Maturation of cortical input to dorsal raphe nucleus increases behavioral persistence in mice
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eLife assessment
In this important study, the authors explore the importance of developmental changes in cortico-DRN innervation in the balance of behavioral control in a foraging task. The authors report somewhat convincing evidence that while juvenile mice and adult mice both perform the task, juveniles exhibit more impulsive behavior due to reduced efficacy of cortico-DRN projections. The authors conclude that the development of cortico-DRN (esp mPFC) projections allows 5HT input to promote perseveration (or exploitation) in the balance of behavioral control. However, reviewers raised issues regarding the strength of the evidence without further experiments.
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Abstract
The ability to persist toward a desired objective is a fundamental aspect of behavioral control whose impairment is implicated in several behavioral disorders. One of the prominent features of behavioral persistence is that its maturation occurs relatively late in development. This is presumed to echo the developmental time course of a corresponding circuit within late-maturing parts of the brain, such as the prefrontal cortex, but the specific identity of the responsible circuits is unknown. Here, we used a genetic approach to describe the maturation of the projection from layer 5 neurons of the neocortex to the dorsal raphe nucleus in mice. Using optogenetic-assisted circuit mapping, we show that this projection undergoes a dramatic increase in synaptic potency between postnatal weeks 3 and 8, corresponding to the transition from juvenile to adult. We then show that this period corresponds to an increase in the behavioral persistence that mice exhibit in a foraging task. Finally, we used a genetic targeting strategy that primarily affected neurons in the medial prefrontal cortex, to selectively ablate this pathway in adulthood and show that mice revert to a behavioral phenotype similar to juveniles. These results suggest that frontal cortical to dorsal raphe input is a critical anatomical and functional substrate of the development and manifestation of behavioral persistence.
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eLife assessment
In this important study, the authors explore the importance of developmental changes in cortico-DRN innervation in the balance of behavioral control in a foraging task. The authors report somewhat convincing evidence that while juvenile mice and adult mice both perform the task, juveniles exhibit more impulsive behavior due to reduced efficacy of cortico-DRN projections. The authors conclude that the development of cortico-DRN (esp mPFC) projections allows 5HT input to promote perseveration (or exploitation) in the balance of behavioral control. However, reviewers raised issues regarding the strength of the evidence without further experiments.
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Reviewer #1 (Public Review):
This study is founded on the idea that 5HT promotes waiting, and tests a clear, and I think novel, hypothesis that input from cortical and particularly prefrontal areas is key to promoting this and that the increase in this relates to declines in impulsive behavior during adolescence. It also nicely tests that hypothesis with integrated behavioral, electrophysiological, and tracing approaches. Overall it makes a compelling argument in favor of the authors ideas. The independent findings also build upon or at least are well supported by prior work, which I think is excellent and increases confidence in the conclusions.
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Reviewer #3 (Public Review):
Studying the late development of neural circuits in relation to developmental changes in behaviour is clearly of great interest, particularly during the period of adolescence when a number of developmental abnormalities can be revealed. This is however not an easy task, since there are many concurrent changes that occur simultaneously during this developmental making it difficult to establish causality rather than correlation.
The study focuses on behavioural and circuit changes that occur between juvenile and adulthood focusing in the prefrontal cortex and on its descending projections to the brainstem raphe nuclei. Because the pathway from the frontal cortex to serotonin raphe neurons has been involved in behavioural and stress control, exerting a top-down control on impulsive behavior, there is a good …
Reviewer #3 (Public Review):
Studying the late development of neural circuits in relation to developmental changes in behaviour is clearly of great interest, particularly during the period of adolescence when a number of developmental abnormalities can be revealed. This is however not an easy task, since there are many concurrent changes that occur simultaneously during this developmental making it difficult to establish causality rather than correlation.
The study focuses on behavioural and circuit changes that occur between juvenile and adulthood focusing in the prefrontal cortex and on its descending projections to the brainstem raphe nuclei. Because the pathway from the frontal cortex to serotonin raphe neurons has been involved in behavioural and stress control, exerting a top-down control on impulsive behavior, there is a good justification to focus on the development of this pathway during a period that is thought to correspond to adolescence.
The authors identified a behavioral change in foraging strategy, which they term persistence. They find that adults tend to be more persistent than juveniles in an exploration for reward. To analyse the maturation of the prefrontal to raphe circuit they use a genetic approach (the Rbp4 promoter which drives expression in layer 5 cortical neurons) recording the synaptic drive elicited by stimulation of the axons arriving into the raphe area. They find that this maturation starts very late in the late adolescent period. They then study the effects of ablation of the layer 5 Rbp4 neurons in adults and find that adult animals have a behavior that is more similar to that of the juveniles. They then conclude that cortical prefrontal projections to the raphe are involved in the control of this behavior.
The study is interesting in showing this new behavioural test quantifying developmental changes in exploratory behavior and indicating that some pathways derived mainly from the frontal cortex continue to mature late. However, there are a number of issues regarding the specificity of the genetic approach used. This makes it difficult to be convinced that the behaviour is related to changes in the cortico-raphe circuit.
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