RESUMO
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.
Assuntos
Sobrevivência Celular , Citoproteção , Perfusão , Suínos , Isquemia Quente , Animais , Morte Celular , Perfilação da Expressão Gênica , Isquemia/metabolismo , Isquemia/patologia , Isquemia/prevenção & controle , Especificidade de Órgãos , Perfusão/métodos , Suínos/anatomia & histologiaRESUMO
The susceptibility of the brain to ischaemic injury dramatically limits its viability following interruptions in blood flow. However, data from studies of dissociated cells, tissue specimens, isolated organs and whole bodies have brought into question the temporal limits within which the brain is capable of tolerating prolonged circulatory arrest. This Review assesses cell type-specific mechanisms of global cerebral ischaemia, and examines the circumstances in which the brain exhibits heightened resilience to injury. We suggest strategies for expanding such discoveries to fuel translational research into novel cytoprotective therapies, and describe emerging technologies and experimental concepts. By doing so, we propose a new multimodal framework to investigate brain resuscitation following extended periods of circulatory arrest.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Neuroproteção/fisiologia , Animais , HumanosRESUMO
BACKGROUND: Acute brain injury with strong surges of adrenergic outflow has resulted in takotsubo cardiomyopathy, but there are surprisingly few reports of takotsubo cardiomyopathy after intracranial hemorrhage, and none have been described from hemorrhage within the brainstem. RESULTS: We describe a patient with reverse and reversible cardiomyopathy following a hemorrhage in the lateral medulla oblongata. While it is limited in size, the location of the hemorrhage caused acute systolic failure with left ventricular ejection fraction of 27% and vasopressor requirement for cardiogenic shock and pulmonary edema. There was full recovery after 7 days. METHODS: Detailed case report. CONCLUSION: Hemorrhage into medulla oblongata pressor centers may result in acute, reversible, stress-induced cardiomyopathy, affirming the adrenergic origin of this condition.
Assuntos
Hemorragias Intracranianas/complicações , Bulbo/patologia , Cardiomiopatia de Takotsubo/etiologia , Cardiomiopatia de Takotsubo/fisiopatologia , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Bulbo/diagnóstico por imagem , Pessoa de Meia-IdadeRESUMO
Finding the cause of acute neurological deterioration in the hours following aneurysmal subarachnoid haemorrhage remains challenging. The presence of blood casts in the ventricles proves that deterioration is secondary to acute hydrocephalus and prompts immediate external ventricular drain placement.
Assuntos
Hemorragia Subaracnóidea/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Feminino , HumanosAssuntos
Vírus da Encefalite Equina do Leste , Encefalomielite Equina do Leste , Encefalomielite Equina , Animais , Connecticut/epidemiologia , Surtos de Doenças , Vírus da Encefalite Equina do Leste/genética , Encefalomielite Equina do Leste/diagnóstico , Encefalomielite Equina do Leste/epidemiologia , Encefalomielite Equina do Leste/veterinária , Cavalos , HumanosRESUMO
Eastern equine encephalitis (EEE) was one of the first-recognized neuroinvasive arboviral diseases in North America, and it remains the most lethal. Although EEE is known to have periodic spikes in infection rates, there is increasing evidence that it may be undergoing a change in its prevalence and its public health burden. Numerous factors shape the scope of EEE in humans, and there are important similarities with other emergent viral diseases that have surfaced or strengthened in recent years. Because environmental and ecological conditions that broadly influence the epidemiology of arboviral diseases also are changing, and the frequency, severity, and scope of outbreaks are expected to worsen, an expanded understanding of EEE will have untold importance in coming years. Here we review the factors shaping EEE transmission cycles and the conditions leading to outbreaks in humans from an updated, multidomain perspective. We also provide special consideration of factors shaping the virology, host-vector-environment relationships, and mechanisms of pathology and treatment as a reference for broadening audiences.
Assuntos
Vírus da Encefalite Equina do Leste , Encefalomielite Equina do Leste , Animais , Cavalos , Humanos , Encefalomielite Equina do Leste/epidemiologia , Encefalomielite Equina do Leste/terapia , Encefalomielite Equina do Leste/veterinária , Surtos de DoençasRESUMO
During early telencephalic development, intricate processes of regional patterning and neural stem cell (NSC) fate specification take place. However, our understanding of these processes in primates, including both conserved and species-specific features, remains limited. Here, we profiled 761,529 single-cell transcriptomes from multiple regions of the prenatal macaque telencephalon. We deciphered the molecular programs of the early organizing centers and their cross-talk with NSCs, revealing primate-biased galanin-like peptide (GALP) signaling in the anteroventral telencephalon. Regional transcriptomic variations were observed along the frontotemporal axis during early stages of neocortical NSC progression and in neurons and astrocytes. Additionally, we found that genes associated with neuropsychiatric disorders and brain cancer risk might play critical roles in the early telencephalic organizers and during NSC progression.
Assuntos
Células-Tronco Neurais , Neurogênese , Telencéfalo , Animais , Feminino , Gravidez , Macaca , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Telencéfalo/citologia , Telencéfalo/embriologia , Neurogênese/genética , Peptídeo Semelhante a Galanina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Neoplasias Encefálicas/genéticaRESUMO
Neuroimaging is crucial for assessing mass effect in brain-injured patients. Transport to an imaging suite, however, is challenging for critically ill patients. We evaluated the use of a low magnetic field, portable MRI (pMRI) for assessing midline shift (MLS). In this observational study, 0.064 T pMRI exams were performed on stroke patients admitted to the neuroscience intensive care unit at Yale New Haven Hospital. Dichotomous (present or absent) and continuous MLS measurements were obtained on pMRI exams and locally available and accessible standard-of-care imaging exams (CT or MRI). We evaluated the agreement between pMRI and standard-of-care measurements. Additionally, we assessed the relationship between pMRI-based MLS and functional outcome (modified Rankin Scale). A total of 102 patients were included in the final study (48 ischemic stroke; 54 intracranial hemorrhage). There was significant concordance between pMRI and standard-of-care measurements (dichotomous, κ = 0.87; continuous, ICC = 0.94). Low-field pMRI identified MLS with a sensitivity of 0.93 and specificity of 0.96. Moreover, pMRI MLS assessments predicted poor clinical outcome at discharge (dichotomous: adjusted OR 7.98, 95% CI 2.07-40.04, p = 0.005; continuous: adjusted OR 1.59, 95% CI 1.11-2.49, p = 0.021). Low-field pMRI may serve as a valuable bedside tool for detecting mass effect.
Assuntos
Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , Acidente Vascular Cerebral/diagnóstico por imagem , Idoso , Connecticut , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/terapiaRESUMO
Brain imaging is essential to the clinical management of patients with ischemic stroke. Timely and accessible neuroimaging, however, can be limited in clinical stroke pathways. Here, portable magnetic resonance imaging (pMRI) acquired at very low magnetic field strength (0.064 T) is used to obtain actionable bedside neuroimaging for 50 confirmed patients with ischemic stroke. Low-field pMRI detected infarcts in 45 (90%) patients across cortical, subcortical, and cerebellar structures. Lesions as small as 4 mm were captured. Infarcts appeared as hyperintense regions on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted imaging sequences. Stroke volume measurements were consistent across pMRI sequences and between low-field pMRI and conventional high-field MRI studies. Low-field pMRI stroke volumes significantly correlated with stroke severity and functional outcome at discharge. These results validate the use of low-field pMRI to obtain clinically useful imaging of stroke, setting the stage for use in resource-limited environments.
RESUMO
The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2, which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates.
Assuntos
Córtex Pré-Frontal Dorsolateral , Evolução Molecular , Primatas , Somatostatina , Tirosina 3-Mono-Oxigenase , Adulto , Animais , Dopamina/metabolismo , Córtex Pré-Frontal Dorsolateral/citologia , Córtex Pré-Frontal Dorsolateral/metabolismo , Humanos , Pan troglodytes , Primatas/genética , Análise de Célula Única , Somatostatina/genética , Somatostatina/metabolismo , Transcriptoma , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Radiological examination of the brain is a critical determinant of stroke care pathways. Accessible neuroimaging is essential to detect the presence of intracerebral hemorrhage (ICH). Conventional magnetic resonance imaging (MRI) operates at high magnetic field strength (1.5-3 T), which requires an access-controlled environment, rendering MRI often inaccessible. We demonstrate the use of a low-field MRI (0.064 T) for ICH evaluation. Patients were imaged using conventional neuroimaging (non-contrast computerized tomography (CT) or 1.5/3 T MRI) and portable MRI (pMRI) at Yale New Haven Hospital from July 2018 to November 2020. Two board-certified neuroradiologists evaluated a total of 144 pMRI examinations (56 ICH, 48 acute ischemic stroke, 40 healthy controls) and one ICH imaging core lab researcher reviewed the cases of disagreement. Raters correctly detected ICH in 45 of 56 cases (80.4% sensitivity, 95%CI: [0.68-0.90]). Blood-negative cases were correctly identified in 85 of 88 cases (96.6% specificity, 95%CI: [0.90-0.99]). Manually segmented hematoma volumes and ABC/2 estimated volumes on pMRI correlate with conventional imaging volumes (ICC = 0.955, p = 1.69e-30 and ICC = 0.875, p = 1.66e-8, respectively). Hematoma volumes measured on pMRI correlate with NIH stroke scale (NIHSS) and clinical outcome (mRS) at discharge for manual and ABC/2 volumes. Low-field pMRI may be useful in bringing advanced MRI technology to resource-limited settings.
Assuntos
Hemorragia Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética/economia , Imageamento por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Neuroimagem/economia , Neuroimagem/instrumentação , Neuroimagem/métodosRESUMO
BACKGROUND AND PURPOSE: Bone morphogenetic proteins and their receptors are expressed in adult brains, and their expression levels increase after cerebral ischemia. The brain also expresses an inhibitor of bone morphogenetic protein signaling, noggin, but the role of noggin in ischemic disease outcome has not been studied. METHODS: We used transgenic mice overexpressing noggin to assess whether inhibition of bone morphogenetic protein signaling affects ischemic injury responses after permanent middle cerebral artery occlusion. RESULTS: Transgenic mice overexpressing noggin mice had significantly smaller infarct volumes and lower motor deficits compared to wild-type mice. CD11b(+) and IBA1(+) microglia along with oligodendroglial progenitors were significantly increased in transgenic mice overexpressing noggin mice at 14 days after permanent middle cerebral artery occlusion. CONCLUSIONS: These results provide genetic evidence that overexpression of noggin reduces ischemic brain injury after permanent middle cerebral artery occlusion via enhanced activation of microglia and oligodendrogenesis.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Proteínas de Transporte/genética , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/terapia , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Infarto Encefálico/terapia , Isquemia Encefálica/fisiopatologia , Proliferação de Células , Citoproteção/fisiologia , Modelos Animais de Doenças , Terapia Genética/métodos , Gliose/patologia , Gliose/fisiopatologia , Gliose/terapia , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Regeneração Nervosa/fisiologia , Oligodendroglia/metabolismo , Paresia/patologia , Paresia/fisiopatologia , Paresia/terapia , Recuperação de Função Fisiológica/fisiologia , Células-Tronco/metabolismoRESUMO
IMPORTANCE: Neuroimaging is a key step in the clinical evaluation of brain injury. Conventional magnetic resonance imaging (MRI) systems operate at high-strength magnetic fields (1.5-3 T) that require strict, access-controlled environments. Limited access to timely neuroimaging remains a key structural barrier to effectively monitor the occurrence and progression of neurological injury in intensive care settings. Recent advances in low-field MRI technology have allowed for the acquisition of clinically meaningful imaging outside of radiology suites and in the presence of ferromagnetic materials at the bedside. OBJECTIVE: To perform an assessment of brain injury in critically ill patients in intensive care unit settings, using a portable, low-field MRI device at the bedside. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, single-center cohort study of 50 patients admitted to the neuroscience or coronavirus disease 2019 (COVID-19) intensive care units at Yale New Haven Hospital in New Haven, Connecticut, from October 30, 2019, to May 20, 2020. Patients were eligible if they presented with neurological injury or alteration, no contraindications for conventional MRI, and a body habitus not exceeding the scanner's 30-cm vertical opening. Diagnosis of COVID-19 was determined by positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction nasopharyngeal swab result. EXPOSURES: Portable MRI in an intensive care unit room. MAIN OUTCOMES AND MEASURES: Demographic, clinical, radiological, and treatment data were collected and analyzed. Brain imaging findings are described. RESULTS: Point-of-care MRI examinations were performed on 50 patients (16 women [32%]; mean [SD] age, 59 [12] years [range, 20-89 years]). Patients presented with ischemic stroke (n = 9), hemorrhagic stroke (n = 12), subarachnoid hemorrhage (n = 2), traumatic brain injury (n = 3), brain tumor (n = 4), and COVID-19 with altered mental status (n = 20). Examinations were acquired at a median of 5 (range, 0-37) days after intensive care unit admission. Diagnostic-grade T1-weighted, T2-weighted, T2 fluid-attenuated inversion recovery, and diffusion-weighted imaging sequences were obtained for 37, 48, 45, and 32 patients, respectively. Neuroimaging findings were detected in 29 of 30 patients who did not have COVID-19 (97%), and 8 of 20 patients with COVID-19 (40%) demonstrated abnormalities. There were no adverse events or complications during deployment of the portable MRI or scanning in an intensive care unit room. CONCLUSIONS AND RELEVANCE: This single-center series of patients with critical illness in an intensive care setting demonstrated the feasibility of low-field, portable MRI. These findings demonstrate the potential role of portable MRI to obtain neuroimaging in complex clinical care settings.
RESUMO
New neurons are added to the adult hippocampus throughout life and contribute to cognitive functions, including learning and memory. It remains unclear whether ongoing neurogenesis arises from self-renewing neural stem cells (NSCs) or from multipotential progenitor cells that cannot self-renew in the hippocampus. This is primarily based on observations that neural precursors derived from the subventricular zone (SVZ) can be passaged long term, whereas hippocampal subgranular zone (SGZ) precursors are rapidly depleted by passaging. We demonstrate here that high levels of bone morphogenetic protein (BMP) signaling occur in hippocampal but not SVZ precursors in vitro, and blocking BMP signaling with Noggin is sufficient to foster hippocampal cell self-renewal, proliferation, and multipotentiality using single-cell clonal analysis. Moreover, NSC maintenance requires continual Noggin exposure, which implicates BMPs as crucial regulators of NSC aging. In vivo, Noggin is expressed in the adult dentate gyrus and limits BMP signaling in proliferative cells of the SGZ. Transgenic Noggin overexpression in the SGZ increases multiple precursor cell populations but proportionally increases the glial fibrillary acidic protein-positive cell population at the expense of other precursors, suggesting that Noggin acts on NSCs in vivo. To confirm this, we used a dual thymidine analog paradigm to repeatedly label slowly dividing cells over a long duration. We find that small populations of label-retaining cells exist in the SGZ and that Noggin overexpression increases their numbers. Thus, we propose that the adult hippocampus contains a population of NSCs, which can be expanded both in vitro and in vivo by blocking BMP signaling.
Assuntos
Células-Tronco Adultas/fisiologia , Proteínas de Transporte/fisiologia , Hipocampo/citologia , Células-Tronco Adultas/efeitos dos fármacos , Análise de Variância , Animais , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/farmacologia , Bromodesoxiuridina/metabolismo , Proteínas de Transporte/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Desoxiuridina/análogos & derivados , Desoxiuridina/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Idoxuridina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Proteínas de Neurofilamentos/metabolismo , Inibidores da Síntese de Ácido Nucleico/farmacologia , Antígenos O/metabolismo , Fosfopiruvato Hidratase/genética , Ácidos Siálicos/metabolismo , Telomerase/metabolismoRESUMO
Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition.
Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Cognição , Neurogênese , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/terapia , Giro Denteado/metabolismo , Expressão Gênica , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo MolecularRESUMO
The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.
Assuntos
Dor Crônica/patologia , Dor Crônica/fisiopatologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Carragenina/toxicidade , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Modelos Animais de Doenças , Método Duplo-Cego , Proteínas do Domínio Duplacortina , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Glicosídeo Hidrolases/farmacologia , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Transtornos do Humor/etiologia , Neurogênese/efeitos dos fármacos , Neurogênese/efeitos da radiação , Neuropeptídeos/metabolismo , Medição da Dor , Limiar da Dor/fisiologia , Estimulação Física/efeitos adversos , Ciática , Natação , Raios X/efeitos adversosRESUMO
Correlated neuronal activity is believed to play an important role in refining and maintaining cortical circuitry during early development. Here we provide evidence that globally and locally correlated activity mediate different forms of adult plasticity. Pulses of broad-spectrum noise were used to activate time-locked responses across large areas of the rat auditory cortex, globally synchronizing cortical activity. Brief tone pips were used to activate relatively small groups of neurons, generating locally correlated activity. Pairing pulsed noises with nucleus basalis (NB) stimulation in awake rats for 4 weeks broadened spectral tuning, disrupted tonotopic maps, and reduced spontaneous discharge correlation in the primary auditory cortex (AI), as examined under anesthesia. Those effects caused AI neurons to appear qualitatively similar to neurons in nonprimary auditory fields of naive animals. Subsequent pairing of tone pips with NB stimulation for a period of 4 weeks completely reversed these effects induced by previous noise-NB pairing. These findings further demonstrate that the adult auditory cortex retains a substantial capacity for receptive field plasticity and tonotopic map reorganization and that locally correlated activity plays an important role in plasticity in the adult, as in the developing cortex.
Assuntos
Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Acústica/métodos , Animais , Córtex Auditivo/anatomia & histologia , Córtex Auditivo/crescimento & desenvolvimento , Núcleo Basal de Meynert/fisiologia , Mapeamento Encefálico , Condicionamento Psicológico , Estimulação Elétrica , Eletrodos Implantados , Feminino , Neurônios/fisiologia , Ruído , Ratos , Ratos Sprague-Dawley , Vigília/fisiologiaRESUMO
Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher in Chat+/- than in Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.