Mediodorsal thalamus contributes to the timing of instrumental actions

Abstract

Interval timing relies on a widely dispersed network of cortical and subcortical brain regions. Despite increasing evidence emphasizing the integrative role of the thalamus in cognition, its contribution to timing behavior is poorly understood. Anatomically connected to brain regions within the canonical timing network such as the prefrontal cortex, amygdala, and striatum, the mediodorsal (MD) nucleus of the thalamus is ideally positioned to support proper timing behavior. In order to investigate the potential role of the MD on interval timing, localized and reversible pharmacological inhibition was done. Mice were trained across multiple timing paradigms in order to assess the generality of MD involvement in timing using an operant 30s peak-interval (PI) procedure as well as a 10s head-fixed (HF) task. Additionally, optical inhibition was conducted during a 30s PI procedure allowing for evaluation of MD contributions to different behavioral stages within a single trial. Lastly, whether the MD provides broad or localized support for cortical regions during timing behavior was investigated through optical inhibition of neurons predominantly innervating the prelimbic (PL) cortex, an area with well-established as important for interval timing behavior. The experiments conducted here provide substantial evidence for MD involvement in timing durations over multiple seconds, with pharmacological inhibition of the MD lead to significant deficits in the accuracy and precision of timing behavior. Additionally, optogenetic experiments found within trial inactivation to be state specific, with MD inhibition leading to delays in the transition from one behavior to another dependent on time of optical inhibition. Inhibition of MD projections localized mainly to the PL were unable to produce significant changes to timing behavior, though the effects were qualitatively similar. Together the work here demonstrates the importance of the MD to interval timing behavior and provides evidence that it does so through broad interactions across the prefrontal cortex.