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Nicola, W.

Publications and source records attributed to Nicola, W..

17 recordsLinked to original sources

Subthreshold Asynchronous States and Computations in Biophysically Detailed Populations of Neurons

Spikes are metabolically costly to generate and transmit, and spiking rates should be kept to a minimum for efficient coding. How low can the spike rate go? We show that computations and asynchronous states based on excitatory/inhibitory balance can exist without firing any spikes through self-sustaining subthreshold voltage fluctuations in networks of biophysically detailed Hodgkin-Huxley neurons. This novel subthreshold asynchronous state, which we call subthreshold voltage chaos, can be controlled for useful computation and pattern generation, also without firing spikes. Further, we identify candidate ion channels, low-voltage-activated T-Type calcium channels that provide a biophysical mechanism for this type of subthreshold computation. Our work here provides computational evidence for the existence of efficient neural circuits that can compute exclusively with subthreshold voltage dynamics.

neuroscience↗

Reservoir Computing with Ultra-Sparse Rings

Many existing models of computation in recurrent neural networks assume dense, unconstrained initial connectivity, where any pair of neurons may be coupled to generate the rich dynamics needed for learning complex temporal patterns. Inspired by invertebrate circuits that often exhibit ring-like connectivity, we show that computation can occur in ultra-sparse spiking and rate reservoirs that are initially coupled as simple unidirectional rings. In contrast to standard recurrent networks, the total number of network parameters in these ring networks scales only linearly with network size, while still producing rich feature sets. We demonstrate that such networks can successfully reproduce a range of dynamical systems tasks, including oscillations, multi-stable switches, and low-dimensional chaotic attractors. Our findings show that structured spatio-temporal dynamics naturally arising from large ring topologies, often observed in invertebrate circuits, are a sufficient mechanism for learning different types of attractors.

neuroscience↗

Versatile Learning without Synaptic Plasticity in a Spiking Neural Network

Learning in the brains cerebral cortex is widely attributed to synaptic plasticity among cortical neurons. However, a growing body of evidence suggests that alternative processes, such as modulation of intrinsic excitability or gating by subcortical inputs, may also serve as important learning mechanisms. We developed the Bias Adaptive Neural Firing Framework (BANFF) as a simplified model of such phenomena embodied by a learnable bias current for each neuron of a rate-based network. Here, we extend this framework to spiking neural networks. We show that learning such biases enables one recurrent spiking neural network with fixed and random synaptic weights to perform well on nine tasks spanning classification, regression, and closed-loop dynamical systems mimicry. The network learnt a unique bias set for each task, and unlike recurrent synapse-based learning, new learning did not interfere with previous learning. The network was robust to non-stationary F-I curves (spike frequency adaptation), and biases could be learned with a learning algorithm (e-prop) that is more biologically plausible than stock gradient descent. Overall, we show that the BANFF can be extended from rate-based to spiking neural networks, maintaining good multi-task performance with a single network of spiking neurons.

neuroscience↗

Direct Training of Networks of Morris-Lecar Neurons withBackprop

Spiking Neural Networks (SNNs) have the potential to replicate the brains computational efficacy by explicitly incorporating action potentials or "spikes", which is not a feature of most artificial neural networks. However, training SNNs is difficult due to the non-differentiable nature of the most common spiking models: integrate-and-fire neurons. This study investigates if some of the difficulty in training SNNs arises from the use of integrate-and-fire neurons, rather than smoother alternatives, like conductance-based neurons. To that end, we considered networks of Morris-Lecar (ML) neurons, a conductance-based neuron model which is differentiable. Networks were built using kinetic synaptic models that smoothly link presynaptic voltage dynamics directly to postsynaptic conductance changes, ensuring that all components remain fully differentiable. Switching to biophysically detailed models of synapses and neurons enabled direct end-to-end training through Backpropagation Through Time (BPTT). Biophysically detailed networks were successfully trained on image classification, regression, and time series prediction tasks. These results demonstrate the feasibility of employing biophysically detailed differentiable point neuron models to create SNNs that function as more accurate paradigms for the study of neural computations and learning. Further, this work confirms that some aspects of the difficulty in translating gradient-based learning algorithms from machine learning may arise from model choice, rather than SNNs being intrinsically difficult to train. 1. Author summaryThe brains information-processing efficiency arises in part from neurons communicating via discrete spikes. Spiking Neural Networks (SNNs) mimic this process at the neuronal level but have been difficult to train as most machine learning algorithms are not directly applicable. Most SNNs use integrate-and-fire neurons, a modelling framework that simplifies spikes into non-differentiable, abrupt voltage changes, which makes them difficult to train with powerful, standard AI training methods that use derivatives to compute gradients (e.g. Backprop). In our work, we asked if this difficulty could be overcome by considering end-to-end differentiable spiking neural networks. We used completely differentiable SNNs using the Morris-Lecar neuron, a biophysically detailed neuron model that produces smooth spikes, along with differentiable kinetic synapses. With the entire network being mathematically differentiable, we found that we could train it directly using standard backpropagation through time on different tasks (regression, classification, and chaotic time series prediction). This work demonstrates that the use of integrate-and-fire models may be limiting applications of machine learning algorithms towards understanding how learning functions in the brain.

neuroscience↗

Rapidly Reconfigurable Dynamic Computing in Neural Networks with Fixed Synaptic Connectivity

Learning and memory in the brains neocortex have long been hypothesised to be primarily mediated by synaptic plasticity. Extensive research in artificial neural networks has shown that training networks by adjusting connection weights faces computational challenges, including large parameter spaces and the tendency of new learning to interfere with previous learning (catastrophic forgetting). We propose that the brain, which is resistant to these challenges, can also learn by modulating the excitability of each neuron in a network rather than changing synaptic strengths. We show here that learning a task-specific set of bias currents enables a feedforward or recurrent network with fixed and randomly assigned connections to perform well on and switch between dozens of tasks, including regression, classification, autonomous time series generation, a game and robotic control. Bias-only learning also provides a novel mechanistic explanation for representational drift. It directly links the noise robustness of neuronal representations on short and long time scales to the ability of neural circuits to preserve learned information while remaining adaptable. We postulate that subcortical structures, such as the basal ganglia or cerebellum, may provide similar bias inputs to the neocortex for rapid task learning and robustness against interference.

neuroscience↗

Hypothalamic recurrent inhibition regulates functional states of stress effector neurons.

Stress triggers rapid and reversible shifts in vital physiological functions from homeostatic operation to emergency response. However, the neural mechanisms regulating such functional stress states remain poorly understood. Here we identify a novel recurrent inhibitory circuit governing functional states of key stress regulatory neurons: corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). Microendoscopic calcium imaging in freely behaving mice revealed synchronized low-activity state at baselines and a reversible high-activity state during mild stress. Ensemble analysis indicated increased dimensionality of network dynamics during high-activity state. Computational modeling of calcium ensemble data, together with independent modeling of single-unit CRHPVN neurons spiking dynamics, converged to show that recurrent inhibition is a key circuit motif for stress-induced functional state transitions. Guided by model predictions, chemogenetic manipulations of PVN-projecting GABAergic neurons (PVN[->]GABA) revealed their roles in constraining CRHPVN neurons to low-activity state at baselines via a prolonged feedback inhibition. Unexpectedly, slow CRHergic excitation was dispensable for driving this prolonged feedback, whereas glutamatergic transmission predominated at CRH[->]PVN[->]GABA excitatory synapses. Incorporating these findings, we refined our computational model to include fast excitation and slow inhibition, yielding new predictions for circuit operation. Together, our results establish recurrent inhibition as a fundamental circuit motif controlling CRHPVN neurons functional states and highlight the value of iterative experiment-model integration in advancing understanding of neural circuits functions.

neuroscience↗

Ion channels that mediate calcium-dependent control of spike patterns are spatially organized across the soma in relation to a cytoskeletal assembly

A spectrin-actin cytoskeleton defines the structure of axons and expression of ion channels that support spike propagation, but it is not known how calcium and potassium channels are organized at the soma to control spike output patterns. The hippocampal pyramidal cell slow afterhyperpolarization (sAHP) is generated by a CaRyK protein complex of Cav1.3 calcium, RyR2, and IK potassium channels reflecting an ER-PM junction. Super resolution imaging and dimension reduction identified a highly organized distribution of CaRyK protein clusters aligned as rows with [~]155 nm periodicity that extended to branchpoints to form a non-rigid lattice-like structure across the soma. All CaRyK proteins proved to align and colocalize with the polygonal spectrin {beta}II cytoskeleton. The data indicate that CaRyK proteins at ER-PM junctions that contribute to the sAHP to control the pattern of spike output are distributed with high precision as functional ion channel nodes across the somatic spectrin cytoskeletal network. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/607230v4_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a60adorg.highwire.dtl.DTLVardef@1c11894org.highwire.dtl.DTLVardef@34b50aorg.highwire.dtl.DTLVardef@59bb39_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

A Markovian neural barcode representing mesoscale cortical spatiotemporal dynamics.

Mesoscale cortical dynamics consist of stereotyped patterns of recurring activity motifs, however the constraints and rules governing how these motifs assemble over time is not known. Here we propose a Continuous Time Markov Chain model that probabilistically describes the temporal sequence of activity motifs using Markov Elements derived using semi-binary non-negative matrix factorization. Although derived from a discovery sample, these can be applied to new recordings from new mice. Unwrapping the associated transition probability matrix creates a Markovian neural barcode describing the probability of Markov element transitions as a compact and interpretable representation of neocortical dynamics. We show broad utility across a range of common mesoscale cortical imaging applications, ranging from time-locked events to pathological models. Moreover, it allows the discovery of new and emergent Markov Elements that unmask the flexibility of constraints governing cortical dynamics. The Markovian neural barcode provides a novel and powerful tool to characterize cortical function.

neuroscience↗

Unilateral hippocampal stroke in freely behaving mice reveals sex differences in contralesional spreading depolarization and associated behavior

Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitors neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical mouse behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization (SD), predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with evidence of contralesional SD. Here, recovery of hippocampal function was lost by blunting peri-stroke SD with NMDAR antagonism, indicating that contralesional SD improves recovery following hippocampal stroke.

neuroscience↗

The hippocampal theta oscillation may be generated by chimera dynamics

The 8-12 Hz theta rhythm observed in hippocampal local field potentials of animals can be regarded as a "clock" that regulates the timing of spikes. While different interneuron sub-types synchronously phase lock to different phases for every theta cycle, the phase of pyramidal neurons spikes asynchronously vary in each theta cycle, depending on the animals position. On the other hand, pyramidal neurons tend to fire slightly faster than the theta oscillation in what is termed hippocampal phase precession. Chimera states are specific solutions to dynamical systems where synchrony and asynchrony coexist, similar to the hippocampal theta oscillation. Here, we test the hypothesis that the hippocampal theta oscillation emerges from chimera dynamics with computational modelling. We utilized multiple network topologies and sizes of Kuramoto oscillator networks that are known to collectively display chimera dynamics. We found that by changing the oscillators intrinsic frequency, the frequency ratio between the synchronized and unsynchronized oscillators can match the frequency ratio between the hippocampal theta oscillation ({approx}8 Hz) and phase precessing pyramidal neurons ({approx}9 Hz). The faster firing population of oscillators also displays theta-sequence-like behaviour and phase precession. Finally, we trained networks of spiking integrate-and-fire neurons to output a chimera state by using the Kuramoto-chimera system as a dynamical supervisor. We found that the firing times of subsets of individual neurons display phase precession. These results imply that the hippocampal theta oscillation may be a chimera state, further suggesting the importance of chimera states in neuroscience.

neuroscience↗

Disk-Drive-Like Operations in the Hippocampus

The rapid computation of re-playable memories within the hippocampus in the form of spike sequences is a near computer-like operation. Information can be encoded once during the initial experience, and replayed numerous times after in a compressed-time representation [1-8]. Theta oscillations, sharp-wave ripples, and attractor dynamics have been posited to collectively play a role in the formation and replay of memories. However, the precise interplay between these dynamical states remains elusive. Here, we show that the memory formation dynamics and operations of the hippocampus are not just computer-like, but map directly onto the dynamics and operations of a disk-drive. We constructed a tripartite spiking neural network model where the hippocampus is explicitly described as a disk drive with a rotating disk, an actuator arm, and a read/write head. In this Neural Disk Drive (NDD) model, hippocampal oscillations map to disk rotations in the rotating disk network while attractor dynamics in the actuator arm network point to "tracks" (spike assemblies) on the disk. The read/write head then writes information onto these tracks, which have temporally-structured spikes. Tracks can be replayed during hippocampal ripples for consolidation. We confirmed the existence of interneuron-ring-sequences, predicted by the rotating disk network, in experimental data. Our results establish the hippocampus as a brain region displaying explicit, computer-like operations. Based on the known interactions between the hippocampus and other brain areas, we anticipate that our results may lead to additional models that revisit the hypothesis that the brain performs explicit, computer-like operations.

neuroscience↗

Particle-Swarm Based Modelling Reveals Two Distinct Classes of CRHPVN Neurons

Electrophysiological recordings can provide detailed information of single neurons dynamical features and shed light into their response to stimuli. Unfortunately, rapidly modeling electrophysiological data for inferring network-level behaviours remains challenging. Here, we investigate how modeled single neuron dynamics lead to network-level responses in the paraventricular nucleus of the hypothalamus (PVN), a critical nucleus for the mammalian stress response. Recordings of corticotropinreleasing hormone neurons from the PVN (CRHPVN) were performed using whole-cell current-clamp. These, neurons, which initiate the endocrine response to stress, were rapidly and automatically fit to a modified Adaptive Exponential Integrate and Fire model (AdEx) with Particle Swarm Optimization (PSO). All CRHPVN neurons were accurately fit by the AdEx model with PSO. Multiple sets of parameters were found that reliably reproduced current-clamp traces for any single neuron. Despite multiple solutions, the dynamical features of the models such as the rheobase current levels, fixed points, and bifurcations, were shown to be stable across fits. We found that CRHPVN neurons can be divided into two sub-types according to their bifurcation at the onset of firing: saddles (integrators) and sub-critical Hopf (resonators). We constructed networks of these fit CRHPVN model neurons to investigate the network level responses of CRHPVN neurons. We found that CRHPVN-resonators maintain baseline firing in networks even when all inputs are inhibitory. The dynamics of a small subset of CRHPVN neurons may be critical to maintaining a baseline firing tone in the PVN. Key PointsO_LICorticotropin-releasing hormone neurons (CRHPVN) in the paraventricular nucleus of the hypothalamus act as the final neural controllers of the stress response. C_LIO_LIWe developed a rapid computational modeling platform that uses Particle-Swarm Optimization to rapidly and accurately fit biophysical neuron models. C_LIO_LIA model was fit to each patched neuron without the use of dynamic clamping, or other procedures requiring sophisticated inputs and fitting procedures. Any neuron undergoing standard current clamping for a few minutes can be fit by this procedure C_LIO_LIThe dynamical analysis of the modeled neurons shows thatCRHPVN comes in two specific flavours: CRHPVN-resonators and CRHPVN-integrators. C_LIO_LINetwork simulations show thatCRHPVN-resonators are critical to retaining the baseline firing rate of the entire network of CRHPVN neurons as these cells can fire rebound spikes and bursts in the presence of strong inhibitory synaptic input. C_LI

neuroscience↗

Photons guided by axons may enable backpropagation-based learning in the brain

Despite great advances in explaining synaptic plasticity and neuron function, a complete understanding of the brains learning algorithms is still missing. Artificial neural networks provide a powerful learning paradigm through the backpropagation algorithm which modifies synaptic weights by using feedback connections. Backpropagation requires extensive communication of information back through the layers of a network. This has been argued to be biologically implausible and it is not clear whether backpropagation can be realized in the brain. Here we suggest that biophotons guided by axons provide a potential channel for backward transmission of information in the brain. Biophotons have been experimentally shown to be produced in the brain, yet their purpose is not understood. We propose that biophotons can propagate from each post-synaptic neuron to its pre-synaptic one to carry the required information backward. To reflect the stochastic character of biophoton emissions, our model includes the stochastic backward transmission of teaching signals. We demonstrate that a three-layered network of neurons can learn the MNIST handwritten digit classification task using our proposed backpropagation-like algorithm with stochastic photonic feedback. We model realistic restrictions and show that our system still learns the task for low rates of biophoton emission, information-limited (one bit per photon) backward transmission, and in the presence of noise photons. Our results suggest a new functionality for biophotons and provide an alternate mechanism for backward transmission in the brain.

biophysics↗

Does the Zebra Finch Mating Song Circuit Use Spike Times Efficiently?

Precise and reliable spike times are thought to subserve multiple possible functions, including improving the accuracy of encoding stimuli or behaviours relative to other coding schemes. Indeed, repeating sequences of spikes with sub-millisecond precision exist in nature, such as the synfire chain of spikes in area HVC of the zebra-finch mating-song circuit. Here, we analyzed what impact precise and reliable spikes have on the encoding accuracy for both the zebra-finch and more generic neural circuits using computational modelling. Our results show that neural circuits can use precisely timed spikes to encode signals with a higher-order accuracy than a conventional rate code. Circuits with precisely timed and reliably emitted spikes increase their encoding accuracy linearly with network size, which is the hallmark signature of an efficient code. This qualitatively differs from circuits that employ a rate code which increase their encoding accuracy with the square-root of network size. However, this improved scaling is dependent on the spikes becoming more accurate and more reliable with larger networks. Finally, we discuss how to test this scaling relationship in the zebra mating song circuit using both neural data and song-spectrogram-based recordings while taking advantage of the natural fluctuation in HVC network size due to neurogenesis. The zebra-finch mating-song circuit may represent the most likely candidate system for the use of spike-timing-based, efficient coding strategies in nature.

neuroscience↗

Deregulation of brain endothelial CD2AP in Alzheimer's disease impairs Reelin-mediated neurovascular coupling

Genetic variations in CD2-associated protein (CD2AP) predispose to Alzheimers disease (AD) but the underlying mechanisms remain unknown. Here, we show that a cerebrovascular loss of CD2AP is associated with cognitive decline in AD and that genetic downregulation of CD2AP in brain endothelial cells impairs memory function in two distinct mouse models. Mice with reduced CD2AP in brain microvessels display decreased resting cerebral blood flow, impaired functional hyperemia and vasomotion. In brain endothelial cells, CD2AP regulates the levels and signaling of ApoE receptor 2 elicited by Reelin glycoprotein. Activation of the CD2AP-ApoER2 pathway with Reelin mitigates the toxic effects of A{beta} on resting blood flow and vasomotion of brain vessels depleted of CD2AP. Thus, we demonstrate that deregulation of CD2AP perturbs specific functions and segments of the cerebral microvasculature and propose that targeting CD2AP molecular partners may offer refined therapeutic strategies for the treatment of AD.

neuroscience↗

Neural Sampling Strategies for Visual Stimulus Reconstruction from Two-photon Imaging of Mouse Primary Visual Cortex

Deciphering the neural code involves interpreting the responses of sensory neurons from the perspective of a downstream population. Performing such a read-out is an important step towards understanding how the brain processes sensory information and has implications for Brain-Machine Interfaces. While previous work has focused on classification algorithms to identify a stimulus in a predefined set of categories, few studies have approached a full-stimulus reconstruction task, especially from calcium imaging recordings. Here, we attempt a pixel-by-pixel reconstruction of complex natural stimuli from two-photon calcium imaging of mouse primary visual cortex. We decoded the activity of 103 neurons from layer 2/3 using an optimal linear estimator and investigated which factors drive the reconstruction performance at the pixel level. We find the density of receptive fields to be the most influential feature. Finally, we use the receptive field data and simulations from a linear-nonlinear Poisson model to extrapolate decoding accuracy as a function of network size. We find that, on this dataset, reconstruction performance can increase by more than 50%, provided that the receptive fields are sampled more uniformly in the full visual field. These results provide practical experimental guidelines to boost the accuracy of full-stimulus reconstruction.

neuroscience↗

The Dance of the Interneurons: How Inhibition Facilitates Fast Compressible and Reversible Learning in Hippocampus

The hippocampus is capable of rapidly learning incoming information, even if that information is only observed once. Further, this information can be replayed in a compressed format in either forward or reversed modes during Sharp Wave Ripples (SPW-R). We leveraged state-of-the-art techniques in training recurrent spiking networks to demonstrate how primarily inhibitory networks of neurons in CA3 and CA1 can: 1) generate internal theta sequences or \"time-cells\" to bind externally elicited spikes in the presence of septal inhibition, 2) reversibly compress the learned representation in the form of a SPW-R when septal inhibition is removed, 3) generate and refine gamma-assemblies during SPW-R mediated compression, and 4) regulate the inter-ripple-interval timing between SPW-Rs in ripple clusters. From the fast time scale of neurons to the slow time scale of behaviors, inhibitory networks serve as the scaffolding for one-shot learning by replaying, reversing, refining, and regulating spike sequences.

neuroscience↗