Neuroscience seminars

Many everyday decisions are based on both external cues and internal hunches. How does the brain put these together? We addressed this question in mice trained to make decisions based on sensory stimuli and on past events. While mice made these decisions, we causally probed the roles of cortical areas and recorded from thousands of neurons throughout the brain, with an emphasis on frontal cortex. The results are not what we thought based on textbook notions of how the brain works. This talk is based on work led by Nick Steinmetz, Peter Zatka-Haas, Armin Lak, and Pip Coen, in the laboratory I share with Kenneth Harris

Migraine is much more than an episodic headache. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing and integration. In a third of patients, the headache is preceded by transient sensory disturbances (aura), whose neurophysiological correlate is cortical spreading depression (CSD). The molecular, cellular and circuit mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. Genetic mouse models of a rare monogenic form of migraine with aura provide a unique experimental system to tackle these key unanswered questions. I will describe the functional alterations we have uncovered in the cerebral cortex of genetic mouse models and discuss the insights into the cellular and circuit mechanisms of migraine obtained from these findings.

The question of how syntactic structure can be built at the neural level has come to the forefront of cognitive neuroscience in the last decade. Neural oscillations have been widely recognised as playing an important role in building syntactic representations. In this talk I will review existing oscillatory approaches to syntactic structure building and assess their functionality in light of basic properties of a hierarchical syntactic structure, such as varied length of syntactic phrases, nesting of constituents, overlap in length between different levels of the syntactic hierarchy and others. I will also briefly discuss key requirements on neural structure building mechanisms from the perspective of a real-time parser.

Neural responses are variable: even under identical experimental conditions, single neuron and population responses typically differ from trial to trial and across time. Recent work has demonstrated that this variability has predictable structure, can be modulated by sensory input and behaviour, and bears critical signatures of the underlying network dynamics and computations. However, current methods for characterising neural variability are primarily geared towards sensory coding in the laboratory: they require trials with repeatable experimental stimuli and behavioural covariates. In addition, they make strong assumptions about the parametric form of variability, rely on assumption-free but data-inefficient histogram-based approaches, or are altogether ill-suited for capturing variability modulation by covariates. Here we present a universal probabilistic spike count model that eliminates these shortcomings. Our method uses scalable Bayesian machine learning techniques to model arbitrary spike count distributions (SCDs) with flexible dependence on observed as well as latent covariates. Without requiring repeatable trials, it can flexibly capture covariate-dependent joint SCDs, and provide interpretable latent causes underlying the statistical dependencies between neurons. We apply the model to recordings from a canonical non-sensory neural population: head direction cells in the mouse. We find that variability in these cells defies a simple parametric relationship with mean spike count as assumed in standard models, its modulation by external covariates can be comparably strong to that of the mean firing rate, and slow low-dimensional latent factors explain away neural correlations. Our approach paves the way to understanding the mechanisms and computations underlying neural variability under naturalistic conditions, beyond the realm of sensory coding with repeatable stimuli.

Establishment of precise neuronal connectivity in the neocortex relies on activity-dependent circuit reorganization during postnatal development. In the mouse somatosensory cortex layer 4, barrels are arranged in one-to-one correspondence to whiskers on the face. Thalamocortical axon termini are clustered in the center of each barrel. The layer 4 spiny stellate neurons are located around the barrel edge, extend their dendrites primarily toward the barrel center, and make synapses with thalamocortical axons corresponding to a single whisker. These organized circuits are established during the first postnatal week through activity-dependent refinement processes. However, activity pattern regulating the circuit formation is still elusive. Using two-photon calcium imaging in living neonatal mice, we found that layer 4 neurons within the same barrel fire synchronously in the absence of peripheral stimulation, creating a ''patchwork'' pattern of spontaneous activity corresponding to the barrel map. We also found that disruption of GluN1, an obligatory subunit of the N-methyl-D-aspartate (NMDA) receptor, in a sparse population of layer 4 neurons reduced activity correlation between GluN1 knockout neuron pairs within a barrel. Our results provide evidence for the involvement of layer 4 neuron NMDA receptors in spatial organization of the spontaneous firing activity of layer 4 neurons in the neonatal barrel cortex. In the talk I will introduce our strategy to analyze the role of NMDA receptor-dependent correlated activity in the layer 4 circuit formation.

The Miniscope Project -- an open-source collaborative effort—was created to accelerate innovation of miniature microscope technology and to increase global access to this technology. Currently, we are working on advancements ranging from optogenetic stimulation and wire-free operation to simultaneous optical and electrophysiological recording. Using these systems, we have uncovered mechanisms underlying temporal memory linking and investigated causes of cognitive deficits in temporal lobe epilepsy. Through innovation and optimization, this work aims to extend the reach of neuroscience research and create new avenues of scientific inquiry.

Large-scale neural recordings contain high-dimensional structure that cannot be easily captured by existing data visualization methods. We therefore developed an embedding algorithm called Rastermap, which captures highly nonlinear relationships between neurons, and provides useful visualizations by assigning each neuron to a location in the embedding space. Compared to standard algorithms such as t-SNE and UMAP, Rastermap finds finer and higher dimensional patterns of neural variability, as measured by quantitative benchmarks. We applied Rastermap to a variety of datasets, including spontaneous neural activity, neural activity during a virtual reality task, widefield neural imaging data during a 2AFC task, artificial neural activity from an agent playing atari games, and neural responses to visual textures. We found within these datasets unique subpopulations of neurons encoding abstract properties of the environment.

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

I will discuss the mechanisms that determine whether a weak visual stimulus will reach consciousness or not. If the stimulus is simple, early visual cortex acts as a relay station that sends the information to higher visual areas. If the stimulus arrives at a minimal strength, it will be stored in working memory and can be reported. However, during more complex visual perceptions, which for example depend on the segregation of a figure from the background, early visual cortex’ role goes beyond a simply relay. It now acts as a cognitive blackboard and conscious perception depends on it. Our results inspire new approaches to create a visual prosthesis for the blind, by creating a direct interface with the visual brain. I will discuss how high-channel-number interfaces with the visual cortex might be used to restore a rudimentary form of vision in blind individuals.

On behalf of NeurotechEU, we are pleased to invite you to participate in the Summit 2021 pre-selection event on October 23, 2021. The event will be held online via the Platform Crowdcast.io, and it is going to be organized by NeurotechEU-The European University of Brain and Technology. Students from all over NeurotechEU have the chance to present their research (bachelor’s thesis, Master’s thesis, PhD, post-doc…) following the methodology of three minutes thesis (3MT from the University of Queensland): https://threeminutethesis.uq.edu.au/resources/3mt-competitor-guide. There will be one session per university and at the end of it, two semi-finalists will be selected from each university. They will compete in the Summit 2021 on November 22nd. There will be prizes for the winners who will be selected by voting of the audience.

In this talk he will present current work in progress on “irruption theory”, a new theory of consciousness that integrates an embodied-enactive account of basic mind with radical formulations of the freedom and efficacy of intentional agency.