Losing Control: Excessive Alcohol Seeking after Selective Inactivation of Cue-Responsive Neurons in the Infralimbic Cortex
Open accessAbstract
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. SIGNIFICANCE STATEMENT: 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.
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Glutamatergic and GABAergic signaling in the ILC contributes to inhibitory control over alcohol seeking and relapse.
“Additionally, glutamatergic and GABAergic signaling in the ILC contributes to inhibitory control over alcohol seeking and relapse (29, 34–37).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [29]
GLP-1R expression in key reward- and stress-related brain regions may contribute to food and alcohol seeking and consumption.
“GLP-1R expression in these key reward- and stress-related brain regions may contribute to food (24-27) and alcohol (28–30) seeking and consumption.”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [29]
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- Authors
- Pfarr, S., Meinhardt, M. W., Klee, M. L., Hansson, A. C., Vengeliene, V., Schonig, K., Bartsch, D., Hope, B. T., Spanagel, R., & Sommer, W. H.
- Affiliations
- National Institutes of Health (US)
- Heidelberg University (DE)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-07-29
- Volume
- 35
- Issue
- 30
- Pages
- 10750-10761
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6605108
- OpenAlex
- W1962536263
- Cited by
- 143
- References
- 65
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 12 · 2023: 18 · 2022: 18 · 2021: 13 · 2020: 6 · 2019: 16 · 2018: 11 · 2017: 19 · 2016: 16
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB1134, SFB 636, subprojects B04)
- Bundesministerium für Bildung und Forschung (01ZX1311A)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- alcohol seeking, infralimbic cortex, medial prefrontal cortex, cue-induced reinstatement, neuronal ensembles, daunorubicin, c-fos, interneurons, stress-induced reinstatement, alcoholism, inhibitory control
- MeSH terms
- Alcoholism, Animals, Cues, Extinction, Psychological, Immunohistochemistry, Male, Neurons, Prefrontal Cortex, Rats, Rats, Transgenic, Drug-Seeking Behavior
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