An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour

Cortical layer 6 neurons are the only projection neuron population in the cortical mantle known to electrophysiologically respond to orexin—a neuropeptide involved in cortical arousal and emotive behaviour. These neurons exhibit extensive intercortical and thalamic projections, yet the exact mechanisms underlying these responses are not fully understood. We hypothesize that cortical circuits activated by orexin sensitive L6 neurons in the medial prefrontal cortex (mPFC) are responsible for detecting salient features of sensory stimuli and are therefore involved in regulating emotional states. Here, we show that Drd1a-Cre+ neurons in the mPFC are selectively sensitive to orexin and gate the activation of the prefrontal network in vivo. Moreover, we demonstrated that chronically “silencing” this subpopulation of L6 neurons (Drd1a-Cre+/+:Snap25fl/fl) across the cortical mantle from birth abolishes the orexin-induced prefrontal activation. Consequently, the chronic silencing of these neurons had strong anxiolytic effects on several anxiety-related behavioural paradigms, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.