Learned motivation drives circadian physiology in the absence of the master circadian clock

Abstract

The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (Meth) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-surgery and SCNX mice were treated with either Meth (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW. Only the association of Meth treatment and restricted RW access successfully reestablished entrained circadian rhythms in mice with SCNX. RW-likely acting as a link between the circadian and reward systems-promotes circadian entrainment of activity. We conclude that a conditioned drug response is a powerful tool to entrain, drive, and restore circadian physiology. Furthermore, an RW should be recognized as a potent input signal in addition to the conventional use as an output signal.-Rawashdeh, O., Clough, S. J., Hudson, R. L., Dubocovich, M. L. Learned motivation drives circadian physiology in the absence of the master circadian clock.

Keywords: SCN lesions; methamphetamine; running wheel.

Figure 1.

Circadian activity rhythms in sham-surgery and SCNX mice. A, B) Sham-surgery mice have a defined period of rest and activity, as evidenced by their actogram (A) and periodogram (B). C) Immunofluorescence (IF) for VIP is highly expressed in the intact SCN of sham-surgery animals. D, E) In contrast, SCNX mice display arrhythmic behavior without a distinct period of rest or activity as evidenced by their actogram (D) and periodogram (E). F) Note the absence of the VIP signal in SCNX mice.

Figure 2.

Meth alone is insufficient to reestablish circadian rhythmicity in SCNX mice. Horizontal activity of C3H/HeN mice that were treated with Meth or Veh was monitored by using HCS. Horizontal activity was recorded for at least 3 d before treatment. Injections began on d 14. A, D) Mice were intraperitoneally injected with either Veh (A) or meth (D) as indicated by the arrowheads. B, E) Intraperitoneal injections of Veh (B) and Meth (E) in sham-surgery mice had no influence on the period of free-running activity rhythms, as evidenced by the periodograms located below the actogram. C, F) Veh-treated (C) and Meth-treated (F) SCNX mice remained arrhythmic after treatment, confirmed by χ² analysis and resulting periodogram.

Figure 3.

Conditioned RW access reestablishes circadian rhythmicity in SCNX mice. Wheel-running activity of C3H/HeN mice treated with Meth or Veh. Mice were given 7 d of access to an RW, followed by a 7-d rest period. Injections and restricted access to RW began on d 14. A, D) Mice were intraperitoneally injected with either Veh (A) or Meth (D), as indicated by the arrows. Restricted access to RW was provided for 8 h/d beginning at the time of injection. After the treatment period, mice were provided with ad libitum access a RW for 7 d. B, E) Sham-surgery animals continued to free run with the same period before and after treatments (see periodogram below actogram), Veh (B) and Meth (E), and without shifting their activity rhythms. C, F) Associating Veh injections with RW access was ineffective in reestablishing rhythmicity in SCNX mice; however, associating Meth injections with RW access (F) successfully established free-running activity rhythms (compare pretreatment periodogram with posttreatment). HC, home cage.

Figure 4.

RW is necessary for the maintenance of circadian rhythmicity in SCNX mice. Wheel-running activity of C3H/HeN mice treated with Meth or Veh. Mice were given 7 d of continuous access to an RW, followed by 7 d with no access to RW, during which horizontal activity was recorded with HCS. Injections and restricted access to RW began on d 14. A, D) Mice were intraperitonally injected with either Veh (A) or Meth (D), as indicated by the arrows. Restricted access to RW was provided for 8 h/d beginning at the time of injection. After the treatment period, horizontal activity was recorded with HCS. B, E) Veh-treated (B) and Meth-treated (E) sham-surgery animals continued their endogenous rhythm posttreatment, as evidenced by the periodograms located below the actogram. C, F) Veh-treated (C) and Meth-treated (F) SCNX animals remained arrhythmic after treatment. HC, home cage.

Figure 5.

Temporal dissociation of Meth and RW treatments prevents reestablishment of circadian rhythmicity in SCNX mice. Wheel-running activity of C3H/HeN mice treated with Meth or Veh. Mice were given 7 d of continuous access to an RW, followed by 7 d without an RW. Injections and restricted access to RW began on d 14. A, D) Mice were intraperitoneally injected with either Veh (A) or Meth (D), as indicated by the arrows. Restricted access to RW was delayed by 8 h from the time of the injections. After the treatment period, mice were provided continuous RW access for 7 d. B, E) Veh-treated (B) and Meth-treated (E) sham-surgery mice maintained their endogenous rhythms posttreatment, as evidenced by the periodograms located below the actogram. C, F) Veh-treated (C) and Meth-treated (F) SCNX animals remained arrhythmic after treatment. HC, home cage.

Figure 6.

Proposed model for the reestablishment of rhythmicity by pairing rewarding stimuli. Meth acts within the mesolimbic system, which feeds into the MASCO. As a result, the animal’s motivation to exercise is enhanced, which drives the mice to operate the RW. After multiple exposures of Meth in conjunction with an RW, the driving properties of Meth are transferred to the RW. Once this conditioning is established, rhythmic RW activity will function to drive the MASCO on a daily basis, which results in cycling circadian activity.