Cold Spring Harbor symposia on quantitative biology最新文献

Drug addiction is a chronic relapsing brain disorder that is characterized by compulsive drug seeking and continued use despite negative outcomes. Current pharmacological therapies target neuronal receptors or transporters upon which drugs of abuse act initially, yet these treatments remain ineffective for most individuals and do not prevent disease relapse after abstinence. Drugs of abuse, in addition to their acute effects, cause persistent plasticity after repeated use, involving dysregulated gene expression in the brain's reward regions, which are thought to mediate the persistent behavioral abnormalities that characterize addiction. Emerging evidence implicates epigenetic priming as a key mechanism that underlies the long-lasting alterations in neuronal gene regulation, which can remain latent until triggered by re-exposure to drug-associated stimuli or the drug itself. Thus, to effectively treat drug addiction, we must identify the precise epigenetic mechanisms that establish and preserve the drug-induced pathology of the brain reward circuitry.

Dravet syndrome is an infantile epileptic encephalopathy primarily caused by loss-of-function variants of the gene SCN1A Standard treatment regimens have very limited efficacy to combat the life-threatening seizures in Dravet syndrome or the behavioral-cognitive comorbidities of the disease. Recently there has been encouraging progress in developing new treatments for this disorder. One of the clinical advances is cannabidiol (CBD), a compound naturally found in cannabis and shown to further reduce convulsive seizures in patients when used together with existing drug regimens. Like many other natural products, the exact therapeutic mechanism of CBD remains undefined. Previously we have established a human cellular model of Dravet syndrome by differentiating patient-derived induced pluripotent stem cells (iPSCs) into telencephalic inhibitory and excitatory neurons. Here we have applied this model to investigate the antiepileptic mechanism(s) of CBD at the cellular level. We first determined the effect of escalating the concentrations of CBD on neuronal excitability, using primary culture of rat cortical neurons. We found modulatory effects on excitability at submicromolar concentrations and toxic effects at high concentrations (15 µM). We then tested CBD at 50 nM, a concentration that corresponds to the estimated human clinical exposure, in telencephalic neurons derived from a patient iPSC line and control cell line H9. This 50 nM of CBD increased the excitability of inhibitory neurons but decreased the excitability of excitatory neurons, without changing the amplitude of sodium currents in either cell type. Our findings suggest a cell type-dependent mechanism for the therapeutic action of CBD in Dravet syndrome that is independent of sodium channel activity.

How confident are you? As humans, aware of our subjective sense of confidence, we can readily answer. Knowing your level of confidence helps to optimize both routine decisions such as whether to go back and check if the front door was locked and momentous ones like finding a partner for life. Yet the inherently subjective nature of confidence has limited investigations by neurobiologists. Here, we provide an overview of recent advances in this field and lay out a conceptual framework that lets us translate psychological questions about subjective confidence into the language of neuroscience. We show how statistical notions of confidence provide a bridge between our subjective sense of confidence and confidence-guided behaviors in nonhuman animals, thus enabling the study of the underlying neurobiology. We discuss confidence as a core cognitive process that enables organisms to optimize behavior such as learning or resource allocation and that serves as the basis of metacognitive reasoning. These approaches place confidence on a solid footing and pave the way for a mechanistic understanding of how the brain implements confidence-based algorithms to guide behavior.

The rapid antidepressant effect of ketamine is arguably one of the most significant advances in the mental health field in the last half century. However, its mechanism of action has remained elusive. Here, we describe our latest discovery on how ketamine blocks N-methyl-D-aspartate receptor (NMDAR)-dependent burst firing of an "antireward" center in the brain, the lateral habenula (LHb), to mediate its antidepressant effects. We also discuss a novel structure-function mechanism at the glia-neuron interface to account for the enhanced LHb bursting during depression. These results reveal new molecular targets for the therapeutic intervention of major depression.