title: Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.
abstract: Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types.
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Crofton
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Miroslav N
authors.initials: MN
authors.lastname: Nenov
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA; Biophysics Graduate Program, Institute of Human Physiology, Universita Cattolica, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Scala
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Page
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: McCue
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Dingge
authors.initials: D
authors.lastname: Li
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Hommel
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Laezza
authors.affiliation: Center for Addiction Research, The University of Texas Medical Branch, Galveston, TX, USA; Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA; Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA. Electronic address: tom.green@utmb.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D016739:Behavior, Addictive / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology; D003863:Depression / Q000235:genetics*; D055785:Gene Knockdown Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000502:physiology*; D007395:Interneurons / Q000502:physiology*; D008297:Male; D009714:Nucleus Accumbens / Q000502:physiology*; D051381:Rats; D012646:Self Administration
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D003042:Cocaine
keywords: Cocaine; Depression; Drug addiction; Nucleus accumbens; Self-administration; Tonically active neurons