title: Acquisition of response thresholds for timed performance is regulated by a calcium-responsive transcription factor, CaRF.
abstract: Interval timing within the seconds-to-minutes range involves the interaction of the prefrontal cortex and basal ganglia via dopaminergic-glutamatergic pathways. Because the secreted protein brain-derived neurotrophic factor (BDNF) is able to modulate dopamine release as well as glutamatergic activity, we hypothesized that BDNF may be important for these timing mechanisms. Recently, the calcium-responsive transcription factor (CaRF) was identified as an important modulator of BDNF expression in the cerebral cortex. In this study, a strain of Carf knockout mice was evaluated for their ability to acquire the 'Start' and 'Stop' response thresholds under sequential and simultaneous training conditions, using multiple (15-second and 45-second) or single (30-second) target durations in the peak-interval procedure. Both Carf(+/-) and Carf(-/-) mice were impaired in their ability to acquire timed response thresholds relative to Carf(+/+) mice. Additionally, control mice given microinjections of BDNF antisense oligodeoxynucleotide to inhibit protein expression in the prefrontal cortex showed timing impairments during acquisition similar to Carf mice. Together, these results suggest that the inhibitory processes required to update response thresholds and exert temporal control of behavior during acquisition may be dependent on CaRF regulation of genes including Bdnf in cortico-striatal circuits.
authors.affiliation: Laboratory of Chronobiology, Department of Science and Technology, National University of Quilmes, Buenos Aires, Argentina.
authors.forename: P V
authors.initials: PV
authors.lastname: Agostino
authors.forename: R-K
authors.initials: RK
authors.lastname: Cheng
authors.forename: C L
authors.initials: CL
authors.lastname: Williams
authors.forename: A E
authors.initials: AE
authors.lastname: West
authors.forename: W H
authors.initials: WH
authors.lastname: Meck
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003214:Conditioning, Classical; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology; D011930:Reaction Time; D013998:Time Perception; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C448259:Carf protein, mouse; D014157:Transcription Factors
keywords: Calcium-responsive transcription factor; GABA; cortico-striatal circuits; dopamine; glutamate; interval timing; time perception