Tuft dendrites in frontal motor cortex enable flexible learning.
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| Title: | Tuft dendrites in frontal motor cortex enable flexible learning. |
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| Authors: | Maristany de las Casas, Eduardo (AUTHOR), Killmann, Kris (AUTHOR), Drüke, Moritz (AUTHOR), Münster, Lukas (AUTHOR), Ebner, Christian (AUTHOR), Sachdev, Robert (AUTHOR), Jaeger, Dieter (AUTHOR), Larkum, Matthew E. (AUTHOR) |
| Source: | Science. 5/7/2026, Vol. 392 Issue 6798, p1-11. 11p. |
| Subjects: | Dendrites, Intracellular calcium, Interneurons, Cognitive flexibility, Pyramidal neurons, Motor cortex |
| Abstract: | Flexible learning relies on integrating sensory and contextual information to adjust behavioral output in different environments. The anterolateral motor cortex (ALM) is a frontal area critical for action selection in rodents. We found that inputs critical to decision-making converge on the apical tuft dendrites of layer 5b pyramidal neurons in ALM. We therefore investigated the role of these dendrites in a rule-switching paradigm. Activation of dendrite-inhibiting layer 1 interneurons impaired relearning, without affecting previously learned behavior. This inhibition profoundly suppressed global calcium activity in dendritic shafts but not local transients in spines, while additionally reducing burst firing. Moreover, excitatory synaptic inputs to tuft dendrites exhibited rule-dependent clustering. We conclude that dendritic calcium signaling is a key computational component of flexible learning. Editor's summary: Flexible adaptive behavior is a hallmark of intelligent systems and requires continuous integration of sensory information and the ability to optimize motor plans in a context-dependent manner. Maristany de las Casas et al. investigated the neuronal mechanisms underlying flexible learning in the mouse anterolateral motor cortex. They used a rule-switching exercise from complex to simple and back to complex tasks. Nonlinear dendritic events were essential for relearning in these tasks. Active dendritic integration is thus a potential mechanism enabling the brain to solve the cognitive challenges posed by adaptive behavior. —Peter Stern INTRODUCTION: The ability to flexibly adapt behavior in changing environments is a hallmark of intelligence, yet the neural mechanisms underlying this capability remain poorly understood. In the mammalian brain, pyramidal neurons (the primary excitatory cells of the cerebral cortex) possess elaborate dendritic trees that extend far from the cell body. These dendrites have two main compartments, corresponding to the main dendritic arborizations (the basal and apical tuft dendrites). The basal compartment is thought to receive feature-specific information (e.g., sensory features in sensory cortex), whereas the apical tuft compartment receives contextual information (e.g., information from an internal source). Although neurons are often modeled as simple integrators that sum their inputs, emerging evidence, including this study, suggests that dendrites can perform complex computations through active electrical properties, potentially enabling sophisticated learning capabilities. RATIONALE: We hypothesized that dendritic computations in frontal motor areas contribute to flexible behavioral adaptation. Apical dendrites of layer 5 pyramidal neurons in the anterolateral motor cortex (ALM) in mice receive convergent inputs from sensory and motor-planning regions. These dendrites can generate calcium-dependent electrical events that may serve as a substrate for learning. To test this hypothesis, we developed a behavioral paradigm where mice must flexibly switch between different stimulus-response rules, allowing us to dissociate task execution from the cognitive demands of relearning. We focused on a specific population of inhibitory neurons [NDNF (neuron-derived neurotrophic factor) interneurons] that selectively target the apical dendrites, providing the means to manipulate dendritic activity. RESULTS: Using a combination of behavioral testing, optical recordings, and targeted neural manipulations, we discovered that calcium activity in the apical tuft dendrite is selectively required for relearning complex, but not simple, behavioral rules. When mice performed our rule-switching task, activating dendrite-inhibiting NDNF interneurons impaired their ability to relearn the complex rule after exposure to the simpler one, while leaving performance of already-learned behaviors unchanged. Two-photon (2P) calcium imaging and electrophysiological recordings revealed that this manipulation abolished global calcium events throughout the dendritic tree while preserving local synaptic activity and only moderately affecting somatic action potentials. Imaging of synaptic inputs to dendrites revealed that they organize into functional clusters during complex rule performance—a spatial arrangement that dissolved during simple rule execution. Notably, the NDNF interneurons themselves reduced their activity specifically when mice made errors during rule switching (and initial learning), suggesting that they gate dendritic plasticity. CONCLUSION: Our findings reveal that calcium signaling in dendritic tufts serves as a critical computational resource for flexible learning. This work establishes that cortical circuits can selectively engage active dendritic computation on the basis of cognitive demands, with inhibitory control providing dynamic gating of these processes during learning. These mechanisms may explain how the brain maintains stable behaviors while retaining the capacity for rapid adaptation, with implications for understanding cognitive flexibility disorders and developing therapeutic interventions. More broadly, our results suggest that the elaborate dendritic trees of pyramidal neurons are not merely passive conduits but active computational units essential for flexible behavior. Flexible learning is dependent on apical dendritic calcium activity.: Mice were trained to transition between a complex task (rule A) and a simple task (rule B). Activation of layer 1 (L1) NDNF interneurons blocked relearning of complex, but not simpler, tasks through the suppression of calcium throughout the apical tuft but not locally in spines. Functional clustering of synapses was associated with task complexity. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Flexible learning relies on integrating sensory and contextual information to adjust behavioral output in different environments. The anterolateral motor cortex (ALM) is a frontal area critical for action selection in rodents. We found that inputs critical to decision-making converge on the apical tuft dendrites of layer 5b pyramidal neurons in ALM. We therefore investigated the role of these dendrites in a rule-switching paradigm. Activation of dendrite-inhibiting layer 1 interneurons impaired relearning, without affecting previously learned behavior. This inhibition profoundly suppressed global calcium activity in dendritic shafts but not local transients in spines, while additionally reducing burst firing. Moreover, excitatory synaptic inputs to tuft dendrites exhibited rule-dependent clustering. We conclude that dendritic calcium signaling is a key computational component of flexible learning. Editor's summary: Flexible adaptive behavior is a hallmark of intelligent systems and requires continuous integration of sensory information and the ability to optimize motor plans in a context-dependent manner. Maristany de las Casas et al. investigated the neuronal mechanisms underlying flexible learning in the mouse anterolateral motor cortex. They used a rule-switching exercise from complex to simple and back to complex tasks. Nonlinear dendritic events were essential for relearning in these tasks. Active dendritic integration is thus a potential mechanism enabling the brain to solve the cognitive challenges posed by adaptive behavior. —Peter Stern INTRODUCTION: The ability to flexibly adapt behavior in changing environments is a hallmark of intelligence, yet the neural mechanisms underlying this capability remain poorly understood. In the mammalian brain, pyramidal neurons (the primary excitatory cells of the cerebral cortex) possess elaborate dendritic trees that extend far from the cell body. These dendrites have two main compartments, corresponding to the main dendritic arborizations (the basal and apical tuft dendrites). The basal compartment is thought to receive feature-specific information (e.g., sensory features in sensory cortex), whereas the apical tuft compartment receives contextual information (e.g., information from an internal source). Although neurons are often modeled as simple integrators that sum their inputs, emerging evidence, including this study, suggests that dendrites can perform complex computations through active electrical properties, potentially enabling sophisticated learning capabilities. RATIONALE: We hypothesized that dendritic computations in frontal motor areas contribute to flexible behavioral adaptation. Apical dendrites of layer 5 pyramidal neurons in the anterolateral motor cortex (ALM) in mice receive convergent inputs from sensory and motor-planning regions. These dendrites can generate calcium-dependent electrical events that may serve as a substrate for learning. To test this hypothesis, we developed a behavioral paradigm where mice must flexibly switch between different stimulus-response rules, allowing us to dissociate task execution from the cognitive demands of relearning. We focused on a specific population of inhibitory neurons [NDNF (neuron-derived neurotrophic factor) interneurons] that selectively target the apical dendrites, providing the means to manipulate dendritic activity. RESULTS: Using a combination of behavioral testing, optical recordings, and targeted neural manipulations, we discovered that calcium activity in the apical tuft dendrite is selectively required for relearning complex, but not simple, behavioral rules. When mice performed our rule-switching task, activating dendrite-inhibiting NDNF interneurons impaired their ability to relearn the complex rule after exposure to the simpler one, while leaving performance of already-learned behaviors unchanged. Two-photon (2P) calcium imaging and electrophysiological recordings revealed that this manipulation abolished global calcium events throughout the dendritic tree while preserving local synaptic activity and only moderately affecting somatic action potentials. Imaging of synaptic inputs to dendrites revealed that they organize into functional clusters during complex rule performance—a spatial arrangement that dissolved during simple rule execution. Notably, the NDNF interneurons themselves reduced their activity specifically when mice made errors during rule switching (and initial learning), suggesting that they gate dendritic plasticity. CONCLUSION: Our findings reveal that calcium signaling in dendritic tufts serves as a critical computational resource for flexible learning. This work establishes that cortical circuits can selectively engage active dendritic computation on the basis of cognitive demands, with inhibitory control providing dynamic gating of these processes during learning. These mechanisms may explain how the brain maintains stable behaviors while retaining the capacity for rapid adaptation, with implications for understanding cognitive flexibility disorders and developing therapeutic interventions. More broadly, our results suggest that the elaborate dendritic trees of pyramidal neurons are not merely passive conduits but active computational units essential for flexible behavior. Flexible learning is dependent on apical dendritic calcium activity.: Mice were trained to transition between a complex task (rule A) and a simple task (rule B). Activation of layer 1 (L1) NDNF interneurons blocked relearning of complex, but not simpler, tasks through the suppression of calcium throughout the apical tuft but not locally in spines. Functional clustering of synapses was associated with task complexity. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adx4358 |
