title: Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex.
abstract: Loss of control over drinking is a key deficit in alcoholism causally associated with malfunction of the medial prefrontal cortex (mPFC), but underlying molecular and cellular mechanisms remain unclear. Cue-induced reinstatement of alcohol seeking activates a subset of mPFC neurons in rats, identified by their common expression of the activity marker cFos and comprised of both principal and interneurons. Here, we used cFos-lacZ and pCAG-lacZ transgenic rats for activity-dependent or nonselective inactivation of neurons, respectively, which by their lacZ encoded β-galactosidase activity convert the inactive prodrug Daun02 into the neurotoxin daunorubicin. We report that activity-dependent ablation of a neuronal ensemble in the infralimbic but not the prelimbic subregion induced excessive alcohol seeking. The targeted neuronal ensemble was specific for the cue-induced response because stress-induced reinstatement was not affected in these animals. Importantly, nonselective inactivation of infralimbic neurons, using pCAG-lacZ rats, was without functional consequence on the cue-induced reinstatement task. Thus, inhibitory control over alcohol seeking is exerted by distinct functional ensembles within the infralimbic cortex rather than by a general inhibitory tone of this region on the behavioral output. This indicates a high level of functional compartmentation within the rat mPFC whereat many functional ensembles could coexist and interact within the same subregion.
  
  
  CONCLUSIONS
  Hebb's (1949) idea of memories as being represented in local neuronal networks is supported by identification of transiently stable activity patterns within subgroups of neurons. However, it is difficult to link individual networks to specific memory tasks, for example a learned behavior. By a novel approach of activity-dependent ablation, here we identify a specific neuronal ensemble located in the infralimbic subregion of the medial prefrontal cortex that controls a seeking response for alcohol in rats. Our data demonstrate that functional output depends on specific neuronal ensembles within a given brain region rather than on the global activity of that region, which raises important questions about the interpretation of numerous earlier experiments using site-directed silencing or stimulation for elucidating brain function.
authors.affiliation: Institute of Psychopharmacology.
authors.forename: Simone
authors.initials: S
authors.lastname: Pfarr
authors.affiliation: Institute of Psychopharmacology, marcus.meinhardt@zi-mannheim.de wolfgang.sommer@zi-mannheim.de.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Meinhardt
authors.affiliation: Institute of Psychopharmacology.
authors.forename: Manuela L
authors.initials: ML
authors.lastname: Klee
authors.affiliation: Institute of Psychopharmacology.
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.affiliation: Institute of Psychopharmacology.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vengeliene
authors.affiliation: Departments of Molecular Biology and.
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.affiliation: Departments of Molecular Biology and.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.affiliation: IRP/ NIDA/ NIH, Behavioral Neuroscience Branch, Baltimore, Maryland 21224.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Hope
authors.affiliation: Institute of Psychopharmacology.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Institute of Psychopharmacology, Addiction Medicine at Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Germany, and marcus.meinhardt@zi-mannheim.de wolfgang.sommer@zi-mannheim.de.
authors.forename: Wolfgang H
authors.identifier: http://orcid.org/0000-0002-5903-6521
authors.initials: WH
authors.lastname: Sommer
mesh_terms: D000437:Alcoholism / Q000503:physiopathology; D000818:Animals; D003463:Cues; D058999:Drug-Seeking Behavior / Q000502:physiology*; D005108:Extinction, Psychological; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D055647:Rats, Transgenic
keywords: Daun02 inactivation method; alcohol self-administration; conditioned cues; medial prefrontal cortex; neuronal ensembles; reinstatement