Properties of synaptic release dictates the core of information transfer in neural circuits. Despite decades of technical and theoretical advances, distinguishing bona fide information content from the multiple sources of synaptic variability remains a challenging problem. Here, we employed a combination of computational approaches with cellular electrophysiology, two-photon uncaging of MNI-Glutamate and imaging at single synapses. We describe and calibrate the use of the fluorescent glutamate sensor iGluSnFR and found that its kinetic profile is close to that of AMPA receptors, therefore providing several distinct advantages over slower methods relying on NMDA receptor activation (i.e., chemical or genetically encoded calcium indicators). Using an array of statistical methods, we further developed, and validated on surrogate data, an expectation-maximization algorithm that, by biophysically constraining release variability, extracts the quantal parameters n (maximum number of released vesicles) and p (unitary probability of release) from single-synapse iGluSnFR-mediated transients. Together, we present a generalizable mathematical formalism which, when applied to optical recordings, paves the way to an increasingly precise investigation of information transfer at central synapses.

Transcranial alternating current stimulation (tACS) represents a promising non-invasive treatment for an increasingly wide range of neurological and neuropsychiatric disorders. The ability to use periodically oscillating electric fields to non-invasively engage neural dynamics opens up the possibility of recruiting synaptic plasticity and to modulate brain function. However, despite consistent reports about tACS clinical effectiveness, strong state-dependence combined with the ubiquitous heterogeneity of cortical networks collectively results in high outcome variability. Introducing variations in intrinsic neuronal timescales, we explored how such heterogeneity influences stimulation-induced change in synaptic connectivity. We examined how spike timing dependent plasticity, at the level of cells, intra- and inter-laminar cortical networks, can be selectively and preferentially engaged by periodic stimulation. Using leaky integrate-and-fire neuron models, we analyzed cortical circuits comprised of multiple cell-types, alongside superficial multi-layered networks expressing distinct layer-specific timescales. Our results show that mismatch in neuronal timescales within and/or between cells—and the resulting variability in excitability, temporal integration properties and frequency tuning—enables selective and directional control on synaptic connectivity by tACS. Our work provides new vistas on how to recruit neural heterogeneity to guide brain plasticity using non-invasive stimulation paradigms.

Synaptic dynamics differ markedly across connections and strongly regulate how action potentials are being communicated. To model the range of synaptic dynamics observed in experiments, we develop a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks. Author summaryUnderstanding how information is transmitted relies heavily on knowledge of the underlying regulatory synaptic dynamics. Existing computational models for capturing such dynamics are often either very complex or too restrictive. As a result, effectively capturing the different types of dynamics observed experimentally remains a challenging problem. Here, we propose a mathematically flexible linear-nonlinear model that is capable of efficiently characterizing synaptic dynamics. We demonstrate the ability of this model to capture different features of experimentally observed data.The nervous system has evolved a communication system largely based on temporal 2 sequences of action potentials. A central feature of this communication is that action 3 potentials are communicated with variable efficacy on short (10 ms -10 s) time 4 scales [1-6]. The dynamics of synaptic efficacy at short time scales, or short-term 5 plasticity (STP), can be a powerful determinant of the flow of information, allowing the 6 same axon to communicate independent messages to different post-synaptic 7 targets [7, 8]. Properties of STP vary markedly across projections [9-11], leading to the 8idea that connections can be conceived as belonging to distinct classes [12,13] and that 9 these distinct classes shape information transmission in vivo [14][15][16]. Thus, to 10 May 29, 2020 1/25 understand the flow of information in neuronal networks, the connectome must be 11 indexed with an accurate description of STP properties. 12One approach to characterizing synaptic dynamics is to perform targeted 13 experiments and extract a summary feature, most commonly the paired-pulse 14 ratio [5,[17][18][19], whereby a synapse can be classified as short-term depressing (STD) or 15 short-term facilitating (STF). However, a single summary feature is insufficient to 16 capture the full extent of STP diversity. Longer or more complex stimulation patterns 17 are required to describe delayed facilitation onset [6], biphasic STP [20, 21] or the 18 distinction between supra-and sub-linear facilitation [22]. Such atypical STP dynamics 19 challenge the traditional dichotomy of STF and STD and suggest that more complex 20 phenotypes can exist and contribute to network function in...

Short-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic dynamics observed in experiments, we have developed a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show that it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.

Experiments have compared the folding of proteins with different amino acid sequences but the same basic structure, or fold. Results indicate that folding is robust to sequence variations for proteins with some nonlocal folds, such as all-b, whereas the folding of more local, all-a proteins typically exhibits a stronger sequence dependence. Here, we use a coarse-grained model to systematically study how variations in sequence perturb the folding energy landscapes of three model sequences with 3a, 4b þ a, and b-barrel folds, respectively. These three proteins exhibit folding features in line with experiments, including expected rank order in the cooperativity of the folding transition and stability-dependent shifts in the location of the freeenergy barrier to folding. Using a generalized-ensemble simulation approach, we determine the thermodynamics of around 2000 sequence variants representing all possible hydrophobic or polar single-and double-point mutations. From an analysis of the subset of stability-neutral mutations, we find that folding is perturbed in a topology-dependent manner, with the b-barrel protein being the most robust. Our analysis shows, in particular, that the magnitude of mutational perturbations of the transition state is controlled in part by the size or ''width'' of the underlying conformational ensemble. This result suggests that the mutational robustness of the folding of the b-barrel protein is underpinned by its conformationally restricted transition state ensemble, revealing a link between sequence and topological effects in protein folding.

Transcranial alternating current stimulation (tACS) represents a promising non-invasive treatment for an increasingly wide range of neurological and neuropsychiatric disorders. The ability to use periodically oscillating electric fields to non-invasively engage neural dynamics opens up the possibility of recruiting synaptic plasticity and to modulate brain function. However, despite consistent reports about tACS clinical effectiveness, strong state-dependence combined with the ubiquitous heterogeneity of cortical networks collectively results in high outcome variability. Introducing variations in intrinsic neuronal timescales, we explored how such heterogeneity influences stimulation-induced change in synaptic connectivity. We examined how spike timing dependent plasticity, at the level of cells, intra- and inter-laminar cortical networks, can be selectively and preferentially engaged by periodic stimulation. Using computational simulations informed by human experimental data, we analyzed cortical circuits comprised of multiple cell-types, alongside superficial multi-layered networks expressing distinct layer-specific timescales. Our results show that mismatch in neuronal timescales within and/or between cells - and the resulting variability in excitability, temporal integration properties and frequency tuning - enables selective and directional control on synaptic connectivity by tACS. Our work provides new vistas on how to recruit neural heterogeneity to guide brain plasticity using non-invasive stimulation paradigms.

Properties of synaptic release dictates the core of information transfer in neural circuits. Despite decades of technical and theoretical advances, distinguishing bona fide information content from the multiple sources of synaptic variability remains a challenging problem. Here, we employed a combination of computational approaches with cellular electrophysiology, two-photon uncaging of MNI-Glutamate and imaging at single synapses. We describe and calibrate the use of the fluorescent glutamate sensor iGluSnFR and found that its kinetic profile is close to that of AMPA receptors, therefore providing several distinct advantages over slower methods relying on NMDA receptor activation (i.e., chemical or genetically encoded Calcium indicators). Using an array of statistical methods, we further developed, and validated on surrogate data, an expectation-maximization algorithm that, by biophysically constraining release variability, extracts the quantal parameters n (maximum number of released vesicles) and p (unitary probability of release) from single-synapse iGluSnFR-mediated transients. Together, we present a generalizable mathematical formalism which, when applied to optical recordings, paves the way to an increasingly precise investigation of information transfer at central synapses.

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