Resumo em Inglês:

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke.

Resumo em Inglês:

'Alzheimer's disease is the most common cause of dementia and its prevalence is expected to increase in the coming years. Therefore, accurate diagnosis is crucial for patients, clinicians and researchers. Neuroimaging techniques have provided invaluable information about Alzheimer's disease and, owing to recent advances, these methods will have an increasingly important role in research and clinical practice. The purpose of this article is to review recent neuroimaging studies of Alzheimer's disease that provide relevant information to clinical practice, including a new modality: in vivo amyloid imaging. Magnetic resonance imaging, single photon emission computed tomography and 18F-fluorodeoxyglucose-positron emission tomography are currently available for clinical use. Patients with suspected Alzheimer's disease are commonly investigated with magnetic resonance imaging because it provides detailed images of brain structure and allows the identification of supportive features for the diagnosis. Neurofunctional techniques such as single photon emission computed tomography and 18F-fluorodeoxyglucose-positron emission tomography can also be used to complement the diagnostic investigation in cases of uncertainty. Amyloid imaging is a non-invasive technique that uses positron emission tomography technology to investigate the accumulation of the β-amyloid peptide in the brain, which is a hallmark of Alzheimer's disease. This is a promising test but currently its use is restricted to very few specialized research centers in the world. Technological innovations will probably increase its availability and reliability, which are the necessary steps to achieve robust clinical applicability. Thus, in the future it is likely that amyloid imaging techniques will be used in the clinical evaluation of patients with Alzheimer's disease.

Resumo em Inglês:

Neuroprosthetic devices based on brain-machine interface technology hold promise for the restoration of body mobility in patients suffering from devastating motor deficits caused by brain injury, neurologic diseases and limb loss. During the last decade, considerable progress has been achieved in this multidisciplinary research, mainly in the brain-machine interface that enacts upper-limb functionality. However, a considerable number of problems need to be resolved before fully functional limb neuroprostheses can be built. To move towards developing neuroprosthetic devices for humans, brain-machine interface research has to address a number of issues related to improving the quality of neuronal recordings, achieving stable, long-term performance, and extending the brain-machine interface approach to a broad range of motor and sensory functions. Here, we review the future steps that are part of the strategic plan of the Duke University Center for Neuroengineering, and its partners, the Brazilian National Institute of Brain-Machine Interfaces and the École Polytechnique Fédérale de Lausanne (EPFL) Center for Neuroprosthetics, to bring this new technology to clinical fruition.

Resumo em Inglês:

Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.

Resumo em Inglês:

Alzheimer disease is the most common cause of dementia among the elderly, accounting for ~60-70% of all cases of dementia. The neuropathological hallmarks of Alzheimer disease are senile plaques (mainly containing p-amyloid peptide derived from amyloid precursor protein) and neurofibrillary tangles (containing hyperphosphorylated Tau protein), along with neuronal loss. At present there is no effective treatment for Alzheimer disease. Given the prevalence and poor prognosis of the disease, the development of animal models has been a research priority to understand pathogenic mechanisms and to test therapeutic strategies. Most cases of Alzheimer disease occur sporadically in people over 65 years old, and are not genetically inherited. Roughly 5% of patients with Alzheimer disease have familial Alzheimer disease-that is, related to a genetic predisposition, including mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes. The discovery of genes for familial Alzheimer disease has allowed transgenic models to be generated through the overexpression of the amyloid precursor protein and/or presenilins harboring one or several mutations found in familial Alzheimer disease. Although none of these models fully replicates the human disease, they have provided valuable insights into disease mechanisms as well as opportunities to test therapeutic approaches. This review describes the main transgenic mouse models of Alzheimer disease which have been adopted in Alzheimer disease research, and discusses the insights into Alzheimer disease pathogenesis from studies in such models. In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble b-amyloid oligomers in disease pathogenesis, as well as of the relationship between p-amyloid and Tau pathologies.

Resumo em Inglês:

Intellectual disability is a prevalent form of cognitive impairment, affecting 2-3% of the general population. It is a daunting societal problem characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. Intellectual disability is a clinically important disorder for which the etiology and pathogenesis are still poorly understood. Moreover, although tremendous progress has been made, pharmacological intervention is still currently non-existent and therapeutic strategies remain limited. Studies in humans have a very limited capacity to explain basic mechanisms of this condition. In this sense, animal models have been invaluable in intellectual disability investigation. Certainly, a great deal of the knowledge that has improved our understanding of several pathologies has derived from appropriate animal models. Moreover, to improve human health, scientific discoveries must be translated into practical applications. Translational research specifically aims at taking basic scientific discoveries and best practices to benefit the lives of people in our communities. In this context, the challenge that basic science research needs to meet is to make use of a comparative approach to benefit the most from what each animal model can tell us. Intellectual disability results from many different genetic and environmental insults. Taken together, the present review will describe several animal models of potential intellectual disability risk factors.

Resumo em Inglês:

Epilepsy is one of the most common neurologic problems worldwide. Unfortunately, individuals with epilepsy are at higher risk of death than the general population, and sudden unexpected death in epilepsy is the most important direct epilepsy-related cause of death. In this review article, our research group focused on the risk factors, mechanisms and preventative measures obtained from clinical and experimental studies on sudden unexpected death in epilepsy.

Resumo em Inglês:

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.