A trace of silence: memory and microRNA at the synapse

Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?     

Network Self-Organization Explains the Statistics and Dynamics of Synaptic Connection Strengths in Cortex

The information processing abilities of neural circuits arise from their synaptic connection patterns. Understanding the laws governing these connectivity patterns is essential for understanding brain function. The overall distribution of synaptic strengths of local excitatory connections in cortex and hippocampus is long-tailed, exhibiting a small number of synaptic connections of very large efficacy. At the same time, new synaptic connections are constantly being created and individual synaptic connection strengths show substantial fluctuations across time. It remains unclear through what mechanisms these properties of neural circuits arise and how they contribute to learning and memory. In this study we show that fundamental characteristics of excitatory synaptic connections in cortex and hippocampus can be explained as a consequence of self-organization in a recurrent network combining spike-timing-dependent plasticity (STDP), structural plasticity and different forms of homeostatic plasticity. In the network, associative synaptic plasticity in the form of STDP induces a rich-get-richer dynamics among synapses, while homeostatic mechanisms induce competition. Under distinctly different initial conditions, the ensuing self-organization produces long-tailed synaptic strength distributions matching experimental findings. We show that this self-organization can take place with a purely additive STDP mechanism and that multiplicative weight dynamics emerge as a consequence of network interactions. The observed patterns of fluctuation of synaptic strengths, including elimination and generation of synaptic connections and long-term persistence of strong connections, are consistent with the dynamics of dendritic spines found in rat hippocampus. Beyond this, the model predicts an approximately power-law scaling of the lifetimes of newly established synaptic connection strengths during development. Our results suggest that the combined action of multiple forms of neuronal plasticity plays an essential role in the formation and maintenance of cortical circuits.     

Activity-induced remodeling of olfactory bulb microcircuits revealed by monosynaptic tracing

The continued addition of new neurons to mature olfactory circuits represents a remarkable mode of cellular and structural brain plasticity. However, the anatomical configuration of newly established circuits, the types and numbers of neurons that form new synaptic connections, and the effect of sensory experience on synaptic connectivity in the olfactory bulb remain poorly understood. Using in vivo electroporation and monosynaptic tracing, we show that postnatal-born granule cells form synaptic connections with centrifugal inputs and mitral/tufted cells in the mouse olfactory bulb. In addition, newly born granule cells receive extensive input from local inhibitory short axon cells, a poorly understood cell population. The connectivity of short axon cells shows clustered organization, and their synaptic input onto newborn granule cells dramatically and selectively expands with odor stimulation. Our findings suggest that sensory experience promotes the synaptic integration of new neurons into cell type-specific olfactory circuits.     

Wiring and rewiring of the retinogeniculate synapse

The formation and refinement of synaptic circuits are areas of research that have fascinated neurobiologists for decades. A recurrent theme seen at many CNS synapses is that neuronal connections are at first imprecise, but refine and can be rearranged with time or with experience. Today, with the advent of new technologies to map and monitor neuronal circuits, it is worthwhile to revisit a powerful experimental model for examining the development and plasticity of synaptic circuits--the retinogeniculate synapse.     

突触可塑性与脑疾病的神经发育基础

大脑神经回路高度有序的神经元活动是高级脑功能的基础,神经元之间的突触联结是神经回路的关键功能节点。神经突触根据神经元活动调整其传递效能的能力,亦即突触可塑性,被认为是神经回路发育和学习与记忆功能的基础。其异常则可能导致如抑郁症和阿尔茨海默病等精神、神经疾病。将介绍这两种疾病与突触可塑性的关系,聚焦于相关分子和细胞机制以及新的研究、治疗手段等进展。     

Possible role of cooperative action of NMDA receptor and GABA function in developmental plasticity

The maturation of cortical circuits is strongly influenced by sensory experience during a restricted critical period. The developmental alteration in the subunit composition of NMDA receptors (NMDARs) has been suggested to be involved in regulating the timing of such plasticity. However, this hypothesis does not explain the evidence that enhancing GABA inhibition triggers a critical period in the visual cortex. Here, to investigate how the NMDAR and GABA functions influence synaptic organization, we examine an spike-timing-dependent plasticity (STDP) model that incorporates the dynamic modulation of LTP, associated with the activity- and subunit-dependent desensitization of NMDARs, as well as the background inhibition by GABA. We show that the competitive interaction between correlated input groups, required for experience-dependent synaptic modifications, may emerge when both the NMDAR subunit expression and GABA inhibition reach a sufficiently mature state. This may suggest that the cooperative action of these two developmental mechanisms can contribute to embedding the spatiotemporal structure of input spikes in synaptic patterns and providing the trigger for experience-dependent cortical plasticity.     

Memory retention in pyramidal neurons: a unified model of energy-based homo and heterosynaptic plasticity with homeostasis

The brain can learn new tasks without forgetting old ones. This memory retention is closely associated with the long-term stability of synaptic strength. To understand the capacity of pyramidal neurons to preserve memory under different tasks, we established a plasticity model based on the postsynaptic membrane energy state, in which the change in synaptic strength depends on the difference between the energy state after stimulation and the resting energy state. If the post-stimulation energy state is higher than the resting energy state, then synaptic depression occurs. On the contrary, the synapse is strengthened. Our model unifies homo- and heterosynaptic plasticity and can reproduce synaptic plasticity observed in multiple experiments, such as spike-timing-dependent plasticity, and cooperative plasticity with few and common parameters. Based on the proposed plasticity model, we conducted a simulation study on how the activation patterns of dendritic branches by different tasks affect the synaptic connection strength of pyramidal neurons. We further investigate the formation mechanism by which different tasks activate different dendritic branches. Simulation results show that compare to the classic plasticity model, the plasticity model we proposed can achieve a better spatial separation of different branches activated by different tasks in pyramidal neurons, which deepens our insight into the memory retention mechanism of brains.     

哺乳动物大脑中神经活动如何改变突触

大脑最基本性质是快速适应周围环境改变的能力,这主要是通过改变各个神经细胞之间的连接来实现的。有多种不同机制可以调节突触的强度,包括突触效率的稳态调节、突触增强和减弱的形态学表现以及钙在其中的作用。当开始了解这些突触改变的细胞生物学机制的时候,也应该考虑这种突触可塑性在完整大脑中的功能意义。因此,应用最新的成像手段来研究经验如何影响皮层环路中突触的改变,尤其是在体双光子显微技术可以在新皮层的单个神经元水平上研究形态和功能可塑性。这些实验将逐渐填补传统的细胞水平和系统水平研究之间的空白,并将有助于更全面充分地理解突触可塑性这种现象及其在皮层功能乃至动物行为中所起的作用。     

Reversible plasticity of fear memory-encoding amygdala synaptic circuits even after fear memory consolidation

It is generally believed that after memory consolidation, memory-encoding synaptic circuits are persistently modified and become less plastic. This, however, may hinder the remaining capacity of information storage in a given neural circuit. Here we consider the hypothesis that memory-encoding synaptic circuits still retain reversible plasticity even after memory consolidation. To test this, we employed a protocol of auditory fear conditioning which recruited the vast majority of the thalamic input synaptic circuit to the lateral amygdala (T-LA synaptic circuit; a storage site for fear memory) with fear conditioning-induced synaptic plasticity. Subsequently the fear memory-encoding synaptic circuits were challenged with fear extinction and re-conditioning to determine whether these circuits exhibit reversible plasticity. We found that fear memory-encoding T-LA synaptic circuit exhibited dynamic efficacy changes in tight correlation with fear memory strength even after fear memory consolidation. Initial conditioning or re-conditioning brought T-LA synaptic circuit near the ceiling of their modification range (occluding LTP and enhancing depotentiation in brain slices prepared from conditioned or re-conditioned rats), while extinction reversed this change (reinstating LTP and occluding depotentiation in brain slices prepared from extinguished rats). Consistently, fear conditioning-induced synaptic potentiation at T-LA synapses was functionally reversed by extinction and reinstated by subsequent re-conditioning. These results suggest reversible plasticity of fear memory-encoding circuits even after fear memory consolidation. This reversible plasticity of memory-encoding synapses may be involved in updating the contents of original memory even after memory consolidation.     

Normal protein composition of synapses in Ts65Dn mice: a mouse model of Down syndrome

Down syndrome (DS) is the most prevalent form of intellectual disability caused by the triplication of ∼230 genes on chromosome 21. Recent data in Ts65Dn mice, the foremost mouse model of DS, strongly suggest that cognitive impairment in individuals with DS is a consequence of reduced synaptic plasticity because of chronic over-inhibition. It remains unclear however whether changes in plasticity are tied to global molecular changes at synapses, or are due to regional changes in the functional properties of synaptic circuits. One interesting framework for evaluating the activity state of the DS brain comes from in vitro studies showing that chronic pharmacological silencing of neuronal excitability orchestrates stereotyped changes in the protein composition of synaptic junctions. In the present study, we use proteomic strategies to evaluate whether synapses from the Ts65Dn cerebrum carry signatures characteristic of inactive cortical neurons. Our data reveal that synaptic junctions do not exhibit overt alterations in protein composition. Only modest changes in the levels of synaptic proteins and in their phosphorylation are observed. This suggests that subtle changes in the functional properties of specific synaptic circuits rather than large-scale homeostatic shifts in the expression of synaptic molecules contribute to cognitive impairment in people with DS.     

Homeostatic plasticity in the CNS: synaptic and intrinsic forms

The study of experience-dependent plasticity has been dominated by questions of how Hebbian plasticity mechanisms act during learning and development. This is unsurprising as Hebbian plasticity constitutes the most fully developed and influential model of how information is stored in neural circuits and how neural circuitry can develop without extensive genetic instructions. Yet Hebbian plasticity may not be sufficient for understanding either learning or development: the dramatic changes in synapse number and strength that can be produced by this kind of plasticity tend to threaten the stability of neural circuits. Recent work has suggested that, in addition to Hebbian plasticity, homeostatic regulatory mechanisms are active in a variety of preparations. These mechanisms alter both the synaptic connections between neurons and the intrinsic electrical properties of individual neurons, in such a way as to maintain some constancy in neuronal properties despite the changes wrought by Hebbian mechanisms. Here we review the evidence for homeostatic plasticity in the central nervous system, with special emphasis on results from cortical preparations.     

Memory Maintenance in Synapses with Calcium-Based Plasticity in the Presence of Background Activity

Most models of learning and memory assume that memories are maintained in neuronal circuits by persistent synaptic modifications induced by specific patterns of pre- and postsynaptic activity. For this scenario to be viable, synaptic modifications must survive the ubiquitous ongoing activity present in neural circuits in vivo. In this paper, we investigate the time scales of memory maintenance in a calcium-based synaptic plasticity model that has been shown recently to be able to fit different experimental data-sets from hippocampal and neocortical preparations. We find that in the presence of background activity on the order of 1 Hz parameters that fit pyramidal layer 5 neocortical data lead to a very fast decay of synaptic efficacy, with time scales of minutes. We then identify two ways in which this memory time scale can be extended: (i) the extracellular calcium concentration in the experiments used to fit the model are larger than estimated concentrations in vivo. Lowering extracellular calcium concentration to in vivo levels leads to an increase in memory time scales of several orders of magnitude; (ii) adding a bistability mechanism so that each synapse has two stable states at sufficiently low background activity leads to a further boost in memory time scale, since memory decay is no longer described by an exponential decay from an initial state, but by an escape from a potential well. We argue that both features are expected to be present in synapses in vivo. These results are obtained first in a single synapse connecting two independent Poisson neurons, and then in simulations of a large network of excitatory and inhibitory integrate-and-fire neurons. Our results emphasise the need for studying plasticity at physiological extracellular calcium concentration, and highlight the role of synaptic bi- or multistability in the stability of learned synaptic structures.     

Long-term plasticity at inhibitory synapses

Experience-dependent modifications of neural circuits and function are believed to heavily depend on changes in synaptic efficacy such as LTP/LTD. Hence, much effort has been devoted to elucidating the mechanisms underlying these forms of synaptic plasticity. Although most of this work has focused on excitatory synapses, it is now clear that diverse mechanisms of long-term inhibitory plasticity have evolved to provide additional flexibility to neural circuits. By changing the excitatory/inhibitory balance, GABAergic plasticity can regulate excitability, neural circuit function and ultimately, contribute to learning and memory, and neural circuit refinement. Here we discuss recent advancements in our understanding of the mechanisms and functional relevance of GABAergic inhibitory synaptic plasticity.     

Synaptic plasticity and addiction

Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems.     

A Developmental Switch for Hebbian Plasticity

Hebbian forms of synaptic plasticity are required for the orderly development of sensory circuits in the brain and are powerful modulators of learning and memory in adulthood. During development, emergence of Hebbian plasticity leads to formation of functional circuits. By modeling the dynamics of neurotransmitter release during early postnatal cortical development we show that a developmentally regulated switch in vesicle exocytosis mode triggers associative (i.e. Hebbian) plasticity. Early in development spontaneous vesicle exocytosis (SVE), often considered as ''synaptic noise'', is important for homogenization of synaptic weights and maintenance of synaptic weights in the appropriate dynamic range. Our results demonstrate that SVE has a permissive, whereas subsequent evoked vesicle exocytosis (EVE) has an instructive role in the expression of Hebbian plasticity. A timed onset for Hebbian plasticity can be achieved by switching from SVE to EVE and the balance between SVE and EVE can control the effective rate of Hebbian plasticity. We further show that this developmental switch in neurotransmitter release mode enables maturation of spike-timing dependent plasticity. A mis-timed or inadequate SVE to EVE switch may lead to malformation of brain networks thereby contributing to the etiology of neurodevelopmental disorders.     

短时程突触可塑性研究概况

突触可塑性是神经系统所具有的重要特征,也是神经系统实现其功能的重要保障。按照持续的时间划分,突触可塑性可分为短时程突触可塑性和长时程突触可塑性。短时程突触可塑性包括短时程增强和短时程压抑两种类型。与长时程突触可塑性不同,短时程突触可塑性的产生主要依赖于神经递质释放概率的变化,其往往决定神经回路的信息处理和反应模式,不仅直接参与了对输入信号的识别和处理,而且还可对长时程突触可塑性的表达产生重要影响。     

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.     

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.     

The neural cell adhesion molecule and synaptic plasticity

Highly stereotyped patterns of neuronal connections are laid down during the development of the nervous system via a range of activity independent and activity dependent mechanisms. Whereas the coarse hard-wiring of the nervous system appears to rely on molecular recognition events between the neuron, its pathway, and its target, the establishment of precisely patterned functional circuits is thought to be driven by neuronal activity. In this review we discuss the role that the neuronal cell adhesion molecule (NCAM) plays in morphological plasticity. Recent studies on NCAM and its probable species homologue in Aplysia (apCAM) suggests that an individual CAM can function to both promote synaptic plasticity and maintain the structure of the synapse. In the adult brain, changes between stability and plasticity are likely to underlie dynamic morphological changes in synaptic structures associated with learning and memory. In this review we use NCAM as an example to illustrate mechanisms that can change the function of an individual CAM from a molecule that promotes plasticity to one that does not. We also discuss evidence that NCAM promotes plasticity by activating a conventional signal transduction cascade, rather than by modulating adhesion perse. Finally, we consider the evidence that supports a role for NCAM in learning and memory. © 1995 John Wiley & Sons, Inc.     

Integrating synaptic plasticity and striatal circuit function in addiction

Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.