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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    McGuire, J. T. & Botvinick, M. M. Prefrontal cortex, cognitive control, and the registration of decision costs. Proc. Natl Acad. Sci. USA 107, 7922–7926 (2010)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Ridderinkhof, K. R., van den Wildenberg, W. P. M., Segalowitz, S. J. & Carter, C. S. Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn. 56, 129–140 (2004)

    Article  Google Scholar 

  3. 3

    Mayberg, H. S. et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999)

    CAS  PubMed  Google Scholar 

  4. 4

    Maes, M. & Meltzer, H. In Psychopharmacology: the Fourth Generation of Progress (eds Bloom, F. E. & Kupfer, D. J. ) 933–944 (Raven Press, 1995)

    Google Scholar 

  5. 5

    Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry 6, 168–176 (2007)

    PubMed  PubMed Central  Google Scholar 

  6. 6

    Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001)

    CAS  Article  Google Scholar 

  7. 7

    Fuster, J. M. The Prefrontal Cortex, Fourth Edition (Academic Press, 2008)

    Google Scholar 

  8. 8

    Elliott, R. et al. Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychol. Med. 27, 931–942 (1997)

    CAS  Article  Google Scholar 

  9. 9

    Austin, M.-P. Cognitive deficits in depression: possible implications for functional neuropathology. Br. J. Psychiatry 178, 200–206 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Ingram, R. E., Bernet, C. Z. & McLaughlin, S. C. Attentional allocation processes in individuals at risk for depression. Cognit. Ther. Res. 18, 317–332 (1994)

    Article  Google Scholar 

  11. 11

    Dalgleish, T. & Watts, F. N. Biases of attention and memory in disorders of anxiety and depression. Clin. Psychol. Rev. 10, 589–604 (1990)

    Article  Google Scholar 

  12. 12

    Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005)

    CAS  Article  Google Scholar 

  13. 13

    Hamani, C. et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol. Psychiatry 67, 117–124 (2010)

    Article  Google Scholar 

  14. 14

    Covington, H. E. et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090 (2010)

    CAS  Article  Google Scholar 

  15. 15

    Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosci. 8, 365–371 (2005)

    CAS  Article  Google Scholar 

  16. 16

    Drevets, W. C. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr. Opin. Neurobiol. 11, 240–249 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Baxter, L. R. et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch. Gen. Psychiatry 46, 243–250 (1989)

    CAS  Article  Google Scholar 

  18. 18

    Porsolt, R. D., Le Pichon, M. & Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730–732 (1977)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Cryan, J. F., Valentino, R. J. & Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci. Biobehav. Rev. 29, 547–569 (2005)

    CAS  Article  Google Scholar 

  20. 20

    Willner, P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90–110 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Vertes, R. P. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51, 32–58 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Gonçalves, L., Nogueira, M. I., Shammah-Lagnado, S. J. & Metzger, M. Prefrontal afferents to the dorsal raphe nucleus in the rat. Brain Res. Bull. 78, 240–247 (2009)

    Article  Google Scholar 

  23. 23

    Celada, P., Puig, M. V., Casanovas, J. M., Guillazo, G. & Artigas, F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J. Neurosci. 21, 9917–9929 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Gabbott, P. L. A., Warner, T. A., Jays, P. R. L., Salway, P. & Busby, S. J. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J. Comp. Neurol. 492, 145–177 (2005)

    Article  Google Scholar 

  25. 25

    Kim, U. & Lee, T. Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur. J. Neurosci. 35, 1253–1269 (2012)

    Article  Google Scholar 

  26. 26

    Matsumoto, M. & Hikosaka, O. Representation of negative motivational value in the primate lateral habenula. Nature Neurosci. 12, 77–84 (2009)

    CAS  Article  Google Scholar 

  27. 27

    Sartorius, A. et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol. Psychiatry 67, e9–e11 (2010)

    Article  Google Scholar 

Download references


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.).

Author information




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.

Corresponding authors

Correspondence to Melissa R. Warden or Karl Deisseroth.

Ethics declarations

Competing interests

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).

Supplementary information

Supplementary Information

This file contains Supplementary Materials and Methods, Supplementary Figures 1-13 and additional references. (PDF 26374 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.