Researchers at the National Institutes of Health (NIH) have made a significant breakthrough in understanding how individual neurons in the primary somatosensory cortex receive brain-wide presynaptic inputs that are involved in encoding behavioral states. This work refines our understanding of cortical activity and challenges previous theories about how sensory information processing and motor control are interrelated in the brain. By mapping presynaptic networks at the single-cell level, the NIH team has provided valuable insights into how sensory information is integrated in cortical circuits, with implications for both normal and disordered brain function.
Neurons in the primary somatosensory cortex (S1) are responsible for processing a wide variety of sensory inputs, including touch, proprioception, and pain. The brain regions involved in this processing, particularly the S1, exhibit distinct activity patterns depending on the type of sensory information they are processing. However, the factors that lead to these differences in activity were not fully understood prior to this study. While previous research highlighted the importance of motor cortical regions in sensory processing related to movement, there has also been recognition that the thalamus plays an essential role beyond merely relaying sensory information to cortical areas.
The team at NIH set out to explore the question of how individual neurons in the somatosensory cortex encode behavioral states such as movement and attention. They used a combination of advanced technologies, including high-resolution single-cell mapping, two-photon calcium imaging, optogenetics, neuropharmacology, and monosynaptic retrograde tracing, to investigate the presynaptic networks that supply individual neurons in the somatosensory cortex with input. The study, titled Brain-wide presynaptic networks of functionally distinct cortical neurons, was published in Nature and represents a landmark achievement in the field of neuroscience.
By tracing neuronal connectivity and recording neuronal activity over several days while mice engaged in spontaneous movements, the team was able to pinpoint which regions of the brain were providing the most significant inputs to specific neurons in the somatosensory cortex. Their findings revealed a surprising result: thalamic input is the primary driver of neurons that encode movement and behavioral states, while inputs from motor cortical areas are much less influential.
More specifically, the NIH researchers found that neurons involved in encoding behavioral states received a greater proportion of their presynaptic input from thalamic regions, especially from the ventral posteromedial nucleus of the thalamus, which is involved in sensory processing related to facial sensations and somatosensory information. In contrast, motor cortical areas played a smaller role in providing input to these neurons, challenging earlier models that emphasized the motor cortex as the main source of input for movement-related cortical activity.
In their study, the researchers also employed optogenetics, a technique that allows for precise control over specific neural circuits, to suppress thalamic input to the somatosensory cortex. When they blocked thalamic input, they observed a reduction in behavioral state-dependent neuronal activity, further supporting the central role of the thalamus in encoding these states. On the other hand, when they blocked neuromodulatory inputs like acetylcholine and noradrenaline, the researchers found minimal effects on movement-related neuronal activity. This suggests that although neuromodulatory signals are important for other aspects of brain function, they do not directly influence the activity of neurons encoding behavioral states in the same way as thalamic input.
One of the most striking findings of this study was that cortical state shifts, which are changes in neural activity patterns associated with different behavioral states (e.g., movement, rest, attention), were found to be stable over several days of recording. This was in contrast to previous models that described these shifts as transient, or short-lived. The study’s results suggest that neuronal activity patterns that encode behavioral states are more stable and persistent than previously thought, even when neuromodulatory inputs are pharmacologically blocked. This stability points to the crucial role of glutamatergic synaptic input, primarily from the thalamus, in maintaining these representations of behavioral states in the cortex.
The research team’s use of single-cell-based monosynaptic retrograde tracing, a method that traces the specific presynaptic neurons that connect to a given target neuron, allowed for an unprecedented level of detail in mapping how individual neurons in the somatosensory cortex receive inputs from other regions of the brain. This approach is important because it provides a more nuanced understanding of how complex behaviors, such as movement, are encoded in the brain. The study revealed that neurons in the somatosensory cortex, particularly those that encode movement and behavioral states, exhibit unique presynaptic network configurations, with distinct anatomical biases in terms of where their inputs come from. Neurons encoding movement, for instance, receive a higher proportion of their inputs from thalamic nuclei, while sensory neurons involved in touch processing tend to receive more direct sensory input.
These findings challenge the traditional view that movement neurons in the somatosensory cortex primarily receive input from the motor cortex. Instead, the NIH team’s work suggests that the thalamus plays a much more significant role in the modulation of cortical activity, particularly with respect to the encoding of behavioral states. The implications of these findings are far-reaching, especially in the context of understanding how the brain integrates sensory and motor information to produce coordinated behavior.
The researchers also discussed the broader implications of their work in a separate research briefing, “Diversity in neuronal activity could be caused by differences in inputs,” which was also published in Nature. In this briefing, study authors Ana R. Inácio and Soohyun Lee elaborated on the idea that the diversity in neuronal activity patterns across different neurons in the somatosensory cortex may be driven by the differences in their presynaptic inputs. These differences in connectivity help shape the identity of neurons, especially movement-related neurons, within the somatosensory cortex. Inácio and Lee also suggested that the modulation of neuronal activity by behavioral state signals, which are not directly related to sensory feedback, is a crucial factor in understanding cortical function.
One intriguing aspect of the study was that movement-related neuron activity persisted even when sensory input from the whisker pad, a common source of sensory feedback in mice, was blocked. This result further supports the idea that thalamic input, rather than direct sensory feedback, plays a crucial role in modulating cortical activity associated with movement and behavioral states.
The authors of the study also explored the potential role of neuromodulatory signals, such as those mediated by acetylcholine and noradrenaline, in shaping neuronal activity. While these signals did not directly drive the activity of movement-related neurons in the somatosensory cortex, the researchers acknowledged that they could still exert indirect effects through their action on thalamic projections. This opens up new avenues for future research on how neuromodulation might influence the processing of sensory information and the encoding of behavioral states in the brain.
The NIH team’s findings have significant implications for understanding how the brain coordinates sensory and motor information to produce adaptive behavior. Disruptions in the connectivity and activity patterns of these cortical neurons could potentially underlie a variety of neurological and psychiatric disorders, such as movement disorders, attention deficits, and sensory processing disorders. Further research into the nature of presynaptic networks and their role in encoding behavioral states could lead to new insights into the pathophysiology of these disorders and may inform the development of novel therapeutic strategies.
More information: Ana R. Inácio et al, Brain-wide presynaptic networks of functionally distinct cortical neurons, Nature (2025). DOI: 10.1038/s41586-025-08631-w
Diversity in neuronal activity could be caused by differences in inputs, Nature (2025). DOI: 10.1038/d41586-025-00634-x