Circadian clock in the lateral habenula affects motor function in mice through the regulation of daily rhythms in the nigrostriatal pathway

ABSTRACT Alterations to the dopaminergic system can have several consequences on behaviour such as the development of disorders like addiction, schizophrenia, and Parkinsons. The lateral habenula (LHb) is uniquely positioned to act on a large group of dopaminergic (DA) neurons, sending inhibitory signals both directly and indirectly to the ventral tegmental area (VTA) and the substantia nigra (SN). Additionally, the LHb houses a circadian clock that appears to function independently from the central circadian pacemaker. We investigated the role of the LHb as a pacemaker for the production and release of DA along the nigrostriatal pathway. Using male and female Bmal1 floxed mice, we injected AAV-2/9 Cre-eGFP virus into the LHb to selectively knockout Bmal1 , a clock gene essential for clock functioning. We found a significant impact on motor functioning in both male and female knockout mice. Analysis of daily rhythms of expression of circadian clock genes and genes involved in DA synthesis, and liquid chromatography coupled mass spectrometry for striatal DA measurements revealed blunting of rhythms in the dorsal striatum (DS) and (SN) of knockout animals, that may contribute to the observed behavioural phenotype. As proper functioning of the striatum is likely maintained by a mutual interaction of the circadian clock and DAergic system, these findings support that disrupting the LHb clock can impact functioning of the nigrostriatal DA pathway.