title: Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes.
abstract: Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner.
authors.affiliation: Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1065, New York, NY 10029, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Lucas
authors.affiliation: Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1065, New York, NY 10029, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Jegarl
authors.affiliation: Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1065, New York, NY 10029, USA. Electronic address: roger.clem@mssm.edu.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Clem
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005260:Female; D007395:Interneurons / Q000378:metabolism*; D007859:Learning Disabilities / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020813:Receptor, trkB / Q000172:deficiency* / Q000235:genetics; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics; D019956:Stereotypic Movement Disorder / Q000235:genetics; D015837:Vestibular Diseases / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D019208:Brain-Derived Neurotrophic Factor; D008164:Luminescent Proteins; D010320:Parvalbumins; C054562:yellow fluorescent protein, Bacteria; D020813:Receptor, trkB
keywords: Circling; Extinction; Fear conditioning; Ntrk2; Vestibular