RESUMO
The thalamus is organized into nuclei that have distinct input and output connectivities with the cortex. Whereas first-order (FO) nuclei - also called core nuclei - relay input from sensory organs on the body surface and project to primary cortical sensory areas, higher-order (HO) nuclei - matrix nuclei - instead receive their driver input from the cortex and project to secondary and associative areas within cortico-thalamo-cortical loops. Input-dependent processes have been shown to play a crucial role in the emergence of FO thalamic neuron identity from a ground-state HO neuron identity, yet how this identity emerges during development remains unknown. Here, using single-cell RNA sequencing of the developing mouse embryonic thalamus, we show that, although they are born together, HO neurons start differentiating earlier than FO neurons. Within the FO visual thalamus, postnatal peripheral input is crucial for the maturation of excitatory, but not inhibitory, neurons. Our findings reveal different differentiation tempos and input sensitivities of HO and FO neurons, and highlight neuron type-specific molecular differentiation programs in the developing thalamus.
Assuntos
Diferenciação Celular , Neurônios , Tálamo , Animais , Camundongos , Neurônios/metabolismo , Neurônios/citologia , Tálamo/embriologia , Tálamo/metabolismo , Neurogênese/genética , Neurogênese/fisiologia , Análise de Célula Única , Regulação da Expressão Gênica no Desenvolvimento , FemininoRESUMO
Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.
Assuntos
Colina , Lipopolissacarídeos , Espectroscopia de Ressonância Magnética , Microglia , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Animais , Colina/metabolismo , Masculino , Espectroscopia de Ressonância Magnética/métodos , Doenças Neuroinflamatórias/metabolismo , Creatina/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Imagem de Difusão por Ressonância Magnética/métodos , Tálamo/metabolismo , FemininoRESUMO
How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance.NEW & NOTEWORTHY Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.
Assuntos
Analgésicos Opioides , Morfina , Receptores Opioides mu , Tálamo , Animais , Receptores Opioides mu/metabolismo , Morfina/farmacologia , Morfina/administração & dosagem , Masculino , Feminino , Camundongos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/administração & dosagem , Tálamo/efeitos dos fármacos , Tálamo/fisiologia , Tálamo/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiologia , Giro do Cíngulo/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Tolerância a Medicamentos/fisiologia , Camundongos Endogâmicos C57BL , Caracteres Sexuais , Transdução de Sinais/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologiaRESUMO
Numerous studies from different international groups have demonstrated that sensations can be propagated along acupuncture channel pathways. The propagated sensation along the channel pathway (PSCP) can be elicited by electroacupuncture (EA), transcutaneous electrical nerve stimulation (TENS), manual acupuncture (MA), and heat applied to distal acupuncture points (acupoints). Nitric oxide (NO) levels were reported to be elevated in the gracile nucleus and skin regions near to the EA sites, with higher levels at acupoints associated with an enhanced expression of NO synthase and transient receptor potential vanilloid type 1. The stimuli, EA, MA, TENS, and heat, have been used to elicit axonal reflexes, which increase local release of NO and neuropeptides such as calcitonin gene related peptide. Furthermore, the sensation of PSCP along the body surface occurs only ipsilaterally to the stimulated acupoints in various human studies, which does not support the involvement of the spinal-thalamic pathway, which would involve cross over transmission of the signals. The gracile nucleus receives ascending input from the sciatic nerve and responds to somatosensory stimulation mainly on the ipsilateral side via the dorsal column pathway. EA at Zusanli (ST36) increases NO release and expression of NO synthase mainly in the ipsilateral side of the gracile nucleus, while the cardiovascular effects and analgesic responses to EA at ST36 are changed by influences of l-arginine-derived NO synthesis in the ipsilateral gracile nucleus in rats. The stimuli-induced release of NOergic molecules and neuropeptides exist high levels in the acupoints, which contain rich neuronal components and blood vessels. Enhanced NOergic molecules at acupoints cause axon reflexes during the stimuli, which elevate cutaneous blood flow. Elevated NOergic molecules and local blood flow may spread over acupoints one after another along the meridian lines differing from nerve pathways following the stimuli to induce PSCP. The same types of stimulation also elicit NO release in the gracile nucleus, which contributes to the somatosensory signal transduction of PSCP through the dorsal medulla-thalamic pathways. Other substances such as serotonin and catecholamines are proposed to mediate responses and certain effects of acupuncture-like stimulation but their mechanisms are poorly-understood. In this review we summarize the current understanding of the neurobiological processes of PSCP research with an emphasis on recent developments of NO mediating stimulation-evoked axon reflexes and somatosensory signal transduction for PSCP perceptions through the dorsal medulla-thalamic pathways. Please cite this article as: Ma SX. Stimuli-evoked NOergic molecules and neuropeptides at acupuncture points and gracile nucleus contribute to signal transduction of propagated sensation along the meridian through the dorsal medulla-thalamic pathways. J Integr Med. 2024; 22(5): 515-522.
Assuntos
Pontos de Acupuntura , Bulbo , Neuropeptídeos , Transdução de Sinais , Humanos , Bulbo/metabolismo , Neuropeptídeos/metabolismo , Meridianos , Animais , Tálamo/metabolismo , Tálamo/fisiologia , Sensação , Óxido Nítrico/metabolismoRESUMO
BACKGROUND: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease, whose primary hallmark is the occurrence of inflammatory lesions in white and grey matter structures. Increasing evidence in MS patients and respective murine models reported an impaired ionic homeostasis driven by inflammatory-demyelination, thereby profoundly affecting signal propagation. However, the impact of a focal inflammatory lesion on single-cell and network functionality has hitherto not been fully elucidated. OBJECTIVES: In this study, we sought to determine the consequences of a localized cortical inflammatory lesion on the excitability and firing pattern of thalamic neurons in the auditory system. Moreover, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener, on disease outcome. METHODS: To resemble the human disease, we focally administered pro-inflammatory cytokines, TNF-α and IFN-γ, in the primary auditory cortex (A1) of MOG35-55 immunized mice. Thereafter, we investigated the impact of the induced inflammatory milieu on afferent thalamocortical (TC) neurons, by performing ex vivo recordings. Moreover, we explored the effect of Kv7 channel modulation with RTG on auditory information processing, using in vivo electrophysiological approaches. RESULTS: Our results revealed that a cortical inflammatory lesion profoundly affected the excitability and firing pattern of neighboring TC neurons. Noteworthy, RTG restored control-like values and TC tonotopic mapping. CONCLUSION: Our results suggest that RTG treatment might robustly mitigate inflammation-induced altered excitability and preserve ascending information processing.
Assuntos
Carbamatos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Neurônios , Fenilenodiaminas , Tálamo , Animais , Camundongos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Fenilenodiaminas/farmacologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Tálamo/metabolismo , Tálamo/efeitos dos fármacos , Carbamatos/farmacologia , Feminino , Córtex Auditivo/efeitos dos fármacos , Córtex Auditivo/metabolismo , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Esclerose Múltipla/metabolismo , Esclerose Múltipla/tratamento farmacológico , Interferon gama/metabolismoRESUMO
We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic, and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when the light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of presumed BLA input, and decreased BLA-driven feedforward inhibition of amygdala output neurons. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.
Assuntos
Luz , Receptor de Glutamato Metabotrópico 5 , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Animais , Masculino , Camundongos , Neuralgia/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Analgésicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos Endogâmicos C57BLRESUMO
To evaluate the protective effect of LIPUS at the early stage of brain trauma in rats, 45 rats were randomly divided into 3 groups: sham (n = 15), TBI (n = 15) and LIPUS treatment groups (n = 15). Ipsilateral and contralateral cortical and thalamic parameters obtained by diffusion tensor imaging (DTI) and fast low-angle shot magnetic resonance imaging (FLASH-MRI) were measured at different times after trauma. For fractional anisotropy (FA) and T2* values, two-way repeated measures ANOVA with Tukey's post hoc was used for intergroup comparisons. With observation time prolonged, the FA values of the ipsilateral cortex in the TBI group gradually increased and were significantly higher than those in the LIPUS treatment group on Day 7 (adjusted P = 0.0067). FA values in the contralateral cortex decreased at this time and were significantly lower than those in the LIPUS treatment group (adjusted P = 0.0192). Meanwhile, compared with LIPUS group, FA values were significantly higher in the injured thalamus (adjusted P = 0.0025). Combined with correlation analysis, FA values were positively correlated with neuronal damage (P = 0.0148, r2 = 0.895). At 7 days after trauma, T2* values in the ipsilateral cortex of the TBI group were significantly lower. After analysis of ferritin content and correlation, we found that T2* values were negatively correlated with ferritin (P = 0.0259, r2 = -0.849). By measuring post-traumatic changes in FA and T2* values, it is possible to demonstrate a neuronal protective effect of LIPUS in the early phase of TBI rats and promote brain rehabilitation.
Assuntos
Lesões Encefálicas Traumáticas , Imagem de Tensor de Difusão , Animais , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Ratos , Masculino , Ratos Sprague-Dawley , Anisotropia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Tálamo/patologia , Imageamento por Ressonância Magnética , Modelos Animais de DoençasRESUMO
Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4ß2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.
Assuntos
Epilepsia Generalizada , Humanos , Feminino , Masculino , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Adulto , Adulto Jovem , Imageamento por Ressonância Magnética , Tálamo/patologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Adolescente , Putamen/patologia , Putamen/diagnóstico por imagem , Putamen/metabolismo , Estudos de Casos e Controles , Hipocampo/patologiaRESUMO
Traumatic brain injuries (TBI) of varying severity are becoming more frequent all over the world. The process of neuroinflammation, in which macrophages and microglia are key players, underlies all types of brain damage. The present study focuses on evaluating the therapeutic potential of N-docosahexaenoylethanolamine (DHEA, synaptamide), which is an endogenous metabolite of docosahexaenoic acid in traumatic brain injury. Previously, several in vitro and in vivo models have shown significant anti-neuroinflammatory and synaptogenic activity of synaptamide. The results of the present study show that synaptamide by subcutaneous administration (10 mg/kg/day, 7 days) exerts anti-inflammatory and anti-apoptotic effects in the thalamus and cerebral cortex of experimental animals (male C57BL/6 mice). Were analyzed the dynamics of changes in the activity of Iba-1- and CD68-positive microglia/macrophages, the level of production of pro-inflammatory cytokines (IL1ß, IL6, TNFα) and pro-apoptotic proteins (Bad, Bax), the expression of pro- and anti-inflammatory markers (CD68, CD206, arg-1). ATF3 transcription factor distribution and neuronal state in the thalamus and cerebral cortex of animals with craniotomy, traumatic brain injury, and therapy are quantitatively assessed. The obtained data showed that synaptamide: (1) has no effect on the total pool of microglia/macrophages; (2) inhibits the activity of pro-inflammatory microglia/macrophages and cytokines they produce; (3) increases the expression of CD206 but not arg-1; (4) has anti-apoptotic effect and (5) improves the morphological state of neurons. The results obtained confirm the high therapeutic potential of synaptamide in the therapy of traumatic brain injury.
Assuntos
Apoptose , Lesões Encefálicas Traumáticas , Córtex Cerebral , Camundongos Endogâmicos C57BL , Microglia , Neurônios , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Apoptose/efeitos dos fármacos , Camundongos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Tálamo/patologia , Citocinas/metabolismo , Etanolaminas/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismoRESUMO
Animals must simultaneously select and balance multiple action contingencies in ambiguous situations: for instance, evading danger during feeding. This has rarely been examined in the context of information selection; despite corticothalamic pathways that mediate sensory attention being relatively well characterized, neural mechanisms filtering conflicting actions remain unclear. Here, we develop a new loom/feed test to observe conflict between naturally induced fear and feeding and identify a novel anterior cingulate cortex (ACC) output to the ventral anterior and ventral lateral thalamus (VA/VL) that adjusts selectivity between these innate actions. Using micro-endoscopy and fiber photometry, we reveal that activity in corticofugal outputs was lowered during unbalanced/singularly occupied periods, as were the resulting decreased thalamic initiation-related signals for less-favored actions, suggesting that the integration of ACC-thalamic firing may directly regulate the output of behavior choices. Accordingly, the optoinhibition of ACC-VA/VL circuits induced high bias toward feeding at the expense of defense. To identify upstream "commander" cortical cells gating this output, we established dual-order tracing (DOT)-translating ribosome affinity purification (TRAP)-a scheme to label upstream neurons with transcriptome analysis-and found a novel population of neurotensin-positive interneurons (ACCNts). The photoexcitation of ACCNts cells indeed caused similarly hyper-selective behaviors. Collectively, this new "corticofugal action filter" scheme suggests that communication in multi-step cingulate circuits may critically influence the summation of motor signals in thalamic outputs, regulating bias between innate action types.
Assuntos
Giro do Cíngulo , Vias Neurais , Neurotensina , Animais , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiologia , Camundongos , Masculino , Vias Neurais/fisiologia , Neurotensina/metabolismo , Tálamo/metabolismo , Tálamo/fisiologia , Camundongos Endogâmicos C57BL , Medo/fisiologia , Comportamento AlimentarRESUMO
OBJECTIVE: The pathogenesis of depression in patients with Parkinson's disease (PD) is poorly understood. Therefore, this study aimed to explore the changes in γ-aminobutyric acid (GABA) and glutamate plus glutamine (Glx) levels in patients with PD with or without depression determined using MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS). MATERIALS AND METHODS: A total of 83 patients with primary PD and 24 healthy controls were included. Patients with PD were categorized into depressed PD (DPD, n = 19) and nondepressed PD (NDPD, n = 64) based on the 17-item Hamilton Depression Rating Scale. All participants underwent T1-weighted imaging and MEGA-PRESS sequence to acquire GABA+ and Glx values. The MEGA-PRESS sequence was conducted using 18.48 mL voxels in the left thalamus and medial frontal cortex. The GABA+, Glx, and creatine values were quantified using Gannet 3.1 software. RESULTS: The GABA+ and Glx values were not significantly disparate between patients with PD and controls in the thalamus and medial frontal cortex. However, the levels of N-acetyl aspartate/creatine and choline/creatine in the left thalamus were significantly lower in patients with PD than in controls (P = .031, P = .009). The GABA+/Water and GABA+/Creatine in the medial frontal cortex were higher in DPD than in NDPD (P = .001, P = .004). The effects of depression on Glx or other metabolite levels were not evident, and no significant difference in metabolite values was noted in the left thalamus among all groups (P > .05). CONCLUSIONS: GABA+ levels increased in the medial frontal cortex in DPD, which may be more closely related to depressive pathology. Thus, alterations in GABAergic function in special brain structures may be related to the clinical manifestations of PD symptoms, and hence mediating this function might help in treating depression in PD.
Assuntos
Depressão , Ácido Glutâmico , Glutamina , Espectroscopia de Ressonância Magnética , Doença de Parkinson , Ácido gama-Aminobutírico , Humanos , Masculino , Feminino , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/complicações , Pessoa de Meia-Idade , Ácido gama-Aminobutírico/metabolismo , Idoso , Depressão/metabolismo , Depressão/etiologia , Depressão/diagnóstico por imagem , Glutamina/metabolismo , Ácido Glutâmico/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Tálamo/metabolismo , Tálamo/diagnóstico por imagemRESUMO
Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1-3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.
Assuntos
Doença de Alzheimer , Encéfalo , Perfilação da Expressão Gênica , Análise de Célula Única , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Astrócitos/classificação , Astrócitos/citologia , Astrócitos/metabolismo , Astrócitos/patologia , Autopsia , Encéfalo/anatomia & histologia , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Colina/metabolismo , Cognição/fisiologia , Redes Reguladoras de Genes , Interneurônios/classificação , Interneurônios/citologia , Interneurônios/metabolismo , Interneurônios/patologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Inibição Neural , Neurônios/classificação , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Poliaminas/metabolismo , Proteína Reelina , Transdução de Sinais , Tálamo/citologia , Tálamo/metabolismo , Tálamo/patologia , TranscriptomaRESUMO
BACKGROUND: Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75NTR) plays a key role in activating angiogenesis. However, the effects of p75NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75NTR facilitates angiogenesis to attenuate secondary thalamic damage via activating hypoxia-inducible factor 1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway mediated by Von Hippel-Lindau (VHL) after distal middle cerebral artery occlusion (dMCAO). METHODS: The male rat model of dMCAO was established. The effects of p75NTR on the angiogenesis was evaluated using RNA-sequencing, immunohistochemistry, western blot, quantitative real-time polymerase chain reaction, magnetic resonance imaging, behavior tests, viral and pharmacological interventions. RESULTS: We found that the p75NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75NTR-VHL interaction was reduced, which promoted the ubiquitination degradation of HIF-1α and reduced VEGF expression after dMCAO. Notably, p75NTR overexpression restrained the ubiquitination degradation of HIF-1α by inhibiting VHL-HIF-1α interaction, further promoted angiogenesis, increased cerebral blood flow of ipsilateral thalamus and improved neurological function after dMCAO. CONCLUSION: For the first time, we highlighted that the enhancement of p75NTR-VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.
Assuntos
Infarto da Artéria Cerebral Média , Neovascularização Fisiológica , Ratos Sprague-Dawley , Tálamo , Animais , Masculino , Ratos , Tálamo/metabolismo , Tálamo/patologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Neovascularização Fisiológica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Receptores de Fator de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/genética , Infarto Cerebral/patologia , Angiogênese , Proteínas do Tecido Nervoso , Receptores de Fatores de CrescimentoRESUMO
Proton magnetic resonance spectroscopy (1H-MRS) has shown inconsistent alterations in the brain metabolites of individuals with chronic pain. We used 3T 1H-MRS to investigate the brain metabolites in the anterior cingulate cortex and thalamus of 22 patients with chronic mild pain and no gait disturbance and 22 healthy controls. The chronic-pain group included patients with chronic low back pain and/or osteoarthritis but none suffering from hypersensitivity. There were no significant between group-differences in glutamate, glutamate plus glutamine (Glx), N-acetylaspartate, glycerophosphorylcholine (GPC), glutamine, creatine plus phosphocreatine, or myo-inositol in the anterior cingulate cortex, but the patients showed a significant decrease in GPC, but not other metabolites, in the thalamus compared to the controls. The GPC values in the patients' thalamus were significantly correlated with pain components on the Short-Form McGill Pain Questionnaire (SF-MPQ-2) and affective empathy components on the Questionnaire of Cognitive and Affective Empathy (QCAE). The GPC in the patients' anterior cingulate cortex showed significant correlations with cognitive empathy components on the QCAE. Myo-inositol in the controls' anterior cingulate cortex and Glx in the patients' thalamus each showed significant relationships with peripheral responsivity on the QCAE. These significances were not significant after Bonferroni corrections. These preliminary findings indicate important roles of GPC, myo-inositol, and Glx in the brain of patients with chronic mild pain.
Assuntos
Dor Crônica , Empatia , Giro do Cíngulo , Tálamo , Humanos , Giro do Cíngulo/metabolismo , Giro do Cíngulo/diagnóstico por imagem , Feminino , Masculino , Dor Crônica/metabolismo , Dor Crônica/diagnóstico por imagem , Pessoa de Meia-Idade , Tálamo/metabolismo , Tálamo/diagnóstico por imagem , Empatia/fisiologia , Adulto , Inositol/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Idoso , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Medição da DorRESUMO
The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and amygdala. A plethora amount of evidence indicates that activation of the V1a subtype of the vasopressin receptors facilitates anxiety-like and fear responses. As an essential structure involved in fear and anxiety responses, the amygdala, especially the lateral nucleus of amygdala (LA), receives glutamatergic innervations from the auditory cortex and auditory thalamus where high density of V1a receptors have been detected. However, the roles and mechanisms of AVP in these two important areas have not been determined, which prevents the understanding of the mechanisms whereby V1a activation augments anxiety and fear responses. Here, we used coronal brain slices and studied the effects of AVP on neuronal activities of the auditory cortical and thalamic neurons. Our results indicate that activation of V1a receptors excited both auditory cortical and thalamic neurons. In the auditory cortical neurons, AVP increased neuronal excitability by depressing multiple subtypes of inwardly rectifying K+ (Kir) channels including the Kir2 subfamily, the ATP-sensitive K+ channels and the G protein-gated inwardly rectifying K+ (GIRK) channels, whereas activation of V1a receptors excited the auditory thalamic neurons by depressing the Kir2 subfamily of the Kir channels as well as activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a persistent Na+ channel. Our results may help explain the roles of V1a receptors in facilitating fear and anxiety responses. Categories: Cell Physiology.
Assuntos
Arginina Vasopressina , Córtex Auditivo , Neurônios , Receptores de Vasopressinas , Tálamo , Animais , Feminino , Masculino , Ratos , Arginina Vasopressina/metabolismo , Arginina Vasopressina/farmacologia , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiologia , Córtex Auditivo/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Tálamo/metabolismo , Tálamo/fisiologiaRESUMO
Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 µg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P < 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5-7.5 nmol/0.5 µl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30-75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.
Assuntos
Modelos Animais de Doenças , Formaldeído , Nociceptividade , Ratos Sprague-Dawley , Receptores de Dopamina D3 , Animais , Ratos , Masculino , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/metabolismo , Formaldeído/toxicidade , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Medição da Dor/métodos , Oxidopamina/toxicidadeRESUMO
The extent of changes in functional connectivity (FC) within functional networks as a common feature across hallucinogenic drug classes is under-explored. This work utilized fMRI to assess the dissociative hallucinogens Psilocybin, a classical serotonergic psychedelic, and Salvinorin-A, a kappa-opioid receptor (KOR) agonist, on resting-state FC in nonhuman primates. We highlight overlapping and differing influence of these substances on FC relative to the thalamus, claustrum, prefrontal cortex (PFC), default mode network (DMN), and DMN subcomponents. Analysis was conducted on a within-subject basis. Findings support the cortico-claustro-cortical network model for probing functional effects of hallucinogens regardless of serotonergic potential, with a potential key paradigm centered around the claustrum, PFC, anterior cingulate cortices (ACC), and angular gyrus relationship. Thalamo-cortical networks are implicated but appear dependent on 5-HT2AR activation. Acute desynchronization relative to the DMN for both drugs was also shown. Our findings provide a framework to understand broader mechanisms at which hallucinogens in differing classes may impact subjects regardless of the target receptor.
Assuntos
Diterpenos Clerodânicos , Alucinógenos , Imageamento por Ressonância Magnética , Psilocibina , Alucinógenos/farmacologia , Diterpenos Clerodânicos/farmacologia , Animais , Psilocibina/farmacologia , Masculino , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Macaca mulatta , Rede de Modo Padrão/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Vias Neurais/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/diagnóstico por imagemRESUMO
During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this process impacts the development of normal exploratory behaviors of adult mice.
Assuntos
Interneurônios , Somatostatina , Tálamo , Animais , Interneurônios/metabolismo , Somatostatina/metabolismo , Somatostatina/genética , Camundongos , Tálamo/metabolismo , Optogenética , Transdução de Sinais , Masculino , Córtex Cerebral/metabolismo , Córtex Cerebral/citologia , Córtex Cerebral/crescimento & desenvolvimento , Feminino , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) are brain metabolites involved in some key neuronal functions within the brain, such as cognitive function. The aim of this study was to investigate whether Parkinson's disease (PD) with different cognitive status induces regional brain metabolite differences. 38 diagnosed PD patients, including 18 PD patients with normal cognitive (PDN), 20 PD subjects with cognitive impairment (PDMCI) and 25 healthy controls (HC) participated in this study. All subjects underwent a single-voxel proton MR spectroscopy (1H-MRS) on a 3T scanner. 1H-MRS were obtained from bilateral PCC, left thalamus and PFC regions in all subjects, respectively. Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. PDMCI patients showed a significant reduction of NAA, Cho and tCr in the PCC and left thalamus, compared to healthy controls; whereas lower levels of NAA and Cho in thalamus were found in PDN patients. Moreover, Cho and tCr levels were positively correlated with MMSE scores. Both NAA and tCr in PCC levels were positively correlated with MMSE and MoCA scores. The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. This study provides preliminary evidence that thalamic, PCC and PFC neurometabolic alterations occur in PD patients with cognition decline. Findings of this study indicate that NAA and tCr abnormalities in PCC and thalamus might be used as a biomarker to track cognitive decline in Parkinson's disease in clinical settings.
Assuntos
Ácido Aspártico , Colina , Disfunção Cognitiva , Creatina , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/diagnóstico por imagem , Masculino , Feminino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Creatina/metabolismo , Colina/metabolismo , Pessoa de Meia-Idade , Idoso , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Tálamo/metabolismo , Tálamo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Testes NeuropsicológicosRESUMO
Parkinsonism is presented as a motor syndrome characterized by rigidity, tremors, and bradykinesia, with Parkinson's disease (PD) being the predominant cause. The discovery that those motor symptoms result from the death of dopaminergic cells in the substantia nigra led to focus most of parkinsonism research on the basal ganglia (BG). However, recent findings point to an active involvement of the cerebellum in this motor syndrome. Here, we have developed a multiscale computational model of the rodent brain's BG-cerebellar network. Simulations showed that a direct effect of dopamine depletion on the cerebellum must be taken into account to reproduce the alterations of neural activity in parkinsonism, particularly the increased beta oscillations widely reported in PD patients. Moreover, dopamine depletion indirectly impacted spike-time-dependent plasticity at the parallel fiber-Purkinje cell synapses, degrading associative motor learning as observed in parkinsonism. Overall, these results suggest a relevant involvement of cerebellum in parkinsonism associative motor symptoms.