Orbitofrontal control of the olfactory cortex regulates olfactory discrimination learning.

Serving as an integral node for cognitive processing and value-based decision-making, the orbitofrontal cortex (OFC) plays a multifaceted role in associative learning and reward-driven behaviours through its widespread synaptic integration with both subcortical structures and sensory cortices. Despite the OFC's robust innervation of the olfactory cortex, the functional implications and underlying mechanisms of this top-down influence remain largely unexplored. In this study, we demonstrated that the OFC formed both direct excitatory and indirect inhibitory synaptic connections with pyramidal neurons in the anterior piriform cortex (aPC). OFC projection predominantly regulated spontaneous and odour-evoked excitatory activity in the aPC of awake mice. Importantly, suppression of this OFC-aPC projection disrupted olfactory discrimination learning, potentially due to a consequent decrease in the excitability of aPC principal output neurons following inhibition of this projection. Whole-cell recordings revealed that olfactory learning increased the intrinsic excitability of aPC neurons while concurrently decreasing OFC input to these neurons. These findings underscore the pivotal influence of orbitofrontal modulation over the olfactory cortex in the context of olfactory learning and provide insight into the associated neurophysiological mechanisms. KEY POINTS: The orbitofrontal cortex (OFC) densely innervates the anterior piriform cortex (aPC) through direct excitatory synaptic connections. The OFC regulates both spontaneous and odour-evoked excitatory activities in the aPC of awake mice. Inhibition of OFC projections disrupts olfactory discrimination learning, probably due to reduced excitability of aPC main output neurons. Following olfactory learning, the intrinsic excitability of aPC neurons increases while the OFC-aPC input decreases, highlighting the importance of adaptable OFC input for olfactory learning. These results provide new perspectives on how the OFC's top-down control modulates sensory integration and associative learning.