乳酸在中枢神经系统中的作用及其与相关疾病的关系

一直以来,乳酸在脑中被视作代谢废物,对其功能认识严重滞后。近年来,越来越多的证据表明,乳酸在多种生理与病理过程中扮演重要角色。在神经细胞中,星形胶质细胞是产生和释放乳酸的主要细胞源,该细胞通过有氧糖酵解过程生成乳酸,随后经跨膜通道释放至胞外进入神经元为其供能。在中枢神经系统中,乳酸对稳态调节发挥着十分重要的作用。乳酸主要通过两种途径,即代谢途径(作为能量底物)与信号途径(作为信号分子)调控神经元的功能活动,广泛参与神经元能量代谢、兴奋性、可塑性、学习记忆及神经系统发育等生理过程调节,亦参与抑郁行为、阿尔兹海默病(AD)和脑损伤等病理过程的调节。在脑组织中,存在着乳酸特异性受体(GPR81),乳酸与其结合后调控胞内的第二信使。此外,还发现乳酸可通过未知受体调节神经元的兴奋性以及作为信号分子的其他作用。本文就乳酸作为能量底物和信号分子及其参与相关神经疾病的研究进展进行阐述,旨在为相关中枢神经系统疾病防治提供新思路。     

药物成瘾及成瘾记忆的研究现状

本文在介绍药物成瘾与学习和记忆密切相关的神经回路及共同分子机制的基础上,围绕学习和记忆在药物成瘾中的作用,综述了关联性学习与复吸,关联性学习与敏化,异常关联性学习与强迫性用药行为,关联性学习及成瘾记忆与成瘾,多重记忆系统与成瘾的发生发展等方面的研究进展,并强调了突触可塑性及成瘾记忆在药物成瘾中的重要性。在此基础上提出：作为慢性脑病的药物成瘾的形成过程的重要特征是它包含着信息的特殊学习类型。药物成瘾与依赖于多巴胺的关联性学习紊乱有密切关系。海马可能在成瘾中扮演重要角色。     

Synaptic plasticity in drug reward circuitry

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.     

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging.

Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood flow and energy metabolism. Positron emission tomography (PET) signals detect blood flow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identifies the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic fluxes in purified preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identified the neurotransmitter glutamate and astrocytes, a specific type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This effect is mediated by specific glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na+. This Na(+)-dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na+/K(+)-ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na+ ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one 'turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule. These data suggest that during activation the brain may transiently resort to aerobic glycolysis occurring in astrocytes, followed by the oxidation of lactate by neurons. The proposed model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with 18F-deoxyglucose (DG)-PET may reflect predominantly uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.     

Age-Dependent Modulation of Synaptic Plasticity and Insulin Mimetic Effect of Lipoic Acid on a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disease that entails impairments of memory, thinking and behavior and culminates into brain atrophy. Impaired glucose uptake (accumulating into energy deficits) and synaptic plasticity have been shown to be affected in the early stages of Alzheimer’s disease. This study examines the ability of lipoic acid to increase brain glucose uptake and lead to improvements in synaptic plasticity on a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) that shows progression of pathology as a function of age; two age groups: 6 months (young) and 12 months (old) were used in this study. 3xTg-AD mice fed 0.23% w/v lipoic acid in drinking water for 4 weeks showed an insulin mimetic effect that consisted of increased brain glucose uptake, activation of the insulin receptor substrate and of the PI3K/Akt signaling pathway. Lipoic acid supplementation led to important changes in synaptic function as shown by increased input/output (I/O) and long term potentiation (LTP) (measured by electrophysiology). Lipoic acid was more effective in stimulating an insulin-like effect and reversing the impaired synaptic plasticity in the old mice, wherein the impairment of insulin signaling and synaptic plasticity was more pronounced than those in young mice.     

药物成瘾的神经生物学机制研究

药物滥用既是全球普遍存在的公共卫生问题,又是危害严重的社会问题。药物成瘾的本质是一种以药物引起的基因表达和神经突触可塑性改变为基础的病理性记忆。主要介绍国内外近年的重要研究成果。     

药物成瘾中的神经细胞骨架

神经细胞骨架对神经元功能有重要作用。药物成瘾会导致神经细胞病态发生,几乎在所有药物成瘾的蛋白质组学的研究中都能检测到细胞骨架蛋白的变化,细胞骨架蛋白在这个过程涉及神经细胞结构、突触可塑性、信号转导、功能蛋白的降解或修饰以及能量代谢等方面。本文综述了神经细胞骨架在药物成瘾中的研究。     

Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory

Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.     

Lactate produced by glycogenolysis in astrocytes regulates memory processing

When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions.     

Targeting reactive astrogliosis by novel biotechnological strategies

Neuroglial cells are fundamental for control of brain homeostasis and synaptic plasticity. Decades of pathological and physiological studies have focused on neurons in neurodegenerative disorders, but it is becoming increasingly evident that glial cells play an irreplaceable part in brain homeostasis and synaptic plasticity. Animal models of brain injury and neurodegenerative diseases have largely contributed to current understanding of astrocyte-specific mechanisms participating in brain function and neurodegeneration. Specifically, gliotransmission (presence of glial neurotransmitters, and their receptors and active transporters), trophic support (release, maturation and degradation of neurotrophins) and metabolism (production of lactate and GSH components) are relevant aspects of astrocyte function in neuronal metabolism, synaptic plasticity and neuroprotection. Morpho-functional changes of astrocytes and microglial cells after traumatic or toxic insults to the central nervous system (namely, reactive gliosis) disrupt the complex neuro-glial networks underlying homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as gliodegenerative processes, in which profound alterations of glial activation have a clear impact on progression and outcomes of neuropathological processes. This review provides an overview of current knowledge of astrocyte functions in the brain and how targeting glial-specific pathways might ultimately impact the development of therapies for clinical management of neurodegenerative disorders.     

A role for Melanin-Concentrating Hormone in learning and memory

The neurobiological substrate of learning process and persistent memory storage involves multiple brain areas. The neocortex and hippocampal formation are known as processing and storage sites for explicit memory, whereas the striatum, amygdala, neocortex and cerebellum support implicit memory. Synaptic plasticity, long-term changes in synaptic transmission efficacy and transient recruitment of intracellular signaling pathways in these brain areas have been proposed as possible mechanisms underlying short- and long-term memory retention. In addition to the classical neurotransmitters (glutamate, GABA), experimental evidence supports a role for neuropeptides in modulating memory processes. This review focuses on the role of the Melanin-Concentrating Hormone (MCH) and receptors on memory formation in animal studies. Possible mechanisms may involve direct MCH modulation of neural circuit activity that support memory storage and cognitive functions, as well as indirect effect on arousal.     

MicroRNAs regulate synaptic plasticity underlying drug addiction

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction.     

Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction

The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse.     

Proteomics in the study of hippocampal plasticity

Synaptic plasticity is the dynamic regulation of the strength of synaptic communication between nerve cells. It is central to neuronal development as well as experience-dependent remodeling of the adult nervous system as occurs during memory formation. Aberrant forms of synaptic plasticity also accompany a variety of neurological and psychiatric diseases, and unraveling the biological basis of synaptic plasticity has been a major goal in neurobiology research. The biochemical and structural mechanisms underlying different forms of synaptic plasticity are complex, involving multiple signaling cascades, reconfigurations of structural proteins and the trafficking of synaptic proteins. As such, proteomics should be a valuable tool in dissecting the molecular events underlying normal and disease-related forms of plasticity. In fact, progress in this area has been disappointingly slow. We discuss the particular challenges associated with proteomic interrogation of synaptic plasticity processes and outline ways in which we believe proteomics may advance the field over the next few years. We pay particular attention to technical advances being made in small sample proteomics and the advent of proteomic imaging in studying brain plasticity.     

Removing pathogenic memories

Experimental research examining the neural bases of nondeclarative memory has offered intriguing insight into how functional and dysfunctional implicit learning affects the brain. Long-term modifications of synaptic transmission, in particular, are currently considered the most plausible mechanism underlying memory trace encoding and compulsions, addiction, anxiety, and phobias. Therefore, an effective psychotherapy must be directed to erase maladaptive implicit memories and aberrant synaptic plasticity. This article describes the neurobiological bases of pathogenic memory disruption to provide some insight into how psychotherapy works. At least two mechanisms of unwanted memory erasing appear to be implicated in the effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Behavioral evidence demonstrated that these two ways to forget are profoundly distinct in nature, and it is increasingly clear that their cellular, synaptic, and molecular underpinnings are different. Accordingly, the blockade of consolidation/reconsolidation erases memories by reversing the plasticity associated with memory maintenance, whereas extinction is a totally new form of plasticity that, similar to the plasticity underlying the old memory, requires protein synthesis-dependent synaptic remodeling.     

Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice

Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3–6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.     

Endocytic Adaptor Epidermal Growth Factor Receptor Substrate 15 (Eps15) Is Involved in the Trafficking of Ubiquitinated α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

AMPA-type glutamate receptors (AMPARs) play a critical role in mediating fast excitatory synaptic transmission in the brain. Alterations in receptor expression, distribution, and trafficking have been shown to underlie synaptic plasticity and higher brain functions, including learning and memory, as well as brain dysfunctions such as drug addiction and psychological disorders. Therefore, it is essential to elucidate the molecular mechanisms that regulate AMPAR dynamics. We have shown previously that mammalian AMPARs are subject to posttranslational modification by ubiquitin, with AMPAR ubiquitination enhancing receptor internalization and reducing AMPAR cell surface expression. Here we report a crucial role for epidermal growth factor receptor substrate 15 (Eps15), an endocytic adaptor, in ubiquitination-dependent AMPAR internalization. We find that suppression or overexpression of Eps15 results in changes in AMPAR surface expression. Eps15 interacts with AMPARs, which requires Nedd4-mediated GluA1 ubiquitination and the ubiquitin-interacting motif of Eps15. Importantly, we find that Eps15 plays an important role in AMPAR internalization. Knockdown of Eps15 suppresses the internalization of GluA1 but not the mutant GluA1 that lacks ubiquitination sites, indicating a role of Eps15 for the internalization of ubiquitinated AMPARs. These results reveal a novel molecular mechanism employed specifically for the trafficking of the ubiquitin-modified AMPARs.     

Myosin IIb-dependent Regulation of Actin Dynamics Is Required for N-Methyl-d-aspartate Receptor Trafficking during Synaptic Plasticity

N-Methyl-d-aspartate receptor (NMDAR) synaptic incorporation changes the number of NMDARs at synapses and is thus critical to various NMDAR-dependent brain functions. To date, the molecules involved in NMDAR trafficking and the underlying mechanisms are poorly understood. Here, we report that myosin IIb is an essential molecule in NMDAR synaptic incorporation during PKC- or θ burst stimulation-induced synaptic plasticity. Moreover, we demonstrate that myosin light chain kinase (MLCK)-dependent actin reorganization contributes to NMDAR trafficking. The findings from additional mutual occlusion experiments demonstrate that PKC and MLCK share a common signaling pathway in NMDAR-mediated synaptic regulation. Because myosin IIb is the primary substrate of MLCK and can regulate actin dynamics during synaptic plasticity, we propose that the MLCK- and myosin IIb-dependent regulation of actin dynamics is required for NMDAR trafficking during synaptic plasticity. This study provides important insights into a mechanical framework for understanding NMDAR trafficking associated with synaptic plasticity.