The brain's calendar: neural mechanisms of seasonal timing

The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal component of the mammalian biological clock, the neural timing system that generates and coordinates a broad spectrum of physiological, endocrine and behavioural circadian rhythms. The pacemaker of the SCN oscillates with a near 24 h period and is entrained to the diurnal light-dark cycle. Consistent with its role in circadian timing, investigations in rodents and non-human primates furthermore suggest that the SCN is the locus of the brain's endogenous calendar, enabling organisms to anticipate seasonal environmental changes. The present review focuses on the neuronal organization and dynamic properties of the biological clock and the means by which it is synchronized with the environmental lighting conditions. It is shown that the functional activity of the biological clock is entrained to the seasonal photic cycle and that photoperiod (day length) may act as an effective zeitgeber. Furthermore, new insights are presented, based on electrophysiological and molecular studies, that the mammalian circadian timing system consists of coupled oscillators and that the clock genes of these oscillators may also function as calendar genes. In summary, there are now strong indications that the neuronal changes and adaptations in mammals that occur in response to a seasonally changing environment are driven by an endogenous circadian clock located in the SCN, and that this neural calendar is reset by the seasonal fluctuations in photoperiod.     

From the Crest to the Periphery: Control of Pigment Cell Migration and Lineage Segregation

Pigment cells are one of many cell types derived from the neural crest. This review focuses on the mechanisms that control the timing and pathways of migration of pigment cells into the epidermis and determinants that control the differentiation of pigment cells. Several factors may control the timing and pattern of pigment cell migration in the dorsolateral space including the loss of inhibitory molecules in the pathway, the appearance of chemotactic molecules emanating from the dispersing dermatome, and the differentiation of pigment cells, which may be the only neural crest derivative capable of utilizing the substratum found in the dorsolateral path Control of pigment cell differentiation remains controversial. A working model presented in this review suggests that multipotent neural crest cells that disperse ventrally upon separation from the neural tube preserve neurogenic ability and lose melanogenic ability, whereas those cells that are arrested at the entrance to the dorsolateral path lose neurogenic ability so that the population becomes primarily melanogenic. During the time that the latter population is arrested in migration it is speculated that the neural crest cells are exposed to an environment comprised of specific extracellular matrix molecules and/or growth factors that enhance pigment cell differentiation.     

FGF signalling pathways in development of the midbrain and anterior hindbrain

Development of the central nervous system is coordinated by intercellular signalling centres established within the neural tube. The isthmic organizer (IsO), located between the midbrain and anterior hindbrain, is one such centre. Important signal molecules secreted by the IsO include members of the fibroblast growth factor and Wnt families. These signals are integrated with dorsally and ventrally derived signals to regulate development of the midbrain and rhombomere 1 of the hindbrain. The IsO is operational for a remarkably long period of time. Depending on the developmental stage, it controls a variety of processes such as cell survival, cell identity, neural precursor proliferation, neuronal differentiation and axon guidance. This review focuses on the fibroblast growth factor signalling, its novel molecular regulatory mechanisms and how this pathway regulates multiple aspects of cell behaviour in the developing midbrain and anterior hindbrain.     

Extracellular Matrix in Neural Plasticity and Regeneration

The extracellular matrix (ECM) is a fundamental component of biological tissues. The ECM in the central nervous system (CNS) is unique in both composition and function. Functions such as learning, memory, synaptogenesis, and plasticity are regulated by numerous ECM molecules. The neural ECM acts as a non-specific physical barrier that modulates neuronal plasticity and axon regeneration. There are two specialized types of ECM in the CNS, diffuse perisynaptic ECM and condensed ECM, which selectively surround the perikaryon and initial part of dendritic trees in subtypes of neurons, forming perineuronal nets. This review presents the current knowledge about the role of important neuronal ECM molecules in maintaining the basic functions of a neuron, including electrogenesis and the ability to form neural circuits. The review mainly focuses on the role of ECM components that participate in the control of key events such as cell survival, axonal growth, and synaptic remodeling. Particular attention is drawn to the numerous molecular partners of the main ECM components. These regulatory molecules are integrated into the cell membrane or disposed into the matrix itself in solid or soluble form. The interaction of the main matrix components with molecular partners seems essential in molecular mechanisms controlling neuronal functions. Special attention is paid to the chondroitin sulfate proteoglycan 4, type 1 transmembrane protein, neural-glial antigen 2 (NG2/CSPG4), whose cleaved extracellular domain is such a molecular partner that it not only acts directly on neural and vascular cells, but also exerts its influence indirectly by binding to resident ECM molecules.

     

Neural strategies for learning during sensitive periods of development

Precise patterns of neural connectivity and synaptic communication are modified by experience during restricted "sensitive" periods of development, and the circuitry and associated behaviors that emerge during such periods are frequently preserved throughout the lifespan. In many neural systems, the expression of various molecules that influence synaptic transmission and neuronal morphology are developmentally regulated and may serve to constrain the timing of enhanced sensitivity to experiential inputs. In this highly selective review I concentrate on recent findings from the visual system and the song system that provide novel insights into the mechanisms that regulate sensitive period plasticity, and that raise new questions concerning what makes sensitive periods so sensitive.     

Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis

The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.     

Epigenetic regulation of neuronal dendrite and dendrite spine development

Dendrites and the dendritic spines of neurons play key roles in the connectivity of the brain and have been recognized as the locus of long-term synaptic plasticity,which is correlated with learning and memory.The development of dendrites and spines in the mammalian central nervous system is a complex process that requires specific molecular events over a period of time.It has been shown that specific molecules are needed not only at the spine's point of contact,but also at a distance,providing signals that initiate a cascade of events leading to synapse formation.The specific molecules that act to signal neuronal differentiation,dendritic morphology,and synaptogenesis are tightly regulated by genetic and epigenetic programs.It has been shown that the dendritic spine structure and distribution are altered in many diseases,including many forms of mental retardation(MR),and can also be potentiated by neuronal activities and an enriched environment.Because dendritic spine pathologies are found in many types of MR,it has been proposed that an inability to form normal spines leads to the cognitive and motor deficits that are characteristic of MR.Epigenetic mechanisms,including DNA methylation,chromatin remodeling,and the noncoding RNA-mediated process,have profound regulatory roles in mammalian gene expression.The study of epigenetics focuses on cellular effects that result in a heritable pattern of gene expression without changes to genomic encoding.Despite extensive efforts to understand the molecular regulation of dendrite and spine development,epigenetic mechanisms have only recently been considered.In this review,we will focus on epigenetic mechanisms that regulate the development and maturation of dendrites and spines.We will discuss how epigenetic alterations could result in spine abnormalities that lead to MR,such as is seen in fragile X and Rett syndromes.We will also discuss both general methodology and recent technological advances in the study of neuronal dendrites and spines.     

Epigenetic regulation of neuronal dendrite and dendritic spine development

Dendrites and the dendritic spines of neurons play key roles in the connectivity of the brain and have been recognized as the locus of long-term synaptic plasticity, which is correlated with learning and memory. The development of dendrites and spines in the mammalian central nervous system is a complex process that requires specific molecular events over a period of time. It has been shown that specific molecules are needed not only at the spine’s point of contact, but also at a distance, providing signals that initiate a cascade of events leading to synapse formation. The specific molecules that act to signal neuronal differentiation, dendritic morphology, and synaptogenesis are tightly regulated by genetic and epigenetic programs. It has been shown that the dendritic spine structure and distribution are altered in many diseases, including many forms of mental retardation (MR), and can also be potentiated by neuronal activities and an enriched environment. Because dendritic spine pathologies are found in many types of MR, it has been proposed that an inability to form normal spines leads to the cognitive and motor deficits that are characteristic of MR. Epigenetic mechanisms, including DNA methylation, chromatin remodeling, and the noncoding RNA-mediated process, have profound regulatory roles in mammalian gene expression. The study of epigenetics focuses on cellular effects that result in a heritable pattern of gene expression without changes to genomic encoding. Despite extensive efforts to understand the molecular regulation of dendrite and spine development, epigenetic mechanisms have only recently been considered. In this review, we will focus on epigenetic mechanisms that regulate the development and maturation of dendrites and spines. We will discuss how epigenetic alterations could result in spine abnormalities that lead to MR, such as is seen in fragile X and Rett syndromes. We will also discuss both general methodology and recent technological advances in the study of neuronal dendrites and spines.     

Rules of engagement: factors that regulate activity-dependent synaptic plasticity during neural network development

Overproduction and pruning during development is a phenomenon that can be observed in the number of organisms in a population, the number of cells in many tissue types, and even the number of synapses on individual neurons. The sculpting of synaptic connections in the brain of a developing organism is guided by its personal experience, which on a neural level translates to specific patterns of activity. Activity-dependent plasticity at glutamatergic synapses is an integral part of neuronal network formation and maturation in developing vertebrate and invertebrate brains. As development of the rodent forebrain transitions away from an over-proliferative state, synaptic plasticity undergoes modification. Late developmental changes in synaptic plasticity signal the establishment of a more stable network and relate to pronounced perceptual and cognitive abilities. In large part, activation of glutamate-sensitive N-methyl-d-aspartate (NMDA) receptors regulates synaptic stabilization during development and is a necessary step in memory formation processes that occur in the forebrain. A developmental change in the subunits that compose NMDA receptors coincides with developmental modifications in synaptic plasticity and cognition, and thus much research in this area focuses on NMDA receptor composition. We propose that there are additional, equally important developmental processes that influence synaptic plasticity, including mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor activation. The goal of this review is to summarize what is known and what is not well understood about developmental changes in functional plasticity at glutamatergic synapses, and in the end, attempt to relate these changes to maturation of neural networks.     

Dtrk, a Drosophila gene related to the trk family of neurotrophin receptors, encodes a novel class of neural cell adhesion molecule.

We report the identification and molecular characterization of Dtrk, a Drosophila gene encoding a receptor tyrosine kinase highly related to the trk family of mammalian neurotrophin receptors. The product of the Dtrk gene, gp160Dtrk, is dynamically expressed during Drosophila embryogenesis in several areas of the developing nervous system, including neurons and fasciculating axons. gp160Dtrk has structural homology with neural cell adhesion molecules of the immunoglobulin superfamily and promotes cell adhesion in a homophilic, Ca2+ independent manner. More importantly, this adhesion process specifically activates its tyrosine protein kinase activity. These findings suggest that gp160Dtrk represents a new class of neural cell adhesion molecules that may regulate neuronal recognition and axonal guidance during the development of the Drosophila nervous system.     

Neural coding and contextual influences in the whisker system

A fundamental problem in neuroscience, to which Prof. Segundo has made seminal contributions, is to understand how action potentials represent events in the external world. The aim of this paper is to review the issue of neural coding in the context of the rodent whiskers, an increasingly popular model system. Key issues we consider are: the role of spike timing; mechanisms of spike timing; decoding and context-dependence. Significant insight has come from the development of rigorous, information theoretic frameworks for tackling these questions, in conjunction with suitably designed experiments. We review both the theory and experimental studies. In contrast to the classical view that neurons are noisy and unreliable, it is becoming clear that many neurons in the subcortical whisker pathway are remarkably reliable and, by virtue of spike timing with millisecond-precision, have high bandwidth for conveying sensory information. In this way, even small (~200 neuron) subcortical modules are able to support the sensory processing underlying sophisticated whisker-dependent behaviours. Future work on neural coding in cortex will need to consider new findings that responses are highly dependent on context, including behavioural and internal states. This article is part of a special issue on Neuronal Dynamics of Sensory Coding.     

Reelin signaling and Cdk5 in the control of neuronal positioning

Neuronal positioning is important for higher brain function because it is the architectural basis of the formation of precise synaptic circuits. Analysis of neurological mutant mice has led to dramatic progress in the identification and characterization of molecules important for neuronal positioning in the developing mammalian brain. Among these molecules, identification of signal pathways mediated by Reelin and Cdk5 kinase has provided a conceptual framework for exploring the molecular mechanisms underlying proper neuronal positioning in the developing mammalian brain. Recent evidence has implicated synergism between Reelin signaling and Cdk5 in contributing to the proper positioning of selective neuronal populations.     

Neurotransmitters as early signals for central nervous system development

During brain ontogenesis, the temporal and spatial generation of the different types of neuronal and glial cells from precursors occurs as a sequence of successive progenitor stages whose proliferation, survival and cell-fate choice are controlled by environmental and cellular regulatory molecules. Neurotransmitters belong to the chemical microenvironment of neural cells, even at the earliest stages of brain development. It is now established that specific neurotransmitter receptors are present on progenitor cells of the developing central nervous system and could play, during neural development, a role that has remained unsuspected until recently. The present review focuses on the occurrence of neurotransmitters and their corresponding ligand-gated ion channel receptors in immature cells, including neural stem cells of specific embryonic and neonatal brain regions. We summarize in vitro and in vivo data arguing that neurotransmitters could regulate morphogenetic events such as proliferation, growth, migration, differentiation and survival of neural precursor cells. The understanding of neurotransmitter function during early neural maturation could lead to the development of pharmacological tools aimed at improving adult brain repair strategies.     

延缓衰老相关的小分子物质研究进展

筛选、研究具有延缓衰老作用的小分子物质,对于发现新的治疗衰老相关性疾病及肿瘤等的有效靶点、开发新型药物、促进人类健康具有重大的现实意义．同时更重要的是,可以这些小分子物质为切入点,对衰老、肿瘤等生命现象的具体分子机制进行深入研究,这对于分子生物学等相关生命科学研究的发展具有重要的推动作用．总结了近一二十年来发现的一些具有代表性的可延缓衰老的小分子物质,并重点论述了其作用的分子机制．     

Molecular interactions of neural chondroitin sulfate proteoglycans in the brain development

Aggrecan family proteoglycans, phosphacan/RPTPzeta/beta, and neuroglycan C (NGC) are the major classes of chondroitin sulfate proteoglycan in the developing mammalian brain. A multidomain is a common structural feature of these proteoglycans which can interact with various molecules including growth factors, cell adhesion molecules, and extracellular matrix molecules. Individual proteoglycans are distributed in the developing brain in a distinct temporal and spatial pattern, suggesting that they are involved in distinct phases of the brain development through multiple molecular interactions. This review mainly summarizes recent studies on the involvement of these three classes of proteoglycan in cell-cell and cell-substratum interactions during the brain development. Their expressions and proposed functional roles in injured brains are also mentioned. In addition, this review briefly covers potential functions of other neural chondroitin sulfate proteoglycans such as decorin, testican, NG2 proteoglycan, and amyloid precursor protein (APP) in developing and injured brains.     

Beyond proliferation--cell cycle control of neuronal survival and differentiation in the developing mammalian brain

Cell cycle proteins are critical regulators of proliferation in dividing cells. Paradoxically, accumulating evidence supports the view that core components of the cell cycle also play key roles in the development of terminally differentiated postmitotic neurons. Distinct cell cycle proteins including cell cycle-dependent kinases may contribute to naturally occurring programmed neuronal cell death in the developing mammalian brain. In addition, recent studies have uncovered a novel role for the cell cycle-associated ubiquitination machinery in the control of axonal growth and patterning in the developing brain. The underlying molecular mechanisms regulating these distinct cell cycle-based developmental events in neurons are just beginning to be understood.