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Publication Highlights

Functional diversity of dopamine axons in prefrontal cortex during classical conditioning 

Abe K, Kambe Y, Majima K, Hu Z, Ohtake M, Momennezhad A, Izumi H, Tanaka T, Matunis A, Stacy E, Itokazu T, Sato TR*, Sato TK*. Functional diversity of dopamine axons in prefrontal cortex during classical conditioning. Elife. 2024 May 15;12:RP91136. doi: 10.7554/eLife.91136. PMID: 38747563; PMCID: PMC11095940.


Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.

Interhemispherically dynamic representation of an eye movement-related activity in mouse frontal cortex

Sato TR*, Itokazu T, Osaki H, Ohtake M, Yamamoto T, Sohya K, Maki T, Sato TK*. (2019)  Interhemispherically dynamic representation of an eye movement-related activity in mouse frontal cortex. Elife 8, doi:10.7554/eLife.50855.


Cortical plasticity is fundamental to motor recovery following cortical perturbation. However, it is still unclear how this plasticity is induced at a functional circuit level. Here, we investigated motor recovery and underlying neural plasticity upon optogenetic suppression of a cortical area for eye movement. Using a visually-guided eye movement task in mice, we suppressed a portion of the secondary motor cortex (MOs) that encodes contraversive eye movement. Optogenetic unilateral suppression severely impaired contraversive movement on the first day. However, on subsequent days the suppression became inefficient and capability for the movement was restored. Longitudinal two-photon calcium imaging revealed that the regained capability was accompanied by an increased number of neurons encoding for ipsiversive movement in the unsuppressed contralateral MOs. Additional suppression of the contralateral MOs impaired the recovered movement again, indicating a compensatory mechanism. Our findings demonstrate that repeated optogenetic suppression leads to functional recovery mediated by the contralateral hemisphere.

Streamlined sensory motor communication through cortical reciprocal connectivity in a visually guided eye movement task

Itokazu T, Hasegawa M, Kimura R, Osaki H, Albrecht UR, Sohya K, Chakrabarti S, Itoh H, Ito T, Sato TK*, Sato TR*. (2018) Streamlined sensory motor communication through cortical reciprocal connectivity in a visually guided eye movement task.  Nature Communications 9(1):338.

Cortical computation is distributed across multiple areas of the cortex by networks of reciprocal connectivity. However, how such connectivity contributes to the communication between the connected areas is not clear. In this study, we examine the communication between sensory and motor cortices. We develop an eye movement task in mice and combine it with optogenetic suppression and two-photon calcium imaging techniques. We identify a small region in the secondary motor cortex (MOs) that controls eye movements and reciprocally connects with a rostrolateral part of the higher visual areas (VRL/A/AL). These two regions encode both motor signals and visual information; however, the information flow between the regions depends on the direction of the connectivity: motor information is conveyed preferentially from the MOs to the VRL/A/AL, and sensory information is transferred primarily in the opposite direction. We propose that reciprocal connectivity streamlines information flow, enhancing the computational capacity of a distributed network.

Selective Suppression of Local Circuits during Movement Preparation in the Mouse Motor Cortex

Hasegawa M, Majima K, Itokazu T, Maki T, Albrecht UR, Castner N, Izumo M, Sohya K, Sato TK, Kamitani Y, Sato TR*. Selective Suppression of Local Circuits during Movement Preparation in the Mouse Motor Cortex. Cell Rep. 2017 Mar 14;18(11):2676-2686. doi: 10.1016/j.celrep.2017.02.043. 


Prepared movements are more efficient than those that are not prepared for. Although changes in cortical activity have been observed prior to a forthcoming action, the circuits involved in motor preparation remain unclear. Here, we use in vivo two-photon calcium imaging to uncover changes in the motor cortex during variable waiting periods prior to a forepaw reaching task in mice. Consistent with previous reports, we observed a subset of neurons with increased activity during the waiting period; however, these neurons did not account for the degree of preparation as defined by reaction time (RT). Instead, the suppression of activity of distinct neurons in the same cortical area better accounts for RT. This suppression of neural activity resulted in a distinct and reproducible pattern when mice were well prepared. Thus, the selective suppression of network activity in the motor cortex may be a key feature of prepared movements.

Sleep-Stage-Specific Regulation of Cortical Excitation and Inhibition

Niethard N, Hasegawa M, Itokazu T, Oyanedel CN, Born J, Sato TR*. Sleep-Stage-Specific Regulation of Cortical Excitation and Inhibition. Curr Biol. 2016 Oct 24;26(20):2739-2749. doi: 10.1016/j.cub.2016.08.035. 


Sleep is characterized by unique patterns of cortical activity alternating between the stages of slow-wave sleep (SWS) and rapid-eye movement (REM) sleep. How these patterns relate to the balanced activity of excitatory pyramidal cells and inhibitory interneurons in cortical circuits is unknown. We investigated cortical network activity during wakefulness, SWS, and REM sleep globally and locally using in vivo calcium imaging in mice. Wide-field imaging revealed a reduction in pyramidal cell activity during SWS compared with wakefulness and, unexpectedly, a further profound reduction in activity during REM sleep. Two-photon imaging on local circuits showed that this suppression of activity during REM sleep was accompanied by activation of parvalbumin (PV)+ interneurons, but not of somatostatin (SOM)+ interneurons. PV+ interneurons most active during wakefulness were also most active during REM sleep. Our results reveal a sleep-stage-specific regulation of the cortical excitation/inhibition balance, with PV+ interneurons conveying maximum inhibition during REM sleep, which might help shape memories in these networks.

The Functional Properties of Barrel Cortex Neurons Projecting to the Primary Motor Cortex

Sato TR*, Svoboda K.  (2010).  The functional properties of barrel cortex neurons projecting to the primary motor cortex.  Journal of Neuroscience 30(12): 4256-60


Nearby neurons, sharing the same locations within the mouse whisker map, can have dramatically distinct response properties. To understand the significance of this diversity, we studied the relationship between the responses of individual neurons and their projection targets in the mouse barrel cortex. Neurons projecting to primary motor cortex (MI) or secondary somatosensory area (SII) were labeled with red fluorescent protein (RFP) using retrograde viral infection. We used in vivo two-photon Ca2+ imaging to map the responses of RFP-positive and neighboring L2/3 neurons to whisker deflections. Neurons projecting to MI displayed larger receptive fields compared with other neurons, including those projecting to SII. Our findings support the view that intermingled neurons in primary sensory areas send specific stimulus features to different parts of the brain.

The Functional Microarchitecture of the Mouse Barrel Cortex

Sato TR*, Gray NW, Mainen ZF, Svoboda K. The functional microarchitecture of the mouse barrel cortex. PLoS Biol. 2007 Jul;5(7):e189. doi: 10.1371/journal.pbio.0050189.


Cortical maps, consisting of orderly arrangements of functional columns, are a hallmark of the organization of the cerebral cortex. However, the microorganization of cortical maps at the level of single neurons is not known, mainly because of the limitations of available mapping techniques. Here, we used bulk loading of Ca2+ indicators combined with two-photon microscopy to image the activity of multiple single neurons in layer (L) 2/3 of the mouse barrel cortex in vivo. We developed methods that reliably detect single action potentials in approximately half of the imaged neurons in L2/3. This allowed us to measure the spiking probability following whisker deflection and thus map the whisker selectivity for multiple neurons with known spatial relationships. At the level of neuronal populations, the whisker map varied smoothly across the surface of the cortex, within and between the barrels. However, the whisker selectivity of individual neurons recorded simultaneously differed greatly, even for nearest neighbors. Trial-to-trial correlations between pairs of neurons were high over distances spanning multiple cortical columns. Our data suggest that the response properties of individual neurons are shaped by highly specific subcolumnar circuits and the momentary intrinsic state of the neocortex.

Effects of stimulus-response compatibility on neural selection in frontal eye field

Sato TR, Schall JD. Effects of stimulus-response compatibility on neural selection in frontal eye field. Neuron. 2003 May 22;38(4):637-48. doi: 10.1016/s0896-6273(03)00237-x.


We investigated the neural basis of visual and saccade selection in the frontal eye field of macaque monkeys using a singleton search task with prosaccade or antisaccade responses. Two types of neurons were distinguished. The first initially selected the singleton even in antisaccade trials, although most subsequently selected the endpoint of the saccade. The time the singleton was located was not affected by stimulus-response compatibility and did not vary with reaction time across trials. The second type of neuron selected only the endpoint of the saccade. The time of endpoint selection by these neurons accounted for most of the effect of stimulus-response compatibility on reaction time. These results indicate that visual selection and saccade selection are different processes.


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