Twice a year, normally diurnal songbirds engage in long-distance nocturnal migrations between their wintering and breeding grounds. If and how songbirds sleep during these periods of increased activity has remained a mystery. We used a combination of electrophysiological recording and neurobehavioral testing to characterize seasonal changes in sleep and cognition in captive white-crowned sparrows (Zonotrichia leucophrys gambelii) across nonmigratory and migratory seasons. Compared to sparrows in a nonmigratory state, migratory sparrows spent approximately two-thirds less time sleeping. Despite reducing sleep during migration, accuracy and responding on a repeated-acquisition task remained at a high level in sparrows in a migratory state. This resistance to sleep loss during the prolonged migratory season is in direct contrast to the decline in accuracy and responding observed following as little as one night of experimenter-induced sleep restriction in the same birds during the nonmigratory season. Our results suggest that despite being adversely affected by sleep loss during the nonmigratory season, songbirds exhibit an unprecedented capacity to reduce sleep during migration for long periods of time without associated deficits in cognitive function. Understanding the mechanisms that mediate migratory sleeplessness may provide insights into the etiology of changes in sleep and behavior in seasonal mood disorders, as well as into the functions of sleep itself.

Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including ⌬ 9 -THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of ⌬ 9 -THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving ⌬ 9 -THC (n ‫؍‬ 3) and SIV-infected macaques administered either vehicle (VEH/ SIV; n ‫؍‬ 4) or THC (THC/SIV; n ‫؍‬ 4). Chronic ⌬ 9 -THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ϳ28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4 ؉ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4...

D9 -Tetrahydrocannabinol (D 9 -THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic D 9 -THC use may impact HIV disease progression. We examined the impact of chronic D 9-THC administration (0.32 mg/kg im, 2Âdaily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV mac251 ; 100 TCID 50 /ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV mac251 inoculation resulted in measurable viral load, decreased lymphocyte CD4 þ /CD8 þ ratio, and increased CD8 þ proliferation. D 9 -THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic D 9 -THC administration decreased early mortality from SIV infection ( p ¼ 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass ( p ¼ NS). In vitro, D 9 -THC (10 mm) decreased SIV (10 TCID 50 ) viral replication in MT4-R5 cells. These results indicate that chronic D 9 -THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for D 9 -THC-mediated modulation of disease progression that warrant further study.T he cannabinoids including cannabidiol, cannabinol, and D 9 -tetrahydrocannabinol (D 9 -THC) exert their effects by binding to two major subtypes of cannabinoid receptor, CB1 and CB2.1 The CB1 receptor is preferentially expressed in the brain where it mediates neurobehavioral effects. The CB2 receptor is expressed primarily in peripheral tissues, particularly in immune cells where they have been shown to affect cytokine production, lymphocyte phenotype, function and survival, cell-mediated immunity, and balance of Th1/ Th2 cells.2 With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease frequently coexisting with chronic use of drugs of abuse, including marijuana. Using a well-established nonhuman primate model of HIV disease, we examined the impact of chronic intramuscular D 9 -THC (provided by the National Institute on Drug Abuse, Research Technical Branch, Rockville, MD) administration on the early phase of simian immunodeficiency virus (SIV) infection in age-matched (4-6 years old) and body weight-matched healthy male Indian-derived rhesus macaques. Chronic administration of D 9 -THC [or 0.05 ml/kg vehicle (VEH)] was initiated prior to SIV with 0.18 mg/kg, a dose that eliminated responding in a complex operant behavioral task in almost all of the subjects. The dose was subsequently increased for each subject to 0.32 mg/kg, over

Abuse of Δ 9 -THC by females during adolescence may produce long-term deficits in complex behavioral processes such as learning, and these deficits may be affected by the presence of ovarian hormones. To assess this possibility, 40 injections of saline or 5.6 mg/kg of Δ 9 -THC were administered i.p. daily during adolescence to gonadally intact or ovariectomized (OVX) female rats, yielding 4 treatment groups (intact/saline, intact/THC, OVX/saline, and OVX/THC). Δ 9 -THC (0.56-10 mg/kg) was then re-administered to each of the 4 groups during adulthood to examine their sensitivity to its disruptive effects. The behavioral task required adult subjects to both learn (acquisition component) different response sequences and repeat a known response sequence (performance component) daily. During baseline (no injection) and control (saline injection) sessions, ovariectomized subjects had significantly higher response rates and lower percentages of error in both behavioral components than the intact groups irrespective of saline or Δ 9 -THC administration during adolescence; the intact group that received Δ 9 -THC had the lowest response rates in each component. Upon re-administration of Δ 9 -THC, the groups that received adolescent ovariectomy alone, adolescent Δ 9 -THC administration alone, or both treatments were found to be less sensitive to the rate-decreasing effects, and more sensitive to the error-increasing effects of Δ 9 -THC than the control group (i.e., intact subjects that received saline during adolescence). Neurochemical analyses of the brains from each adolescent-treated group indicated that there were also persistent effects on cannabinoid type-1 (CB-1) receptor levels in the hippocampus and striatum that depended on the brain region and the presence of ovarian hormones. In addition, autoradiographic analyses of the brains from adolescent-treated, but behaviorally-naïve, subjects indicated that ovariectomy and Δ 9 -THC administration produced effects on receptor coupling in some of the same brain regions. In summary, chronic administration of Δ 9 -THC during adolescence in female rats produced long-term effects on operant learning and performance tasks and on the cannabinoid system that were mediated by the presence of ovarian hormones, and that altered their sensitivity to Δ 9 -THC as adults.

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