Progressive engagement of SST+ interneurons via Elfn1 regulates the barrel-septa response identity in the somatosensory cortex of mice

Abstract

Just as separated digits and repeated sampling enhance somatosensation in humans, mice sense objects through multiple segregated whiskers through successive contacts. Individual whisker identity is maintained through the somatotopic organization of the Whisker[->]Brainstem[->]Thalamus[->]Cortex axis, culminating in distinct cortical domains: barrels and the surrounding septa. By performing simultaneous recordings using in-vivo electrophysiology in wild-type (WT) mice, we identify a progressive divergence in spiking activity between these domains upon repeated behaviorally relevant (10Hz) single- and multi-whisker stimulation. While the spiking activity ratio of multi- to single-whisker stimulation remains stable in barrels, it increases progressively in septa, suggesting inhibitory cell recruitment. Using genetic fate-mapping and tissue clearing, we indeed reveal that SST+ and VIP+ interneurons exhibit distinct laminar and regional distributions in barrel and septa domains. Further, calcium imaging of SST+ and VIP+ interneurons shows that while both neuron types respond to single-whisker stimulus, SST+ interneurons preferentially engage more in 10Hz multi-whisker stimulation, indicating their critical role in progressive stimulus preference. Genetic removal of Elfn1, which regulates the incoming excitatory synaptic dynamics onto SST+ interneurons, leads to the loss of the progressive increase in septal spiking ratio (MWS/SWS) upon stimulation. The importance of the loss of functional segregation of barrels, versus septa is revealed by cumulative temporal decoding analysis, supporting the notion that SST+ interneuron-mediated inhibition contributes to temporal encoding and stimulus integration. Finally, viral tracing combined with whole brain clearing and imaging reveals that barrel and septa domains project differentially to secondary somatosensory (S2) and motor (M1) cortices. These distinct projection patterns suggest that differential inhibitory processing in barrels and septa may contribute to functionally specialized downstream signaling. Together, our findings indicate that the progressive engagement of SST+ interneurons, mediated by Elfn1-dependent synaptic facilitation, underlies the preferential integration of multi-whisker stimuli in septa. This local inhibitory mechanism likely contributes to the functional segregation of barrel and septa domains and their distinct cortical projections, shaping how sensory information is processed and relayed to higher-order brain regions.