title: Compulsive Social Behavior Emerges after Selective Ablation of Striatal Cholinergic Interneurons.
abstract: The mechanisms underlying social dysfunction in neuropsychiatric conditions such as obsessive-compulsive disorder and Tourette syndrome remain uncertain. However, it is known that dysfunctions in basal ganglia, including a reduced number of striatal cholinergic interneurons (SCIN), are involved in their pathophysiology. To explore the role of SCIN in relation to perseverative behaviors, we characterized a new transgenic mouse model in which inducible ablation of SCIN is achieved with high efficiency in a cell-type- and region-specific manner. Mice were subjected to extensive behavioral testing, including assessment of social behaviors, and corticostriatal functional connectivity was evaluatedin vivoSelective SCIN ablation leads to altered social interactions together with exacerbated spontaneously emitted repetitive behaviors. Lesioned mice showed normal motor coordination, balance, and general locomotion. Interestingly, only environmentally driven, but not self-directed, repetitive behaviors were exacerbated in lesioned mice. Remarkably, in mice with SCIN ablation, the normal pattern of social exploration was replayed continuously. The emerging pattern of social interactions is highly predictable and invariant across time.In vivoelectrophysiological recordings indicate that SCIN ablation results in an increase of the functional connectivity between different cortical areas and the motor, but not associative, region of the striatum. Our results identify a role of SCIN in suppressing perseverative behaviors, including socially related ones. In sum, SCIN ablation in mice leads to exacerbated ritualistic-like behaviors that affect social performance, providing a link between SCIN dysfunction and the social impairments present in psychiatric disorders.SIGNIFICANCE STATEMENTWe sought to uncover the impact of striatal cholinergic interneuron (SCIN) degeneration on perseverative behaviors related to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We found that extensive SCIN ablation results in exacerbated social interactions, in which normal social contacts were replayed continuously in a highly stereotyped, ritualistic pattern. SCIN ablation also leads to an increase in other spontaneously emitted repetitive behaviors without alteration of motor coordination, balance, or locomotion. Moreover, we identify an increase of functional connectivity between frontal cortical areas and the motor region of the striatum as a putative substrate for the observed behavioral alterations. Therefore, perseveration induced by SCIN ablation extends to social performance as occurs in neuropsychiatric conditions such as OCD and TS.
authors.affiliation: Universidad de Buenos Aires. Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina, and CONICET-Universidad de Buenos Aires, Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay), Grupo de Neurociencia de Sistemas, Buenos Aires 1121, Argentina.
authors.forename: Yanina V
authors.initials: YV
authors.lastname: Martos
authors.affiliation: Universidad de Buenos Aires. Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina, and CONICET-Universidad de Buenos Aires, Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay), Grupo de Neurociencia de Sistemas, Buenos Aires 1121, Argentina.
authors.forename: Barbara Y
authors.identifier: 0000-0002-9296-5031
authors.initials: BY
authors.lastname: Braz
authors.affiliation: Universidad de Buenos Aires. Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina, and CONICET-Universidad de Buenos Aires, Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay), Grupo de Neurociencia de Sistemas, Buenos Aires 1121, Argentina.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Beccaria
authors.affiliation: Universidad de Buenos Aires. Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina, and CONICET-Universidad de Buenos Aires, Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay), Grupo de Neurociencia de Sistemas, Buenos Aires 1121, Argentina.
authors.forename: M Gustavo
authors.initials: MG
authors.lastname: Murer
authors.affiliation: Universidad de Buenos Aires. Facultad de Medicina, Departamento de Fisiología, Buenos Aires, Argentina, and CONICET-Universidad de Buenos Aires, Instituto de Fisiología y Biofísica "Bernardo Houssay" (IFIBIO-Houssay), Grupo de Neurociencia de Sistemas, Buenos Aires 1121, Argentina jbelforte@fmed.uba.ar.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Belforte
mesh_terms: D000200:Action Potentials; D000818:Animals; D059329:Cholinergic Neurons; D003192:Compulsive Behavior / Q000150:complications / Q000503:physiopathology*; D003342:Corpus Striatum / Q000503:physiopathology*; D007395:Interneurons; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000503:physiopathology; D012919:Social Behavior; D012920:Social Behavior Disorders / Q000150:complications / Q000503:physiopathology*
keywords: cholinergic interneurons; corticostriatal connectivity; genetic ablation; mice; social behavior; striatum