To study the effect of basal forebrain optogenetic cholinergic activation in an interval timing task in freely behaving animals.

Cholinergic deficit is a major feature in patients with Alzheimer’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Parkinson’s and Alzheimer’s patients can have impairments in interval timing, or the ability to control movements in time. Timing is preserved across mammalian species, and timing tasks require subjects to estimate an interval of several seconds. These tasks require attention to time and working memory for temporal rules. Mice receiving scopolamine, a cholinergic inhibitor, perform poorly during timing tasks. Interval timing involves medial prefrontal cortical areas that receive prominent cholinergic input; our recent work showed that scopolamine impairs interval timing through disrupting stimulus-processing rather than temporal processing in the medial prefrontal cortex. However, it is unclear whether basal forebrain cholinergic neuron activation could improve timing performance.     

ChAT-Cre transgenic mice were trained on a 12s interval timing task before bilateral basal forebrain stereotactic AAV-DIO-ChR2 injection and optic canulae implantation (AP -0.7, ML +/-1.8, DV AAV injection at -4.0 and -5.0, with optic canulae at -3.5). Laser (473nm) stimulation was assigned on/off randomly across trials, and interval timing tasks were performed 30 min after intraperitoneal scopolamine (1mg/kg) or normal saline injections.

Scopolamine induced interval-timing deficits were partially reversed by optogenetic activation of basal forebrain cholinergic neurons with 20Hz stimulation but not 4 Hz.

Optogenetic activation of the basal forebrain cholinergic neurons improves interval timing performance. These data may have relevance for our understanding of cholinergic function in human diseases such as Parkinson’s disease and Alzheimer’s disease.