Phenotypic variation of transcriptomic cell types in mouse motor cortex.

Cortical neurons exhibit extreme diversity in gene expression as well as in morphological and electrophysiological properties1,2. Most existing neural taxonomies are based on either transcriptomic3,4 or morpho-electric5,6 criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells7. Here we used Patch-seq8 to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of more than 1,300 neurons in adult mouse primary motor cortex, providing a morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (those expressing Vip, Pvalb, Sst and so on) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neuronal types in the neocortex do not always form discrete entities. Instead, neurons form a hierarchy that consists of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.

Real-Time Machine Learning Strategies for a New Kind of Neuroscience Experiments.

Function and dysfunctions of neural systems are tied to the temporal evolution of neural states. The current limitations in showing their causal role stem largely from the absence of tools capable of probing the brain's internal state in real-time. This gap restricts the scope of experiments vital for advancing both fundamental and clinical neuroscience. Recent advances in real-time machine learning technologies, particularly in analyzing neural time series as nonlinear stochastic dynamical systems, are beginning to bridge this gap. These technologies enable immediate interpretation of and interaction with neural systems, offering new insights into neural computation. However, several significant challenges remain. Issues such as slow convergence rates, high-dimensional data complexities, structured noise, non-identifiability, and a general lack of inductive biases tailored for neural dynamics are key hurdles. Overcoming these challenges is crucial for the full realization of real-time neural data analysis for the causal investigation of neural computation and advanced perturbation based brain machine interfaces. In this paper, we provide a comprehensive perspective on the current state of the field, focusing on these persistent issues and outlining potential paths forward. We emphasize the importance of large-scale integrative neuroscience initiatives and the role of meta-learning in overcoming these challenges. These approaches represent promising research directions that could redefine the landscape of neuroscience experiments and brain-machine interfaces, facilitating breakthroughs in understanding brain function, and treatment of neurological disorders.

Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas.

Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking interneurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ interneurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are used across the cortex as building blocks to assemble cortical circuits.

Author Correction: Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.