Maturation of cortical input to dorsal raphe nucleus increases behavioral persistence in mice

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Abstract

The ability to persist towards 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 (mPFC), 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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All data analyzed and visualized during this study are included in form of Source Data files that have been provided for all figures present in the current manuscript.

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Nicolas Gutierrez-Castellanos

Synaptic Plasticity and Behavior Group, Champalimaud Foundation, Lisbon, Portugal

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8442-4243
Dario Sarra

Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal

Competing interests
The authors declare that no competing interests exist.
Beatriz S Godinho

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Zachary F Mainen

Champalimaud Neuroscience Program, Champalimaud Foundation, Lisbon, Portugal

For correspondence
zmainen@neuro.fchampalimaud.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7913-9109

Funding

European Research Council (671251)

Zachary F Mainen

Fundação para a Ciência e a Tecnologia (FCT-PTDC/MED-NEU/28830/2017)

Zachary F Mainen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures were approved and performed in accordance with theChampalimaud Centre for the Unknown Ethics Committee guidelines and by the PortugueseVeterinary General Board (Direcção-Geral de Veterinária, approval 0421/000/000/2016).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.