22,605 research outputs found
Preconditioning of low-frequency repetitive transcranial magnetic stimulation with transcranial direct current stimulation: evidence for homeostatic plasticity in the human motor cortex
Recent experimental work in animals has emphasized the importance of homeostatic plasticity as a means of stabilizing the properties of neuronal circuits. Here, we report a phenomenon that indicates a homeostatic pattern of cortical plasticity in healthy human subjects. The experiments combined two techniques that can produce long-term effects on the excitability of corticospinal output neurons: transcranial direct current stimulation (TDCS) and repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex. "Facilitatory preconditioning" with anodal TDCS caused a subsequent period of 1 Hz rTMS to reduce corticospinal excitability to below baseline levels for >20 min. Conversely, "inhibitory preconditioning" with cathodal TDCS resulted in 1 Hz rTMS increasing corticospinal excitability for at least 20 min. No changes in excitability occurred when 1 Hz rTMS was preceded by sham TDCS. Thus, changing the initial state of the motor cortex by a period of DC polarization reversed the conditioning effects of 1 Hz rTMS. These preconditioning effects of TDCS suggest the existence of a homeostatic mechanism in the human motor cortex that stabilizes corticospinal excitability within a physiologically useful range
Experience-driven formation of parts-based representations in a model of layered visual memory
Growing neuropsychological and neurophysiological evidence suggests that the
visual cortex uses parts-based representations to encode, store and retrieve
relevant objects. In such a scheme, objects are represented as a set of
spatially distributed local features, or parts, arranged in stereotypical
fashion. To encode the local appearance and to represent the relations between
the constituent parts, there has to be an appropriate memory structure formed
by previous experience with visual objects. Here, we propose a model how a
hierarchical memory structure supporting efficient storage and rapid recall of
parts-based representations can be established by an experience-driven process
of self-organization. The process is based on the collaboration of slow
bidirectional synaptic plasticity and homeostatic unit activity regulation,
both running at the top of fast activity dynamics with winner-take-all
character modulated by an oscillatory rhythm. These neural mechanisms lay down
the basis for cooperation and competition between the distributed units and
their synaptic connections. Choosing human face recognition as a test task, we
show that, under the condition of open-ended, unsupervised incremental
learning, the system is able to form memory traces for individual faces in a
parts-based fashion. On a lower memory layer the synaptic structure is
developed to represent local facial features and their interrelations, while
the identities of different persons are captured explicitly on a higher layer.
An additional property of the resulting representations is the sparseness of
both the activity during the recall and the synaptic patterns comprising the
memory traces.Comment: 34 pages, 12 Figures, 1 Table, published in Frontiers in
Computational Neuroscience (Special Issue on Complex Systems Science and
Brain Dynamics),
http://www.frontiersin.org/neuroscience/computationalneuroscience/paper/10.3389/neuro.10/015.2009
Protein synthesis at synaptic sites on dendrites
Studies over the past 20 years have revealed that gene expression in neurons is carried out by a distributed network of translational machinery. One component of this network is localized in dendrites, where polyribosomes and associated membranous elements are positioned beneath synapses and translate a particular population of dendritic mRNAs. The localization of translation machinery and mRNAs at synapses endows individual synapses with the capability to independently control synaptic strength through the local synthesis of proteins. The present review discusses recent studies linking synaptic plasticity to dendritic protein synthesis and mRNA trafficking and considers how these processes are regulated. We summarize recent information about how synaptic signaling is coupled to local translation and to the delivery of newly transcribed mRNAs to activated synaptic sites and how local translation may play a role in activity-dependent synaptic modification
Fundamental activity constraints lead to specific interpretations of the connectome
The continuous integration of experimental data into coherent models of the
brain is an increasing challenge of modern neuroscience. Such models provide a
bridge between structure and activity, and identify the mechanisms giving rise
to experimental observations. Nevertheless, structurally realistic network
models of spiking neurons are necessarily underconstrained even if experimental
data on brain connectivity are incorporated to the best of our knowledge.
Guided by physiological observations, any model must therefore explore the
parameter ranges within the uncertainty of the data. Based on simulation
results alone, however, the mechanisms underlying stable and physiologically
realistic activity often remain obscure. We here employ a mean-field reduction
of the dynamics, which allows us to include activity constraints into the
process of model construction. We shape the phase space of a multi-scale
network model of the vision-related areas of macaque cortex by systematically
refining its connectivity. Fundamental constraints on the activity, i.e.,
prohibiting quiescence and requiring global stability, prove sufficient to
obtain realistic layer- and area-specific activity. Only small adaptations of
the structure are required, showing that the network operates close to an
instability. The procedure identifies components of the network critical to its
collective dynamics and creates hypotheses for structural data and future
experiments. The method can be applied to networks involving any neuron model
with a known gain function.Comment: J. Schuecker and M. Schmidt contributed equally to this wor
Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.
Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli
The gut-brain axis, BDNF, NMDA and CNS disorders
Gastro-intestinal (GI) microbiota and the ‘gut-brain axis’ are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-d-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders
Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus
Autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) at threonine-286 produces Ca2+-independent kinase activity and has been proposed to be involved in induction of long-term potentiation by tetanic stimulation in the hippocampus. We have used an immunocytochemical method to visualize and quantify the pattern of autophosphorylation of CaMKII in hippocampal slices after tetanization of the Schaffer collateral pathway. Thirty minutes after tetanic stimulation, autophosphorylated CaM kinase II (P-CaMKII) is significantly increased in area CA1 both in apical dendrites and in pyramidal cell somas. In apical dendrites, this increase is accompanied by an equally significant increase in staining for nonphosphorylated CaM kinase II. Thus, the increase in P-CaMKII appears to be secondary to an increase in the total amount of CaMKII. In neuronal somas, however, the increase in P-CaMKII is not accompanied by an increase in the total amount of CaMKII. We suggest that tetanic stimulation of the Schaffer collateral pathway may induce new synthesis of CaMKII molecules in the apical dendrites, which contain mRNA encoding its alpha-subunit. In neuronal somas, however, tetanic stimulation appears to result in long-lasting increases in P-CaMKII independent of an increase in the total amount of CaMKII. Our findings are consistent with a role for autophosphorylation of CaMKII in the induction and/or maintenance of long-term potentiation, but they indicate that the effects of tetanus on the kinase and its activity are not confined to synapses and may involve induction of new synthesis of kinase in dendrites as well as increases in the level of autophosphorylated kinase
Regulation of neuronal excitability through pumilio-dependent control of a sodium channel gene
Dynamic changes in synaptic connectivity and strength, which occur during both embryonic development and learning, have the tendency to destabilize neural circuits. To overcome this, neurons have developed a diversity of homeostatic mechanisms to maintain firing within physiologically defined limits. In this study, we show that activity-dependent control of mRNA for a specific voltage-gated Na+ channel [encoded by paralytic (para)] contributes to the regulation of membrane excitability in Drosophila motoneurons. Quantification of para mRNA, by real-time reverse-transcription PCR, shows that levels are significantly decreased in CNSs in which synaptic excitation is elevated, whereas, conversely, they are significantly increased when synaptic vesicle release is blocked. Quantification of mRNA encoding the translational repressor pumilio (pum) reveals a reciprocal regulation to that seen for para. Pumilio is sufficient to influence para mRNA. Thus, para mRNA is significantly elevated in a loss-of-function allele of pum (pumbemused), whereas expression of a full-length pum transgene is sufficient to reduce para mRNA. In the absence of pum, increased synaptic excitation fails to reduce para mRNA, showing that Pum is also necessary for activity-dependent regulation of para mRNA. Analysis of voltage-gated Na+ current (INa) mediated by para in two identified motoneurons (termed aCC and RP2) reveals that removal of pum is sufficient to increase one of two separable INa components (persistent INa), whereas overexpression of a pum transgene is sufficient to suppress both components (transient and persistent). We show, through use of anemone toxin (ATX II), that alteration in persistent INa is sufficient to regulate membrane excitability in these two motoneurons
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