Acquisition of response thresholds for timed performance is regulated by a calcium‐responsive transcription factor, CaRF

• Published in: Genes, brain and behavior Vol. 12; no. 6; pp. 633 - 644
• Main Authors: Agostino, P. V., Cheng, R.‐K., Williams, C. L., West, A. E., Meck, W. H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2013; Blackwell; John Wiley & Sons, Inc
• Subjects: Acquisitions & mergers; Animals; Behavioral psychophysiology; Biological and medical sciences; Brain; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Calcium‐responsive transcription factor; Conditioning, Classical; cortico‐striatal circuits; dopamine; Fundamental and applied biological sciences. Psychology; GABA; glutamate; interval timing; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Miscellaneous; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiology; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Reaction Time; Time Perception; Transcription Factors - genetics; Transcription Factors - metabolism; Calcium-responsive transcription factor; Calcium; Central nervous system; Cognition; Genetic determinism; Encephalon; Learning; Regulation(control); Acquisition process; interval timing; Genetics; Time interval; Brain derived neurotrophic factor; Transcription factor; Dopamine; Rodentia; Basal ganglion; Corpus striatum; Catecholamine; Gene expression; Glutamate; cortico-striatal circuits; Time perception; Vertebrata; Mammalia; Mouse; Animal; Knockout mouse; Excitatory aminoacid; Neurotransmitter; GABA; Timing; time perception; dopamine; glutamate
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12059

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. This is the first demonstration that the processes required to set response thresholds for short‐interval estimation, and thus the exertion of temporal control of behavior, may be dependent on CaRF (calcium‐response factor) regulation of genes including brain‐derived nerve growth factor (Bdnf) in cortico‐striatal circuits. As a consequence, these findings are of potential interest to scientists studying signal transduction mechanisms in the brain that are coupled to the learning of specific behaviors, including interval timing.