Moberg, S. | Search bioRxiv

bioRxiv2026

Thalamic input drives co-timed excitation and inhibition to suppress cortical neuronal variability during movement initiation

Cortical activity is inherently dynamic, with ongoing fluctuations introducing variability into sensory-to-motor transformations. During movement initiation, neural variability in the motor cortex is sharply reduced, or "quenched," a general phenomenon thought to ensure reliable population responses across cortical areas. However, the synaptic and circuit-level basis for this reduction in neural variability remains unclear. Here, we show that excitatory and inhibitory neurons in layer 5B of mouse motor cortex are co-activated during movement initiation in a cued forelimb push task. Co-timed excitation and inhibition drive pyramidal neuron membrane potential (Vm) trajectories towards the compound synaptic reversal potential, stabilizing the Vm and reducing trial-by-trial variability. Gain- and loss-of-function experiments demonstrate that thalamocortical input is critical for the coordinated recruitment of both excitation and inhibition and variability quenching at the cellular level, while also driving a cortical network state permissive for the expression of reproducible output dynamics. Our findings uncover a simple yet fundamental feedforward mechanism where thalamic input drives neural variability quenching to ensure reliable, structured population dynamics during movement initiation.

neuroscience↗

bioRxiv2025

Distinct roles of cortical layer 5 subtypes in associative learning

Adaptive behavior is critically dependent on associative learning, where environmental cues are linked with subsequent positive or negative outcomes. In mammals, primary neocortical sensory areas serve as pivotal nodes in this process, processing stimuli and distributing information to cortical and subcortical networks. Layer 5 (L5) of the cortex comprises two types of pyramidal projection neurons--intratelencephalic (IT) and extratelencephalic (ET) neurons--each with distinct downstream targets. Despite the crucial function of L5 as a main output node of the cortex, the specific contributions of these L5 neuronal subtypes to associative learning remain poorly understood. In the present study, by leveraging transgenic mouse lines, we distinguished IT and ET neurons in the primary somatosensory cortex and examined their roles in a whisker-based frequency-discrimination learning task. Longitudinal two-photon calcium imaging revealed distinct response characteristics between IT and ET neurons throughout learning. Interestingly, the activity of IT neurons hardly changed over the five days of learning, while the activity of ET neurons developed robustly. Furthermore, IT neurons appeared to show stimuli encoding from the beginning, whereas the ET neurons became increasingly responsive to stimuli associated with reward. Chemogenetic silencing of either IT or ET neurons both impaired learning, but in strikingly distinct ways, each associated with a different phase of learning. By modeling the response characteristics of IT and ET neurons using a reinforcement learning framework, we show that IT neurons primarily encode sensory stimuli, and their representations are critical for forming stimulus-reward associations. ET neurons instead represent the value of the stimulus, used for refining behavior. Thus, our results delineate the distinct roles of L5 IT and ET neurons, underscoring their integral and complementary contributions to associative learning.

neuroscience↗