"The technical support from SLAC Accelerator Directorate, Technology Innovation Directorate, LCLS laser division and Test Facility Division is gratefully acknowledged. We thank S.P. Weathersby, R.K. ...Jobe, D. McCormick, A. Mitra, S. Carron and J. Corbett for their invaluable help and technical assistance. Research at SLAC was supported through the SIMES Institute which like the LCLS and SSRL user facilities is funded by the Office of Basic Energy Sciences of the U.S. Department of Energy under Contract No. DE-AC02-76SF00515. The UED work was performed at SLAC MeV-UED, which is supported in part by the DOE BES SUF Division Accelerator & Detector R&D program, the LCLS Facility, and SLAC under contract Nos. DE-AC02-05-CH11231 and DE-AC02-76SF00515. Use of the Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515."and"Work at BNL was supported by DOE BES Materials Science and Engineering Division under Contract No: DE-AC02-98CH10886. J.C. would like to acknowledge the support from National Science Foundation Grant No. 1207252. E.E.F. would like to acknowledge support from the U.S. Department of Energy (DOE), Office of Basic Energy Sciences (BES) under Award No. DE-SC0003678."This has been corrected in both the PDF and HTML versions of the Article.
Abstract
Introduction:
Cerebral serotonin expression and sleep share a complex and as yet unclear association in early development. Though serotonin is linked with sleep-wake patterns in early ...childhood, whether this association emerges during infancy remains to be discovered. We hypothesized that the developing serotonergic system will be associated with the development of sleep-wake patterns.
Methods:
We investigated the associations between cerebral serotonin expression and sleep development during the first month of life in 152 nursery-reared infant rhesus macaques (Macaca mulatta). Cerebral serotonin expression was determined using cerebrospinal fluid serotonin metabolite 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, relative to weight, sampled at 2 and 4 weeks post-birth. Sleep-wake states were rated by trained observers every two hours from 0800-2000 hours. Sleep-wake states were scored as awake=1, drowsy=2, or asleep=3. For analyses, daytime sleep-wake states were averaged across the 7 days prior to each CSF sampling. Paired-samples t-test, Wilcoxon signed ranks test, and Spearman’s ρ were utilized to explore associations between time points, averages, and change scores (week 4 minus week 2) for both CSF 5-HIAA and sleep-wake states.
Results:
Daytime sleep (t(239)=17.27, p<.001) and CSF 5-HIAA (Z = -9.9, p<.001) decreased significantly from week 2 to week 4. Higher CSF 5-HIAA was associated with more daytime sleep during the first month of development (ρ=.25, p=.003). Lower week 2 CSF 5-HIAA predicted greater reductions in sleep from week 2-week 4 (ρ=.16, p=.05). Greater reductions in CSF 5-HIAA from week 2 to week 4 predicted lower sleep at week 4 (ρ=-.18, p =.03).
Conclusion:
These important findings are among the first to demonstrate that, from birth, daytime sleep-wake patterns are predicted by cerebral serotonin expression. Considering the link between serotonin, sleep, and mood disorders later in life, these results have exciting implications for improving sleep with serotonin interventions.
Support (If Any):
This research was supported by the Laboratory of Comparative Ethology at the National Institute of Child Health & Human Development, National Institute of Health.
In humans and macaques, a promoter polymorphism that decreases transcription of the serotonin transporter gene is associated with anxiety. Serotonin transporter gene disruption in rodents produces ...anxious animals with exaggerated limbic–hypothalamic–pituitary–adrenal (LHPA) responses to stress. We wanted to determine whether serotonin transporter gene promoter variation (rh-5HTTLPR) and rearing condition would interact to influence endocrine responses to stress in infant rhesus macaques.
Animals were reared with their mothers (MR,
n = 141) or in peer-only groups (PR,
n = 67). At 6 months of age, adrenocorticotropic hormone (ACTH) and cortisol levels were determined at baseline and during separation stress. Serotonin transporter genotype (
l/l and
l/s) was determined with polymerase chain reaction followed by gel electrophoresis.
Cortisol levels increased during separation, and there was a main effect of rearing condition, with decreased cortisol levels among PR macaques. Animals with
l/s rh5-HTTLPR genotypes had higher ACTH levels than did
l/l animals. Adrenocorticotropic hormone levels increased during separation, and there was a separation × rearing × rh5-HTTLPR interaction, such that PR-
l/s animals had higher ACTH levels during separation than did other animals studied.
These data demonstrate that serotonin transporter gene variation affects LHPA axis activity and that the influence of rh5-HTTLPR on hormonal responses during stress is modulated by early experience.
Vanadium dioxide (VO2), an archetypal correlated-electron material, undergoes an insulator-metal transition near room temperature that exhibits electron-correlation-driven and structurally driven ...physics. Using ultrafast temperature- and fluence-dependent optical spectroscopy and x-ray scattering, we show that multiple interrelated electronic and structural processes in the nonequilibrium dynamics in VO2 can be disentangled in the time domain. Specifically, following intense subpicosecond terahertz (THz) electric-field excitation, a partial collapse of the insulating gap occurs within the first picosecond. At temperatures sufficiently close to the transition temperature and for THz peak fields above a threshold of approximately 1 MV/cm, this electronic reconfiguration initiates a change in lattice symmetry taking place on a slower timescale. We identify the kinetic energy increase of electrons tunneling in the strong electric field as the driving force, illustrating a promising method to control electronic and structural interactions in correlated materials on an ultrafast timescale.
We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the ...stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.
Primate behavior is influenced by both heritable factors and environmental experience during development. Previous studies of rhesus macaques (
Macaca mulatta
) examined the effects of genetic ...variation on expressed behavior and related neurobiological traits (heritability and/or genetic association) using a variety of study designs. Most of these prior studies examined genetic effects on the behavior of adults or adolescent rhesus macaques, not in young macaques early in development. To assess environmental and additive genetic variation in behavioral reactivity and response to novelty among infants, we investigated a range of behavioral traits in a large number (
N
= 428) of pedigreed infants born and housed in large outdoor corrals at the Oregon National Primate Research Center (ONPRC). We recorded the behavior of each subject during a series of brief tests, involving exposure of each infant to a novel environment, to a social threat without the mother present, and to a novel environment with its mother present but sedated. We found significant heritability (
h
2
) for willingness to move away from the mother and explore a novel environment (
h
2
= 0.25 ± 0.13;
P
= 0.003). The infants also exhibited a range of heritable behavioral reactions to separation stress or to threat when the mother was not present (
h
2
= 0.23 ± 0.13–0.24 ± 0.15,
P
< 0.01). We observed no evidence of maternal environmental effects on these traits. Our results extend knowledge of genetic influences on temperament and reactivity in nonhuman primates by demonstrating that several measures of behavioral reactivity among infant rhesus macaques are heritable.
Studies on brain serotonin metabolism in human and nonhuman primates have indicated that dysfunction of serotonin transmission may play a role in the biological vulnerability to dependence on ...alcohol. Among young men, low sensitivity to alcohol intoxication predicts subsequent alcohol abuse and dependence.
The authors used single photon emission computed tomography and the radioligand (I)123beta-CIT ((I)123methyl 3beta-(4-iodophenyl) tropane-2-carboxylate) to measure the availability of serotonin transporters in 11 male rhesus monkeys, and the monkeys were genotyped for a functional polymorphism of the serotonin transporter gene. The 11 monkeys had experienced parental separation after birth; their behavior and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in CSF had been assessed regularly.
In the 5-year-old monkeys, there was a significant negative correlation between beta-CIT binding to serotonin transporters in the brainstem and 5-HIAA concentrations in CSF. Animals with greater beta-CIT binding and low CSF 5-HIAA concentrations displayed greater aggressiveness and were less sensitive to alcohol-induced intoxication. The genetic constitution of the serotonin transporter promoter gene did not significantly contribute to the availability of brainstem serotonin transporters as measured by beta-CIT binding.
In adult nonhuman primates who underwent early developmental stress, variables indicating a low serotonin turnover rate were associated with behavior patterns similar to those predisposing to early-onset alcoholism among humans.
Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from ...depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation/retardation. We studied the effects of 434 µg of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and18Ffluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments.
The purpose of this study was to assess the impact of early rearing and stress-induced rise of plasma cortisol collected during infancy as a biological predictors of adult alcohol consumption in ...nonhuman primates.
Ninety-seven female and male rhesus macaques (Macaca mulatta) were investigated. They were reared for their first 6 months of life either without mothers or other adults but with constant access to same-aged peers (peer-reared), or as controls with their mothers (mother-reared). When subjects reached 6 months of age, they underwent a series of four sequential weeks of 4-day social separations. Blood was drawn 1 and 2 hr after initiation of the 4-day separation periods, and the plasma was assayed for plasma cortisol concentrations. When the subjects were young adults (approximately 50 months of age), they were tested for voluntary intake of alcohol for 1 hr per day, 4 days a week, during a period of 5 to 7 weeks under normal living conditions.
The social separation challenge increased infant plasma cortisol concentrations, with peer-reared subjects exhibiting higher stress-induced cortisol concentrations than mother-reared animals. Subjects that responded to the social separation challenge with high cortisol levels consumed significantly more alcohol per kilogram of body weight as adults than subjects with a low cortisol response to the separation challenge, regardless of rearing condition. In addition, male and peer-reared subjects consumed significantly more alcohol than female and mother-reared subjects, respectively.
These findings suggest that early rearing experiences, such as adult absence, and high plasma cortisol concentrations early in life after a social separation stressor, are useful psychobiological predictors of future high alcohol consumption among nonhuman primates.
A nontrivial balance between Coulomb repulsion and kinematic effects determines the electronic structure of correlated electron materials. The use of electromagnetic fields strong enough to rival ...these native microscopic interactions allows us to study the electronic response as well as the time scales and energies involved in using quantum effects for possible applications. We use element-specific transient x-ray absorption spectroscopy and high-harmonic generation to measure the response to ultrashort off-resonant optical fields in the prototypical correlated electron insulator NiO. Surprisingly, fields of up to 0.22 V/angstrom lead to no detectable changes in the correlated Ni 3d orbitals contrary to previous predictions. A transient directional charge transfer is uncovered, a behavior that is captured by first-principles theory. Our results highlight the importance of retardation effects in electronic screening and pinpoints a key challenge in functionalizing correlated materials for ultrafast device operation.
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