Cyfip2 allelic variation in C57BL/6J and C57BL/6NJ mice alters free-choice ethanol drinking but not binge-like drinking or wheel-running activity.

Background: Since the origin of the C57BL/6 (B6) mouse strain, several phenotypically and genetically distinct B6 substrains have emerged. For example, C57BL/6J mice (B6J) display greater voluntary ethanol consumption and locomotor response to psychostimulants and differences in nucleus accumbens synaptic physiology relative to C57BL/6N (B6N) mice. A non-synonymous serine to phenylalanine point mutation (S968F) in the cytoplasmic FMR1-interacting protein 2 (Cyfip2) gene underlies both the differential locomotor response to cocaine and the accumbal physiology exhibited by these substrains.

Neurobiology of Circadian Rhythm Regulation.

In this review, we provide a summary of the field of mammalian circadian neurobiology circa 2015. While many additional details have emerged in the intervening 7 years, understanding of the fundamental structure and function of this critical neural system remains intact. Thus, the present review continues to provide a valuable introduction for those seeking an integrative multilevel overview of the circadian system.

Photic Regulation of Circadian Rhythms and Voluntary Ethanol Intake: Role of Melanopsin-expressing Intrinsically Photosensitive Retinal Ganglion Cells.

"Non-image-forming" (NIF) effects of light are mediated primarily by a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment, melanopsin (OPN4). These NIF functions include circadian entrainment, pupillary reflexes, and photic effects on sleep, mood, and cognition. We recently reported that mice of multiple genotypes exhibit reduced voluntary ethanol intake under both constant darkness (DD) and constant light (LL) relative to standard light-dark (LD) conditions.

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice.

Background: In alcohol-dependent individuals, acute alcohol withdrawal results in severe physiological disruption, including potentially lethal central nervous system hyperexcitability. Although benzodiazepines successfully mitigate such symptoms, this treatment does not significantly reduce recidivism rates in postdependent individuals. Instead, persistent affective disturbances that often emerge weeks to months after initial detoxification appear to play a significant role in relapse risk; however, it remains unclear whether genetic predispositions contribute to their emergence, severity, and/or duration.

Suppression of voluntary ethanol intake in mice under constant light and constant darkness.

Seasonal variations in photoperiod are associated with alterations in human mood and behavior. Similarly, manipulation of the environmental lighting regimen can exert pronounced effects on affective behavior in experimental animals. These observations may be due, in part, to light-induced alterations in circadian rhythms, but it seems likely that other, non-circadian factors also contribute.

Affective Behavior in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant Mice during Long-Term Alcohol Abstinence.

Background: While the acute alcohol withdrawal syndrome has been well characterized both in human clinical studies and in experimental animals, much less is known regarding long-term affective disturbances that can sometimes persist during protracted abstinence. Nevertheless, since relapse often occurs long after acute detoxification and may be predicted by persistent affective disruption, a better understanding of the long-term behavioral consequences of prior alcohol dependence may lead to improved strategies for relapse prevention.

Methods: Male and female Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice from the second selection replicate (WSP-2, WSR-2) were exposed to a 10-day chronic-intermittent ethanol vapor protocol (CIE) or plain air and then tested repeatedly on the sucrose preference test (SPT), marble burying test (MBT), and the light-dark box test (LDT) over 7 weeks of (forced) abstinence.

Neurobiology of Circadian Rhythm Regulation.

Over the past few decades, multilevel research has elucidated the basic neuroanatomy, neurochemistry, and molecular neurobiology of the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). The circadian timing system is composed of a large number of cellular oscillators located in the SCN, in non-SCN brain structures, and throughout the body. Cellular-level oscillations are generated by a molecular feedback loop in which circadian clock genes rhythmically regulate their own transcription, as well as that of hundreds of clock-controlled genes.

Chronobiology of ethanol: animal models.

Clinical and epidemiological observations have revealed that alcohol abuse and alcoholism are associated with widespread disruptions in sleep and other circadian biological rhythms. As with other psychiatric disorders, animal models have been very useful in efforts to better understand the cause and effect relationships underlying the largely correlative human data. This review summarizes the experimental findings indicating bidirectional interactions between alcohol (ethanol) consumption and the circadian timing system, emphasizing behavioral studies conducted in the author's laboratory.

Circadian activity rhythms and voluntary ethanol intake in male and female ethanol-preferring rats: effects of long-term ethanol access.

Chronic alcohol (ethanol) intake alters fundamental properties of the circadian clock. While previous studies have reported significant alterations in free-running circadian period during chronic ethanol access, these effects are typically subtle and appear to require high levels of intake. In the present study we examined the effects of long-term voluntary ethanol intake on ethanol consumption and free-running circadian period in male and female, selectively bred ethanol-preferring P and HAD2 rats.

Sex and regional differences in effects of chronic intermittent ethanol exposure on subsequent excitotoxic challenges in hippocampal slice cultures.

The organotypic hippocampal slice culture technique was used to study how the effects of repeated ethanol withdrawal might differ between males and females at the cellular level, including potential modulation of subsequent insults. A chronic intermittent ethanol (CIE) exposure paradigm was employed, with 3 days of exposure followed by 24 h withdrawal for 3 cycles. Slices were next exposed to corticosterone (CORT) or pentylenetetrazol (PTZ) for 24 h then imaged for propidium iodide (PI) signal intensities.

Selective breeding for ethanol-related traits alters circadian phenotype.

Previous studies in mice and rats have shown that selective breeding for high and low ethanol preference results in divergence of circadian phenotype in the selected lines. These results indicate that some alleles influencing ethanol preference also contribute to circadian rhythm regulation. Selective breeding has also been used to produce lines of mice differing in a number of other ethanol-related traits, while studies of phenotypic and genetic correlation indicate that diverse ethanol-related traits are influenced by both shared and unshared genetics.

Chronobiology of alcohol: studies in C57BL/6J and DBA/2J inbred mice.

Human alcoholics display dramatic disruptions of circadian rhythms that may contribute to the maintenance of excessive drinking, thus creating a vicious cycle. While clinical studies cannot establish direct causal mechanisms, recent animal experiments have revealed bidirectional interactions between circadian rhythms and ethanol intake, suggesting that the chronobiological disruptions seen in human alcoholics are mediated in part by alterations in circadian pacemaker function. The present study was designed to further explore these interactions using C57BL/6J (B6) and DBA/2J (D2) inbred mice, two widely employed strains differing in both circadian and alcohol-related phenotypes.

Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats.

We recently found that voluntary wheel running attenuated ethanol withdrawal-induced increased susceptibility to chemoconvulsant-induced seizures in male rats. Since female rats recover from ethanol withdrawal (EW) more quickly than male rats across several behavioral measures, this study was designed to determine whether the effects of exercise on EW seizures also exhibited sex differences. Animals were maintained under no-wheel, locked-wheel or free-wheel conditions and ethanol was administered by liquid diet for 14 days with control animals pair-fed an isocaloric diet, after which seizure thresholds were determined at 1 day or 3 days of EW.

Escalation of intake under intermittent ethanol access in diverse mouse genotypes.

Experimental animals offered continuous 24-hour free choice access to ethanol rarely display voluntary ethanol consumption at levels sufficient to induce intoxication or to engender dependence. One of the simplest ways to increase voluntary ethanol intake is to impose temporal limitations on ethanol availability. Escalation of ethanol intake has been observed in both rats and mice under a variety of different schedules of alternating ethanol access and deprivation.

Chronic shift-lag alters the circadian clock of NK cells and promotes lung cancer growth in rats.

Prolonged subjection to unstable work or lighting schedules, particularly in rotating shift-workers, is associated with an increased risk of immune-related diseases, including several cancers. Consequences of chronic circadian disruption may also extend to the innate immune system to promote cancer growth, as NK cell function is modulated by circadian mechanisms and plays a key role in lysis of tumor cells. To determine if NK cell function is disrupted by a model of human shift-work and jet-lag, Fischer (344) rats were exposed to either a standard 12:12 light-dark cycle or a chronic shift-lag paradigm consisting of 10 repeated 6-h photic advances occurring every 2 d, followed by 5-7 d of constant darkness.

Running wheel activity protects against increased seizure susceptibility in ethanol withdrawn male rats.

Ethanol withdrawal is a dysphoric condition that arises from termination of ethanol intake by dependent individuals. Common withdrawal symptoms include anxiety, increased reactivity to stimuli and increased seizure susceptibility as well as the risk of increased seizure severity. We use an animal model of dependence and withdrawal to study withdrawal behaviors and potential underlying neurobiological mechanisms.

Effects of withdrawal from chronic intermittent ethanol vapor on the level and circadian periodicity of running-wheel activity in C57BL/6J and C3H/HeJ mice.

Background: Alcohol withdrawal is associated with behavioral and chronobiological disturbances that may persist during protracted abstinence. We previously reported that C57BL/6J (B6) mice show marked but temporary reductions in running-wheel activity, and normal free-running circadian rhythms, following a 4-day chronic intermittent ethanol (CIE) vapor exposure (16 hours of ethanol vapor exposure alternating with 8 hours of withdrawal). In the present experiments, we extend these observations in 2 ways: (i) by examining post-CIE locomotor activity in C3H/HeJ (C3H) mice, an inbred strain characterized by high sensitivity to ethanol withdrawal, and (ii) by directly comparing the responses of B6 and C3H mice to a longer-duration CIE protocol.

Circadian wheel-running activity during withdrawal from chronic intermittent ethanol exposure in mice.

Alcohol withdrawal is associated with affective-behavioral disturbances in both human alcoholics and in animal models. In general, these phenomena are potentiated by increased alcohol exposure duration and by prior withdrawal episodes. Previous studies have also reported locomotor hypoactivity during ethanol withdrawal in rats and mice, but only in novel test environments and not in the home cage.

Effects of repeated light-dark phase shifts on voluntary ethanol and water intake in male and female Fischer and Lewis rats.

Several lines of evidence implicate reciprocal interactions between excessive alcohol (ethanol) intake and dysregulation of circadian biological rhythms. Thus, chronic alcohol intake leads to widespread circadian disruption in both humans and experimental animals, while in turn, chronobiological disruption has been hypothesized to promote or sustain excessive alcohol intake. Nevertheless, the effects of circadian disruption on voluntary ethanol intake have not been investigated extensively, and prior studies have reported both increased and decreased ethanol intake in rats maintained under "shift-lag" lighting regimens mimicking those experienced by shift workers and transmeridian travelers.

Circadian clock genes: non-circadian roles in sleep, addiction, and psychiatric disorders?

Elucidation of the cellular and molecular mechanisms of the circadian clock, along with the realization that these mechanisms are operative in both central and peripheral tissues, has revolutionized circadian biology. Further, these observations have resulted in an explosion of interest in the health implications of circadian organization and disorganization at both molecular and physiological levels. Thus, recent research has implicated mutations and polymorphisms of circadian clock genes in diabetes and obesity, cardiovascular disease, and cancer.

Functional neuroanatomy of sleep and circadian rhythms.

The daily sleep-wake cycle is perhaps the most dramatic overt manifestation of the circadian timing system, and this is especially true for the monophasic sleep-wake cycle of humans. Considerable recent progress has been made in elucidating the neurobiological mechanisms underlying sleep and arousal, and more generally, of circadian rhythmicity in behavioral and physiological systems. This paper broadly reviews these mechanisms from a functional neuroanatomical and neurochemical perspective, highlighting both historical and recent advances.

Chronic ethanol intake alters circadian phase shifting and free-running period in mice.

Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms.

Repeated light-dark phase shifts modulate voluntary ethanol intake in male and female high alcohol-drinking (HAD1) rats.

Background: Chronic disruption of sleep and other circadian biological rhythms, such as occurs in shift work or in frequent transmeridian travel, appears to represent a significant source of allostatic load, leading to the emergence of stress-related physical and psychological illness. Recent animal experiments have shown that these negative health effects may be effectively modeled by exposure to repeated phase shifts of the daily light-dark (LD) cycle. As chronobiological disturbances are thought to promote relapse in abstinent alcoholics, and may also be associated with increased risk of subsequent alcohol abuse in nonalcoholic populations, the present experiment was designed to examine the effects of repeated LD phase shifts on voluntary ethanol intake in rats.

Chronic ethanol intake modulates photic and non-photic circadian phase responses in the Syrian hamster.

Chronic alcohol intake disrupts sleep and other circadian biological rhythms in both human alcoholics and in experimental animals. Recent studies from our laboratory indicate that these effects may be due, in part, to ethanol-induced alterations in fundamental properties of the circadian pacemaker. The present study explored the effects of chronic voluntary ethanol intake (25% v/v) on circadian phase responses to both photic and non-photic stimuli in Syrian hamsters.