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

By Melissa R. Warden, Aslihan Selimbeyoglu, J. J. Mirzabekov, Maisie Lo, K. Thompson, Sung-Yon Kim, Avishek Adhikari, K. Tye, Loren M. Frank, Karl Deisseroth. Nature, 2012

615 citations recorded by the source corpus.

The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. 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 disorder, 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.

Subfields: Cognitive Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c2b43904b863dbd1af15a09836eabcd17d01ccca

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Citations in the corpus

Natural neural projection dynamics underlying social behavior. (2014, positive): “…that share the same physical location and genetic type, causally relevant subpopulations may be present that are differentially connected (e.g., Warden et al., 2012) in a way that is resolvable by projection targeting; we thus next sought to identify and probe not only causal sufficiency, but…”
Closed-loop and activity-guided optogenetic control. (2015, positive): “…that different afferent projections of the same general class (e.g., excitatory/glutamatergic) to the same target region can have very different behavioral effects from each other or from direct modulation (such as excitation) of the target region (e.g., Warden et al., 2012; Britt et al., 2012).”
Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences (2016, neutral): “…have been characterized by electrophysiological recording and cellular-resolution fluorescence Ca2+ imaging (Hayden et al., 2008; Insel and Barnes, 2015; Ito et al., 1776 Cell 165, 1776–1788, June 16, 2016 ª 2016 Elsevier Inc. 2003; Matsumoto et al., 2007; Pinto and Dan, 2015; Warden et al., 2012).”