Corticostriatal plasticity is necessary for learning intentional neuroprosthetic skills

The ability to learn new skills and perfect them with practice applies not only to physical skills but also to abstract skills, like motor planning or neuroprosthetic actions. Although plasticity in corticostriatal circuits has been implicated in learning physical skills, it remains unclear if similar circuits or processes are required for abstract skill learning. Here we use a novel behavioural task in rodents to investigate the role of corticostriatal plasticity in abstract skill learning. Rodents learned to control the pitch of an auditory cursor to reach one of two targets by modulating activity in primary motor cortex irrespective of physical movement. Degradation of the relation between action and outcome, as well as sensory-specific devaluation and omission tests, demonstrate that these learned neuroprosthetic actions are intentional and goal-directed, rather than habitual. Striatal neurons change their activity with learning, with more neurons modulating their activity in relation to target-reaching as learning progresses. Concomitantly, strong relations between the activity of neurons in motor cortex and the striatum emerge. Specific deletion of striatal NMDA receptors impairs the development of this corticostriatal plasticity, and disrupts the ability to learn neuroprosthetic skills. These results suggest that corticostriatal plasticity is necessary for abstract skill learning, and that neuroprosthetic movements capitalize on the neural circuitry involved in natural motor learning.     

Latent synaptic pathways revealed after tetanic stimulation in the hippocampus

Synaptic plasticity may result from changes at existing synapses or from alterations in the number of functional synaptic connections. In the hippocampus excitatory synaptic strength is persistently enhanced after tetanic stimulation. Here we report that latent synaptic pathways may also become functional. Simultaneous intracellular recordings were made from pairs of CA3 pyramidal cells in slices from guinea pig hippocampus. After stimulating afferent fibres repetitively, polysynaptic excitatory pathways between previously unconnected cells became apparent. The efficacy of recurrent inhibitory circuits was also reduced. The loss of inhibitory control is of interest because latent excitatory pathways are revealed after pharmacological suppression of inhibition. This plasticity in local synaptic circuits leads to the emergence of synchronous firing in groups of CA3 cells. The formation of groups of associated cells and the ability of some cells to initiate synchronous firing in a larger cell group through recurrent pathways is reminiscent of several models of information storage and recall in the cortex.     

视觉信息加工及其脑机制

 视觉是人们感知外部世界最重要的途径之一。视觉信号通过视网膜接收后传递到大脑皮层进行加工处理,最终形成人们所意识到的画面。目前为止,已有大量研究从不同水平不同角度探讨大脑如何对视觉信息进行加工和表征,但仍有很多未解的问题。本文综述了视觉信息加工的研究进展,回顾了脑视觉信息加工过程及组织形式,总结了近年来有关视觉可塑性、知觉学习、生物社会信息知觉等方面的研究进展。     

Covert skill learning in a cortical-basal ganglia circuit

We learn complex skills such as speech and dance through a gradual process of trial and error. Cortical-basal ganglia circuits have an important yet unresolved function in this trial-and-error skill learning; influential 'actor-critic' models propose that basal ganglia circuits generate a variety of behaviours during training and learn to implement the successful behaviours in their repertoire. Here we show that the anterior forebrain pathway (AFP), a cortical-basal ganglia circuit, contributes to skill learning even when it does not contribute to such 'exploratory' variation in behavioural performance during training. Blocking the output of the AFP while training Bengalese finches to modify their songs prevented the gradual improvement that normally occurs in this complex skill during training. However, unblocking the output of the AFP after training caused an immediate transition from naive performance to excellent performance, indicating that the AFP covertly gained the ability to implement learned skill performance without contributing to skill practice. In contrast, inactivating the output nucleus of the AFP during training completely prevented learning, indicating that learning requires activity within the AFP during training. Our results suggest a revised model of skill learning: basal ganglia circuits can monitor the consequences of behavioural variation produced by other brain regions and then direct those brain regions to implement more successful behaviours. The ability of the AFP to identify successful performances generated by other brain regions indicates that basal ganglia circuits receive a detailed efference copy of premotor activity in those regions. The capacity of the AFP to implement successful performances that were initially produced by other brain regions indicates precise functional connections between basal ganglia circuits and the motor regions that directly control performance.     

Polyamine-dependent facilitation of postsynaptic AMPA receptors counteracts paired-pulse depression.

At many glutamatergic synapses in the brain, calcium-permeable alpha - amino - 3 - hydro - 5 - methyl - 4 - isoxazolepropionate receptor (AMPAR) channels mediate fast excitatory transmission. These channels are blocked by endogenous intracellular polyamines, which are found in virtually every type of cell. In excised patches, use-dependent relief of polyamine block enhances glutamate-evoked currents through recombinant and native calcium-permeable, polyamine-sensitive AMPAR channels. The contribution of polyamine unblock to synaptic currents during high-frequency stimulation may be to facilitate currents and maintain current amplitudes in the face of a slow recovery from desensitization or presynaptic depression. Here we show, on pairs and triples of synaptically connected neurons in slices, that this mechanism contributes to short-term plasticity in local circuits formed by presynaptic pyramidal neurons and postsynaptic multipolar interneurons in layer 2/3 of rat neocortex. Activity-dependent relief from polyamine block of postsynaptic calcium-permeable AMPARs in the interneurons either reduces the rate of paired-pulse depression in a frequency-dependent manner or, at a given stimulation frequency, induces facilitation of a synaptic response that would otherwise depress. This mechanism for the enhancement of synaptic gain appears to be entirely postsynaptic.     

Inhibitory threshold for critical-period activation in primary visual cortex

Neuronal circuits across several systems display remarkable plasticity to sensory input during postnatal development. Experience-dependent refinements are often restricted to well-defined critical periods in early life, but how these are established remains mostly unknown. A representative example is the loss of responsiveness in neocortex to an eye deprived of vision. Here we show that the potential for plasticity is retained throughout life until an inhibitory threshold is attained. In mice of all ages lacking an isoform of GABA (gamma-aminobutyric acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before the onset of their natural critical period, benzodiazepines selectively reduced a prolonged discharge phenotype to unmask plasticity. Enhancing GABA-mediated transmission early in life rendered mutant animals insensitive to monocular deprivation as adults, similar to normal wild-type mice. Short-term presynaptic dynamics reflected a synaptic reorganization in GAD65 knockout mice after chronic diazepam treatment. A threshold level of inhibition within the visual cortex may thus trigger, once in life, an experience-dependent critical period for circuit consolidation, which may otherwise lie dormant.     

A disinhibitory microcircuit for associative fear learning in the auditory cortex

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.     

Regulation of synaptic connectivity by glia

The human brain contains more than 100 trillion (10(14)) synaptic connections, which form all of its neural circuits. Neuroscientists have long been interested in how this complex synaptic web is weaved during development and remodelled during learning and disease. Recent studies have uncovered that glial cells are important regulators of synaptic connectivity. These cells are far more active than was previously thought and are powerful controllers of synapse formation, function, plasticity and elimination, both in health and disease. Understanding how signalling between glia and neurons regulates synaptic development will offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases.     

脑整体工作机理探究

本文在现代脑研究资料基础上,主要从脑的解剖、病理、电生理和生化角度,探讨了脑整体工作机理。其中认为;脑工作的基本条件是依赖脑的内源性振荡器对脑各系统连续不断的激励;信息在脑中的编码方式是由信息所产生的冲动使神经元突触建立“连接”—网路而实现;信息在脑中的存储就是这种网路的稳定,海马在此过程中起决定性作用;信息在丘脑—皮层的网路中存在着循环,并具有优势—网状结构对循环的选择、控制作用;信息在脑中被进一步处理的方式是依赖循环而实现,通过循环使脑中网路之间建立关系并创造新信息。     

Reverberatory activity in neuronal networks in vitro

It has been proposed that during cognitive processes, "online" memory traces in the brain are carried by reverberatory activity in neuronal circuits. However, the nature of such reverberation has remained elusive from experimental studies, largely due to the enormous complexity of intact circuits. Recent works have attempted to address this issue using cultured neuronal network and have revealed new dynamic properties of network reverberation as well as the underlying cellular mechanisms. These results demo...     

A synaptic memory trace for cortical receptive field plasticity

Receptive fields of sensory cortical neurons are plastic, changing in response to alterations of neural activity or sensory experience. In this way, cortical representations of the sensory environment can incorporate new information about the world, depending on the relevance or value of particular stimuli. Neuromodulation is required for cortical plasticity, but it is uncertain how subcortical neuromodulatory systems, such as the cholinergic nucleus basalis, interact with and refine cortical circuits. Here we determine the dynamics of synaptic receptive field plasticity in the adult primary auditory cortex (also known as AI) using in vivo whole-cell recording. Pairing sensory stimulation with nucleus basalis activation shifted the preferred stimuli of cortical neurons by inducing a rapid reduction of synaptic inhibition within seconds, which was followed by a large increase in excitation, both specific to the paired stimulus. Although nucleus basalis was stimulated only for a few minutes, reorganization of synaptic tuning curves progressed for hours thereafter: inhibition slowly increased in an activity-dependent manner to rebalance the persistent enhancement of excitation, leading to a retuned receptive field with new preference for the paired stimulus. This restricted period of disinhibition may be a fundamental mechanism for receptive field plasticity, and could serve as a memory trace for stimuli or episodes that have acquired new behavioural significance.     

Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex

Do new synapses form in the adult cortex to support experience-dependent plasticity? To address this question, we repeatedly imaged individual pyramidal neurons in the mouse barrel cortex over periods of weeks. We found that, although dendritic structure is stable, some spines appear and disappear. Spine lifetimes vary greatly: stable spines, about 50% of the population, persist for at least a month, whereas the remainder are present for a few days or less. Serial-section electron microscopy of imaged dendritic segments revealed retrospectively that spine sprouting and retraction are associated with synapse formation and elimination. Experience-dependent plasticity of cortical receptive fields was accompanied by increased synapse turnover. Our measurements suggest that sensory experience drives the formation and elimination of synapses and that these changes might underlie adaptive remodelling of neural circuits.     

Non-commutativity in the brain.

In non-commutative algebra, order makes a difference to multiplication, so that a x b not equal to b x a. This feature is necessary for computing rotary motion, because order makes a difference to the combined effect of two rotations. It has therefore been proposed that there are non-commutative operators in the brain circuits that deal with rotations, including motor circuits that steer the eyes, head and limbs, and sensory circuits that handle spatial information. This idea is controversial: studies of eye and head control have revealed behaviours that are consistent with non-commutativity in the brain, but none that clearly rules out all commutative models. Here we demonstrate non-commutative computation in the vestibulo-ocular reflex. We show that subjects rotated in darkness can hold their gaze points stable in space, correctly computing different final eye-position commands when put through the same two rotations in different orders, in a way that is unattainable by any commutative system.     

Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo

Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.     

Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons

Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours. Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine. Here we report that, following repeated exposure to cocaine in vivo, excitatory synapses to rat VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre- and postsynaptic activity. This facilitated LTP induction is caused by cocaine-induced reduction of GABA(A) (gamma-aminobutyric acid) receptor-mediated inhibition of these dopamine neurons. In midbrain slices from rats treated with saline or a single dose of cocaine, LTP could not be induced in VTA dopamine neurons unless GABA-mediated inhibition was reduced by bicuculline or picrotoxin. However, LTP became readily inducible in slices from rats treated repeatedly with cocaine; this LTP induction was prevented by enhancing GABA-mediated inhibition using diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABA-mediated synaptic currents and increased the probability of spike initiation in VTA dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in the VTA may be important for the formation of drug-associated memory.     

Reverberatory activity in neuronal networks in vitro

It has been proposed that during cognitive processes, ＂online＂ memory traces in the brain are carried by reverberatory activity in neuronal circuits. However, the nature of such reverberation has remained elusive from experimental studies, largely due to the enormous complexity of intact circuits. Recent works have attempted to address this issue using cultured neuronal network and have revealed new dynamic properties of network reverberation as well as the underlying cellular mechanisms. These results demonstrate the effectiveness of in vitro networks as a useful tool for mechanistic dissection of neuronal circuit dynamics.     

A brain-specific microRNA regulates dendritic spine development

MicroRNAs are small, non-coding RNAs that control the translation of target messenger RNAs, thereby regulating critical aspects of plant and animal development. In the mammalian nervous system, the spatiotemporal control of mRNA translation has an important role in synaptic development and plasticity. Although a number of microRNAs have been isolated from the mammalian brain, neither the specific microRNAs that regulate synapse function nor their target mRNAs have been identified. Here we show that a brain-specific microRNA, miR-134, is localized to the synapto-dendritic compartment of rat hippocampal neurons and negatively regulates the size of dendritic spines--postsynaptic sites of excitatory synaptic transmission. This effect is mediated by miR-134 inhibition of the translation of an mRNA encoding a protein kinase, Limk1, that controls spine development. Exposure of neurons to extracellular stimuli such as brain-derived neurotrophic factor relieves miR-134 inhibition of Limk1 translation and in this way may contribute to synaptic development, maturation and/or plasticity.     

NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus

New neurons are continuously integrated into existing neural circuits in adult dentate gyrus of the mammalian brain. Accumulating evidence indicates that these new neurons are involved in learning and memory. A substantial fraction of newly born neurons die before they mature and the survival of new neurons is regulated in an experience-dependent manner, raising the possibility that the selective survival or death of new neurons has a direct role in a process of learning and memory--such as information storage--through the information-specific construction of new circuits. However, a critical assumption of this hypothesis is that the survival or death decision of new neurons is information-specific. Because neurons receive their information primarily through their input synaptic activity, we investigated whether the survival of new neurons is regulated by input activity in a cell-specific manner. Here we developed a retrovirus-mediated, single-cell gene knockout technique in mice and showed that the survival of new neurons is competitively regulated by their own NMDA-type glutamate receptor during a short, critical period soon after neuronal birth. This finding indicates that the survival of new neurons and the resulting formation of new circuits are regulated in an input-dependent, cell-specific manner. Therefore, the circuits formed by new neurons may represent information associated with input activity within a short time window in the critical period. This information-specific addition of new circuits through selective survival or death of new neurons may be a unique attribute of new neurons that enables them to play a critical role in learning and memory.     

Developmental and activity-dependent regulation of kainate receptors at thalamocortical synapses.

Most of the fast excitatory synaptic transmission in the mammalian brain is mediated by ionotrophic glutamate receptors, of which there are three subtypes: AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate), NMDA (N-methyl-D-aspartate) and kainate. Although kainate-receptor subunits (GluR5-7, KA1 and 2) are widely expressed in the mammalian central nervous system, little is known about their function. The development of pharmacological agents that distinguish between AMPA and kainate receptors has now allowed the functions of kainate receptors to be investigated. The modulation of synaptic transmission by kainate receptors and their synaptic activation in a variety of brain regions have been reported. The expression of kainate receptor subunits is developmentally regulated but their role in plasticity and development is unknown. Here we show that developing thalamocortical synapses express postsynaptic kainate receptors as well as AMPA receptors; however, the two receptor subtypes do not colocalize. During the critical period for experience-dependent plasticity, the kainate-receptor contribution to transmission decreases; a similar decrease occurs when long-term potentiation is induced in vitro. This indicates that during development there is activity-dependent regulation of the expression of kainate receptors at thalamocortical synapses.     

Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models

The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation. Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.