Direct Midbrain Dopamine Input to the Suprachiasmatic Nucleus Accelerates Circadian Entrainment

Abstract

Summary Dopamine (DA) neurotransmission controls behaviors important for survival including voluntary movement, reward processing, and detection of salient events such as food or mate availability. Dopaminergic tone also influences circadian physiology and behavior. Although the evolutionary significance of this input is appreciated, its precise neurophysiological architecture remains unknown. Here, we identify a novel, direct connection between the DA-neurons of the ventral tegmental area (VTA) and the suprachiasmatic nucleus (SCN). We demonstrate that D1 dopamine receptor (Drd1) signaling within the SCN is necessary for properly timed resynchronization of activity rhythms to phase-shifted light:dark cycles and that elevation of DA tone through selective activation of VTA DA-neurons accelerates photoentrainment. Our findings demonstrate a previously unappreciated role for direct DA input to the master circadian clock and highlight the importance of an evolutionarily significant relationship between the circadian system and the neuromodulatory circuits that govern motivational behaviors.

The intertwined roles of circadian rhythmsand neuronal metabolism fueling drug reward and addiction

“…These neurons concomitantly load DA vesicles with glutamate to facilitate this activity-dependent increase in DA loading and release. Recently, DA neurons from the VTA were shown to project directly to the SCN to resynchronize activity rhythms to photic phase shifting, implying alterations of dopaminergic neurotransmission to NAc may also impact the S N [145]. Further appreciation of subpopulations of midbrain dopaminergic projection neurons may help understand their possible pathway specific involvement in arousal, motivation, and reward [146].…”

Blunted Diurnal Firing in Lateral Habenula Projections to Dorsal Raphe Nucleus and Delayed Photoentrainment in Stress-Susceptible Mice

“…entrainment that modulate behaviours such as food gathering and social interactions (36,37). In light of observations that decreased VTA dopamine input to the SCN slows the rate of photoentrainment (38), decreased diurnal firing in cells DRN®SCN may be responsible for the delayed initial rate of photoentrainment in susceptible-mice. Moreover, our observations that the resilient-mice are able to photoentrainment much faster may be indicative of homeostatic adaptations resulting in large increases in day-time firing that we observed in DRN cells, a subset of which may be projecting to the SCN.…”

Circadian clock neurons mediate time-of-day dependent responses to light

“…After recovery, mice were transferred to wheel-running cages and housed in DD in a light-tight, temperature-and humidity-controlled chamber with food and water provided ad libitum. After allowing mice to free-run for multiple days, we injected them with clozapine-N-oxide (CNO, 1 mg/kg; Hello Bio) intraperitoneally 30 min prior to activity onset (Grippo et al, 2017). Mice were returned to their cages and allowed to free-run for multiple days and then injected again with CNO at CT 11.5, 30 min prior to a 15-min light pulse (bright (ranging from 5 x 10 15 to 2 x 10 16 photons/s/cm 2 throughout the cage) or dim (~4 x 10 14 photons/s/cm 2 ) light pulse, returned to their cages and allowed to free run for multiple days.…”

“…40 μm coronal sections containing the SCN were collected using a cryostat (Leica) and stored at 4℃ in PBS. Immunostaining was performed as previously described (Grippo et al, 2017;Tso et al, 2017). Primary antibodies used were rabbit anti-mCherry (ab168453, Abcam, 1:1000) and goat anti-c-Fos (sc52-G, Santa Cruz, 1:1000).…”