Molecular Bases of Caloric Restriction Regulation of Neuronal Synaptic Plasticity

Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging. The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators. In this review, we will present and discuss the effect of CR in synaptic processes underlying analgesia and cognitive improvement in healthy, sick, and aging animals. We will also discuss the possible role of mitochondrial biogenesis induced by CR in regulation of neuronal synaptic plasticity.     

Polysialic acid in the plasticity of the developing and adult vertebrate nervous system

Polysialic acid (PSA) is a cell-surface glycan with an enormous hydrated volume that serves to modulate the distance between cells. This regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells and the growth and targeting of axons. PSA is also involved in a number of plasticity-related responses in the adult CNS, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory. The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue.     

Learning in sensorimotor circuits

The study of plasticity in the central nervous system is a major and very dynamic neuroscience research field with enormous clinical potential. Considerable advances in this field have been made during the past 10 years. It now appears that most circuits in the brain and spinal cord show plasticity and that they can be modified by experience. Knowledge of the mechanisms of plasticity in the nervous system is therefore essential for the understanding of how the nervous system is wired during development and how it adapts in response to changes in the body and environment. Recent findings indicate that functional sensorimotor modules probe the sensory signals from the body that are generated as a consequence of module specific activity and use this sensory feedback to calibrate the strength in its input-output connections. This experience-dependent signal adapts the circuitry in the sensorimotor module to the body anatomy and biomechanics.     

Presynaptically Silent Synapses Studied with Light Microscopy

Synaptic plasticity likely underlies the nervous system''s ability to learn and remember and may also represent an adaptability that prevents otherwise damaging insults from becoming neurotoxic. We have been studying a form of presynaptic plasticity that is interesting in part because it is expressed as a digital switching on and off of a presynaptic terminal s ability to release vesicles containing the neurotransmitter glutamate. Here we demonstrate a protocol for visualizing the activity status of presynaptic terminals in dissociated cell cultures prepared from the rodent hippocampus. The method relies on detecting active synapses using staining with a fixable form of the styryl dye FM1-43, commonly used to label synaptic vesicles. This staining profile is compared with immunostaining of the same terminals with an antibody directed against the vesicular glutamate transporter 1 (vGluT-1), a stain designed to label all glutamate synapses regardless of activation status. We find that depolarizing stimuli induce presynaptic silencing. The population of synapses that is silent under baseline conditions can be activated by prolonged electrical silencing or by activation of cAMP signaling pathways.Open in a separate windowClick here to view.^{(61M, flv)}     

Insulin signalling underlies both plasticity and divergence of a reproductive trait in Drosophila

Phenotypic plasticity is the ability of a single genotype to yield distinct phenotypes in different environments. The molecular mechanisms linking phenotypic plasticity to the evolution of heritable diversification, however, are largely unknown. Here, we show that insulin/insulin-like growth factor signalling (IIS) underlies both phenotypic plasticity and evolutionary diversification of ovariole number, a quantitative reproductive trait, in Drosophila. IIS activity levels and sensitivity have diverged between species, leading to both species-specific ovariole number and species-specific nutritional plasticity in ovariole number. Plastic range of ovariole number correlates with ecological niche, suggesting that the degree of nutritional plasticity may be an adaptive trait. This demonstrates that a plastic response conserved across animals can underlie the evolution of morphological diversity, underscoring the potential pervasiveness of plasticity as an evolutionary mechanism.     

Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms

Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and therapeutic approaches for neurodegenerative disorders.     

Polysialic acid and activity-dependent synapse remodeling

Polysialic acid (PSA) is a large carbohydrate added post-translationally to the extracellular domain of the Neural Cell Adhesion Molecule (NCAM) that influences its adhesive and other functional properties. PSA-NCAM is widely distributed in the developing nervous system where it promotes dynamic cell interactions, like those responsible for axonal growth, terminal sprouting and target innervation. Its expression becomes restricted in the adult nervous system where it is thought to contribute to various forms of neuronal and glial plasticity. We here review evidence, obtained mainly from hypothalamic neuroendocrine centers and the olfactory system, that it intervenes in structural synaptic plasticity and accompanying neuronal-glial transformations, making possible the formation and elimination of synapses that occur under particular physiological conditions. While the mechanism of action of this complex sugar is unknown, it is now clear that it is a necessary molecular component of various cell transformations, including those responsible for activity-dependent synaptic remodeling.Key words: adhesion, synaptic plasticity, astrocytes, central nervous system, hypothalamus, olfactory system     

Nerve growth factor: two receptors,multiple functions

Nerve growth factor (NGF) was characterized over 4 decades ago, and like the other neurotrophins subsequently discovered, it is best known for its trophic role, including the prevention of programmed cell death in specific populations of neurones in the peripheral nervous system. This property can be accounted for by the activation of a tyrosine kinase receptor. NGF also regulates neuronal function, as illustrated by its role in pain and inflammation, and in synaptic plasticity. Finally, NGF recently was shown to activate the neurotrophin receptor p75 (p75^NTR), a receptor with no intrinsic catalytic activity and with similarities to members of the tumor necrosis factor receptor family. During normal development, the activation of p75^NTR by NGF actually kills cells in the central nervous system. One remarkable property of NGF is then that it controls cell numbers in opposite ways in the developing nervous system, a result of its unique ability to activate two different receptor types. BioEssays 20:137–145, 1998. © 1998 John Wiley & Sons, Inc.     

Numb isoforms containing a short PTB domain promote neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death of PC12 Cells

The development of the nervous system is regulated by trophic signals that control cell proliferation, differentiation, and survival. Numb is an evolutionarily conserved protein identified by its ability to control cell fate in the nervous system of Drosophila. Mammals express four isoforms of Numb that differ in the length of a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). Using PC12 cells stably expressing each of the human isoforms, we show that Numb regulates sensitivity of the cells to neurotrophic factor-induced differentiation and neurotrophic factor withdrawal-induced death in an isoform-specific manner. Numb isoforms containing a short PTB domain enhance the differentiation response to NGF and enhance apoptosis upon NGF withdrawal; Numb isoforms containing a long PTB domain exhibit the same sensitivity to NGF as vector-transfected cells. These effects of Numb were found to be independent of the length of the PRR. In undifferentiated conditions, the levels of full-length TrkA and of phosphorylated p44/p42 mitogen-activated protein kinase (MAPK) are increased in cells expressing Numb isoforms with a short PTB domain, indicating an up-regulation of NGF signaling pathways. Furthermore, we provide evidence that the mechanism whereby short PTB domain Numb isoforms sensitize cells to trophic factor deprivation-induced apoptosis involves elevations in intracellular calcium concentrations. Our results suggest that Numb sensitizes cells to neurotrophin responses in an isoform-specific manner, an effect that may play an important role in the development and plasticity of the nervous system.     

SHH信号通路在海马神经可塑性及相关神经系统疾病中的作用

音猬因子（sonic hedgehog,SHH）是一种分泌蛋白质,可在发育过程中控制神经祖细胞、神经元和神经胶质细胞的形成。研究发现,海马是学习和记忆中至关重要的大脑区域,SHH在海马神经元回路的形成和可塑性中发挥重要作用,可介导海马神经的发生和突触的可塑性调节。海马神经元树突中SHH受体的激活是跨神经元信号通路的组成部分,该信号通路可加速轴突的生长并增强谷氨酸从突触前末端的释放。SHH信号通路转导受损可导致中枢神经系统损伤和相关疾病（如自闭症、抑郁症和神经退行性疾病等）发生。因此,控制SHH信号通路转导,如使用SHH通路抑制剂或激动剂可能有助于相关疾病的治疗。综述了SHH信号通路的海马神经可塑性及其在中枢神经系统发育和相关疾病中的影响,以期为阐明SHH信号转导受损导致的海马神经受损和中枢神经系统相关疾病的机制奠定一定的理论依据。     

Regulation of synaptic functions in central nervous system by endocrine hormones and the maintenance of energy homoeostasis

Energy homoeostasis, a co-ordinated balance of food intake and energy expenditure, is regulated by the CNS (central nervous system). The past decade has witnessed significant advances in our understanding of metabolic processes and brain circuitry which responds to a broad range of neural, nutrient and hormonal signals. Accumulating evidence demonstrates altered synaptic plasticity in the CNS in response to hormone signals. Moreover, emerging observations suggest that synaptic plasticity underlies all brain functions, including the physiological regulation of energy homoeostasis, and that impaired synaptic constellation and plasticity may lead to pathological development and conditions. Here, we summarize the current knowledge on the regulation of postsynaptic receptors such as AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), NMDA (N-methyl-D-aspartate) and GABA (γ-aminobutyric acid) receptors, and the presynaptic components by hormone signals. A detailed understanding of the neurobiological mechanisms by which hormones regulate energy homoeostasis may lead to novel strategies in treating metabolic disorders.     

Nicotine's oxidative and antioxidant properties in CNS

Nicotine has been reported to be therapeutic in some patients with certain neurodegenerative diseases and to have neuroprotective effects in the central nervous system. However, nicotine administration may result in oxidative stress by inducing the generation of reactive oxygen species in the periphery and central nervous system. There is also evidence suggesting that nicotine may have antioxidant properties in the central nervous system. The antioxidant properties of nicotine may be intracellular through the activation of the nicotinic receptors or extracellular by acting as a radical scavenger in that it binds to iron. The possibility that nicotine might be used to treat some symptoms of certain neurodegenerative diseases underlies the necessity to determine whether nicotine has pro-oxidant, antioxidant or properties of both. This review discusses the studies that have addressed this issue, the behavioral effects of nicotine, and the possible mechanisms of action that result from nicotine administration or nicotinic receptor activation.     

Calcium ions and the nervous system plasticity

The nervous system is different from all other systems of the organism by extreme flexibility of the structural and functional properties of its elements. This unique feature of the nervous system can be best described as plasticity in a broad sense of the word. All forms of plastic changes in the nervous system functioning have common basic mechanisms, the changes at the free Ca2+ cytosol ions being the most important one. These "calcium signals" trigger an extremely complicated intracellular machinery capable of controlling the structural and functional properties of the nervous system during the whole life span. This review summarises data on the intracellular Ca2+ ions mechanisms controlling the developmental plasticity of neuronal elements, synaptic plasticity of the mature nervous system, and the decline of plastic capabilities with ageing.     

Neurobiology of exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.     

Iron deficiency on neuronal function

Because of the intrinsic ability of iron to catalyze the formation of reactive oxygen species, it has been associated with oxidative stress and neurodegenerative diseases. However, iron deficiency (ID) also negatively impacts various functions of the brain, suggesting that iron plays an important physiological role in neuronal processes such as myelination, synaptogenesis, behavior and synaptic plasticity (SP). ID not only produces changes in the hippocampus, striatum, amygdale or prefrontal cortex, it also affects the interaction among these systems. In both humans and rodents, the perturbations of these structures are associated to cognitive deficits. These cognitive alterations have been well correlated with changes in neural plasticity, the possible cellular substrate of memory and learning. Given that SP is strongly affected by early ID and the lasting-neurological consequences remain even after ID has been corrected, it is important to prevent ID as well as to seek effective therapeutic interventions that reduce or reverse the long-term effects of the ID in the nervous system. This review will give an overview of the literature on the effects of iron deficit in neuronal functions such as behavior, neurotransmission and SP. We also discuss our recent data about the possible oxidative effect of iron on the mechanisms involved in neural plasticity.     

Divergent Sex-Specific Plasticity in Long-Lived Vertebrates with Contrasting Sexual Dimorphism

Sex-specific plasticity can profoundly affect sexual size dimorphism (SSD), but its influence in female-larger-SSD vertebrates remains obscure. Theory predicts that sex-specific plasticity may drive SSD evolution if the larger sex benefits from optimal-growth conditions when available (condition-dependent hypothesis), or if attaining a suboptimal size is penalized by selection (adaptive canalization hypothesis). Sex-specific plasticity enhances the size of the larger sex in male-larger-SSD turtles but whether the same occurs in female-larger species is unknown. Sexual shape dimorphism (SShD) is also widespread in nature but is understudied, and whether SShD derives from sex-specific responses to identical selective pressures or from sex-specific selection remains unclear. Here we tested whether sex-specific growth plasticity underlies the development of sexual size and shape dimorphism in the female-larger-SSD turtle, Podocnemis expansa. Individuals hatched from several incubation temperatures and were raised under common-garden conditions with varying temperature and resources. Body size and shape were plastic and sexually dimorphic, but plasticity did not differ between the sexes, opposite to the male-larger turtle Chelydra serpentina. Maternal effects (egg size) were significant on size and shape, suggesting that females increase their fitness by allocating greater energy to enhance offspring growth. Results ruled out the sex-specific plasticity hypotheses in P. expansa, indicating that SSD and SShD do not derive form differential responses to identical drivers but from sex-specific selective pressures. Our results indicate that differential plasticity does not favor males inherently, nor the larger sex, as would be expected if it was a pervasive driver of macroevolutionary patterns of sexual dimorphism across turtle lineages.     

Evolution of eumetazoan nervous systems: insights from cnidarians

Cnidarians, the sister group to bilaterians, have a simple diffuse nervous system. This morphological simplicity and their phylogenetic position make them a crucial group in the study of the evolution of the nervous system. The development of their nervous systems is of particular interest, as by uncovering the genetic programme that underlies it, and comparing it with the bilaterian developmental programme, it is possible to make assumptions about the genes and processes involved in the development of ancestral nervous systems. Recent advances in sequencing methods, genetic interference techniques and transgenic technology have enabled us to get a first glimpse into the molecular network underlying the development of a cnidarian nervous system—in particular the nervous system of the anthozoan Nematostella vectensis. It appears that much of the genetic network of the nervous system development is partly conserved between cnidarians and bilaterians, with Wnt and bone morphogenetic protein (BMP) signalling, and Sox genes playing a crucial part in the differentiation of neurons. However, cnidarians possess some specific characteristics, and further studies are necessary to elucidate the full regulatory network. The work on cnidarian neurogenesis further accentuates the need to study non-model organisms in order to gain insights into processes that shaped present-day lineages during the course of evolution.     

Structural Plasticity Can Produce Metaplasticity

Background

Synaptic plasticity underlies many aspect of learning memory and development. The properties of synaptic plasticity can change as a function of previous plasticity and previous activation of synapses, a phenomenon called metaplasticity. Synaptic plasticity not only changes the functional connectivity between neurons but in some cases produces a structural change in synaptic spines; a change thought to form a basis for this observed plasticity. Here we examine to what extent structural plasticity of spines can be a cause for metaplasticity. This study is motivated by the observation that structural changes in spines are likely to affect the calcium dynamics in spines. Since calcium dynamics determine the sign and magnitude of synaptic plasticity, it is likely that structural plasticity will alter the properties of synaptic plasticity.

Methodology/Principal Findings

In this study we address the question how spine geometry and alterations of N-methyl-D-aspartic acid (NMDA) receptors conductance may affect plasticity. Based on a simplified model of the spine in combination with a calcium-dependent plasticity rule, we demonstrated that after the induction phase of plasticity a shift of the long term potentiation (LTP) or long term depression (LTD) threshold takes place. This induces a refractory period for further LTP induction and promotes depotentiation as observed experimentally. That resembles the BCM metaplasticity rule but specific for the individual synapse. In the second phase, alteration of the NMDA response may bring the synapse to a state such that further synaptic weight alterations are feasible. We show that if the enhancement of the NMDA response is proportional to the area of the post synaptic density (PSD) the plasticity curves most likely return to the initial state.

Conclusions/Significance

Using simulations of calcium dynamics in synaptic spines, coupled with a biophysically motivated calcium-dependent plasticity rule, we find under what conditions structural plasticity can form the basis of synapse specific metaplasticity.     

糖皮质激素在慢性疼痛中的双重作用机制

糖皮质激素(glucocorticoid,GC)是下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴分泌的最终效应激素,通过与糖皮质激素受体(glucocorticoid receptors,GR)结合行使功能。研究发现,GC在慢性疼痛中表现双重作用,内源性GC作为抗炎类固醇通过募集免疫细胞、抑制激酶通路、调节神经胶质细胞在部分类型的神经病理性疼痛及炎性痛中发挥抑痛作用,但在应激情况下,GC水平异常升高参与中枢神经系统神经元的凋亡、兴奋、记忆等,通过调控不同的信号反应或微环境促进病理性疼痛。本文综述GC在慢性疼痛中的作用,了解其发挥镇痛或致痛的双重作用机制。     

Neuronal‐specific proteasome augmentation via Prosβ5 overexpression extends lifespan and reduces age‐related cognitive decline

Cognitive function declines with age throughout the animal kingdom, and increasing evidence shows that disruption of the proteasome system contributes to this deterioration. The proteasome has important roles in multiple aspects of the nervous system, including synapse function and plasticity, as well as preventing cell death and senescence. Previous studies have shown neuronal proteasome depletion and inhibition can result in neurodegeneration and cognitive deficits, but it is unclear if this pathway is a driver of neurodegeneration and cognitive decline in aging. We report that overexpression of the proteasome β5 subunit enhances proteasome assembly and function. Significantly, we go on to show that neuronal‐specific proteasome augmentation slows age‐related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly, neuronal‐specific augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging.