Biology subjects

Schmidt, E. R.

Publications and source records attributed to Schmidt, E. R..

3 recordsLinked to original sources

bioRxiv2026

A human-specific genetic modifier reconfigures large-scale cortical network dynamics underlying behavioral performance

Cortical expansion in the human lineage was accompanied by alterations in cortical circuit architecture, including an elaboration of cortico-cortical connectivity. Yet how these changes reshape network computation to support behavior remains poorly understood. Here we leverage a mouse model expressing SRGAP2C, a human-specific gene duplication that modifies cortical circuit development and increases cortico-cortical connectivity, to ask how this remodeled architecture shapes network dynamics during learning. As mice acquire expertise on a sensory discrimination task, SRGAP2C drives broader interhemispheric correlation, distributed task-relevant encoding, and enhanced directed influence from frontal and associative regions. Texture representations in primary sensory cortex become more separable during motor preparation, supporting improved discrimination under demanding conditions. These findings demonstrate that human-specific changes in cortical circuit architecture do not simply scale up but rather reconfigure the cortical dynamics that organize sensory-to-motor transformation in a manner that tracks behavioral performance under demanding conditions, linking genomic innovations in the Homo lineage to large-scale cortical network function.

neuroscience↗

bioRxiv2020

Deep and superficial layers of the primary somatosensory cortex are critical for whisker-based texture discrimination in mice

The neocortex, comprised of multiple distinct layers, processes sensory input from the periphery, makes decisions, and executes actions. Despite extensive investigation of cortical anatomy and physiology, the contributions of different cortical layers to sensory guided behaviors remain unknown. Here, we developed a two-alternative forced choice (2AFC) paradigm in which head-fixed mice use a single whisker to either discriminate textures of parametrically varied roughness or detect the same textured surfaces. Lesioning the barrel cortex revealed that 2AFC texture discrimination, but not detection, was cortex-dependent. Paralyzing the whisker pad had little effect on performance, demonstrating that passive can rival active perception and cortical dependence is not movement-related. Transgenic Cre lines were used to target inhibitory opsins to excitatory cortical neurons of specific layers for selective perturbations. Both deep and superficial layers were critical for texture discrimination. We conclude that even basic cortical computations require coordinated transformation of sensory information across layers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/245381v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@16c4d20org.highwire.dtl.DTLVardef@13b8832org.highwire.dtl.DTLVardef@16ac3aborg.highwire.dtl.DTLVardef@5426d8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Human-specific gene duplications (HSGD) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGD generated proteins that, in neurons, are intrinsically unstable and upon hetero-dimerization with SRGAP2A, reduces SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, compared to SRGAP2B, and despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique, compared to SRGAP2B, in its ability to induce long-lasting changes in synaptic density throughout adulthood. The non-synonymous mutations specifically targeting arginine residues led to the unique ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.

neuroscience↗