Complex motor behaviors, such as reaching for objects and bringing them to the mouth, rely on the integration of multiple cortical and subcortical brain regions. The research team, led by Li, An, Mulcahey, and colleagues, employed an innovative combination of wide-field calcium imaging and targeted photoinhibition techniques to map activity patterns across the mouse cortex during a reach-and-withdraw-to-drink (RWD) task. This ethologically relevant behavior mimics a natural sequence where mice extend their forelimb toward a spout, grasp the liquid source, and withdraw it toward the mouth for drinking, thereby engaging both forelimb and orofacial motor systems.

Wide-field imaging revealed a distributed cortical network dynamically engaged throughout the RWD behavior, highlighting a central area within the secondary motor cortex (MOs-c) as a key node. This region emerges as a high-order motor control hub where signals related to action progression converge. Targeting the MOs-c with photoinhibition selectively impaired components of the reach-to-consume sequence, affirming its essential role in finely tuned motor coordination. Such manipulation underscored the concept that this cortical locus orchestrates the timing and sequencing critical for effective sensorimotor integration.

The study went further to dissect the contributions of distinct projection neuron types within the MOs-c. Electrophysiological recordings complemented with cell-specific photoinhibition revealed remarkable functional divergence between pyramidal tract neurons and corticothalamic neurons (abbreviated CT^MOs). While both contribute to motor output, CT^MOs exhibited sustained firing spanning the entire RWD action duration, suggesting a unique integrative role that transcends simple motor execution. This finding sheds light on how neural circuits achieve ongoing coordination rather than merely initiating movement.

One of the most striking discoveries of the research lies in the interplay between CT^MOs neurons and thalamic circuits. CT^MOs neurons project to higher-order motor thalamic nuclei, which in turn send reciprocal feedback to cortical regions involved in motor planning. The authors demonstrated that CT^MOs amplify behaviorally relevant neural activity in postsynaptic thalamic neurons during the RWD behavior. Photoinhibition within these thalamic nodes additionally disrupted hand-to-mouth coordination, indicating that corticothalamic circuits serve as a bidirectional information highway crucial for synchronizing complex motor actions.

Monosynaptic tracing experiments revealed that CT^MOs neurons receive converging inputs from diverse forelimb and orofacial sensorimotor cortices. This anatomical convergence positions CT^MOs as integrative hubs where multimodal sensorimotor information is combined before influencing thalamic circuits. The reciprocal thalamocortical loop thus forms a feedback system that progressively refines motor output throughout ongoing behavior. This mechanistic insight elevates our understanding of higher-order motor control beyond traditional cortico-spinal paradigms.

The implications of these findings are profound: they challenge the long-held notion that cortical outputs to the spinal cord solely drive movement execution. Instead, the corticothalamic pathway provides a sophisticated modulatory channel that enhances the fidelity of sensorimotor integration. By selectively amplifying thalamic activity related to relevant motor programs, CT^MOs neurons ensure smooth transitions between successive motor phases required for functionally coherent actions like drinking.

Technically, the research employs a state-of-the-art combination of wide-field calcium imaging, which captures large-scale neural activity with high temporal resolution, and optogenetic photoinhibition, which enables cell-type specific and temporally precise suppression of neural populations. This methodology allowed the authors to systematically probe causal roles of neuronal subtypes and cortical areas during a naturalistic behavior, preserving ecological validity often lacking in simplified motor tasks.

Furthermore, the use of multichannel electrophysiology concurrently in cortical and thalamic regions enabled fine-grained assessment of neural dynamics underlying the coordinated motor sequence. Data revealed that not only do CT^MOs neurons sustain firing during action sequences, but postsynaptic thalamic neurons also show enhanced, temporally locked responses to these spike trains. Such synchronized corticothalamic activity likely underpins the neural computations supporting action progression and sensorimotor integration.

Behaviorally, disrupting this corticothalamic circuitry impaired the fluid coordination of forelimb reaching and mouth movements, underscoring the functional necessity of this pathway. These results provide a neurophysiological substrate for understanding disorders of motor coordination and perhaps offer targeted avenues for therapeutic interventions in diseases affecting skilled motor control, such as stroke or neurodegenerative conditions.

Taken together, this study paints a compelling picture of a distributed cortical network unified by a key corticothalamic axis that amplifies sensorimotor signals to choreograph complex, ethologically meaningful actions. It accentuates the central role of the secondary motor cortex’s corticothalamic output and its reciprocal thalamic partners as essential contributors to motor skill execution, coordination, and sequencing.

Beyond motor neuroscience, these insights may extend broadly to how the brain integrates multisensory inputs with motor plans, potentially informing artificial intelligence models of sensorimotor control and brain-machine interfaces. Emulating the corticothalamic feedback loops may enable more adaptive and fluid robotic control systems that better mimic naturalistic movement patterns.

As the field moves forward, further probing these corticothalamic circuits in diverse behavioral contexts and mapping their neuromodulatory regulation will be critical. Unraveling how these loops interact with basal ganglia, cerebellar, and spinal circuits could lead to a unified model of hierarchical motor coordination. Ultimately, this line of inquiry closes key gaps in understanding the neural logic of skilled behavior essential to survival.

The researchers’ achievement in delineating the specific roles of cortical projection neuron subtypes and their thalamic targets during a naturalistic action represents a milestone in systems neuroscience. It demonstrates the power of marrying advanced neurotechnological tools with ethologically relevant tasks to dissect the architecture of behaviorally critical neural circuits.

Li, An, Mulcahey and their team’s work not only clarifies how the brain executes seamless reach-to-consume movements but also sets the stage for translational breakthroughs targeting motor dysfunction. Their findings spotlight corticothalamic communication as an indispensable axis for action coordination, providing a paradigm for future studies to explore motor control mechanisms underlying complex behaviors in health and disease.

Subject of Research: Neural circuits underlying coordinated forelimb and orofacial movements during skilled motor behavior.

Article Title: Corticothalamic communication for action coordination in a skilled motor behavior.

Article References:
Li, Y., An, X., Mulcahey, P.J. et al. Corticothalamic communication for action coordination in a skilled motor behavior. Nat Neurosci (2026). https://doi.org/10.1038/s41593-025-02195-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41593-025-02195-8

Decades of research have highlighted choice-related neural activity primarily within frontoparietal regions of the primate cortex. These cortical areas exhibit ramping neuronal firing patterns consistent with the accumulation of sensory evidence leading to a behavioral choice. However, the present study expands this paradigm by focusing on rodents, leveraging advanced population decoding techniques and single-cell analyses to track the emergence and dynamics of choice signals in an array of brain regions, both cortical and subcortical.

By decoding neural population activity within a narrow 100-millisecond window just prior to movement onset, the researchers identified widespread representations of upcoming left versus right choices in numerous brain territories. Remarkably, some of the strongest choice signals were located deep within the brainstem’s hindbrain regions, including the gigantocellular reticular nucleus (GRN), pontine nuclei (PRNr), and medial accessory reticular nucleus (MARN). Alongside these areas, the thalamus, midbrain nuclei such as the substantia nigra pars reticulata (SNr), and the hypothalamus also exhibited pronounced choice-related modulations.

The study’s use of rigorous single-cell statistical models corrected for confounding factors such as stimulus presentation and task block effects, underscoring that a greater fraction of neurons responded specifically to choice direction than to the sensory stimuli themselves. This finding challenges traditional views that cortical sensory processing regions dominate the decision formation process, instead positioning multiple subcortical areas as critical hubs for choice coding.

Among these subcortical territories, the GRN stood out as a prime example of a region where individual neurons exhibited robust selectivity for right versus left choices. This choice preference was clearly delineated both in spike raster plots and in model-based encoding predictions, which faithfully captured variance in firing rates attributable solely to choice parameters. Population trajectory analyses further revealed that neural ensembles within the GRN evolved along distinct paths in state-space corresponding to each choice, highlighting a dynamic and gradual separation well before the animal’s first movement.

Furthermore, this population-level choice encoding was also strong in other hindbrain nuclei such as the intermediate reticular nucleus (IRN) and pontine reticular nucleus caudalis (PRNc), as well as in midbrain structures including the mesencephalic reticular nucleus (MRN) and superior colliculus (SCm). These results suggest that decision-related signals are not exclusively the province of higher cortical circuits but emerge from a concerted interaction of multiple, often evolutionarily conserved, brain regions.

Temporal analyses of choice signal latency demonstrated that some of the earliest neural differentiation between left and right choices appeared nearly simultaneously in both thalamic nuclei and cortical visual areas. This near synchrony implies a rapid, distributed initiation of decision signals rather than a strictly hierarchical, sequential processing model. Subsequently, a broader network encompassing numerous cortical and subcortical centers became engaged, with particular emphasis on brainstem reticular formation structures involved in motor preparation and execution.

Intriguingly, the study also found that movement onset represented distinct patterns of neural encoding across regions depending on the timing of behavioral responses. For example, in trials with early movements, certain subcortical structures like the periaqueductal gray (PAG) contributed significantly to model fits, whereas their influence waned in late-response trials. Conversely, secondary visual areas and motor cortical regions maintained consistent involvement regardless of response latency, suggesting differential recruitment dynamics across the brain depending on behavioral context.

The inclusion of cerebellar nuclei such as the central lobule (CENT2) in the ensemble of regions with strong choice encoding highlights the cerebellum’s emergent role in decision-making circuits, beyond its classical attribution to motor coordination. These findings align with growing evidence that cerebellar outputs participate in cognitive functions and behavioral planning.

Collectively, this extensive dataset paints a holistic picture of choice representation as a multifaceted phenomenon, wherein cortical sensory and motor regions interface with subcortical hubs to shape action plans. Such distributed coding likely affords the brain the flexibility and robustness needed for rapid, context-dependent decision-making in complex environments.

This study’s methodological sophistication—combining high-density electrophysiology, causal modeling, and advanced population decoding—sets a new standard for dissecting brain-wide neural dynamics during behavior. It directly confronts long-standing assumptions regarding the primacy of cortical circuits in decision formation and opens up promising avenues for exploring how subcortical regions contribute causally to behavior.

Understanding this distributed network’s precise mechanisms may have profound implications for neurological disorders where decision-making or motor control is compromised. By targeting subcortical nuclei implicated in choice formation, future therapeutic strategies could be more finely tuned to restore or modulate decision-related neural activity.

This landmark work exemplifies how collaborative, large-scale neuroscience efforts can unravel the complexity of neural computations underpinning behavior. As technological and analytical tools continue to advance, the prospect of fully mapping the brain’s decision circuitry with even greater resolution and causal specificity appears within reach.

In sum, the International Brain Laboratory’s study ushers in a new era of brain-wide investigation, revealing the intricate, multi-regional choreography of neurons that orchestrate choice, movement preparation, and execution. These findings underscore the importance of looking beyond traditional cortical territories, recognizing the concerted action of diverse brain areas that together enable adaptive, goal-directed behavior.

Subject of Research: Neural representation of choice across distributed brain regions during behavior

Article Title: A brain-wide map of neural activity during complex behaviour

Article References:
International Brain Laboratory., Angelaki, D., Benson, B. et al. A brain-wide map of neural activity during complex behaviour. Nature 645, 177–191 (2025). https://doi.org/10.1038/s41586-025-09235-0

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41586-025-09235-0

Keywords: neural decoding, choice representation, subcortical nuclei, cortex, brainstem, decision making, rodent neuroscience, population dynamics, electrophysiology, motor preparation