A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge

Abstract

The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions1); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action2, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood3. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal’s decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder4, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.

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Figure 1: The automated FST provides a high-temporal-resolution behavioural read-out that can be synchronized with simultaneously recorded neural data.
Figure 2: Prefrontal neuronal activity encodes FST behavioural state.
Figure 3: Optogenetic stimulation of mPFC axons in the DRN, but not excitatory mPFC cell bodies, induces behavioural activation.
Figure 4: Behavioural activation resulting from stimulation of DRN-projecting mPFC axons is specific to the mPFC–DRN synapse.

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Acknowledgements

We would like to thank H. Mayberg, R. Malenka, L. Gunaydin, J. Mattis, I. Ellwood and I. Witten for helpful comments on the manuscript; I. Ellwood, I. Witten, R. Airan, L. Meltzer, M. Roy, V. Gradinaru, A. Andalman, T. Davidson, R. Durand, M. Bower and M. Carr for useful discussions; and all members of the K.D. laboratory for their support. We are grateful to S. Pak, C. Ramakrishnan and C. Perry for technical assistance. This work was supported by the Wiegers Family Fund (K.D.), NARSAD (M.R.W. and K.R.T.), Stanford Graduate Fellowship (A.S.), Samsung Scholarship (S.-Y.K.), Berry Foundation Fellowship (A.A.), NIMH (1F32MH088010-01, K.M.T.), and NIMH, NIDA, the DARPA REPAIR Program, the Keck Foundation, the McKnight Foundation, the Yu, Snyder, Tarlton and Alice Woo Foundations, and the Gatsby Charitable Foundation (K.D.).

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M.R.W., L.M.F. and K.D. contributed to study design with assistance from A.S. and K.M.T. M.R.W., L.M.F. and K.D. contributed to data interpretation and manuscript revision. M.R.W., A.S., K.M.T., J.J.M., M.L., K.R.T., S-Y.K. and A.A. contributed to data collection. M.R.W. coordinated all experiments, developed the induction coil and forced swim test electrophysiology methods, and performed all behavioural and in vivo electrophysiology analyses. K.D. supervised all aspects of the project. M.R.W and K.D. wrote the paper.

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Correspondence to Melissa R. Warden or Karl Deisseroth.

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M.R.W. and K.D. have disclosed these findings to the Stanford Office of Technology Licensing, which has filed a patent application for the possible use of the findings and methods in identifying new treatments for depression. All materials, methods and reagents remain freely available for academic and non-profit research in perpetuity through the Deisseroth optogenetics website (http://www.optogenetics.org).

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Warden, M., Selimbeyoglu, A., Mirzabekov, J. et al. A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428–432 (2012). https://doi.org/10.1038/nature11617

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