Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex.

Summary

This is the foundational mechanism paper behind NEU-002. The auditory cortex normally only rewires its responses when a sound is paired with something behaviorally meaningful, not from sound alone. This study found that cholecystokinin (CCK), released onto the auditory cortex by projection neurons from the nearby entorhinal cortex, is the missing signal that permits that rewiring: infusing CCK directly onto the auditory cortex let neurons strengthen their responses to a paired tone and even start responding to tones they previously ignored, while blocking CCK receptors prevented these new associations from forming. It establishes CCK signaling as a switch that opens a window for auditory cortex plasticity, the same receptor pathway NEU-002 was later designed to target pharmacologically.

Key findings

• Entorhinal cortex projection neurons that reach the auditory cortex are predominantly cholecystokinin (CCK) positive.
• Local infusion of CCK onto the auditory cortex let neurons potentiate their responses to a paired tone and develop new responses to previously ineffective tones.
• Blocking CCK receptors prevented the formation of these new cross-sensory associations.
• Activating the entorhinal cortex directly boosted auditory cortex responses through a CCK-dependent pathway.