Neuromodulatory control of cortical function: Cell-type-specific regulation of neuronal information transfer

Neuromodulatory systems such as dopamine and acetylcholine enable cortical circuits to rapidly shift between behavioral states, yet it remains unclear how receptor-specific signaling reshapes what single neurons compute. Here, we combined whole-cell recordings from excitatory and inhibitory neurons in layer 2/3 of mouse somatosensory cortex with information-theoretic analyses under frozen-noise stimulation. We quantified stimulus-to-spike information transfer and profiled each neuron across four functional domains: passive membrane biophysics, action potential dynamics, intrinsic adaptation currents, and input feature selectivity captured by spike-triggered averages. Activation of D1, D2, or M1 receptors revealed three main findings. First, neuromodulators altered fractional information and firing output in a cell-type- and receptor-specific manner, demonstrating selective regulation of encoding. Second, unsupervised clustering based on functional attribute sets showed that receptor activation reorganizes baseline functional grouping, consistent with a dynamic computational phenotype. Third, multiset correlation and factor analysis revealed that neuromodulation systematically reorganizes covariance among functional domains. In excitatory neurons, dopaminergic activation decreased coordination between input feature selectivity and other functional properties while strengthening coordination among response-based features such as spike dynamics and adaptation. Inhibitory neurons, by contrast, generally exhibited increased coordination across domains. In unison, these findings identify neuromodulation as a reconfiguration signal that reshapes not only individual cellular properties, but also the statistical architecture linking them across the recorded cohort, thereby revealing a higher-dimensional mode of single-neuron regulatory control in the cortex.