The Secondary Motor Cortex Encodes Aversive Signals and Exerts an Inhibitory Control of Motor Sequence Learning in...

The secondary motor cortex (M2) is engaged in behavioral planning, movement preparation, and the execution of complex motor sequences in a specific order. However, the nature of neuronal signals encoded by M2 neurons (i.e., reward or aversive) and their behavioral effects on motor sequence learning remain unclear. This study aimed to elucidate the nature of these signals and their regulatory roles in motor behavior.

We combined in vivo fiber photometry with optogenetics in mice undergoing conditioning paradigms and motor sequence learning tasks. Calcium signals were recorded from general M2 neurons, PV⁺ interneurons, and VgluT2⁺ projection neurons in response to reward (sucrose) and aversive (foot-shock, LiCl) stimuli. Furthermore, M2 neurons were optogenetically activated during reward delivery in the motor sequence learning task. The behavioral outcomes were further dissected using progressive ratio and open-field tests to distinguish between motivational and direct motor effects.

M2 neurons, including PV⁺ and VgluT2⁺ subpopulations, consistently encoded aversive signals, exhibiting negative responses to rewards and positive responses to aversive stimuli. Crucially, optogenetic activation of M2 neurons during reward delivery significantly suppressed the initiation and execution of motor sequences. This behavioral impairment was driven by a reduction in motivational vigor, indicated by decreased lever pressing and a lower break point in the progressive ratio test.

M2 neurons encode aversive signals that functionally devalue rewards, thereby reducing motivation and inhibiting motor sequence learning. These results identify M2 as a critical node in neural circuits that adaptively gates motor output based on negative motivational valence.