Dual regulation of clock gene Per2 expression in discrete brain areas by the circadian pacemaker and...

Area of Science:

• Neuroscience
• Chronobiology
• Pharmacology

Background:

• Behavioral rhythms induced by methamphetamine (MAP) are known to be independent of the suprachiasmatic nucleus (SCN), the brain's master circadian pacemaker.
• The precise location and mechanism of the MAP-induced oscillator (MAO) remain largely unknown.

Purpose of the Study:

• To investigate the site and mechanism of the MAP-induced oscillator (MAO).
• To examine extra-SCN circadian rhythms in discrete brain areas following restricted MAP administration.

Main Methods:

• Rats were administered MAP in drinking water at a restricted time daily for 14 days (R-MAP) or ad libitum (ad-MAP). Control rats received plain water at a restricted time (R-Water).
• Clock gene Per2 expression was measured using a bioluminescence reporter in cultured brain tissues from SCN-intact and SCN-lesioned rats.
• Behavioral rhythms and Per2 expression rhythms were analyzed in the SCN, olfactory bulb (OB), caudate-putamen (CPU), and substantia nigra (SN).

Main Results:

• In SCN-intact rats, R-MAP induced MAO, leading to phase-delayed behavioral rhythms under ad-MAP. Circadian Per2 rhythms were unaffected in the SCN but phase-advanced in the OB, CPU, and SN.
• Following SCN lesion, MAO phase-shifted more slowly and lacked relative coordination. Circadian Per2 rhythms were significantly phase-shifted in the OB and SN compared to SCN-intact rats.
• These findings indicate that MAO induction by restricted MAP administration is associated with phase shifts in extra-SCN circadian oscillators within brain dopaminergic areas.

Conclusions:

• Extra-SCN oscillators in dopaminergic brain regions are components of the MAP-induced oscillator (MAO).
• These extra-SCN oscillators receive dual regulation from both the MAO and the SCN circadian pacemaker.
• This study elucidates the extra-SCN basis of methamphetamine-induced behavioral rhythms.