Worthy, A. E. | Search bioRxiv

bioRxiv2026

Synchrony within Aβ mechanoreceptor subtypes governs signal propagation to primary somatosensory cortex

Fast-conducting A{beta} slowly adapting type I low threshold mechanoreceptors (SAI-LTMRs) and A{beta} rapidly adapting type I (RAI-) LTMRs are critical for discriminative touch from glabrous skin. Recent studies used mouse genetic loss-of-function and optogenetic gain-of-function manipulations to determine that signals from these A{beta} LTMRs are integrated subcortically to build the cortical representation of touch. However, the precise influence of each subtype on downstream responses is unclear, in part because previous manipulations lacked the capacity to reproduce physiological firing patterns in individual A{beta} LTMR subtypes. Here, we took advantage of a fast variant of channelrhodopsin, CatCh, which enabled us to generate physiological spiking rates and patterns in either subtype while monitoring responses in mouse primary somatosensory cortex (S1). Doing so revealed that propagation of steady-state signals from sustained responses of A{beta} SAI-LTMRs to neural activity (spiking and local field potential) in S1 is dependent on synchronous activation of multiple A{beta} SAI-LTMRs. Asynchronous activation of the same A{beta} SAI-LTMRs rarely produced sustained responses in S1 measured at the level of single unit spiking as well as local field potentials. This suggests that the irregular firing patterns of A{beta} SAI-LTMRs during static indentations contribute to the preponderance of transient cortical responses. By contrast, both synchronous and asynchronous activation of multiple A{beta} RAI-LTMRs resulted in robust S1 responses. Overall, the temporal patterning and synchrony of activity within A{beta} LTMR subtypes govern how well their signals propagate through the ascending somatosensory system. Key PointsO_LICatCh, a sensitive and fast channelrhodopsin variant, enables pulsed-light generation of physiological spiking patterns in A{beta} low threshold mechanoreceptor (LTMR) subtypes. C_LIO_LIThe synchrony of multiple mechanoreceptors within a subtype controls the extent to which their signals influence activity in primary somatosensory cortex. C_LIO_LIA{beta} rapidly adapting type I (RAI-) LTMRs drive stronger cortical responses than A{beta} slowly adapting type I (SAI-) LTMRs, especially when considering asynchronous activation of A{beta} LTMRs within each subtype. C_LI

neuroscience↗

bioRxiv2023

SPINAL V1 INHIBITORY INTERNEURON CLADES DIFFER IN BIRTHDATE, PROJECTIONS TO MOTONEURONS AND HETEROGENEITY

Spinal cord interneurons play critical roles shaping motor output, but their precise identity and connectivity remain unclear. Focusing on the V1 interneuron cardinal class we defined four major V1 subsets according to neurogenesis timing, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Birthdate delineates two early born (Renshaw and Pou6f2) and two late born (Foxp2 and Sp8) V1 clades, showing that sequential neurogenesis produces different V1 subsets. Early born Renshaw cells and late born Foxp2-V1 interneurons are tightly coupled to motoneurons, while early born Pou6f2-V1 and late born Sp8-V1 interneurons are not, indicating that timing of neurogenesis does not correlate with motoneuron targeting. V1 clades also differ in cell numbers and diversity. Lineage labeling shows that the Foxp2-V1 clade contains over half of all V1 interneurons, provides the largest inhibitory input to motoneuron cell bodies and includes subgroups that differ in birthdate, location, and proprioceptive input. Notably, one Foxp2-V1 subgroup, defined by postnatal Otp expression is positioned near the lateral motor column and receives substantial input from proprioceptors, consistent with an involvement in reciprocal inhibitory pathways. Combined tracing of ankle flexor sensory afferents and interneurons monosynaptically connected to ankle extensors confirmed placement of Foxp2-V1 interneurons in reciprocal inhibitory pathways. Our results validate previously proposed V1 clades as unique functional subtypes that differ in circuit placement, with Foxp2-V1 cells forming the most heterogeneous subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for their diverse ontogenetic and phylogenetic origins. SIGNIFICANCE STATEMENTThe complexity of spinal interneuron diversity and circuit organization represents a challenge to understand neural control of movement in normal adults as well as during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn, and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits, and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion. This increased diversity is reflected in the size and heterogeneity of the Foxp2-V1 clade, a group closely associated with limb motor pools. We show that Foxp2-V1 interneurons establish the densest direct inhibitory input to motoneurons, especially on cell bodies. These findings are particularly significant because recent studies have shown that motor neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) affect inhibitory V1 synapses on motoneuron cell bodies and Foxp2-V1 interneurons themselves in the earliest stages of pathology.

neuroscience↗