Activity in developing prefrontal cortex is shaped by sleep and sensory experience
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eLife assessment
This manuscript examines the functional relationship between neural activities in several cortical areas (such as the primary and secondary motor cortex and the medial prefrontal cortex) and the different sleep states or under anesthesia. The quality of the recordings in infant rats is excellent. Results are important in the field of research into the role of active sleep in the neuronal and circuit mechanisms of early cortical development. Some of the findings presented and hypothesis developed are novel, but the overall demonstration remains incomplete and further in-depth analysis and additional experiments are required to fully support the authors' claims.
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Abstract
In developing rats, behavioral state exerts a profound modulatory influence on neural activity throughout the sensorimotor system, including primary motor cortex (M1). We hypothesized that similar state-dependent modulation occurs in prefrontal cortical areas with which M1 forms functional connections. Here, using 8- and 12-day-old rats cycling freely between sleep and wake, we record neural activity in M1, secondary motor cortex (M2), and medial prefrontal cortex (mPFC). At both ages in all three areas, neural activity increased during active sleep (AS) compared with wake. Also, regardless of behavioral state, neural activity in all three areas increased during periods when limbs were moving. The movement-related activity in M2 and mPFC, like that in M1, is driven by sensory feedback. Our results, which diverge from those of previous studies using anesthetized pups, demonstrate that AS-dependent modulation and sensory responsivity extend to prefrontal cortex. These findings expand the range of possible factors shaping the activity-dependent development of higher-order cortical areas.
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eLife assessment
This manuscript examines the functional relationship between neural activities in several cortical areas (such as the primary and secondary motor cortex and the medial prefrontal cortex) and the different sleep states or under anesthesia. The quality of the recordings in infant rats is excellent. Results are important in the field of research into the role of active sleep in the neuronal and circuit mechanisms of early cortical development. Some of the findings presented and hypothesis developed are novel, but the overall demonstration remains incomplete and further in-depth analysis and additional experiments are required to fully support the authors' claims.
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Reviewer #1 (Public Review):
The paper by Gomez et al. describes investigations employing extracellular recordings of neural spiking in rat pups across different sleep states in primary (M1) and secondary (M2) cortices as well as in the prefrontal cortex (PFC) in response to spontaneous motor activity and tactile stimulation. The authors demonstrate activity across these areas that are associated with active sleep (AS) and identify responses in each region to internally generated movements and external stimuli. Because these results contradict earlier findings in the same areas under anesthesia, they also perform similar recordings in urethane anesthetized animals and show that similar responses are not observed under these conditions. Based on findings from anesthetized and unanesthetized recordings, the authors conclude that early …
Reviewer #1 (Public Review):
The paper by Gomez et al. describes investigations employing extracellular recordings of neural spiking in rat pups across different sleep states in primary (M1) and secondary (M2) cortices as well as in the prefrontal cortex (PFC) in response to spontaneous motor activity and tactile stimulation. The authors demonstrate activity across these areas that are associated with active sleep (AS) and identify responses in each region to internally generated movements and external stimuli. Because these results contradict earlier findings in the same areas under anesthesia, they also perform similar recordings in urethane anesthetized animals and show that similar responses are not observed under these conditions. Based on findings from anesthetized and unanesthetized recordings, the authors conclude that early responses associated with AS occur in higher cortical areas, a novel observation for the brain regions studied which had been missed in previous studies because they are absent under anesthesia. Finally, in their discussion, the authors consider the potential roles of state dependent activity in development and contend that differences in activity patterns between motor cortical areas and PFC reflect the diversity or heterogeneity of the inputs they respond to.
The finding presented, particularly the observation of state specific activity in the PFC similar to that observed in more sensory linked areas of the motor cortex, are novel and of interest for their potential relevance to development. However, analysis of the recordings presented in the current manuscript are largely descriptive and do not convey much functional insight beyond simple observation of the phenomenon. In addition, some of the claims made, particularly those related to the differences between PFC and motor cortex, are not clearly supported by the data as currently presented. For these reasons, the study should be revised to including by incorporating additional analysis and potentially further experiments. In addition, clarification of the text and figures is needed to allow the findings to be clearly understood. Resolution of these issues would be important to improve the quality of the manuscript.
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Reviewer #2 (Public Review):
The way a child sleeps is much different than the way an adolescent or an adult sleeps. One difference concerns the time spent in active sleep (AS, also called paradoxical or REM sleep), which is very high in early stages of development and thought to favor brain plasticity that is relevant for circuit development. This study is a step forward to understand the neuronal activity patterns by which REMS promotes this plasticity.
The study addresses this question in particular for higher-order cortical areas. It finds that activity in M2 and mPFC is greater for AS than for wakefulness. Within AS, activity is further elevated in relation to spontaneous limb movements that are characteristic for this state. At P8 but less so at P12, both M2 and mPFC also respond to external sensory stimulation. Therefore, the …
Reviewer #2 (Public Review):
The way a child sleeps is much different than the way an adolescent or an adult sleeps. One difference concerns the time spent in active sleep (AS, also called paradoxical or REM sleep), which is very high in early stages of development and thought to favor brain plasticity that is relevant for circuit development. This study is a step forward to understand the neuronal activity patterns by which REMS promotes this plasticity.
The study addresses this question in particular for higher-order cortical areas. It finds that activity in M2 and mPFC is greater for AS than for wakefulness. Within AS, activity is further elevated in relation to spontaneous limb movements that are characteristic for this state. At P8 but less so at P12, both M2 and mPFC also respond to external sensory stimulation. Therefore, the authors have identified the time window over which these higher cortical areas are sensory responsive yet decline to do so over a period of four days. Through contrasting their results with naturally sleeping with the ones of urethane-anesthetized pups, they further support the unique status of AS in the regulation of neuronal activity and sensory responsiveness that is critical for development. This will enable precise further manipulation to study the anatomo-functional basis of this sensory responsiveness and its role for the development of the sensorimotor system.
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