Different Forms Of Plasticity Research Articles

Multiomics approach towards characterization of tumor cell plasticity and its significance in precision and personalized medicine.

Cellular plasticity refers to the ability of cells to change their identity or behavior, which can be advantageous in some cases (e.g., tissue regeneration) but detrimental in others (e.g., cancer metastasis). With a better understanding of cellular plasticity, the complexity of cancer cells, their heterogeneity, and their role in metastasis is being unraveled. The plasticity of the cells could also prove as a nemesis to their characterization. In this review, we have attempted to highlight the possibilities and benefits of using multiomics approach in characterizing the plastic nature of cancer cells. There is a need to integrate fragmented evidence at different levels of cellular organization (DNA, RNA, protein, metabolite, epigenetics, etc.) to facilitate the characterization of different forms of plasticity and cell types. We have discussed the role of cellular plasticity in generating intra-tumor heterogeneity. Different omics level evidence is being provided to highlight the variety of molecular determinants discovered using different techniques. Attempts have been made to integrate some of this information to provide a quantitative assessment and scoring of the plastic nature of the cells. However, there is a huge gap in our understanding of mechanisms that lead to the observed heterogeneity. Understanding of these mechanism(s) is necessary for finding targets for early detection and effective therapeutic interventions in metastasis. Targeting cellular plasticity is akin to neutralizing a moving target. Along with the advancements in precision and personalized medicine, these efforts may translate into better clinical outcomes for cancer patients, especially in metastatic stages.

Different Forms of Plasticity Interact in Adult Humans.

Neuroplasticity is maximal during development and declines in adulthood, especially for sensory cortices. On the other hand, the motor and prefrontal cortices retain plasticity throughout the lifespan. This difference has led to a modular view of plasticity in which different brain regions have their own plasticity mechanisms that do not depend or translate on others. Recent evidence shows that visual and motor plasticity share common neural mechanisms (e.g., GABAergic inhibition), indicating a possible link between these different forms of plasticity, however, the interaction between visual and motor plasticity has never been tested directly. Here, we show that when visual and motor plasticity are elicited at the same time in adult humans, visual plasticity is impaired, while motor plasticity is spared. Moreover, simultaneous activation of working memory and visual plasticity also leads to impairment in visual plasticity. These unilateral interactions between visual, working memory, and motor plasticity demonstrate a clear link between these three forms of plasticity. We conclude that local neuroplasticity in separate systems might be regulated globally, to preserve overall homeostasis in the brain.

GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity

It is known that GABAergic transmission onto pyramidal neurons shows different forms of plasticity. However, GABAergic cells innervate also other inhibitory interneurons and plasticity phenomena at these projections remain largely unknown. Several mechanisms underlying plastic changes, both at inhibitory and excitatory synapses, show dependence on integrins, key proteins mediating interaction between intra- and extracellular environment. We thus used hippocampal slices to address the impact of integrins on long-term plasticity of GABAergic synapses on specific inhibitory interneurons (containing parvalbumin, PV + or somatostatin, SST +) known to innervate distinct parts of principal cells. Administration of RGD sequence-containing peptide induced inhibitory long-term potentiation (iLTP) at fast-spiking (FS) PV + as well as on SST + interneurons. Interestingly, treatment with a more specific peptide GA(C)RRETAWA(C)GA (RRETAWA), affecting α5β1 integrins, resulted in iLTP in SST + and iLTD in FS PV + interneurons. Brief exposure to NMDA is known to induce iLTP at GABAergic synapses on pyramidal cells. Intriguingly, application of this protocol for considered interneurons evoked iLTP in SST + and iLTD in PV + interneurons. Moreover, we showed that in SST + cells, NMDA-evoked iLTP depends on the incorporation of GABAA receptors containing α5 subunit to the synapses, and this iLTP is occluded by RRETAWA peptide, indicating a key role of α5β1 integrins. Altogether, our results revealed that plasticity of inhibitory synapses at GABAergic cells shows interneuron-specificity and show differences in the underlying integrin-dependent mechanisms. This is the first evidence that neuronal disinhibition may be a highly plastic process depending on interneuron type and integrins’ activity.

Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine.

Major depression (MD) is one of the most common psychiatric disorders worldwide. Currently, the first-line treatment for MD targets the serotonin system but these drugs, notably the selective serotonin reuptake inhibitors, usually need 4 to 6 weeks before the benefit is felt and a significant proportion of patients shows an unsatisfactory response. Numerous treatments have been developed to circumvent these issues as venlafaxine, a mixed serotonin-norepinephrine reuptake inhibitor that binds and blocks both the SERT and NET transporters. Despite this pharmacological profile, it is difficult to have a valuable insight into its ability to produce more robust efficacy than single-acting agents. In this review, we provide an in-depth characterization of the pharmacological properties of venlafaxine from in vitro data to preclinical and clinical efficacy in depressed patients and animal models of depression to propose an indirect comparison with the most common antidepressants. Preclinical studies show that the antidepressant effect of venlafaxine is often associated with an enhancement of serotonergic neurotransmission at low doses. High doses of venlafaxine, which elicit a concomitant increase in 5-HT and NE tone, is associated with changes in different forms of plasticity in discrete brain areas. In particular, the hippocampus appears to play a crucial role in venlafaxine-mediated antidepressant effects notably by regulating processes such as adult hippocampal neurogenesis or the excitatory/inhibitory balance. Overall, depending on the dose used, venlafaxine shows a high efficacy on depressive-like symptoms in relevant animal models but to the same extent as common antidepressants. However, these data are counterbalanced by a lower tolerance. In conclusion, venlafaxine appears to be one of the most effective treatments for treatment of major depression. Still, direct comparative studies are warranted to provide definitive conclusions about its superiority.

Brain Plasticity in Humans and Model Systems: Advances, Challenges, and Future Directions.

Plasticity, and in particular, neurogenesis, is a promising target to treat and prevent a wide variety of diseases (e.g., epilepsy, stroke, dementia). There are different types of plasticity, which vary with age, brain region, and species. These observations stress the importance of defining plasticity along temporal and spatial dimensions. We review recent studies focused on brain plasticity across the lifespan and in different species. One main theme to emerge from this work is that plasticity declines with age but that we have yet to map these different forms of plasticity across species. As part of this effort, we discuss our recent progress aimed to identify corresponding ages across species, and how this information can be used to map temporal variation in plasticity from model systems to humans.

Unveiling the role of plasticity rules in reservoir computing

Reservoir Computing (RC) is an appealing approach in Machine Learning that combines the high computational capabilities of Recurrent Neural Networks with a fast and easy training method. Likewise, successful implementation of neuro-inspired plasticity rules into RC artificial networks has boosted the performance of the original models. In this manuscript, we analyze the role that plasticity rules play on the changes that lead to a better performance of RC. To this end, we implement synaptic and non-synaptic plasticity rules in a paradigmatic example of RC model: the Echo State Network. Testing on nonlinear time series prediction tasks, we show evidence that improved performance in all plastic models are linked to a decrease of the pair-wise correlations in the reservoir, as well as a significant increase of individual neurons ability to separate similar inputs in their activity space. Here we provide new insights on this observed improvement through the study of different stages on the plastic learning. From the perspective of the reservoir dynamics, optimal performance is found to occur close to the so-called edge of instability. Our results also show that it is possible to combine different forms of plasticity (namely synaptic and non-synaptic rules) to further improve the performance on prediction tasks, obtaining better results than those achieved with single-plasticity models.

NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice

IntroductionN-Methyl-D-aspartate receptors (NMDARs) play a critical role in different forms of plasticity in the central nervous system. NMDARs are always assembled in tetrameric form, in which two GluN1 subunits and two GluN2 and/or GluN3 subunits combine together. Previous studies focused mainly on the hippocampus. The anterior cingulate cortex (ACC) is a key cortical region for sensory and emotional functions. NMDAR GluN2A and GluN2B subunits have been previously investigated, however much less is known about the GluN2C/2D subunits.ResultsIn the present study, we found that the GluN2C/2D subunits are expressed in the pyramidal cells of ACC of adult mice. Application of a selective antagonist of GluN2C/2D, (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP145), significantly reduced NMDAR-mediated currents, while synaptically evoked EPSCs were not affected. UBP145 affected neither the postsynaptic long-term potentiation (post-LTP) nor the presynaptic LTP (pre-LTP). Furthermore, the long-term depression (LTD) was also not affected by UBP145. Finally, both UBP145 decreased the frequency of the miniature EPSCs (mEPSCs) while the amplitude remained intact, suggesting that the GluN2C/2D may be involved in presynaptic regulation of spontaneous glutamate release.ConclusionsOur results provide direct evidence that the GluN2C/2D contributes to evoked NMDAR mediated currents and mEPSCs in the ACC, which may have significant physiological implications.

NMDA receptors in axons: there's no coincidence.

In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.

A unified computational model for cortical post-synaptic plasticity.

Signalling pathways leading to post-synaptic plasticity have been examined in many types of experimental studies, but a unified picture on how multiple biochemical pathways collectively shape neocortical plasticity is missing. We built a biochemically detailed model of post-synaptic plasticity describing CaMKII, PKA, and PKC pathways and their contribution to synaptic potentiation or depression. We developed a statistical AMPA-receptor-tetramer model, which permits the estimation of the AMPA-receptor-mediated maximal synaptic conductance based on numbers of GluR1s and GluR2s predicted by the biochemical signalling model. We show that our model reproduces neuromodulator-gated spike-timing-dependent plasticity as observed in the visual cortex and can be fit to data from many cortical areas, uncovering the biochemical contributions of the pathways pinpointed by the underlying experimental studies. Our model explains the dependence of different forms of plasticity on the availability of different proteins and can be used for the study of mental disorder-associated impairments of cortical plasticity.

Synaptic Plasticity at Inhibitory Synapses in the Ventral Tegmental Area Depends upon Stimulation Site.

Drug exposure induces cell and synaptic plasticity within the brain reward pathway that could be a catalyst for progression to addiction. Several cellular adaptations have been described in the ventral tegmental area (VTA), a central component of the reward pathway that is the major source of dopamine release. For example, administration of morphine induces long-term potentiation (LTP) of excitatory synapses on VTA dopamine cells and blocks LTP at inhibitory synapses. Drug-induced synaptic changes have a common endpoint of increasing dopamine cell firing and dopamine release. However, gaining a complete picture of synaptic plasticity in the VTA is hindered by its complex circuitry of efferents and afferents. Most studies of synaptic plasticity in the VTA activated a mixed population of afferents, potentially yielding an incomplete and perhaps misleading view of how drugs of abuse modify VTA synapses. Here, we use midbrain slices from mice and find that electrical stimulation in two different regions induces different forms of plasticity, including two new forms of LTP at inhibitory synapses. High-frequency stimulation (HFS) induces LTP independently of NMDA receptor (NMDAR) activation, and surprisingly, some inhibitory inputs to the VTA also undergo NMDAR-independent LTP after a low-frequency stimulation (LFS) pairing protocol.

The Potential for Rapid Evolution under Anthropogenic Climate Change.

Understanding how natural populations will respond to rapid anthropogenic climate change is one of the greatest challenges for ecologists and evolutionary biologists. Much research has focussed on whether physiological traits can evolve quickly enough under rapidly increasing temperatures. While the simple Breeder's equation helps to understand how extreme temperatures and genetic variation might drive within-population evolution under climate change, it does not consider two key areas: how different forms of phenotypic plasticity interact and variation among populations. Plasticity can modify the exposure to climatic extremes and the strength of selection from those extremes, while differences among populations provide adaptive diversity not apparent within them. Here, we focus on terrestrial vertebrates and, with a case study on a tropical lizard, demonstrate the complex interplay between spatial, genetic and plastic contributions to variation in climate-relevant physiological traits. We identify several problems that need to be better understood: which traits are under selection in a changing climate; the different forms of plasticity relevant to population persistence and rapid evolution; plastic versus genetic contributions to geographic variation in climate-associated traits and whether plasticity can be harnessed to promote persistence of species. Given ongoing uncertainties around whether natural populations can evolve rapidly enough to persist, we advocate the use of field trials aimed at increasing rates of adaptation, especially in systems known to be strongly impacted by human-driven changes in climate.

128. Neuroplasticity and Psychopathology: Master Regulators With a Focus on Doublecortin (DCX) and Fear Processing

An important approach to understanding multifaceted risk for disease is through understanding "master regulators" of plasticity. Wnt, and Otx2 may constitute master regulators of different forms of plasticity which have are implicated in learning and stress-related disorders. Here we also focus on Doublecortin (DCX), which mediates multiple aspects of neural development, including neuronal migration and dendritic outgrowth. However, its role in amygdala-dependent learning and adult plasticity are unexplored.

Calcium extrusion mechanisms in dendrites of mouse hippocampal CA1 inhibitory interneurons

Local circuit GABAergic inhibitory interneurons control the integration and transfer of information in many brain regions. Several different forms of plasticity reported at interneuron excitatory synapses are triggered by cell- and synapse-specific postsynaptic calcium (Ca2+) mechanisms. To support this function, the spatiotemporal dynamics of dendritic Ca2+ elevations must be tightly regulated. While the dynamics of postsynaptic Ca2+ signaling through activation of different Ca2+ sources has been explored, the Ca2+ extrusion mechanisms that operate in interneuron dendrites during different patterns of activity remain largely unknown. Using a combination of whole-cell patch-clamp recordings and two-photon Ca2+ imaging in acute mouse hippocampal slices, we characterized the Ca2+ extrusion mechanisms activated by Ca2+ transients (CaTs) associated with backpropagating action potentials (bAPs) in dendrites of hippocampal CA1 stratum radiatum interneurons. Our data showed that Ca2+ clearance increased as a function of activity, pointing to an activity-dependent recruitment of specific Ca2+ extrusion mechanisms. bAP-CaTs were significantly prolonged in the presence of the plasma membrane Ca2+ ATPase (PMCA) and Na+/Ca2+ exchanger (NCX) inhibitors as well as the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) and the mitochondria Ca2+ uniporter (MCU) blockers. While PMCA, NCX and SERCA pumps cooperated in the cytosolic Ca2+ removal at a wide range of concentrations, the MCU was only activated at higher Ca2+ loads produced by repetitive interneuron firing. These results identify a division of labor between distinct Ca2+ extrusion mechanisms shaping dendritic Ca2+ dynamics and possibly contributing to activity-dependent regulation of synaptic inputs in interneurons. In addition, the MCU activated by larger Ca2+ levels may be involved in the activity-dependent ATP production or interneuron-selective vulnerability associated with cytosolic Ca2+ overloads under pathological conditions.

Serotonin and Adenosine G-protein Coupled Receptor Signaling for Ventilatory Acclimatization to Sustained Hypoxia.

Different patterns of hypoxia evoke different forms of plasticity in the neural control of ventilation. For example, acute intermittent hypoxia produces long term facilitation (LTF) of ventilation, while chronic sustained hypoxia (CH) causes ventilatory acclimatization to hypoxia (VAH). In both LTF and VAH, ventilation in normoxia is greater than normal after the hypoxic stimulus is removed and the acute hypoxic ventilatory response can increase. However, the mechanisms of LTF and VAH are thought to be different based on previous results showing serotonin 5HT2 receptors, which are G protein coupled receptors (GPCR) that activate GQ signaling, contribute to LTF but not VAH. Newer results show that a different GPCR, namely adenosine A2A receptors and the GS signaling pathway, cause LTF with more severe intermittent hypoxia, i.e., PaO2 = 25–30 Torr for GS versus 35–45 Torr for LTF with the GQ signaling pathway. We hypothesized adenosine A2A receptors and GS signaling are involved in establishing VAH with longer term moderate CH and tested this in adult male rats by measuring ventilatory responses to O2 and CO2 with barometric pressure plethysmography after administering MSX-3 or ketanserin (A2A and 5HT2 antagonists, respectively, both 1 mg/Kg i.p.) during CH for 7 days. Blocking GS or GQ signals throughout CH exposure, significantly decreased VAH. After VAH was established, GQ blockade did not affect ventilation while GS blockade increased VAH. Similar to LTF, data support roles for both GQ and GS pathways in the development of VAH but after VAH has been established, the GS pathway inhibits VAH.

F143 Systemic assessment of motor pathophysiology of corticobasal syndrome

Introduction Corticobasal syndrome (CBS) is a kind of tauopathy with parkinsonism presenting chronic onset of progressive unilateral motor impairment, including subjective weakness, dystonia and parkinsonism, and cognition change, such as apraxia, sensory-motor dysfunction or memory impairment. Although several types of pathophysiology have been reported on CBS, a systemic physiological study on CBS has been lacking. Seeing the symptoms of CBS is a mixture of parkinsonism and other movement disorders, e.g. dystonia, we designed this study to investigate a wide range of motor physiology, including different forms of plasticity, the connection between the premotor cortex (PMd) and M1, and inhibitory circuits in the cortex, brainstem and spinal cord, in patients with CBS. Methods We rolled in 21 patients with CBS diagnosed by Cambridge criteria and age-matched health subjects. All subjects signed informed consent under supervision of approval of the Ethics Board of Chang Gung Memorial Hospital at Linkou. Studied protocols included (1) Motor LTP-like plasticity by cTBSc0: cTBS followed by 1-min slightly voluntary contraction of the contralateral FDI muscle, (2) SICI recruitment curve before and after cTBSc0, (3) depotentiation assessed by cTBSc0 and subsequent 10 s of cTBS (cTBS150), (4) brainstem blink reflex recovery cycle (BR), (5) spinal reciprocal inhibition (RI), and (6) PMd-M1 connectivity by assessing M1 excitability change in response to cTBS given to PMd. Results Although cTBSc0 successfully induced LTP, depotentiation was abnormal in patients with CBS. The SICI recruitment curve shifted to the left as compared to the controls in the baseline, and was moved toward to normal after cTBSc0. The blink reflex recovery curve was identical between CBS patients and healthy controls. RI showed reduced 3rd phase and normal 1st and 2nd phases, and the PMd-M1 connectivity was abnormal in patients with CBS. Conclusion Different from a previous study showing reduced LTP using iTBS, the current study revealed normal motor plasticity in CBS. Similar results were also found in PD patient at the medication ON state, in which cTBSc0, but not iTBS, was able to induce motor plasticity. The abnormal depotentiation in CBS who has not dyskinesia is different from that in PD patients and could be closer to the pathophysiology of dystonia. Abnormal SICI, which was normalized by cTBSc0, abnormal the third, but not other, phase(s) of RI and normal blink reflex recovery curve suggest the pathophysiology is mainly located in the cerebrum, while the brainstem and spinal cord are preserved. The abnormal PMd-M1 connectivity may be unspecific and has been also seen in both PD and dystonia. In summary, patients with CBS show unique presentation in a combination of different physiological assessments, suggesting the possibility of development of physiological biomarker for CBS. Moreover, rTMS over M1 may improve CBS according to the results in SICI.

Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders.

The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so-called “master regulators” of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of Tailless (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders.

Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons.

The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.NEW & NOTEWORTHY We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.

Selective Erasure of Distinct Forms of Long-Term Synaptic Plasticity Underlying Different Forms of Memory in the Same Postsynaptic Neuron

Generalization of fear responses to non-threatening stimuli is a feature of anxiety disorders. It has beenchallenging to target maladaptive generalized memories without affecting adaptive memories. Synapse-specific long-term plasticity underlying memory involves the targeting of plasticity-related proteins (PRPs) to activated synapses. If distinct tags and PRPs are used for different forms of plasticity, one could selectively remove distinct forms of memory. Using a stimulation paradigm in which associative long-term facilitation (LTF) occurs at one input and non-associative LTF at another input to the same postsynaptic neuron in an Aplysia sensorimotor preparation, we found that each form of LTF is reversed by inhibiting distinct isoforms of protein kinase M (PKM), putative PRPs, in the postsynaptic neuron. A dominant-negative (dn) atypical PKM selectively reversed associative LTF, while a dn classical PKM selectively reversed non-associative LTF. Although both PKMs are formed from calpain-mediated cleavage of protein kinase C (PKC) isoforms, each form of LTF is sensitive to a distinct dn calpain expressed in the postsynaptic neuron. Associative LTF is blocked by dn classical calpain, whereas non-associative LTF is blocked by dn smalloptic lobe (SOL) calpain. Interfering with a putative synaptic tag, the adaptor protein KIBRA, which protects the atypical PKM from degradation, selectively erases associative LTF. Thus, the activity of distinct PRPs and tags in a postsynaptic neuron contribute to the maintenance of different forms ofsynaptic plasticity at separate inputs, allowing for selective reversal of synaptic plasticity and providing a cellular basis for developing therapeuticstrategies for selectively reversing maladaptive memories.

Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling.

Synapses are complex because they perform multiple functions, including at least six mechanistically different forms of plasticity. Here, I comment on recent developments regarding these processes. (i) Short-term potentiation (STP), a Hebbian process that requires small amounts of synaptic input, appears to make strong contributions to some forms of working memory. (ii) The rules for long-term potentiation (LTP) induction in CA3 have been clarified: induction does not depend obligatorily on backpropagating sodium spikes but, rather, on dendritic branch-specific N-methyl-d-aspartate (NMDA) spikes. (iii) Late LTP, a process that requires a dopamine signal (and is therefore neoHebbian), is mediated by trans-synaptic growth of the synapse, a growth that occurs about an hour after LTP induction. (iv) LTD processes are complex and include both homosynaptic and heterosynaptic forms. (v) Synaptic scaling produced by changes in activity levels are not primarily cell-autonomous, but rather depend on network activity. (vi) The evidence for distance-dependent scaling along the primary dendrite is firm, and a plausible structural-based mechanism is suggested.Ideas about the mechanisms of synaptic function need to take into consideration newly emerging data about synaptic structure. Recent super-resolution studies indicate that glutamatergic synapses are modular (module size 70-80 nm), as predicted by theoretical work. Modules are trans-synaptic structures and have high concentrations of postsynaptic density-95 (PSD-95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These modules function as quasi-independent loci of AMPA-mediated transmission and may be independently modifiable, suggesting a new understanding of quantal transmission.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity.'

Closed-Loop Brain Model of Neocortical Information-Based Exchange.

Here we describe an “information-based exchange” model of brain function that ascribes to neocortex, basal ganglia, and thalamus distinct network functions. The model allows us to analyze whole brain system set point measures, such as the rate and heterogeneity of transitions in striatum and neocortex, in the context of neuromodulation and other perturbations. Our closed-loop model is grounded in neuroanatomical observations, proposing a novel “Grand Loop” through neocortex, and invokes different forms of plasticity at specific tissue interfaces and their principle cell synapses to achieve these transitions. By implementing a system for maximum information-based exchange of action potentials between modeled neocortical areas, we observe changes to these measures in simulation. We hypothesize that similar dynamic set points and modulations exist in the brain's resting state activity, and that different modifications to information-based exchange may shift the risk profile of different component tissues, resulting in different neurodegenerative diseases. This model is targeted for further development using IBM's Neural Tissue Simulator, which allows scalable elaboration of networks, tissues, and their neural and synaptic components toward ever greater complexity and biological realism.