Long-term effects of neonatal alcohol exposure on photic reentrainment and phase-shifting responses of the activity rhythm in adult rats

Abstract

In rats, neonatal alcohol (EtOH) exposure coinciding with the period of rapid brain growth produces structural damage in some brain regions that often persists into adulthood and thus may have longterm consequences in the neural regulation of behavior. Because recent findings indicate that the circadian clock located in the rat suprachiasmatic nucleus is vulnerable to alcohol-induced insults during development, the present study examined the long-term effects of neonatal alcohol exposure on the photic regulation of circadian behavior in adult rats. Rat pups were exposed to alcohol (3.0, 4.5, or 6.0 g·kg -1 ·day -1 ) or isocaloric milk formula on postnatal days 4-9 using artificial-rearing methods. At 2 months of age, animals were housed individually and circadian wheel-running behavior was continuously analyzed to determine the effects of neonatal alcohol treatment on the rate of reentrainment to a 6-h advance in the 12-h light:12-h dark photoperiod and the phase-shifting properties of free-running rhythms in response to discrete light pulses on a background of constant darkness. For all doses, neonatal alcohol exposure had a significant effect in reducing the time for reentrainment such that EtOH-treated rats required four to five fewer days than control animals for stable realignment of the activity rhythm to the shifted light-dark cycle. Coupled with the accelerated rate of reentrainment, the amplitude of light-evoked phase delays at circadian time 14 and advances at circadian time 22 in the 4.5 and 6.0 g·kg -1 ·day -1 EtOH groups was almost twofold greater than that observed in control animals. The present observations indicate that the mechanisms by which photic signals regulate circadian behavior are permanently altered following alcohol exposure during the period of rapid brain development. These long-term alterations in the photic regulation of circadian rhythms may account, at least partially, for some neurobehavioral consequences of prenatal alcohol exposure in humans such as depression.

Effects of neonatal alcohol exposure on vasoactive intestinal polypeptide neurons in the rat suprachiasmatic nucleus

“…Initial evidence for alcohol-induced damage to the RHT–SCN photoentrainment pathway during brain development is derived from functional studies indicating that prenatal exposure to alcohol alters the light–dark regulation of the rat rhythm in deep body temperature (Sei et al, 2003). Consistent with this effect of alcohol exposure during brain development on SCN timekeeping function, our previous studies demonstrate that neonatal alcohol treatment produces long-term changes in the photic regulation of rat circadian rhythm in wheel-running behavior, including the pattern of photoentrainment, rate of re-entrainment to shifted light–dark cycles, and phase-shifting responses to light (Allen et al, 2005a, 2005b; Farnell et al, 2004). …”

“…To maintain consistency with our previous studies analyzing the long-term effects of neonatal alcohol exposure on circadian behavior (Allen et al, 2005a, 2005b; Farnell et al, 2004), male subjects were used exclusively in the present experiments. All animals were born and reared in the vivarium at the Texas A&M University System Health Science Center under a standard 12 h light:12 h dark photoperiod (LD 12:12; lights-on at 0600 h).…”

“…Neonatal alcohol treatment produces long-term perturbations in the photic regulation of the circadian rhythm in rat wheel-running activity, including the phase angle of entrainment to LD 12:12 (Allen et al, 2005b), the rate of re-entrainment to an abrupt shift in the light–dark cycle (Allen et al, 2005a), and phase-shifting responses to brief pulses of light (Allen et al, 2005a; Farnell et al, 2004). The potential link between the observed reduction in the population of VIP neurons within the SCN and these alterations in the light–dark regulation of the activity rhythm in alcohol-exposed rats is corroborated by the observations that (1) SCN neurons containing VIP receive direct retinal innervation (Ibata et al, 1989); (2) when delivered to the SCN in vivo or in vitro, this neuropeptide produces phase shifts similar to those induced by light (Albers et al, 1984; Meyer-Spasche and Piggins, 2004; Piggins et al, 1995); and (3) circadian entrainment to LD cycles and phase-shifting responses to light pulses are altered in mice lacking the VIP receptor, VPAC2 (Vipr2 −/− ) (Hughes and Piggins, 2008).…”

Characteristics of Home Cage Locomotion in Cynomolgus Monkeys

“…It is well-known that various drugs such as caffeine, theophylline, and lithium can affect circadian rhythms (Ehret et al, 1975;McEachron et al, 1982). In fact, various toxicants such as cholinergic neurotoxin, alcohol, acetylcholinesterase inhibitor and cocaine have been reported to cause changes in circadian rhythms and locomotor activity in experimental animals (Endo et al, 2001;Allen, 2005;Timofeeva and Gordon, 2002). These findings indicate that behavioral changes may be associated with the adverse effects of many toxicants.…”

“…It is possible that the behavioral changes of the monkeys may be an index of the toxic effect, since the cage-side observation of monkeys might cause them to seldom or never show any overt toxic signs in toxicological studies. In fact, various toxicants such as cholinergic neurotoxin, alcohol, acetylcholinesterase inhibitor, and cocaine have been reported to cause changes in circadian rhythms and locomotor activity in experimental animals (Endo et al, 2001;Allen, 2005;Timofeeva and Gordon, 2002). Therefore, the present finding of overall animal movements using a camera system may serve as useful basic data for behavioral assessment in toxicological studies using monkeys.…”