CBBS Paper of the year 2025
Can humans learn new motor skills during pauses lasting only a few seconds?
Learning enables us to acquire new skills throughout life, from everyday actions to highly skilled behaviours. It is also the foundation of rehabilitation after injury and many therapeutic interventions for neurological and psychiatric disorders. It is therefore not surprising that a recent hypothesis proposing that newly learned motor skills can be consolidated within seconds during brief pauses has had a major impact on the field.
The hypothesis is based on the observation that people often perform sequences of finger movements better immediately after a training break lasting only a few seconds than they did just before it. This phenomenon, known as micro-offline gains, has been interpreted as evidence that the brain continues learning during the pause through rapid hippocampal replay - the automatic reactivation of the neural activity associated with the newly learned skill.
In our study, we tested this influential idea through seven behavioural experiments involving more than 600 participants. We demonstrate that the the phenomenon on which this hypothesis is based, i.e., the improvement in performance from the end of one practice period to the beginning of the next, does not reflect genuine learning. Instead, the apparent improvement (1) is a transient recovery in performance rather than a gain in skill, (2) occurs even for random movement sequences that cannot be learned, showing that it is inconsistent with sequence-specific replay as its explanation, and (3) is explained, at least in part, by motor planning before movement resumes.
By challenging a central assumption in motor learning research, our findings call for a reassessment of how early motor skill acquisition is understood and caution against interpreting micro-offline gains as a behavioural marker of hippocampal replay or rapid memory consolidation.
PMID: 41150724
Winning publication in the field of human research: Das, Karagiorgis, Diedrichsen, Stenner, Azañón, PNAS, PMID: 41150724
Winning publication in the field of animal research: Oelschlegel , Pöpplau, Ryzynski, Hradsky, Reddy, Navarro, Reyes-Resina, Yuanxiang, Sosulina, Kaneko, Sahu, Günther, Andres-Alonso, Lopez-Rojas, Aly, Bauer, Mikulovic, Xia, Mikhaylova , Remy, Hanganu-Opatz, Karpova, Kreutz, Neuron, PMID: 41412129
Elevated calneuron-1, an accessory subunit of muscarinic receptors, induces frontotemporal dysconnectivity and schizophrenia-like deficits
Numerous studies have shown that genetic factors substantially increase the risk of developing schizophrenia; however, the underlying biological processes that cause the disorder remain poorly understood. Through our mechanistic study, we sought to understand how relatively subtle molecular alterations can give rise to this complex and severe psychiatric disease. We identify a molecular mechanism that may contribute to the core features of schizophrenia. Calneuron-1 is a Ca²⁺ sensor protein that has been linked to schizophrenia in several genome-wide association studies, yet the underlying mechanism remained unknown.
We demonstrate that Calneuron-1 expression is elevated in the dorsolateral prefrontal cortex (PFC) of patients with schizophrenia and that increased Calneuron-1 levels induce schizophrenia-like behavioral phenotypes in mice. At the cellular level, Calneuron-1 modulates M1 muscarinic receptor-dependent long-term depression (LTD), a form of synaptic plasticity associated with impaired sensory gating in psychosis. We show that Calneuron-1 functions as a receptor-associated subunit: it binds to the M1 receptor and traffics with it to the plasma membrane, where elevated intracellular Ca²⁺ levels enable Calneuron-1 to interrupt G-protein signaling. Increased Calneuron-1 expression shifts the excitation-inhibition balance toward excitation and disrupts functional coupling between the hippocampus and prefrontal cortex, particularly within the theta-frequency range.
Thus, the frontotemporal dysconnectivity induced by Calneuron-1 recapitulates key aspects of schizophrenia pathology. Importantly, the M1 receptor agonist Xanomeline disrupts the interaction between M1 receptors and Calneuron-1 and restores normal synaptic plasticity. Our findings provide a mechanistic explanation for the therapeutic efficacy of KarXT (xanomeline-trospium), a recently approved antipsychotic treatment for schizophrenia, and underscore the clinical relevance of the identified pathogenic mechanism.
PMID: 41412129