamo/metabolismo , Tálamo/fisiologia , Estimulação Elétrica Nervosa TranscutâneaRESUMO
T-type calcium channels (Cav3) are key mediators of thalamic bursting activity, but also regulate single cells excitability, dendritic integration, synaptic strength and transmitter release. These functions are strongly influenced by the subcellular and subsynaptic localization of Cav3 channels along the somatodendritic domain of thalamic cells. In Parkinson's disease, T-type calcium channels dysfunction in the basal ganglia-receiving thalamic nuclei likely contributes to pathological thalamic bursting activity. In this study, we analyzed the cellular, subcellular, and subsynaptic localization of the Cav3.1 channel in the ventral anterior (VA) and centromedian/parafascicular (CM/Pf) thalamic nuclei, the main thalamic targets of basal ganglia output, in normal and parkinsonian monkeys. All thalamic nuclei displayed strong Cav3.1 neuropil immunoreactivity, although the intensity of immunolabeling in CM/Pf was significantly lower than in VA. Ultrastructurally, 70-80 % of the Cav3.1-immunoreactive structures were dendritic shafts. Using immunogold labeling, Cav3.1 was commonly found perisynaptic to asymmetric and symmetric axo-dendritic synapses, suggesting a role of Cav3.1 in regulating excitatory and inhibitory neurotransmission. Significant labeling was also found at non-synaptic sites along the plasma membrane of thalamic neurons. There was no difference in the overall pattern and intensity of immunostaining between normal and parkinsonian monkeys, suggesting that the increased rebound bursting in the parkinsonian state is not driven by changes in Cav3.1 expression. Thus, T-type calcium channels are located to subserve neuronal bursting, but also regulate glutamatergic and non-glutamatergic transmission along the whole somatodendritic domain of basal ganglia-receiving neurons of the primate thalamus.
Assuntos
Canais de Cálcio Tipo T/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Sinapses/metabolismo , Tálamo/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Núcleos Intralaminares do Tálamo/metabolismo , Núcleos Intralaminares do Tálamo/ultraestrutura , Macaca mulatta , Neurônios/ultraestrutura , Transtornos Parkinsonianos/metabolismo , Sinapses/ultraestrutura , Tálamo/ultraestrutura , Núcleos Ventrais do Tálamo/metabolismo , Núcleos Ventrais do Tálamo/ultraestruturaRESUMO
Quinolinic acid (QUIN) has been suggested to be involved in infections, inflammatory neurological disorders and in the development of psychiatric disorders. In this view, several studies have been performed to investigate QUIN localization in the brain and its neurotoxic effects. However, evidence is lacking regarding QUIN in healthy, control conditions. The aim of this study was to investigate the region-specific distribution and pattern of QUIN expression in the naïve mouse brain. In addition, possible sex differences in QUIN-immunoreactivity and its link with affect-related behavioural observations were assessed. For this purpose, naïve mice were subjected to the forced swim test (FST) and 20 min open field (OF) testing to measure affect-related behaviour. Afterwards, brains were assessed for QUIN-immunoreactivity. QUIN-immunoreactivity was particularly observed in the cingulate cortex (CC), highlighting clearly delineated cells, and the thalamic reticular nucleus (TRN), showing a more diffuse staining pattern. Subsequently, QUIN-positive cells in the CC were counted, while QUIN-immunoreactivity in the TRN was examined using gray value measurements. No significant differences between sexes were observed for the number of QUIN-positive cells in the CC, neither in levels of QUIN-immunoreactivity in the TRN. A direct correlation was found between QUIN-positive cells in the CC and QUIN-immunoreactivity in the TRN. Moreover, in male mice, a very strong correlation (rsp=.943; p<.01) between QUIN-immunoreactivity at the level of the TRN and motor activity in the OF was observed. Thus, our results suggest that QUIN - detected in the CC and the TRN - may play a role in regulating motor activity in normal conditions.
Assuntos
Encéfalo/metabolismo , Ácido Quinolínico/metabolismo , Afeto , Animais , Feminino , Giro do Cíngulo/metabolismo , Núcleos Intralaminares do Tálamo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores SexuaisRESUMO
The GABAergic neurons of the thalamic reticular nucleus (nRt) provide the primary source of inhibition within the thalamus. Using physiology, pharmacology, and immunohistochemistry in mice, we characterized postsynaptic developmental changes in these inhibitory projection neurons. First, at postnatal days 3-5 (P3-5), inhibitory postsynaptic currents (IPSCs) decayed very slowly, followed by a biphasic developmental progression, becoming faster at P6-8 and then slower again at P9-11 before stabilizing in a mature form around P12. Second, the pharmacological profile of GABA(A) receptor (GABA(A)R)-mediated IPSCs differed between neonatal and mature nRt neurons, and this was accompanied by reciprocal changes in α3 (late) and α5 (early) subunit expression in nRt. Zolpidem, selective for α1- and α3-containing GABA(A)Rs, augmented only mature IPSCs, whereas clonazepam enhanced IPSCs at all stages. This effect was blocked by the α5-specific inverse agonist L-655,708, but only in immature neurons. In α3(H126R) mice, in which α3-subunits were mutated to become benzodiazepine insensitive, IPSCs were enhanced compared with those in wild-type animals in early development. Third, tonic GABA(A)R activation in nRt is age dependent and more prominent in immature neurons, which correlates with early expression of α5-containing GABA(A)Rs. Thus neonatal nRt neurons show relatively high expression of α5-subunits, which contributes to both slow synaptic and tonic extrasynaptic inhibition. The postnatal switch in GABA(A)R subunits from α5 to α3 could facilitate spontaneous network activity in nRt that occurs at this developmental time point and which is proposed to play a role in early circuit development.
Assuntos
Núcleos Intralaminares do Tálamo/metabolismo , Receptores de GABA-A/metabolismo , Animais , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Potenciais Pós-Sinápticos Inibidores , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/crescimento & desenvolvimento , Núcleos Intralaminares do Tálamo/fisiologia , Camundongos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de GABA-A/genéticaRESUMO
The striatum is the key input nucleus of the basal ganglia, and is implicated in motor control and learning. Despite the importance of striatal circuits, the mechanisms associated with their development are not well established. Previously, Ten-m3, a member of the Ten-m/teneurin/odz family of transmembrane glycoproteins, was found to be important in the mapping of binocular visual pathways. Here, we investigated a potential role for Ten-m3 in striatal circuit formation. In situ hybridisation revealed a patchy distribution of Ten-m3 mRNA expression superimposed on a high-dorsal to low-ventral gradient in a subregion of the striatal matrix. A survey of afferent/efferent structures associated with the matrix identified the parafascicular thalamic nucleus (PF) as a potential locus of action. Ten-m3 was also found to be expressed in a high-dorsal to low-ventral gradient in the PF, corresponding topographically to its expression in the striatum. Further, a subset of thalamic terminal clusters overlapped with Ten-m3-positive domains within the striatal matrix. Studies in wild-type (WT) and Ten-m3 knockout (KO) mice revealed no differences in overall striatal or PF structure. Thalamostriatal terminals in KOs, however, while still confined to the matrix subregion, lost their clustered appearance. Topography was also altered, with terminals from the lateral PF projecting ectopically to ventral and medial striatum, rather than remaining confined dorsolaterally as in WTs. Behaviorally, Ten-m3 KOs displayed delayed motor skill acquisition. This study demonstrates that Ten-m3 plays a key role in directing the formation of thalamostriatal circuitry, the first molecular candidate reported to regulate connectivity within this pathway.
Assuntos
Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Núcleos Intralaminares do Tálamo/crescimento & desenvolvimento , Núcleos Intralaminares do Tálamo/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Corpo Estriado/anatomia & histologia , Hibridização In Situ , Núcleos Intralaminares do Tálamo/anatomia & histologia , Aprendizagem/fisiologia , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Destreza Motora/fisiologia , Proteínas do Tecido Nervoso/genética , Vias Neurais/anatomia & histologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Técnicas de Rastreamento Neuroanatômico , RNA Mensageiro/metabolismo , Teste de Desempenho do Rota-Rod , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The laboratory mouse is increasingly a subject for visual system investigation, but there has been no comprehensive evaluation of this species' visual projections. Here, projections were visualized and mapped following intraocular injection of cholera toxin B subunit. Tissue was processed using standard procedures applied to 30 µm free-floating sections with diaminobenzidine as the chromogen. The mouse retina projects to ~46 brain regions, including 14 not previously described in this species. These include two amygdaloid nuclei, the horizontal limb of the diagonal band, the paraventricular hypothalamic nucleus, several visual thalamic nuclei, the paranigral nucleus, several pretectal nuclei, and the dorsal cortex of the inferior colliculus. Dense retinal patches were also observed in a narrow portion of the ipsilateral intermediate layer of the superior colliculus. The superior fasciculus of the accessory optic tract, which innervates the medial terminal nucleus, was also determined to be a terminal zone throughout its length. The results are compared with previous descriptions of projections from mouse intrinsically photoreceptive retinal ganglion cells, and with data from the hamster, Nile grass rat, and laboratory rat. The retinal projection patterns are similar in all four species, although there are many differences with respect to the details. The specific visual functions of most retinorecipient areas are unknown, but there is substantial convergence of retinal projections onto regions concerned with olfaction and audition.
Assuntos
Mapeamento Encefálico , Núcleos Intralaminares do Tálamo/fisiologia , Camundongos/anatomia & histologia , Retina/anatomia & histologia , Vias Visuais/fisiologia , Animais , Toxina da Cólera/metabolismo , Lateralidade Funcional , Núcleos Intralaminares do Tálamo/metabolismo , Camundongos Endogâmicos C57BL , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Opsinas de Bastonetes/metabolismo , Vias Visuais/metabolismoRESUMO
AIMS: Thalamostriatal fibers are involved in cognitive tasks such as acquisition, learning, processing of sensory events, and behavioral flexibility and might play a role in Parkinson's disease. The aim of the present study was the in vivo electrochemical characterization of the projection from the lateral aspect of the parafascicular thalamus (Pfl) to the dorsolateral aspect of the nucleus accumbens (dNAc). Since nitric oxide (NO) plays a crucial role in striatal synaptic transmission, its implication in Pfl-evoked signaling within the dNAc was investigated. MAIN METHODS: The Pfl was electrically stimulated utilizing paired pulses and extracellular potentials were recorded within the dNAc. Simultaneously, the dNAc was superfused using the push-pull superfusion technique for local application of compounds and for assessing the influence of NO on release of glutamate, aspartate and GABA. KEY FINDINGS: Stimulation of the Pfl evoked a negative-going component at 9-14 ms followed by a positive-going component at 39-48 ms. The early response was current-dependent and diminished by superfusion of the dNAc with tetrodotoxin, kynurenic acid or N(G)-nitro-l-arginine methyl ester (L-NAME), while 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA/NO) increased this evoked potential. Transmitter release was inhibited by L-NAME and facilitated by PAPA/NO. SIGNIFICANCE: This study describes for the first time in vivo extracellular electrical responses of the dNAc on stimulation of the Pfl. Synaptic transmission within the dNAc on stimulation of the Pfl seems to be facilitated by NO.