RESUMO
Thalamic regulation of cortical function is important for several behavioral aspects including attention and sensorimotor control. This region has also been studied for its involvement in seizure activity. Among the NMDA receptor subunits GluN2C and GluN2D are particularly enriched in several thalamic nuclei including nucleus reticularis of the thalamus (nRT). We have previously found that GluN2C deletion does not have a strong influence on the basal excitability and burst firing characteristics of reticular thalamus neurons. Here we find that GluN2D ablation leads to reduced depolarization-induced spike frequency and reduced hyperpolarization-induced rebound burst firing in nRT neurons. Furthermore, reduced inhibitory neurotransmission was observed in the ventrobasal thalamus (VB). A model with preferential downregulation of GluN2D from parvalbumin (PV)-positive neurons was generated. Conditional deletion of GluN2D from PV neurons led to a decrease in excitability and burst firing. In addition, reduced excitability and burst firing was observed in the VB neurons together with reduced inhibitory neurotransmission. Finally, young mice with GluN2D downregulation in PV neurons showed significant resistance to pentylenetetrazol-induced seizure and differences in sensitivity to isoflurane anesthesia but were normal in other behaviors. Conditional deletion of GluN2D from PV neurons also affected expression of other GluN2 subunits and GABA receptor in the nRT. Together, these results identify a unique role of GluN2D-containing receptors in the regulation of thalamic circuitry and seizure susceptibility which is relevant to mutations in GRIN2D gene found to be associated with pediatric epilepsy.
Assuntos
Receptores de N-Metil-D-Aspartato , Tálamo , Animais , Camundongos , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Transmissão Sináptica , Núcleos Talâmicos/metabolismo , Tálamo/metabolismoRESUMO
Parvalbumin-expressing dorsal striatal fast-spiking interneurons, comprising â¼1% of the total dorsal striatal neuronal population, are necessary for the expression of compulsive-like ethanol consumption mice. Fast-spiking interneurons are driven to fire by glutamatergic inputs derived primarily from the cortex. However, these neurons also receive substantial GABAergic input from two sources: the globus pallidus and the reticular nucleus of the thalamus. How ethanol modulates inhibitory input onto fast-spiking neurons is unclear and, more broadly, alcohol effects on GABAergic synaptic transmission onto GABAergic interneurons are understudied. Examining this, we found that acute bath application of ethanol (50 mM) potentiated GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto fast-spiking interneurons in mouse of both sexes. This ethanol-induced potentiation required postsynaptic calcium and was not accompanied by a sustained change in presynaptic GABA release probability. Examining whether this ethanol effect persisted following chronic intermittent ethanol exposure, we found attenuated acute-ethanol potentiation of GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto striatal fast-spiking interneurons. These data underscore the impact of ethanol on GABAergic signaling in the dorsal striatum and support the notion that ethanol may disinhibit the dorsolateral striatum.
Assuntos
Corpo Estriado , Etanol , Neurônios GABAérgicos , Interneurônios , Animais , Feminino , Masculino , Camundongos , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Etanol/administração & dosagem , Etanol/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Globo Pálido/citologia , Globo Pálido/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Núcleos Talâmicos/citologia , Núcleos Talâmicos/efeitos dos fármacos , Núcleos Talâmicos/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Cálcio/metabolismoRESUMO
The external globus pallidus (GP) is a GABAergic node involved in motor control regulation and coordinates firing and synchronization in the basal ganglia-thalamic-cortical network through inputs and electrical activity. In Parkinson's disease, high GABA levels alter electrical activity in the GP and contribute to motor symptoms. Under normal conditions, GABA levels are regulated by GABA transporters (GATs). GAT type 1 (GAT-1) is highly expressed in the GP, and pharmacological blockade of GAT-1 increases the duration of currents mediated by GABA A receptors and induces tonic inhibition. The functional contribution of the pathway between the GP and the reticular thalamic nucleus (RTn) is unknown. This pathway is important since the RTn controls the flow of information between the thalamus and cortex, suggesting that it contributes to cortical dynamics. In this work, we investigated the effect of increased GABA levels on electrical activity in the RTn by obtaining single-unit extracellular recordings from anesthetized rats and on the motor cortex (MCx) by corticography. Our results show that high GABA levels increase the spontaneous activity rate of RTn neurons and desynchronize oscillations in the beta frequency band in the MCx. Our findings provide evidence that the GP exerts tonic control over RTn activity through the GP-reticular pathway and functionally contributes to cortical oscillation dynamics.
Assuntos
Globo Pálido , Núcleos Talâmicos , Animais , Gânglios da Base , Globo Pálido/fisiologia , Neurônios/metabolismo , Ratos , Núcleos Talâmicos/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Cerebellar outputs take polysynaptic routes to reach the rest of the brain, impeding conventional tracing. Here, we quantify pathways between the cerebellum and forebrain by using transsynaptic tracing viruses and a whole-brain analysis pipeline. With retrograde tracing, we find that most descending paths originate from the somatomotor cortex. Anterograde tracing of ascending paths encompasses most thalamic nuclei, especially ventral posteromedial, lateral posterior, mediodorsal, and reticular nuclei. In the neocortex, sensorimotor regions contain the most labeled neurons, but we find higher densities in associative areas, including orbital, anterior cingulate, prelimbic, and infralimbic cortex. Patterns of ascending expression correlate with c-Fos expression after optogenetic inhibition of Purkinje cells. Our results reveal homologous networks linking single areas of the cerebellar cortex to diverse forebrain targets. We conclude that shared areas of the cerebellum are positioned to provide sensory-motor information to regions implicated in both movement and nonmotor function.
Assuntos
Cerebelo/metabolismo , Vias Neurais/fisiologia , Animais , Córtex Cerebral/metabolismo , Feminino , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Simplexvirus/genética , Núcleos Talâmicos/metabolismoRESUMO
The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.
Assuntos
Encefalopatias/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Tálamo/metabolismo , Encefalopatias/classificação , Mapeamento Encefálico/métodos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Loci Gênicos/genética , Genoma Humano/genética , Humanos , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética/métodos , Transtornos Mentais/classificação , Transtornos Mentais/genética , Locos de Características Quantitativas/genética , Núcleos Talâmicos/diagnóstico por imagem , Núcleos Talâmicos/metabolismo , Tálamo/diagnóstico por imagemRESUMO
The mechanisms that govern thalamocortical transmission are poorly understood. Recent data have shown that sensory stimuli elicit activity in ensembles of cortical neurons that recapitulate stereotyped spontaneous activity patterns. Here, we elucidate a possible mechanism by which gating of patterned population cortical activity occurs. In this study, sensory-evoked all-or-none cortical population responses were observed in the mouse auditory cortex in vivo and similar stochastic cortical responses were observed in a colliculo-thalamocortical brain slice preparation. Cortical responses were associated with decreases in auditory thalamic synaptic inhibition and increases in thalamic synchrony. Silencing of corticothalamic neurons in layer 6 (but not layer 5) or the thalamic reticular nucleus linearized the cortical responses, suggesting that layer 6 corticothalamic feedback via the thalamic reticular nucleus was responsible for gating stochastic cortical population responses. These data implicate a corticothalamic-thalamic reticular nucleus circuit that modifies thalamic neuronal synchronization to recruit populations of cortical neurons for sensory representations.
Assuntos
Córtex Auditivo/fisiologia , Vias Auditivas/fisiologia , Percepção Auditiva , Sincronização Cortical , Audição , Filtro Sensorial , Transmissão Sináptica , Núcleos Talâmicos/fisiologia , Estimulação Acústica , Animais , Córtex Auditivo/metabolismo , Vias Auditivas/metabolismo , Estimulação Elétrica , Potenciais Evocados Auditivos , Feminino , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural , Núcleos Talâmicos/metabolismo , Fatores de TempoRESUMO
Here we report the unusual presence of thalamic reticular neurons immunoreactive for tyrosine hydroxylase in equids. The diencephalons of one adult male of four equid species, domestic donkey (Equus africanus asinus), domestic horse (Equus caballus), Cape mountain zebra (Equus zebra zebra) and plains zebra (Equus quagga), were sectioned in a coronal plane with series of sections stained for Nissl substance, myelin, or immunostained for tyrosine hydroxylase, and the calcium-binding proteins parvalbumin, calbindin and calretinin. In all equid species studied the thalamic reticular nucleus was observed as a sheet of neurons surrounding the rostral, lateral and ventral portions of the nuclear mass of the dorsal thalamus. In addition, these thalamic reticular neurons were immunopositive for parvalbumin, but immunonegative for calbindin and calretinin. Moreover, the thalamic reticular neurons in the equids studied were also immunopositive for tyrosine hydroxylase. Throughout the grey matter of the dorsal thalamus a terminal network also immunoreactive for tyrosine hydroxylase was present. Thus, the equid thalamic reticular neurons appear to provide a direct and novel potentially catecholaminergic innervation of the thalamic relay neurons. This finding is discussed in relation to the function of the thalamic reticular nucleus and the possible effect of a potentially novel catecholaminergic pathway on the neural activity of the thalamocortical loop.
Assuntos
Neurônios/metabolismo , Núcleos Talâmicos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Calbindina 2/metabolismo , Calbindinas/metabolismo , Equidae , Masculino , Parvalbuminas/metabolismoRESUMO
The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition1-5. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders6-9. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN-thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits.
Assuntos
Redes Reguladoras de Genes , Núcleos Talâmicos/citologia , Núcleos Talâmicos/metabolismo , Animais , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Hibridização in Situ Fluorescente , Metaloendopeptidases/metabolismo , Camundongos , Vias Neurais , Neurônios/metabolismo , Osteopontina/metabolismo , Técnicas de Patch-Clamp , RNA-Seq , Análise de Célula Única , Sono/genética , Sono/fisiologia , Núcleos Talâmicos/fisiologia , TranscriptomaRESUMO
Perineuronal nets (PNNs) are extracellular matrix (ECM) structures that envelop neurons and regulate synaptic functions. Long thought to be stable structures, PNNs have been recently shown to respond dynamically during learning, potentially regulating the formation of new synapses. We postulated that PNNs vary during sleep, a period of active synaptic modification. Notably, PNN components are cleaved by matrix proteases such as the protease cathepsin-S. This protease is diurnally expressed in the mouse cortex, coinciding with dendritic spine density rhythms. Thus, cathepsin-S may contribute to PNN remodeling during sleep, mediating synaptic reorganization. These studies were designed to test the hypothesis that PNN numbers vary in a diurnal manner in the rodent and human brain, as well as in a circadian manner in the rodent brain, and that these rhythms are disrupted by sleep deprivation. In mice, we observed diurnal and circadian rhythms of PNNs labeled with the lectin Wisteria floribunda agglutinin (WFA+ PNNs) in several brain regions involved in emotional memory processing. Sleep deprivation prevented the daytime decrease of WFA+ PNNs and enhances fear memory extinction. Diurnal rhythms of cathepsin-S expression in microglia were observed in the same brain regions, opposite to PNN rhythms. Finally, incubation of mouse sections with cathepsin-S eliminated PNN labeling. In humans, WFA+ PNNs showed a diurnal rhythm in the amygdala and thalamic reticular nucleus (TRN). Our results demonstrate that PNNs vary in a circadian manner and this is disrupted by sleep deprivation. We suggest that rhythmic modification of PNNs may contribute to memory consolidation during sleep.
Assuntos
Ritmo Circadiano , Matriz Extracelular , Animais , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Camundongos , Rede Nervosa , Neurônios/metabolismo , Núcleos Talâmicos/metabolismoRESUMO
This review focuses on the studies that have been reviewed to determine the influence of the thalamic reticular nucleus on neuropsychiatric diseases and deep brain stimulation. The literature reviewed to date describes how alterations in the thalamic reticular nucleus affect several functions that regulated brain rhythms and provokes symptoms of many disorders. The observations as the basis for the renewed interest in the thalamic reticular nucleus in experimental models and testing its effectiveness in patients with resistant neuropsychiatric disorders. The preclinical studies showed that deep brain stimulation in the thalamic reticular nucleus could have beneficial effects on EEG activity, including synchronization and desynchronization activity of the brain, as well as promoting an alleviate to neuropsychiatric diseases. These observations open up the possibility of studying the role played by neurotransmitters in the pathologic process and the deep brain stimulation in the thalamic reticular nucleus in experimental animal models and offer evidence of its possible action in the human brain.
Assuntos
Estimulação Encefálica Profunda/métodos , Transtornos Mentais/fisiopatologia , Transtornos Mentais/terapia , Núcleos Talâmicos/fisiologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Humanos , Transtornos Mentais/metabolismo , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Núcleos Talâmicos/metabolismoRESUMO
The reticular thalamic nucleus (Rt) is a sheet of neurons that surrounds the dorsal thalamus laterally, along its dorso-ventral and rostro-caudal axes. It consists of inhibitory neurons releasing gamma-aminobutyric acid (GABA). This nucleus participates in the circuitry between the thalamus and the cerebral cortex, and its impairment is associated with neuro-psychiatric disorders. In this study, we investigated the Rt anatomy of Engrailed-2 knockout mice (En2-/- ), a mouse model of autism spectrum disorder (ASD), using parvalbumin as an immunohistochemical marker. We compared 4- and 6-week-old wild type (WT) and En2-/- mice using various morphometric parameters: cell area, shape factor, circularity and cell density. Significant differences were present in 6-week-old male mice with different genetic background (WT vs. En2-/- ): the Rt neurons of En2-/- mice showed a bigger cell area, shape factor and circularity when compared with WT. Age (4 weeks vs. 6 weeks) influenced the shape factor of WT females, the circularity and cell density of En2-/- males, and the shape factor and circularity of En2-/- females. Gender affected cell density in 4-week-old WT mice, shape factor and cellularity of 6-week-old WT mice, and cell area, shape factor and cell density of En2-/- at 6 weeks. Intrasubject (left-right) asymmetry of Rt was never observed. These results show for the first time that sex- and age-related changes occur in the Rt GABAergic neurons of the En2-/- ASD mouse model.
Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Núcleos Talâmicos/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Parvalbuminas/metabolismo , Fatores SexuaisRESUMO
Neurosteroids are potent allosteric modulators of GABAA receptors (GABAA Rs). Although the effects of exogenous neurosteroids on GABAA R function are well documented, less is known about effects of neurosteroids produced by local endogenous biosynthesis. The neurosteroidogenic enzymes 5α-reductase and 3α-hydroxysteroid dehydrogenase are expressed in two nuclei of somatosensory thalamus, the thalamic reticular nucleus (nRT) and ventrobasal nucleus (VB). Here, the effects of acute blockade of neurosteroidogenesis by the 5α-reductase inhibitor finasteride on phasic and tonic GABAA R-mediated currents were examined in nRT and VB of mice. In nRT, finasteride altered the decay and amplitude, but not the frequency, of phasic currents, with no effect on tonic inhibition. In VB neurons, by contrast, finasteride reduced both the size and frequency of phasic currents, and also reduced the degree of tonic inhibition. These studies thus provide novel evidence for endogenous modulation of GABAA R function by 5α-reduced neurosteroids in the mature thalamus.
Assuntos
Inibição Neural , Neuroesteroides/metabolismo , Núcleos Talâmicos/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/farmacologia , Animais , Feminino , Finasterida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de GABA-A/metabolismo , Núcleos Talâmicos/efeitos dos fármacos , Núcleos Talâmicos/fisiologiaRESUMO
Cav3 / T-type Ca2+ channels are dynamically regulated by intracellular Ca2+ ions, which inhibit Cav3 availability. Here, we demonstrate that this inhibition becomes irreversible in the presence of non-hydrolysable ATP analogs, resulting in a strong hyperpolarizing shift in the steady-state inactivation of the residual Cav3 current. Importantly, the effect of these ATP analogs was prevented in the presence of intracellular BAPTA. Additional findings obtained using intracellular dialysis of inorganic phosphate and alkaline phosphatase or NaN3 treatment further support the involvement of a phosphorylation mechanism. Contrasting with Cav1 and Cav2 Ca2+ channels, the Ca2+-dependent modulation of Cav3 channels appears to be independent of calmodulin, calcineurin and endocytic pathways. Similar findings were obtained for the native T-type Ca2+ current recorded in rat thalamic neurons of the central medial nucleus. Overall, our data reveal a new Ca2+ sensitive phosphorylation-dependent mechanism regulating Cav3 channels, with potentially important physiological implications for the multiple cell functions controlled by T-type Ca2+ channels.
Assuntos
Canais de Cálcio Tipo T/metabolismo , Cálcio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Canais de Cálcio Tipo T/genética , Feminino , Masculino , Fosfatos/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Núcleos Talâmicos/metabolismoRESUMO
Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's Adjuvant (CFA) model of hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity pathway analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, Western blot analysis shows increased expression of metabotropic glutamate receptor 2 in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.SIGNIFICANCE STATEMENT There is an imminent need for safe and efficient chronic pain medications. Regulator of G-protein signaling 4 (RGS4) is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice, we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hindpaw inflammation or hindlimb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
Assuntos
Dor Crônica/metabolismo , Hiperalgesia/metabolismo , Proteínas RGS/metabolismo , Núcleos Talâmicos/metabolismo , Animais , Dor Crônica/genética , Regulação para Baixo , Feminino , Hiperalgesia/genética , Masculino , Camundongos , Camundongos Knockout , Medição da Dor , Proteínas RGS/genética , Fatores Sexuais , Transdução de Sinais/fisiologiaRESUMO
The fast-spiking parvalbumin (PV) interneurons play a critical role in neural circuit activity and dysfunction of these cells has been implicated in the cognitive deficits typically observed in schizophrenia patients. Due to the high metabolic demands of PV neurons, they are particularly susceptible to oxidative stress. Given the extant literature exploring the pathological effects of oxidative stress on PV cells in cortical regions linked to schizophrenia, we decided to investigate whether PV neurons in other select brain regions, including sub-cortical structures, may be differentially affected by redox dysregulation induced oxidative stress during neurodevelopment in mice with a genetically compromised glutathione synthesis (Gclm KO mice). Our analyses revealed a spatio-temporal sequence of PV cell deficit in Gclm KO mice, beginning with the thalamic reticular nucleus at postnatal day (P) 20 followed by a PV neuronal deficit in the amygdala at P40, then in the lateral globus pallidus and the ventral hippocampus Cornu Ammonis 3 region at P90 and finally the anterior cingulate cortex at P180. We suggest that PV neurons in different brain regions are developmentally susceptible to oxidative stress and that anomalies in the neurodevelopmental calendar of metabolic regulation can interfere with neural circuit maturation and functional connectivity contributing to the emergence of developmental psychopathology.
Assuntos
Tonsila do Cerebelo , Globo Pálido , Giro do Cíngulo , Hipocampo , Interneurônios/metabolismo , Rede Nervosa , Oxirredução , Estresse Oxidativo/fisiologia , Parvalbuminas , Esquizofrenia/metabolismo , Núcleos Talâmicos , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Modelos Animais de Doenças , Globo Pálido/crescimento & desenvolvimento , Globo Pálido/metabolismo , Glutamato-Cisteína Ligase/genética , Giro do Cíngulo/crescimento & desenvolvimento , Giro do Cíngulo/metabolismo , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/crescimento & desenvolvimento , Rede Nervosa/metabolismo , Núcleos Talâmicos/crescimento & desenvolvimento , Núcleos Talâmicos/metabolismoRESUMO
The reticular thalamic nucleus (RTn) controls the overall activity of thalamo-cortical neurons information processing. GABAergic RTn neurons have one of the highest densities of D4-type dopamine receptors in subcortical structures. The unitary electrical activity of RTn neurons was recorded in vivo in Wistar rats in order to study the effects of local activation and blockade of D4 receptors under both conditions, normal and ipsilateral lesion of the dopaminergic pathways. Our data suggest that: i) there is a tonic dopaminergic input to the RTn; ii) local activation of D4 receptors increases the basal firing rate of RTn neurons in normal and lesioned rats, and iii) local blockade of D4 receptors diminishes the firing rate in normal but not in lesioned rats. Altogether, our findings support that dopamine contributes to the spontaneous basal firing of the RTn neurons through D4-type dopamine receptors.
Assuntos
Dopamina/metabolismo , Receptores de Dopamina D4/metabolismo , Núcleos Talâmicos/metabolismo , Animais , Fenômenos Eletrofisiológicos/fisiologia , Neurônios GABAérgicos/metabolismo , Masculino , Vias Neurais/fisiologia , Ratos , Ratos Wistar , Receptores de Dopamina D4/fisiologia , Núcleos Talâmicos/fisiologiaRESUMO
The thalamic reticular nucleus (TRN), part of the thalamus, is a thin GABAergic cell layer adjacent to the relay nuclei of the dorsal thalamus. It receives input from the cortex and other thalamic nuclei and provides major inhibitory input to each thalamic nucleus, particularly the mediodorsal nucleus (MD). As the MD is important for supporting optimal cortico-thalamo-cortical interactions during brain maturation, we hypothesized that that early damage to the TRN will cause major disturbances to the development and the functioning of the prefrontal cortex (PFC) and the MD. Rat pups at P4 were randomized in three groups: electrolytic lesion of TRN, TRN-sham-lesion group, and the classical control group. Seven weeks later, all rats were tested with several behavioral and cognitive paradigms, and then perfused for histological and immunohistochemical studies. Results showed that TRN lesion rats exhibited reduced spontaneous activity, high level of anxiety, learning and recognition memory impairments. Besides the behavioral effects observed after early TRN lesions, our study showed significant cytoarchitectural and functional changes in the cingulate cortex, the dorsolateral and prelimbic subdivisions of the PFC, as well as in the MD. The assessment of the basal levels of neuronal activity revealed a significant reduction of the basal expression of C-Fos levels in the PFC. These experiments, which are the first to highlight the effects of early TRN lesions, provided evidence that early damage of the anterior part of the TRN leads to alterations that may control the development of the thalamocortical-corticothalamic pathways.
Assuntos
Ansiedade/fisiopatologia , Aprendizagem/fisiologia , Reconhecimento Psicológico/fisiologia , Núcleos Talâmicos/metabolismo , Animais , Masculino , Vias Neurais/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos Sprague-Dawley , Núcleos Talâmicos/patologiaRESUMO
Conventional magnetic resonance imaging (MRI) characteristics of canine brain diseases are often nonspecific. Single- and multi-voxel spectroscopy techniques allow quantification of chemical biomarkers for tissues of interest and may help to improve diagnostic specificity. However, published information is currently lacking for the in vivo performance of these two techniques in dogs. The aim of this prospective, methods comparison study was to compare the performance of single- and multi-voxel spectroscopy in the brains of eight healthy, juvenile dogs using 3 Tesla MRI. Ipsilateral regions of single- and multi-voxel spectroscopy were performed in symmetric regions of interest of each brain in the parietal (n = 3), thalamic (n = 2), and piriform lobes (n = 3). In vivo single-voxel spectroscopy and multi-voxel spectroscopy metabolite ratios from the same size and multi-voxel spectroscopy ratios from different sized regions of interest were compared. No significant difference was seen between single-voxel spectroscopy and multi-voxel spectroscopy metabolite ratios for any lobe when regions of interest were similar in size and shape. Significant lobar single-voxel spectroscopy and multi-voxel spectroscopy differences were seen between the parietal lobe and thalamus (P = 0.047) for the choline to N-acetyl aspartase ratios when large multi-voxel spectroscopy regions of interest were compared to very small multi-voxel spectroscopy regions of interest within the same lobe; and for the N-acetyl aspartase to creatine ratios in all lobes when single-voxel spectroscopy was compared to combined (pooled) multi-voxel spectroscopy datasets. Findings from this preliminary study indicated that single- and multi-voxel spectroscopy techniques using 3T MRI yield comparable results for similar sized regions of interest in the normal canine brain. Findings also supported using the contralateral side as an internal control for dogs with brain lesions.
Assuntos
Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária , Espectroscopia de Ressonância Magnética/métodos , Animais , Encéfalo/metabolismo , Cães , Feminino , Imageamento por Ressonância Magnética/métodos , Masculino , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/metabolismo , Córtex Piriforme/diagnóstico por imagem , Córtex Piriforme/metabolismo , Estudos Prospectivos , Núcleos Talâmicos/diagnóstico por imagem , Núcleos Talâmicos/metabolismoRESUMO
Huntington's disease is a devastating neurodegenerative genetic disorder that causes progressive motor dysfunction, emotional disturbances, and cognitive impairment. Unfortunately, there is no treatment to cure or slow the progression of the disease. Neuroinflammation is one hallmark of Huntington's disease, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. The relationship between neuroinflammation markers and the disease pathology is still poorly understood. To improve our understanding of neuroinflammation in Huntington's disease, we measured translocator protein (TSPO) expression using 11C-PBR28 and simultaneous PET/MRI. Standardized-uptake-value ratios, normalized by whole brain uptake, were calculated for data acquired 60-90 min after radiotracer administration. We identified distinct patterns of regional neuroinflammation (as defined by TSPO overexpression relative to a control group) in the basal ganglia of Huntington's disease patients. These patterns were observed at the individual level in all patients, with region of interest analysis confirming significant differences between patients and the control group in the putamen and the pallidum. Additionally, we observed further distinct regional and subregional signatures, which may provide insights into phenotypical variability. For example, in certain Huntington's disease patients, we observed in vivo elevation of the level of TSPO binding in subnuclei in the thalamus and brainstem that have been previously associated with visual function, motor function, and motor coordination. Our main result is an objective score, based solely on 11C-PBR28 measurements, that correlates well with measurements of brain atrophy. We conclude that PET/MR imaging using 11C-PBR28 provides a high signal-to-background ratio and has the potential to be used to assess Huntington's disease progression. Our results suggest 11C-PBR28 might prove useful in clinical trials evaluating therapies targeting neuroinflammation.
Assuntos
Encéfalo/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Acetamidas , Idoso , Astrócitos/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudos de Casos e Controles , Progressão da Doença , Feminino , Globo Pálido/diagnóstico por imagem , Globo Pálido/metabolismo , Humanos , Doença de Huntington/imunologia , Doença de Huntington/metabolismo , Inflamação , Imageamento por Ressonância Magnética , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Putamen/metabolismo , Piridinas , Compostos Radiofarmacêuticos , Receptores de GABA/metabolismo , Núcleos Talâmicos/diagnóstico por imagem , Núcleos Talâmicos/metabolismoRESUMO
Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity.