Nonlinear slow-timescale mechanisms in synaptic plasticity.

Learning and memory rely on synapses changing their strengths in response to neural activity. However, there is a substantial gap between the timescales of neural electrical dynamics (1-100 ms) and organism behaviour during learning (seconds-minutes). What mechanisms bridge this timescale gap? What are the implications for theories of brain learning? Here I first cover experimental evidence for slow-timescale factors in plasticity induction. Then I review possible underlying cellular and synaptic mechanisms, and insights from recent computational models that incorporate such slow-timescale variables. I conclude that future progress in understanding brain learning across timescales will require both experimental and computational modelling studies that map out the nonlinearities implemented by both fast and slow plasticity mechanisms at synapses, and crucially, their joint interactions.

Bayesian analysis of phase data in EEG and MEG.

Electroencephalography and magnetoencephalography recordings are non-invasive and temporally precise, making them invaluable tools in the investigation of neural responses in humans. However, these recordings are noisy, both because the neuronal electrodynamics involved produces a muffled signal and because the neuronal processes of interest compete with numerous other processes, from blinking to day-dreaming. One fruitful response to this noisiness has been to use stimuli with a specific frequency and to look for the signal of interest in the response at that frequency. Typically this signal involves measuring the coherence of response phase: here, a Bayesian approach to measuring phase coherence is described. This Bayesian approach is illustrated using two examples from neurolinguistics and its properties are explored using simulated data. We suggest that the Bayesian approach is more descriptive than traditional statistical approaches because it provides an explicit, interpretable generative model of how the data arises. It is also more data-efficient: it detects stimulus-related differences for smaller participant numbers than the standard approach.

Phase coherence is a measurement of waves, for example, brain waves, which quantifies the similarity of their oscillatory behaviour at a fixed frequency. That is, while the waves may vibrate the same number of times per minute, the relative timing of the waves with respect to each other may be different (incoherent) or similar (coherent). In neuroscience, scientists study phase coherence in brain waves to understand how the brain responds to external stimuli, for example if they occur at a fixed frequency during an experiment. To do this, phase coherence is usually quantified with a statistic known as 'inter-trial phase coherence' (ITPC). When ITPC equals one, the waves are perfectly coherent, that is, there is no shift between the two waves and the peaks and troughs occur at exactly the same time. When ITPC equals zero, the waves are shifted from each other in an entirely random way. Phase coherence can also be modelled on phase angles ­ which describe the shift in each wave relative to a reference angle of zero ­ and wrapped distributions. Wrapped distributions are probability distributions over phase angles that express their relative likelihood. Wrapped distributions have statistics, including a mean and a variance. The variance of a wrapped distribution can be used to model phase coherence because it explicitly represents the similarity of phase angles relative to the mean: larger variance means less coherence. While the ITPC is a popular method for analysing phase coherence, it is a so-called 'summary statistic'. Analyses using the ITPC discard useful information in the trial-to-trial-level data, which might not be lost using phase angles. Thus, Dimmock, O'Donnell and Houghton set out to determine whether they could create a model of phase coherence that works directly on phase angles (rather than on the ITPC) and yields better results than existing methods. Dimmock, O'Donnell and Houghton compare their model to the ITPC using both experimental and simulated data. The comparison demonstrates that their model can detect entrainment of the brain to grammatical phrases compared to ungrammatical ones at smaller sample sizes than ITPC, and with fewer false positives. Traditional tools for studying how the brain processes language often yield a lot of noise in the data, which makes it difficult to analyse measurements. Dimmock, O'Donnell and Houghton demonstrates that the brain is not simply responding to the 'surprise factor' of words in a phrase, as some have suggested, but also to their grammatical category. These results of this study will benefit scientists who analyse phase coherence. By using the model in addition to other approaches to study phase coherence, researchers can provide a different perspective on their results and potentially identify new features in their data. This will be particularly powerful in studies with small sample sizes, such as pilot studies where maximising the use of data is important.

A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics.

Discovering the rules of synaptic plasticity is an important step for understanding brain learning. Existing plasticity models are either (1) top-down and interpretable, but not flexible enough to account for experimental data, or (2) bottom-up and biologically realistic, but too intricate to interpret and hard to fit to data. To avoid the shortcomings of these approaches, we present a new plasticity rule based on a geometrical readout mechanism that flexibly maps synaptic enzyme dynamics to predict plasticity outcomes. We apply this readout to a multi-timescale model of hippocampal synaptic plasticity induction that includes electrical dynamics, calcium, CaMKII and calcineurin, and accurate representation of intrinsic noise sources. Using a single set of model parameters, we demonstrate the robustness of this plasticity rule by reproducing nine published ex vivo experiments covering various spike-timing and frequency-dependent plasticity induction protocols, animal ages, and experimental conditions. Our model also predicts that in vivo-like spike timing irregularity strongly shapes plasticity outcome. This geometrical readout modelling approach can be readily applied to other excitatory or inhibitory synapses to discover their synaptic plasticity rules.

Fast-local and slow-global neural ensembles in the mouse brain.

Ensembles of neurons are thought to be coactive when participating in brain computations. However, it is unclear what principles determine whether an ensemble remains localised within a single brain region, or spans multiple brain regions. To address this, we analysed electrophysiological neural population data from hundreds of neurons recorded simultaneously across nine brain regions in awake mice. At fast subsecond timescales, spike count correlations between pairs of neurons in the same brain region were stronger than for pairs of neurons spread across different brain regions. In contrast at slower timescales, within- and between-region spike count correlations were similar. Correlations between high-firing-rate neuron pairs showed a stronger dependence on timescale than low-firing-rate neuron pairs. We applied an ensemble detection algorithm to the neural correlation data and found that at fast timescales each ensemble was mostly contained within a single brain region, whereas at slower timescales ensembles spanned multiple brain regions. These results suggest that the mouse brain may perform fast-local and slow-global computations in parallel.

L-DOPA increases slow-wave sleep duration and selectively modulates memory persistence in older adults.

Introduction: Millions of people worldwide take medications such as L-DOPA that increase dopamine to treat Parkinson's disease. Yet, we do not fully understand how L-DOPA affects sleep and memory. Our earlier research in Parkinson's disease revealed that the timing of L-DOPA relative to sleep affects dopamine's impact on long-term memory. Dopamine projections between the midbrain and hippocampus potentially support memory processes during slow wave sleep. In this study, we aimed to test the hypothesis that L-DOPA enhances memory consolidation by modulating NREM sleep. Methods: We conducted a double-blind, randomised, placebo-controlled crossover trial with healthy older adults (65-79 years, n = 35). Participants first learned a word list and were then administered long-acting L-DOPA (or placebo) before a full night of sleep. Before sleeping, a proportion of the words were re-exposed using a recognition test to strengthen memory. L-DOPA was active during sleep and the practice-recognition test, but not during initial learning. Results: The single dose of L-DOPA increased total slow-wave sleep duration by approximately 11% compared to placebo, while also increasing spindle amplitudes around slow oscillation peaks and around 1-4 Hz NREM spectral power. However, behaviourally, L-DOPA worsened memory of words presented only once compared to re-exposed words. The coupling of spindles to slow oscillation peaks correlated with these differential effects on weaker and stronger memories. To gauge whether L-DOPA affects encoding or retrieval of information in addition to consolidation, we conducted a second experiment targeting L-DOPA only to initial encoding or retrieval and found no behavioural effects. Discussion: Our results demonstrate that L-DOPA augments slow wave sleep in elderly, perhaps tuning coordinated network activity and impacting the selection of information for long-term storage. The pharmaceutical modification of slow-wave sleep and long-term memory may have clinical implications. Clinical trial registration: Eudract number: 2015-002027-26; https://doi.org/10.1186/ISRCTN90897064, ISRCTN90897064.

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/- rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/- rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model.

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.

Neural circuit function redundancy in brain disorders.

Redundancy is a ubiquitous property of the nervous system. This means that vastly different configurations of cellular and synaptic components can enable the same neural circuit functions. However, until recently, very little brain disorder research has considered the implications of this characteristic when designing experiments or interpreting data. Here, we first summarise the evidence for redundancy in healthy brains, explaining redundancy and three related sub-concepts: sloppiness, dependencies and multiple solutions. We then lay out key implications for brain disorder research, covering recent examples of redundancy effects in experimental studies on psychiatric disorders. Finally, we give predictions for future experiments based on these concepts.

Simplicity, Flexibility, and Interpretability in a Model of Dendritic Protein Distributions.

In this issue of Neuron, Fonkeu et al. (2019) present a mathematical model of mRNA and protein synthesis, degradation, diffusion, and trafficking in neuronal dendrites. The model can predict the spatial distribution and temporal dynamics of proteins along dendrites. The authors use the model to account for in situ imaging data of CaMKII⍺ mRNA and protein in hippocampal neurons.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders.

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Distance-dependent gradient in NMDAR-driven spine calcium signals along tapering dendrites.

Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuring N-methyl-d-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.

The Population Tracking Model: A Simple, Scalable Statistical Model for Neural Population Data.

Our understanding of neural population coding has been limited by a lack of analysis methods to characterize spiking data from large populations. The biggest challenge comes from the fact that the number of possible network activity patterns scales exponentially with the number of neurons recorded ([Formula: see text]). Here we introduce a new statistical method for characterizing neural population activity that requires semi-independent fitting of only as many parameters as the square of the number of neurons, requiring drastically smaller data sets and minimal computation time. The model works by matching the population rate (the number of neurons synchronously active) and the probability that each individual neuron fires given the population rate. We found that this model can accurately fit synthetic data from up to 1000 neurons. We also found that the model could rapidly decode visual stimuli from neural population data from macaque primary visual cortex about 65 ms after stimulus onset. Finally, we used the model to estimate the entropy of neural population activity in developing mouse somatosensory cortex and, surprisingly, found that it first increases, and then decreases during development. This statistical model opens new options for interrogating neural population data and can bolster the use of modern large-scale in vivo Ca[Formula: see text] and voltage imaging tools.

Dendritic trafficking faces physiologically critical speed-precision tradeoffs.

Nervous system function requires intracellular transport of channels, receptors, mRNAs, and other cargo throughout complex neuronal morphologies. Local signals such as synaptic input can regulate cargo trafficking, motivating the leading conceptual model of neuron-wide transport, sometimes called the 'sushi-belt model' (Doyle and Kiebler, 2011). Current theories and experiments are based on this model, yet its predictions are not rigorously understood. We formalized the sushi belt model mathematically, and show that it can achieve arbitrarily complex spatial distributions of cargo in reconstructed morphologies. However, the model also predicts an unavoidable, morphology dependent tradeoff between speed, precision and metabolic efficiency of cargo transport. With experimental estimates of trafficking kinetics, the model predicts delays of many hours or days for modestly accurate and efficient cargo delivery throughout a dendritic tree. These findings challenge current understanding of the efficacy of nucleus-to-synapse trafficking and may explain the prevalence of local biosynthesis in neurons.

Street View of the Cognitive Map.

To understand the origins of spatial navigational signals, Acharya et al. record the activity of hippocampal neurons in rats running in open two-dimensional environments in both the real world and in virtual reality. They find that a subset of hippocampal neurons have directional tuning that persists in virtual reality, where vestibular cues are absent.

Spontaneous action potentials and neural coding in unmyelinated axons.

The voltage-gated Na and K channels in neurons are responsible for action potential generation. Because ion channels open and close in a stochastic fashion, spontaneous (ectopic) action potentials can result even in the absence of stimulation. While spontaneous action potentials have been studied in detail in single-compartment models, studies on spatially extended processes have been limited. The simulations and analysis presented here show that spontaneous rate in unmyelinated axon depends nonmonotonically on the length of the axon, that the spontaneous activity has sub-Poisson statistics, and that neural coding can be hampered by the spontaneous spikes by reducing the probability of transmitting the first spike in a train.

Systematic analysis of the contributions of stochastic voltage gated channels to neuronal noise.

Electrical signaling in neurons is mediated by the opening and closing of large numbers of individual ion channels. The ion channels' state transitions are stochastic and introduce fluctuations in the macroscopic current through ion channel populations. This creates an unavoidable source of intrinsic electrical noise for the neuron, leading to fluctuations in the membrane potential and spontaneous spikes. While this effect is well known, the impact of channel noise on single neuron dynamics remains poorly understood. Most results are based on numerical simulations. There is no agreement, even in theoretical studies, on which ion channel type is the dominant noise source, nor how inclusion of additional ion channel types affects voltage noise. Here we describe a framework to calculate voltage noise directly from an arbitrary set of ion channel models, and discuss how this can be use to estimate spontaneous spike rates.

Selective memory generalization by spatial patterning of protein synthesis.

Protein synthesis is crucial for both persistent synaptic plasticity and long-term memory. De novo protein expression can be restricted to specific neurons within a population, and to specific dendrites within a single neuron. Despite its ubiquity, the functional benefits of spatial protein regulation for learning are unknown. We used computational modeling to study this problem. We found that spatially patterned protein synthesis can enable selective consolidation of some memories but forgetting of others, even for simultaneous events that are represented by the same neural population. Key factors regulating selectivity include the functional clustering of synapses on dendrites, and the sparsity and overlap of neural activity patterns at the circuit level. Based on these findings, we proposed a two-step model for selective memory generalization during REM and slow-wave sleep. The pattern-matching framework we propose may be broadly applicable to spatial protein signaling throughout cortex and hippocampus.

Dendritic spine dynamics regulate the long-term stability of synaptic plasticity.

Long-term synaptic plasticity requires postsynaptic influx of Ca²âº and is accompanied by changes in dendritic spine size. Unless Ca²âº influx mechanisms and spine volume scale proportionally, changes in spine size will modify spine Ca²âº concentrations during subsequent synaptic activation. We show that the relationship between Ca²âº influx and spine volume is a fundamental determinant of synaptic stability. If Ca²âº influx is undercompensated for increases in spine size, then strong synapses are stabilized and synaptic strength distributions have a single peak. In contrast, overcompensation of Ca²âº influx leads to binary, persistent synaptic strengths with double-peaked distributions. Biophysical simulations predict that CA1 pyramidal neuron spines are undercompensating. This unifies experimental findings that weak synapses are more plastic than strong synapses, that synaptic strengths are unimodally distributed, and that potentiation saturates for a given stimulus strength. We conclude that structural plasticity provides a simple, local, and general mechanism that allows dendritic spines to foster both rapid memory formation and persistent memory storage.

Tuning of synaptic responses: an organizing principle for optimization of neural circuits.

Neuron types are classically defined by anatomical and physiological properties that determine how synaptic inputs are integrated. Here, we provide an overview of the evidence that, among neurons of a single type, integration of synaptic responses is further tuned according to the particular function that individual neurons carry out. Recent data suggest that tuning of synaptic responses is not restricted to sensory pathways, but extends to cognitive and motor circuits. We propose that tuning of synaptic integration results from general cellular mechanisms for optimization of information processing that are distinct from, but complementary to, homeostasis and memory storage. These cellular tuning mechanisms might be crucial for distributed computations underlying sensory, motor and cognitive functions.