Cell. 2016 Jun 16;165(7):1776-1788. doi: 10.1016/j.cell.2016.05.010. Epub 2016 May 26.

Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences.

Ye L¹, Allen WE², Thompson KR³, Tian Q⁴, Hsueh B⁵, Ramakrishnan C⁶, Wang AC⁶, Jennings JH⁶, Adhikari A⁶, Halpern CH⁷, Witten IB³, Barth AL⁸, Luo L⁹, McNab JA⁴, Deisseroth K¹⁰.

Author information

1: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; CNC Program, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
2: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Neurosciences Program, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
3: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
4: Department of Radiology, Stanford University, Stanford, CA 94305, USA.
5: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; CNC Program, Stanford University, Stanford, CA 94305, USA; Neurosciences Program, Stanford University, Stanford, CA 94305, USA.
6: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; CNC Program, Stanford University, Stanford, CA 94305, USA.
7: Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
8: Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
9: Department of Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
10: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; CNC Program, Stanford University, Stanford, CA 94305, USA; Department of Psychiatry, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: deissero@stanford.edu.

Abstract

A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states.