A calcium-based plasticity model for predicting long-term potentiation and depression in the neocortex

Pyramidal cells (PCs) form the backbone of the layered structure of the neocortex, and plasticity of their synapses is thought to underlie learning in the brain. However, such long-term synaptic changes have been experimentally characterized between only a few types of PCs, posing a significant barrier for studying neocortical learning mechanisms. Here we introduce a model of synaptic plasticity based on data-constrained postsynaptic calcium dynamics, and show in a neocortical microcircuit model that a single parameter set is sufficient to unify the available experimental findings on long-term potentiation (LTP) and long-term depression (LTD) of PC connections. In particular, we find that the diverse plasticity outcomes across the different PC types can be explained by cell-type-specific synaptic physiology, cell morphology and innervation patterns, without requiring type-specific plasticity. Generalizing the model to in vivo extracellular calcium concentrations, we predict qualitatively different plasticity dynamics from those observed in vitro. This work provides a first comprehensive null model for LTP/LTD between neocortical PC types in vivo, and an open framework for further developing models of cortical synaptic plasticity.We thank Michael Hines for helping with synapse model implementation in NEURON; Mariana Vargas-Caballero for sharing NMDAR data; Veronica Egger for sharing in vitro data and for clarifications on the analysis methods; Jesper Sjöström for sharing in vitro data, helpful discussions, and feedback on the manuscript; Ralf Schneggenburger for helpful discussions and clarifications on the NMDAR calcium current model; Fabien Delalondre for helpful discussions; Francesco Casalegno and Taylor Newton for helpful discussion on model fitting; Daniel Keller for helpful discussions on the biophysics of synaptic plasticity; Natali Barros-Zulaica for helpful discussions on MVR modeling and generalization; Srikanth Ramaswamy, Michael Reimann and Max Nolte for feedback on the manuscript; Wulfram Gerstner and Guillaume Bellec for helpful discussions on synaptic plasticity modeling. This study was supported by funding to the Blue Brain Project, a research center of the École polytechnique fédérale de Lausanne, from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology. E.B.M. received additional support from the CHU Sainte-Justine Research Center (CHUSJRC), the Institute for Data Valorization (IVADO), Fonds de Recherche du Québec–Santé (FRQS), the Canada CIFAR AI Chairs Program, the Quebec Institute for Artificial Intelligence (Mila), and Google. R.B.P. and J.DF. received support from the Spanish “Ministerio de Ciencia e Innovación” (grant PGC2018-094307-B-I00). M.D. and I.S. were supported by a grant from the ETH domain for the Blue Brain Project, the Gatsby Charitable Foundation, and the Drahi Family Foundation

Cliques of Neurons Bound into Cavities Provide a Missing Link between Structure and Function

A recent publication provides the network graph for a neocortical microcircuit comprising 8 million connections between 31,000 neurons (H. Markram, et al., Reconstruction and simulation of neocortical microcircuitry, Cell, 163 (2015) no. 2, 456-492). Since traditional graph-theoretical methods may not be sufficient to understand the immense complexity of such a biological network, we explored whether methods from algebraic topology could provide a new perspective on its structural and functional organization. Structural topological analysis revealed that directed graphs representing connectivity among neurons in the microcircuit deviated significantly from different varieties of randomized graph. In particular, the directed graphs contained in the order of $10^7$ simplices {\DH} groups of neurons with all-to-all directed connectivity. Some of these simplices contained up to 8 neurons, making them the most extreme neuronal clustering motif ever reported. Functional topological analysis of simulated neuronal activity in the microcircuit revealed novel spatio-temporal metrics that provide an effective classification of functional responses to qualitatively different stimuli. This study represents the first algebraic topological analysis of structural connectomics and connectomics-based spatio-temporal activity in a biologically realistic neural microcircuit. The methods used in the study show promise for more general applications in network science

Reconstruction and simulation of neocortical microcircuitry

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies

Towards a unified understanding of synaptic plasticity:parsimonious modeling and simulation of the glutamatergic synapse life-cycle

Understanding how learning and memory formation work in the brain is a major challenge in neuroscience, with important implications for many other fields, including medicine and industry. It is nowadays widely accepted that synaptic plasticity is the biological foundation of these higher order brain functions. So far, many different plastic behaviors have been intensively studied and characterized, leading to the definition of several forms of plasticity: structural, functional, homeostatic, inhibitory, and many others. Unfortunately, despite all the interest and efforts of the scientific community, a complete and consistent understanding of synaptic plasticity is still lacking. The main goal of this study is to unify data and theories on synaptic plasticity in a comprehensive model, suitable for studying learning and memory down to the synapse level. To reach our objective, we identified a minimal set of biological mechanisms responsible for plastic dynamics and integrated them into a single synapse model, relying whenever possible on well accepted sub-models from literature. We designed a data-driven fitting and generalization strategy to parameterize all excitatory-to-excitatory synapses in a large scale reconstruction of neocortical tissue [Markram et al., 2015]. Finally, we tested the effects of functional synaptic plasticity on neural circuits in simulations. Our model was able to capture not only the outcome of Spike Timing Dependent Plasticity (STDP) protocols used in the training phase, but also the one of all others available in the same experimental dataset [Markram et al., 1997b]. Moreover, it correctly reproduced results on distance-dependent synaptic plasticity [Sjöström and Häusser, 2006], even though this dataset was never used during fitting. In network simulations, we observed the emergence of a self-regulatory homeostatic mechanism, preventing runaway excitation. Furthermore, we noticed the strengthening of connections between neurons that are similarly innervated, as previously shown in vitro [Perin et al., 2011]

Timed Synaptic Inhibition Shapes NMDA Spikes, Influencing Local Dendritic Processing and Global I/O Properties of Cortical Neurons

Summary: The NMDA spike is a long-lasting nonlinear phenomenon initiated locally in the dendritic branches of a variety of cortical neurons. It plays a key role in synaptic plasticity and in single-neuron computations. Combining dynamic system theory and computational approaches, we now explore how the timing of synaptic inhibition affects the NMDA spike and its associated membrane current. When impinging on its early phase, individual inhibitory synapses strongly, but transiently, dampen the NMDA spike; later inhibition prematurely terminates it. A single inhibitory synapse reduces the NMDA-mediated Ca2+ current, a key player in plasticity, by up to 45%. NMDA spikes in distal dendritic branches/spines are longer-lasting and more resilient to inhibition, enhancing synaptic plasticity at these branches. We conclude that NMDA spikes are highly sensitive to dendritic inhibition; sparse weak inhibition can finely tune synaptic plasticity both locally at the dendritic branch level and globally at the level of the neuron’s output. : The NMDA spike is a nonlinear dendritic phenomenon involved in synaptic plasticity and in shaping the I/O properties of neurons. Doron et al. use a theoretical approach to study the fine-tuned and powerful modulation of the NMDA spike by timed synaptic inhibition. They provide a mechanistic explanation for the interaction between timed inhibition and excitation and explore the implications for dendritic and somatic computations. Keywords: NMDA-spike, synaptic inhibition, nonlinear dendrites, synaptic plasticity, dendritic spines, cortical pyramidal cell

Estimating the Readily-Releasable Vesicle Pool Size at Synaptic Connections in the Neocortex

Previous studies based on the 'Quantal Model' for synaptic transmission suggest that neurotransmitter release is mediated by a single release site at individual synaptic contacts in the neocortex. However, recent studies seem to contradict this hypothesis and indicate that multi-vesicular release (MVR) could better explain the synaptic response variability observed in vitro. In this study we present a novel method to estimate the number of release sites per synapse, also known as the size of the readily releasable pool (N-RRP), from paired whole-cell recordings of connections between layer 5 thick tufted pyramidal cell (L5_TTPC) in the juvenile rat somatosensory cortex. Our approach extends the work of Loebel et al. (2009) by leveraging a recently published data-driven biophysical model of neocortical tissue. Using this approach, we estimated N-RRP to be between two to three for synaptic connections between L5_TTPCs. To constrain N-RRP values for other connections in the microcircuit, we developed and validated a generalization approach using published data on the coefficient of variation (CV) of the amplitudes of post-synaptic potentials (PSPs) from literature and comparing them against in silico experiments. Our study predicts that transmitter release at synaptic connections in the neocortex could be mediated by MVR and provides a data-driven approach to constrain the MVR model parameters in the microcircuit