Nonsynaptic Plasticity Research Articles

Intrinsic and synaptic determinants of receptive field plasticity in Purkinje cells of the mouse cerebellum

Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation or plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either synaptic or intrinsic plasticity. Spatial analysis of calcium signals demonstrated that intrinsic, but not synaptic plasticity, enhances the spread of dendritic parallel fiber response potentiation. Simultaneous dendrite and axon initial segment recordings confirm these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of long-term potentiation on neuronal responsiveness.

On the functions of astrocyte-mediated neuronal slow inward currents.

Slow inward currents are known as neuronal excitatory currents mediated by glutamate release and activation of neuronal extrasynaptic N-methyl-D-aspartate receptors with the contribution of astrocytes. These events are significantly slower than the excitatory postsynaptic currents. Parameters of slow inward currents are determined by several factors including the mechanisms of astrocytic activation and glutamate release, as well as the diffusion pathways from the release site towards the extrasynaptic receptors. Astrocytes are stimulated by neuronal network activity, which in turn excite neurons, forming an astrocyte-neuron feedback loop. Mostly as a consequence of brain edema, astrocytic swelling can also induce slow inward currents under pathological conditions. There is a growing body of evidence on the roles of slow inward currents on a single neuron or local network level. These events often occur in synchrony on neurons located in the same astrocytic domain. Besides synchronization of neuronal excitability, slow inward currents also set synaptic strength via eliciting timing-dependent synaptic plasticity. In addition, slow inward currents are also subject to non-synaptic plasticity triggered by long-lasting stimulation of the excitatory inputs. Of note, there might be important region-specific differences in the roles and actions triggering slow inward currents. In greater networks, the pathophysiological roles of slow inward currents can be better understood than physiological ones. Slow inward currents are identified in the pathophysiological background of autism, as slow inward currents drive early hypersynchrony of the neural networks. Slow inward currents are significant contributors to paroxysmal depolarizational shifts/interictal spikes. These events are related to epilepsy, but also found in Alzheimer's disease, Parkinson's disease, and stroke, leading to the decline of cognitive functions. Events with features overlapping with slow inward currents (excitatory, N-methyl-D-aspartate-receptor mediated currents with astrocytic contribution) as ischemic currents and spreading depolarization also have a well-known pathophysiological role in worsening consequences of stroke, traumatic brain injury, or epilepsy. One might assume that slow inward currents occurring with low frequency under physiological conditions might contribute to synaptic plasticity and memory formation. However, to state this, more experimental evidence from greater neuronal networks or the level of the individual is needed. In this review, I aimed to summarize findings on slow inward currents and to speculate on the potential functions of it.

Relationship-specific and relationship-independent behavioural adaptivity in affiliation and bonding: A multi-adaptive dynamical systems approach

Humans often adapt their behaviour toward each other when they interact. From a neuroscientific perspective, such adaptivity can involve mechanisms based on adaptive connections (synaptic plasticity) and adaptive excitability thresholds (nonsynaptic plasticity) within the mental or neural network concerned. It is, however, often left unaddressed which of the types of adaptation are specific for the relationship and which are more general for multiple relationships. We focus on this differentiation between relationship-specific and relationship-independent adaptation in social interactions. We analysed computationally how an interplay of adaptive relation-specific and relation-independent mechanisms occurs within the causal pathways for social interaction. As part of this, we cover also the context-sensitive control of these types of adaptation (adaptive speeds and strengths of adaptation), which is sometimes termed higher-order adaptation or metaplasticity. The model was evaluated by a number of explored runs where within a group of four agents each agent randomly has episodes of interaction with one of the three other agents. The outcomes of the analysis of the (stochastic) simulation results show a strong dependence of adaptation on the extent of social interaction: more social interaction leads to more adaptation of the interaction behaviour. This holds both for the short-term and long-term first-order adaptation and for the second-order adaptation, which is long-term.

The nonsynaptic plasticity in Parkinson's disease: Insights from an animal model

BackgroundThe 6-OHDA nigro-striatal lesion model has already been related to disorders in the excitability and synchronicity of neural networks and variation in the expression of transmembrane proteins that control intra and extracellular ionic concentrations, such as cation-chloride cotransporters (NKCC1 and KCC2) and Na+/K+-ATPase and, also, to the glial proliferation after injury. All these non-synaptic mechanisms have already been related to neuronal injury and hyper-synchronism processes. ObjectiveThe main objective of this study is to verify whether mechanisms not directly related to synaptic neurotransmission could be involved in the modulation of nigrostriatal pathways. MethodsMale Wistar rats, 3 months old, were submitted to a unilateral injection of 24 µg of 6-OHDA, in the striatum (n = 8). The animals in the Control group (n = 8) were submitted to the same protocol, with the replacement of 6-OHDA by 0.9% saline. The analysis by optical densitometry was performed to quantify the immunoreactivity intensity of GFAP, NKCC1, KCC2, Na+/K+-ATPase, TH and Cx36. ResultsThe 6-OHDA induced lesions in the striatum, were not followed by changes in the expression cation-chloride cotransporters and Na+/K+-ATPase, but with astrocytic reactivity in the lesioned and adjacent regions of the nigrostriatal. Moreover, the dopaminergic degeneration caused by 6-OHDA is followed by changes in the expression of connexin-36. ConclusionsThe use of the GJ blockers directly along the nigrostriatal pathways to control PD motor symptoms is conjectured. Electrophysiology of the striatum and the substantia nigra, to verify changes in neuronal synchronism, comparing brain slices of control animals and experimental models of PD, is needed.

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer's Disease and Identifying Promising Drug Targets.

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

Immune-Triggered Forms of Plasticity Across Brain Regions.

Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.

Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

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.

Bidirectional learning in upbound and downbound microzones of the cerebellum.

Over the past several decades, theories about cerebellar learning have evolved. Arelatively simple view that highlighted the contribution of one major form of heterosynaptic plasticity to cerebellar motor learning has given way to a plethora of perspectives that suggest that many different forms of synaptic and non-synaptic plasticity, acting at various sites, can control multiple types of learning behaviour. However, there still seem to be contradictions between the various hypotheses with regard to the mechanisms underlying cerebellar learning. The challenge is therefore to reconcile these different views and unite them into a single overall concept. Here I review our current understanding of the changes in the activity of cerebellar Purkinje cells in different 'microzones' during various forms of learning. I describe an emerging model that indicates that the activity of each microzone is bound to either increase or decrease during the initial stages of learning, depending on the directional and temporal demands of its downstream circuitry and the behaviour involved.

Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala

Increasing evidence indicates that excessive inflammatory responses play a crucial role in the pathophysiology of psychiatric diseases, including depression and anxiety disorders. The dysfunctional neural plasticity in amygdala has long been proposed as the vital cause for the progression of psychiatric disorders. However, the effect of neuroinflammation on the functional changes of the amygdala remains largely unknown. Here, by using a mouse model of inflammation induced by lipopolysaccharide (LPS) injection, we investigated the effect of LPS-induced neuroinflammation on the synaptic and non-synaptic plasticity in basolateral amygdala (BLA) projection neurons (PNs) and their contribution to the LPS-induced anxiety- and depressive-like behavior. The results showed that LPS treatment led to the activation of microglia and production of proinflammatory cytokines in the BLA. Furthermore, LPS treatment increased excitatory but not inhibitory synaptic transmission due to the enhanced presynaptic glutamate release, thus leading to the shift of excitatory/inhibitory balance towards excitatory. In addition, the intrinsic neuronal excitability of BLA PNs was also increased by LPS treatment through the loss of expression and function of small-conductance, calcium-activated potassium channel. Chronic fluoxetine pretreatment significantly prevented these neurophysiological changes induced by LPS, and alleviated anxiety and depressive-like behavior, indicating that LPS-induced neuronal dysregulation of BLA PNs may contribute to the development of psychiatry disorders. Collectively, these findings provide evidence that dysregulation of synaptic and non-synaptic transmission in the BLA PNs may account for neuroinflammation-induced anxiety- and depressive-like behavior.

Synergistic excitability plasticity in cerebellar functioning

The cerebellum, a universal processor for sensory acquisition and internal models, and its association with synaptic and nonsynaptic plasticity have been envisioned as the biological correlates of learning, perception, and even thought. Indeed, the cerebellum is no longer considered merely as the locus of motor coordination and its learning. Here, we introduce the mechanisms underlying the induction of multiple types of plasticity in cerebellar circuit and give an overview focusing on the plasticity of nonsynaptic intrinsic excitability. The discovery of long-term potentiation of synaptic responsiveness in hippocampal neurons led investigations into changes of their intrinsic excitability. This activity-dependent potentiation of neuronal excitability is distinct from that of synaptic efficacy. Systematic examination of excitability plasticity has indicated that the modulation of various types of Ca2+ - and voltage-dependent K+ channels underlies the phenomenon, which is also triggered by immune activity. Intrinsic plasticity is expressed specifically on dendrites and modifies the integrative processing and filtering effect. In Purkinje cells, modulation of the discordance of synaptic current on soma and dendrite suggested a novel type of cellular learning mechanism. This property enables a plausible synergy between synaptic efficacy and intrinsic excitability, by amplifying electrical conductivity and influencing the polarity of bidirectional synaptic plasticity. Furthermore, the induction of intrinsic plasticity in the cerebellum correlates with motor performance and cognitive processes, through functional connections from the cerebellar nuclei to neocortex and associated regions: for example, thalamus and midbrain. Taken together, recent advances in neuroscience have begun to shed light on the complex functioning of nonsynaptic excitability and the synergy.

Non-synaptic Plasticity in Leech Touch Cells.

The role of Na+/K+-pumps in activity-dependent synaptic plasticity has been described in both vertebrates and invertebrates. Here, we provide evidence that the Na+/K+-pump is also involved in activity-dependent non-synaptic cellular plasticity in leech sensory neurons. We show that the resting membrane potential (RMP) of T cells hyperpolarizes in response to repeated somatic current injection, while at the same time their spike count (SC) and the input resistance (IR) increase. Our Hodgkin–Huxley-type neuron model, adjusted to physiological T cell properties, suggests that repetitive action potential discharges lead to increased Na+/K+-pump activity, which then hyperpolarizes the RMP. In consequence, a slow, non-inactivating current decreases, which is presumably mediated by voltage-dependent, low-threshold potassium channels. Closing of these putative M-type channels due to hyperpolarization of the resting potential increases the IR of the cell, leading to a larger number of spikes. By this mechanism, the response behavior switches from rapidly to slowly adapting spiking. These changes in spiking behavior also effect other T cells on the same side of the ganglion, which are connected via a combination of electrical and chemical synapses. An increased SC in the presynaptic T cell results in larger postsynaptic responses (PRs) in the other T cells. However, when the number of elicited presynaptic spikes is kept constant, the PR does not change. These results suggest that T cells change their responses in an activity-dependent manner through non-synaptic rather than synaptic plasticity. These changes might act as a gain-control mechanism. Depending on the previous activity, this gain could scale the relative impacts of synaptic inputs from other mechanoreceptors, versus the spike responses to tactile skin stimulation. This multi-tasking ability, and its flexible adaptation to previous activity, might make the T cell a key player in a preparatory network, enabling the leech to perform fast behavioral reactions to skin stimulation.

Experience-Dependent Intrinsic Plasticity During Auditory Learning.

Song learning in zebra finches (Taeniopygia guttata) requires exposure to the song of a tutor, resulting in an auditory memory. This memory is the foundation for later sensorimotor learning, resulting in the production of a copy of the tutor's song. The cortical premotor nucleus HVC (proper name) is necessary for auditory and sensorimotor learning as well as the eventual production of adult song. We recently discovered that the intrinsic physiology of HVC neurons changes across stages of song learning, but are those changes the result of learning or are they experience-independent developmental changes? To test the role of auditory experience in driving intrinsic changes, patch-clamp experiments were performed comparing HVC neurons in juvenile birds with varying amounts of tutor exposure. The intrinsic physiology of HVC neurons changed as a function of tutor exposure. Counterintuitively, tutor deprivation resulted in juvenile HVC neurons showing an adult-like phenotype not present in tutor-exposed juveniles. Biophysical models were developed to predict which ion channels were modulated by experience. The models indicate that tutor exposure transiently suppressed the Ih and T-type Ca2+ currents in HVC neurons that target the basal ganglia, whereas tutor exposure increased the resting membrane potential and decreased the spike amplitude in HVC neurons that drive singing. Our findings suggest that intrinsic plasticity may be part of the mechanism for auditory learning in the HVC. More broadly, models of learning and memory should consider intrinsic plasticity as a possible mechanism by which the nervous system encodes the lasting effects of experience.SIGNIFICANCE STATEMENT It is well established that learning involves plasticity of the synapses between neurons. However, the activity of a neural circuit can also be dramatically altered by changes in the intrinsic properties (ion channels) of the component neurons. The present experiments show experience-dependent changes in the intrinsic physiology of neurons in the cortical premotor nucleus HVC (proper name) in juvenile zebra finches (Taeniopygia guttata) during auditory learning of a tutor's song. Tutor deprivation does not "arrest" development of intrinsic properties, but rather results in neurons with a premature adult-like physiological phenotype. It is possible that auditory learning involves a form of nonsynaptic plasticity and that experience-dependent suppression of specific ion channels may work in concert with synaptic plasticity to promote vocal learning.

Nonsynaptic plasticity model of long-term memory engrams.

Using steady-state electrical properties of non-ohmic dendrite based on cable theory, we derive electrotonic potentials that do not change over time and are localized in space. We hypothesize that clusters of such stationary, local and permanent pulses are the electrical signatures of enduring memories which are imprinted through nonsynaptic plasticity, encoded through epigenetic mechanisms, and decoded through electrotonic processing. We further hypothesize how retrieval of an engram is made possible by integration of these permanently imprinted standing pulses in a neural circuit through neurotransmission in the extracellular space as part of conscious recall that acts as a guiding template in the reconsolidation of long-term memories through novelty characterized by uncertainty that arises when new fragments of memories reinstate an engram by way of nonsynaptic plasticity that permits its destabilization. Collectively, these findings seem to reinforce this hypothesis that electrotonic processing in non-ohmic dendrites yield insights into permanent electrical signatures that could reflect upon enduring memories as fragments of long-term memory engrams.

Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells.

The plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst-pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses. Pause plasticity is absent from mice lacking SK2-type potassium channels (SK2(-/-) mice) and in occlusion experiments using the SK channel blocker apamin, while apamin wash-in mimics pause reduction. Our findings demonstrate that spike pauses can be regulated through an activity-dependent, exclusively non-synaptic, SK2 channel-dependent mechanism and suggest that pause plasticity-by altering the Purkinje cell output-may be crucial to cerebellar information storage and learning.

Compartmentalization of Non-Synaptic Plasticity in Neurons at the Subcellular Level

One efficient by which the nervous system responds to a diversity of external and internal signals consists of increases in the excitability of individual neurons acquired, for example, during the learning process. It is now well established that persistent non-synaptic neuronal plasticity arises after learning and, like synaptic plasticity, can serve as a substrate for long-term memory. However, it remains unknown how nonsynaptic plasticity contributes to changes in the state of the neural networks on which memory is directly dependent. Attempts to find an explanation of how non-synaptic plasticity is translated into a modified state of the neural network and altered behavior constitute one of the most important tasks in contemporary studies of learning and memory. There is also little information on the specific neuronal compartments undergoing plastic changes in the context of the morphological characteristics of a given neuron and the mechanisms regulating the efficiency of its input and output synapses when non-synaptic changes occur in cells. The present review addresses the most important questions of compartmentalization of nonsynaptic plasticity and the effects of non-synaptic plastic changes on the efficiency of the synapses of the neuron concerned.

Calcium regulation of HCN supports persistent activity associated with working memory: a multiscale model of prefrontal cortex

The Hyperpolarization-activated cyclic-nucleotide gated channel (HCN; Ih current) has been hypothesized to facilitate short-term memory storage in the prefrontal cortex (PFC) via a cascade of signalling events involving second messengers including protein kinases and intracellular calcium (Ca) accumulation [1]. This memory mechanism is effected via alterations in the dynamics of the network, two scales above the underlying molecular level. To determine the factors that enable persistent activity to emerge, we developed a multiscale model (molecular to network level) of PFC that displays the persistent activity associated with working memory. The network contained 800 cells arranged in 6 neocortical layers. Cell classes included pyramidal cells, and fast-spiking and low-threshold-spiking interneurons. Each neuron contained Na, K, Ca, and HCN channels. Cells were interconnected probabilistically using detailed anatomical data from M1, with AMPA/NMDA, and GABAA synapses. Intracellular Ca was admitted via NMDA and L-type Ca channels. Intracellular signaling components which contributed to persistent activity included: diffusible Ca, diffusible Ca buffering proteins, intracellular endoplasmic reticulum (ER) compartments for sequestering Ca, diffusible inositol triphosphate (IP3), ER IP3 receptors (IP3R) which release Ca from ER upon IP3/Ca binding, sarco/endoplasmic reticulum Ca-ATP-ase pumps (SERCA) which pump cytosolic Ca into the ER, Ca/IP3 degradation reactions. Pyramidal cells had HCN channels regulated by protein kinases bound to intracellular Ca. The model was implemented in parallel NEURON with reaction-diffusion [2]. 18 seconds of simulation time ran over 24 Intel XEON CPUs in ~7 minutes. We assessed influences between intracellular signaling and network dynamics to isolate sources needed for emergence of short-term memory representations. We provided excitatory stimuli to a subset of pyramidal cells which represented the memory. Stimulus-induced depolarization led to Ca influx which increased HCN conductance and excitability of the stimulated population (firing increased from 0.5-2 Hz). Activation of the stimulated population lasted for 5-10 seconds and also increased beta/gamma (~15-35 Hz) oscillations. In contrast, non-stimulated populations were suppressed (firing rate reduction up to 50%) due to higher inhibition caused by the activated cells providing stronger drive to the interneurons. Knocking out specific pathways showed that persistent activity of activated cells was only viable in the presence of Ca influx, Ca regulation of HCN channels, and interactions between excitatory and inhibitory populations, which led to network-derived inhibition activating HCN. Lowering concentrations and binding rates of Ca buffering proteins reduced the network’s ability to represent specific inputs, due to the higher levels of intracellular Ca saturating HCN channels in all pyramidal neurons. This predicts that Ca buffering proteins contribute to regulation of Ca at time-scales relevant for maintaining distinct short-term memory representations. We also used our model to demonstrate nonsynaptic plasticity - initial stimuli cause Ca sequestration in the ER of activated neurons, allowing for later, selective modulation of their excitability via metabotropic glutamate receptor activation of IP3Rs, which releases the stored Ca. Our model demonstrates how electro-chemical interactions at the nanoscale may lead to network consequences that produce persistent activity associated with working memory.

Neuroplasticity and Post-Synaptic Rebound-Induced Spiking at Purkinje Cell-Deep Cerebellar Nuclei Synapses

Background: Within the cerebellum white matter are located four pairs of nuclei, collectively known as the deep cerebellar nuclei (DCN) (1). In the cerebellum, signal integration from pre-cerebellar structures via excitatory parallel fibers and climbing fibers in the cerebellar cortex occurs in GABAergic Purkinje cells (PC) (2). The main target of these PC cells is the DCN (2) and approximately 85% of GABAergic input on the DCN is from PCs (3). Furthermore, PCs outnumber DCN neurons (26:1) (2). Therefore, despite receiving substantial inhibition from Purkinje cells, DCN neurons are still active at rest showing regular spiking or spontaneous bursts (4). DCN neurons fire spontaneously at approximately 10-50 Hz (5). Given this unique anatomy of PC-DCN synapses, characterization of this synaptic circuit is important in understanding the overall role of the DCN in the brain.
 Methods: The findings of 28 studies, including a few reviews, are reported in this paper. Studies selected focused principally on characterization of DCN circuitry properties and the role these properties have in the functioning of the DCN. Most studies employed in vivo and/or in vitro cellular recordings in rodents, among other models. Studies ranged from 1984 to 2013.
 Summary: This review outlines current findings on the forms of plasticity found in the DCN, the function of the DCN and the connections between the DCN and other brain regions. In short, neurons in the DCN demonstrate both synaptic and non-synaptic plasticity. Cerebellar involvement in motor activity has been extensively studied therefore, not surprisingly; DCN neurons form connections with the motor cortex but also the prefrontal cortex. PC input on the DCN influences spike rate and timing through fluctuations in PC synchrony, and rebound depolarization.

Synaptic and nonsynaptic plasticity approximating probabilistic inference.

Learning and memory operations in neural circuits are believed to involve molecular cascades of synaptic and nonsynaptic changes that lead to a diverse repertoire of dynamical phenomena at higher levels of processing. Hebbian and homeostatic plasticity, neuromodulation, and intrinsic excitability all conspire to form and maintain memories. But it is still unclear how these seemingly redundant mechanisms could jointly orchestrate learning in a more unified system. To this end, a Hebbian learning rule for spiking neurons inspired by Bayesian statistics is proposed. In this model, synaptic weights and intrinsic currents are adapted on-line upon arrival of single spikes, which initiate a cascade of temporally interacting memory traces that locally estimate probabilities associated with relative neuronal activation levels. Trace dynamics enable synaptic learning to readily demonstrate a spike-timing dependence, stably return to a set-point over long time scales, and remain competitive despite this stability. Beyond unsupervised learning, linking the traces with an external plasticity-modulating signal enables spike-based reinforcement learning. At the postsynaptic neuron, the traces are represented by an activity-dependent ion channel that is shown to regulate the input received by a postsynaptic cell and generate intrinsic graded persistent firing levels. We show how spike-based Hebbian-Bayesian learning can be performed in a simulated inference task using integrate-and-fire (IAF) neurons that are Poisson-firing and background-driven, similar to the preferred regime of cortical neurons. Our results support the view that neurons can represent information in the form of probability distributions, and that probabilistic inference could be a functional by-product of coupled synaptic and nonsynaptic mechanisms operating over several timescales. The model provides a biophysical realization of Bayesian computation by reconciling several observed neural phenomena whose functional effects are only partially understood in concert.

Chapter 2 - The Organization of Plasticity in the Cerebellar Cortex: From Synapses to Control

The cerebellum is thought to play a critical role in procedural learning, but the relationship between this function and the underlying cellular and synaptic mechanisms remains largely speculative. At present, at least nine forms of long-term synaptic and nonsynaptic plasticity (some of which are bidirectional) have been reported in the cerebellar cortex and deep cerebellar nuclei. These include long-term potentiation (LTP) and long-term depression at the mossy fiber-granule cell synapse, at the synapses formed by parallel fibers, climbing fibers, and molecular layer interneurons on Purkinje cells, and at the synapses formed by mossy fibers and Purkinje cells on deep cerebellar nuclear cells, as well as LTP of intrinsic excitability in granule cells, Purkinje cells, and deep cerebellar nuclear cells. It is suggested that the complex properties of cerebellar learning would emerge from the distribution of plasticity in the network and from its dynamic remodeling during the different phases of learning. Intrinsic and extrinsic factors may hold the key to explain how the different forms of plasticity cooperate to select specific transmission channels and to regulate the signal-to-noise ratio through the cerebellar cortex. These factors include regulation of neuronal excitation by local inhibitory networks, engagement of specific molecular mechanisms by spike bursts and theta-frequency oscillations, and gating by external neuromodulators. Therefore, a new and more complex view of cerebellar plasticity is emerging with respect to that predicted by the original "Motor Learning Theory," opening issues that will require experimental and computational testing.