Diverse cortical layer 1 circuits for auditory perception and plasticity

The ability to learn and adapt in a changing sensory environment requires the brain to flexibly integrate external stimuli with internal state and contextual information. In auditory cortex (ACtx), this integration occurs within specialized microcircuits in layer 1 (L1), a sparse but strategically connected layer that receives both ascending thalamic input and neuromodulatory signals linked to arousal, movement, and reward. L1 is populated by diverse subtypes of inhibitory interneurons (L1-INs) that regulate cortical excitability and plasticity. Using retrograde tracing, in vitro electrophysiology, and in vivo two-photon imaging in mouse ACtx, we uncover unexpected features of L1-IN connectivity and function. Most thalamic input to L1-INs arises from the ventral division of the medial geniculate body (MGBv), and distinct neuromodulatory pathways recruit specific L1-IN subtypes. These interneurons form local networks that shape sound-evoked activity, modulated by state and circuit dynamics. In turn, L1-INs influence deeper-layer neurons through release of diverse neurotransmitters and neuropeptides. Vasoactive intestinal peptide (VIP) emerges as a modulator of plasticity, released during learning to induce long-term potentiation at thalamocortical synapses. Ongoing work uses precision optogenetics to define how small L1-IN ensembles influence cortical activity and behavior. Together, this research reveals how distinct L1 circuits contribute to adaptive auditory plasticity.