Effects of circadian desynchrony during adolescent alcohol exposure on immediate and long-term risk of alcohol addiction: role of sleep homeostasis and stress signaling - Despite ample evidence that adolescent alcohol abuse differs dramatically from adult alcohol dependence in
terms of both drinking habits and treatment needs, few interventions address the unique circumstances of the
typical teen. More than half of teenagers do not get enough sleep on a regular basis. This sleep disruption
increases sensitivity to stress and drives alcohol consumption in response to both sleep problems and anxiety.
19% of 12- to 20-year-olds report binge drinking in the past month, and 30% drink alcohol on a regular basis. In
addition to immediate risks such as academic difficulty, car accidents and even violence, almost half of these
adolescents will struggle with alcohol dependence at some point in their lives. To reduce alcohol abuse, we
need to improve sleep and reduce the stressors that lead adolescents to over-indulge in the first place. We have
developed a novel protocol to generate a weekday-weekend sleep pattern in adolescent mice, in order to model
circadian sleep disruption and study the ensuing effects on stress and alcohol intake. The proposed studies will
examine how circadian desynchrony and sleep homeostasis impact the self-perpetuating cycle of sleep
disruption, stress, and alcohol drinking in adolescence, the period of greatest vulnerability to the neurobiological
changes underlying addiction, and the long-term effects of this cycle on drinking in adulthood. Next, we will test
whether melatonin, which resets the internal clock and serves as a potent systemic cue for the switch from
daylight to nighttime physiological patterns, can restore sleep and reduce both stress and alcohol intake in our
models. In the first Aim, circadian phenotyping cages will be used to generate circadian desynchrony, then we
will assess alcohol drinking and sleep patterns, stress reactivity, and alcohol seeking after punishment in
adolescent male and female melatonin-proficient C57BL/6 mice, and we will correlate behavioral patterns with
the rhythmic release of corticosterone and melatonin, as well as with the rhythmic expression of circadian genes
and corticotropin releasing factor receptors. In a second group, we will follow the same adolescent protocol,
allow mice to age, then test the same behavioral measures in adulthood. In the second Aim, we will use timed
sleep restriction to awaken adolescent mice earlier than their natural wake-up time and follow the same
assessments as in Aim 1. We propose that circadian sleep disruptions will increase alcohol intake by disrupting
sleep, increasing stress activation, and increasing motivation to work for alcohol despite punishment. In Aim 3,
we will further explore the effects of alcohol and circadian sleep disruption on stress by examining how these
factors impact the activity of the molecular stress axis itself. This will provide an essential foundation of
knowledge about the interactions between the circadian sleep system and the stress axis in adolescent alcohol
abuse, the long-term effects of these interactions, and the potential for melatonin to both reduce alcohol intake
in adolescents and to reduce the risk of developing alcohol use disorders later in adulthood.
