Esa1p is an essential histone acetyltransferase required for cell cycle progression.

Histones are dynamically modified during chromatin assembly, as specific transcriptional patterns are established, and during mitosis and development. Modifications include acetylation, phosphorylation, ubiquitination, methylation, and ADP-ribosylation, but the biological significance of each of these is not well understood. For example, distinct acetylation patterns correlate with nucleosome formation and with transcriptionally activated or silenced chromatin, yet mutations in genes encoding several yeast histone acetyltransferase (HAT) activities result in either no cellular phenotype or only modest growth defects. Here we report characterization of ESA1, an essential gene that is a member of the MYST family that includes two yeast silencing genes, human genes associated with leukemia and with the human immunodeficiency virus type 1 Tat protein, and Drosophila mof, a gene essential for male dosage compensation. Esa1p acetylates histones in a pattern distinct from those of other yeast enzymes, and temperature-sensitive mutant alleles abolish enzymatic activity in vitro and result in partial loss of an acetylated isoform of histone H4 in vivo. Strains carrying these mutations are also blocked in the cell cycle such that at restrictive temperatures, esa1 mutants succeed in replicating their DNA but fail to proceed normally through mitosis and cytokinesis. Recent studies show that Esa1p enhances transcription in vitro and thus may modulate expression of genes important for cell cycle control. These observations therefore link an essential HAT activity to cell cycle progression, potentially through discrete transcriptional regulatory events.

Fluoxetine treatment alters leukocyte trafficking in the intrathecal compartment of the young primate.

To evaluate possible long-term effects of exposure to monoaminergic drugs, blood and cerebrospinal fluid (CSF) samples were collected from adolescent monkeys that had been treated with desipramine and fluoxetine in infancy. This evaluation focused on the number and type of leukocytes in CSF as a reflection of cell trafficking in the intrathecal compartment. Monkeys administered fluoxetine 2 years prior to the sample collection evinced significantly higher numbers of leukocytes in CSF than did either control or desipramine-treated subjects. The elevated cell count was accounted for primarily by increased numbers of CD4+ and CD8+ lymphocytes. The finding of higher cell numbers in CSF was replicated in a second sample from the fluoxetine-treated monkey obtained 1.5 years later. Because the cell profile in blood was unaffected by the prior drug treatments, these observations indicate a need for further study of serotonergic influences on regulation of the intrathecal compartment in the developing individual.

Biogenic amine activity in response to fluoxetine and desipramine in differentially reared rhesus monkeys.

BACKGROUND: It has been hypothesized that adverse early experience may be a mechanism by which children become vulnerable to later psychopathology via alteration of neurochemical or hormonal systems associated with such disorders. Such effects may in turn affect later responses to pharmacologic agents that act on these systems. METHODS: In this study, 18 mother-reared (MR) and 18 peer-reared (PR) rhesus monkeys experienced six 1-week separations from cagemates interspersed with 1-week reunions, while housed in like-reared groups of 3. Within rearing groups, equal numbers of animals received either fluoxetine (2 mg/kg), desipramine (5 mg/kg) or placebo delivered daily beginning 4 weeks before the first separation. Levels of norepinephrine (NE), the NE metabolite MHPG, the dopamine metabolites DOPAC and HVA, and the serotonin metabolite 5HIAA were measured in CSF samples collected approximately every 2 to 3 weeks during these procedures. RESULTS: Following treatment, DMI increased NE and decreased MHPG in the DMI-treated groups, while 5HIAA was decreased in the fluoxetine-treated groups following treatment. The increase in NE was followed by a sharp decline over the course of treatment, which was accompanied by an increase in MHPG. The rearing groups did not show a differential response to the drug treatments, and the separation manipulation itself had few effects. The mother-reared group showed higher levels of NE and DOPAC over all samples and higher levels of HVA in most samples. CONCLUSIONS: These rearing effects on biogenic amine activity were observed even in the presence of pharmacologic treatments that effectively altered the activity of these systems, and are consistent with previous findings from the same subject. The higher NE values observed in mother-reared infants over separations and reunions may have been due to higher basal levels of NE than peer-reared monkeys or to greater responsiveness to the stress of repeated social disruption or both. These findings agree with other primate studies showing that rearing differences persist beyond the infancy period and add to growing evidence of the important influence of the early social environment on neurobiologic development in primates.

Rearing experience and biogenic amine activity in infant rhesus monkeys.

In this report we present evidence that early social experience influences aspects of the function of brain biogenic amine systems, most notably the noradrenergic system. Biogenic amine activity was studied in mother- vs. peer-reared monkey infants over the first 6 months of life and in response to two housing transitions. Norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebrospinal fluid (CSF) were measured. Peer-reared monkeys showed significantly higher CSF levels of norepinephrine and MHPG than mother-reared animals over early development, but showed an attentuated NE response to separation and group formation compared to mother-reared animals. Peer-reared monkeys showed a greater developmental decline in 5-HIAA levels than mother-reared monkeys. There were no rearing effects for DOPAC or HVA over early development; however, peer-reared monkeys showed significantly lower HVA and DOPAC concentrations at 6-8 months of age. The results add to evidence for the influence of primate mothers on the psychobiological development of central nervous system neurotransmitter systems in their infants, and suggest that the noradrenergic system is among the more sensitive of these to early experience.

Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys.

Susceptibility to several human psychopathological disorders is under partial genetic influence, and many of these disorders have biological correlates that may form part of the basis of this vulnerability. In humans, alterations in cerebrospinal fluid (CSF) metabolite levels of the amine transmitters norepinephrine, dopamine, and serotonin have been associated with several forms of psychopathology, and altered levels of these metabolites have been found in healthy probands with a familial history of such illnesses. We report evidence for heritability of CSF levels of biogenic amine measures in rhesus monkeys, Macaca mulatta. In a pilot study of 54 monkeys with known pedigrees, significant differences among sire families were found for CSF levels of norepinephrine (p = 0.04), homovanillic acid (p = 0.02), and 5-hydroxyindoleacetic acid (p = 0.04). These data indicate that variation in bioaminergic measures is associated with pedigree, and that model systems incorporating both genetic and environmental factors can contribute to the understanding of the function of aminergic systems implicated in vulnerability to psychopathology.

The behavioral neurobiology of self-injurious behavior in rhesus monkeys.

1. Self-injurious behavior (SIB) is prevalent among institutionalized children, but the efficacy of current behavioral and pharmacological treatments is marginal. 2. There is evidence that SIB in humans has a neurobiological basis. A better understanding of the neurobiological factors that may promote or cause SIB is necessary for the development of effective pharmacologic treatments. 3. SIB that is similar in some respects to SIB in humans occurs in nonhuman primates that have been deprived of social experience early in life. An analysis of the "cause" of SIB suggests that it is a relatively straight-forward example of the development of neurobiological and behavioral aspects of aggressive behavior in the absence of social factors that would normally bring the behavior under environmental control. Once induced, however, it becomes environmentally autonomous and its proximal cause is neurobiological in nature. 4. There are three lines of evidence that nonhuman primate SIB is linked to malfunctions in the norepinephrine (NE) and serotonin (5HT) neurotransmitter systems. The activity of these systems appears to be altered by psychosocial deprivation. The functional relationship between the two systems appears to be altered or absent in socially deprived monkeys. Pharmacologic agents that act on these systems alter SIB in monkeys. 5. Preliminary data from socially deprived rhesus monkeys are consistent in major respects with studies linking altered serotonin systems to self-injurious behavior and suicidal motivation in humans who also probably suffer from social deprivation. 6. Taken together, these findings indicate that developmental study of biogenic amine systems, particularly finding ways to circumvent deficits in, or restore functional linkages between, the 5HT and NE systems, will lead to a greater understanding of the neurobiologic basis of SIB in humans and animals and will enable us to develop more effective treatments of SIB.

Dominance rank, cortisol concentrations, and reproductive maturation in male rhesus macaques.

Among adolescent male rhesus macaques, Macaca mulatta, the highest ranking individual within a cohort has higher testosterone concentrations at a younger age, earlier in the mating season, and for a longer duration than his lower ranking conspecifics. We sought to determine whether such a rank-related pattern of reproductive maturation could be a function of differences in glucocorticoid levels. A 2-yr longitudinal study of a cohort of adolescent males living in a heterosexual group in a one acre outdoor enclosure revealed no differences in cortisol concentrations between high and low status males. Cortisol was not inversely correlated with testosterone in either adolescent or adult males. Young pubescent males had increases in cortisol levels coincident with maturation, while older adolescent males had cortisol concentrations comparable to those of adult males. Low ranking males tended to have more variable cortisol concentrations across time. We conclude that cortisol concentrations are not a function of dominance status and that the timing of reproductive maturation in male rhesus macaques is independent of cortisol concentrations.

Antidepressant treatment during social challenge prior to 1 year of age affects immune and endocrine responses in adult macaques.

Antidepressants are widely used in treating depression and other behavioral problems in children and adolescents. Little is known about the long-term effects of these agents, particularly on physiological systems. The effects of previous antidepressant treatment during a social challenge in 9-month-old rhesus monkeys (Macaca mulatta) on their adult immune and endocrine responses were studied. Prior to the social challenge, the monkeys were reared either by their mother or in a peer group. Monkeys were treated with either a serotonergic agonist (fluoxetine), a noradrenergic agonist (desipramine), or saline during social separation. Non-separated, saline-treated monkeys served as control monkeys. In order to evaluate immune effects of early antidepressant treatment, adult monkeys were immunized with a novel antigen, tetanus toxoid. Blood samples were collected prior to and at 4-5-day intervals for 28 days after immunization. Plasma total immunoglobulins (IgG and IgM), complement levels (C3 and C4), tetanus antibody titers, and cortisol were assessed. Antibody levels were lowest in monkeys treated with antidepressants regardless of specific drug treatment or early rearing condition. Drug-treated subjects had elevated plasma immunoglobulins and complement protein levels. Cortisol was also highest in drug-treated subjects. These results should be considered when prescribing commonly used antidepressants for treatment of childhood disorders.

Effects of rearing condition on HPA axis response to fluoxetine and desipramine treatment over repeated social separations in young rhesus monkeys.

Normal hypothalamic-pituitary-adrenal (HPA) axis activity is disrupted in several types of human psychiatric disorders, and has been widely reported to be altered as a result of early experience in rodents. In this study the effects of early social experience on later response of the HPA axis to separations from cagemates and pharmacologic treatments were examined in rhesus monkeys. HPA axis activity was measured in mother-reared and peer-reared monkey infants in conjunction with six repeated separations from and reunions with their cagemates. Within each rearing group, infants were assigned to one of three treatment groups that received continuous treatment with either fluoxetine (2 mg/kg), desipramine (DMI, 5 mg/kg) or placebo (saline) beginning 2 weeks prior to separations. At 2 weeks after drug treatment, fluoxetine increased ACTH and cortisol in the treated groups, while DMI decreased ACTH and cortisol in both treated groups; however, these effects were not persistent over the separations. While these treatment effects tended to be more pronounced in the mother-reared group, the rearing groups did not show a clearly differential response to either of the treatments. The most prominent finding was that mother-reared monkeys showed significantly higher ACTH and cortisol levels than peer-reared monkeys over all samples, an effect that may have mitigated a potential rearing group difference in treatment response. The results add to growing evidence for the influence of primate mothers on the functional development of psychobiological systems in their infants, and suggest that the HPA axis is among the more sensitive of these systems to postnatal experience.

Behavioral contrasts between male cynomolgus and lion-tailed macaques.

Evidence indicates that primate species differ not only in social structure and concordant social propensities, but also in their approach toward novel objects, environments, and procedures. These differences in response dispositions have been described as being based on differences in characteristic stances toward the environment, also called temperaments. This report extends previous comparative primate research by describing behavioral contrasts observed among males of two macaque species, liontailed and cynomolgus macaques. The lion-tails demonstrated more interest in other animals, more vigilance and instrumental behavior, and more readily adapted to training to enter a small and unfamilar cage than the cynomolgus. These results suggest temperamental differences between the two species. Lion-tails may be characterized as bold, curious, and instrumental in their approach to the environment, while cynomolgus may be characterized as more passive or "reserved". These differences may form the basis for the well-developed sensorimotor abilities observed in liontails such as the manufacture and use of tools, and may also be related to their highly omnivorous diet. © 1993 Wiley-Liss, Inc.

Extended postpregnancy estrous cycles in fernale lion-tailed macaques.

Past studies of female primate reproduction have focused on regularly cycling females, and thus the reproductive characteristics of females in other reproductive states (e.g., pregnant, or lactating) have rarely been investigated. In this study, data were collected on estrous swellings and sexual and proceptive behavior in six female lion-tailed macaques during recovery from lactational amenorrhea for the first three to five postpregnancy cycles. For these females, the length of the first lactational recovery swelling cycle averaged 81 days, nearly three times the length of cycles exhibited by nonparturient, isosexually housed females Actual swelling durations were also nearly three times the length of those seen in nonlactating females, and occupied a larger proportion of the cycle For most females, cycle duration and sexual and proceptive behavior declined progressively over successive cycles. The alpha female in each group accounted for the majority of copulations in the first three cycles, and this effect was pronounced in the first cycle. Extended postpregnancy cycles in this species may be related to female reproductive competition and /or a tactic to attract extra-group males. © 1993 Wiley-Liss, Inc.

Responses of female rhesus macaques to an environmental enrichment apparatus.

Environmental enrichment devices are a potential way to enhance psychological well-being in laboratory animals. The effects of such devices need to be systematically evaluated before they are recommended for widespread use. The purpose of this research was to monitor the behavioural and physiological responses of adult female rhesus macaques to a simple enrichment device. The apparatus consisted of a box attached to the monkey's home cage that contained a radio and a food dispenser, which could be controlled by the monkeys via contact detectors. Radio and food dispenser use were automatically recorded. Whole blood serotonin (WBS), plasma cortisol and abnormal behaviour were measured in 5 monkeys before, during and after a 20-week period in which the monkey's cages were equipped with the device. All monkeys used the device (3 of the 5 subjects earned an average of more than 200 food pellets per day). Mean plasma cortisol and whole blood serotonin did not differ across sampling times, suggesting that the apparatus had no effect on basal stress levels. There was an inverse relationship between apparatus use and cortisol levels in 76% of the samples, but only 3 of 17 coefficients were significant. There was a significant but small negative correlation between apparatus use and self-abusive behaviour. This enrichment device was readily used by adult rhesus monkeys and could be adapted for use in a wide variety of laboratory settings.

Social rearing effects on HPA axis activity over early development and in response to stress in rhesus monkeys.

Previous studies have found evidence of behavioral and psychophysiological differences between nonhuman primates reared in different social environments, however, few of these have employed longitudinal study of the animals over early development. In this study, HPA axis activity was assessed via measurement of ACTH and cortisol values over the first 6 months of life and in response to two stressful housing transitions in 48 infant rhesus monkeys that were either mother- or peer-reared. ACTH and cortisol values declined over the first 6 months in both rearing groups. Peer-reared monkeys showed lower levels of ACTH over the first 6 months of life than mother-reared, but the rearing groups did not differ in basal cortisol values over this period. Mother-reared animals showed a greater ACTH response to the mild stress of being moved to a new cage, and male monkeys showed higher values than females. Mother-reared animals showed the largest cortisol increase in response to the caging transition. Both groups showed increases in ACTH and cortisol in response to the more severe stress of separation from their rearing partners and housing with unfamiliar age-mates. Mother-reared animals again showed the largest increase in ACTH in response to these events, but increases in cortisol were similar among both sexes and rearing groups. These results suggest an interaction of sex and rearing history in response to stressful events.

Contributions of behavioral primatology to veterinary science and comparative medicine.

Behavioral primatology is a subdiscipline of the research area referred to as primatology. Like primatology, behavioral primatology is an eclectic field of study made up of researchers from diverse basic disciplines having very different historical roots and employing extremely different methodologies biased by emphases and assumptions dictated by their histories. Psychologists, zoologists, anthropologists, and psychiatrists make up the majority of those currently active in behavioral primatology, but others, including those in veterinary science, are active in research in the area. Behavioral data can be useful to veterinary scientists and to those in comparative medicine and are interesting in their own right. Veterinarians and medical scientists may specialize in behavioral disorders. In addition, those not directly interested in behavior itself may still make use of behavioral indices of potential physiologic and morphologic abnormality. Often an animal may be inadvertently stressed by social and nonsocial environmental factors, and such stress effects may be first and best recognized by behavioral means. A recognition by those not in the behavioral sciences of the basic feral behavior of primates can go a long way toward prevention or alleviation of both behavioral and physical stress of primates in captivity. Studies of free-ranging but captive troops are sources of information almost as good as, and sometimes even better than, field studies. In addition, there is a growing realization that "natural experiments" on primates in zoos can be of value, especially since many species held in zoologic parks are those least well known in more traditional captive research settings. It must be recognized that the findings from research done on captive primates living in large field cages are not directly comparable to those derived from more directly invasive but more experimental laboratory settings. A comparative perspective on captive environments, as well as on species, is strongly recommended. Behavioral primatologists, and particularly psychologists, have long been interested in behavioral development in various species of primates. A recognition of the importance of the effects of early experience, of species differences in development, of sex differences in development, of differences in species-specific social structures and in the relative plasticity of these, and of differences in symptoms of behavioral abnormality can contribute to the arsenal of techniques that might be used to improve the well-being of the primates and can help in the selection of appropriate animal models of disorder in humans for those in comparative medicine.(ABSTRACT TRUNCATED AT 400 WORDS)

Prenatal stress has long-term effects on behavioral responses to stress in juvenile rhesus monkeys.

The effect of maternal psychological disturbance during pregnancy on postnatal responses of the offspring to stressful events was investigated in juvenile rhesus monkeys. Six pregnant monkeys were repeatedly removed from their home cages and briefly exposed to unpredictable noise during mid to late gestation (Days 90-145 postconception). Six undisturbed pregnant mothers served as controls. Behavioral data were later collected from the 18-month-old offspring under a baseline and four progressively stressful conditions. Social behaviors were considerably more affected by prenatal treatment than nonsocial behaviors. Prenatally stressed offspring showed more abnormal social behavior (mutual clinging) and less normal social behavior (proximity, contact) than controls. These results suggest that offspring of mothers stressed during pregnancy may show enhanced responsivity to stressors later in life, and concur with rodent findings indicating that prenatal stress may have long-term effects on behavioral reactivity.

Interspecific contrasts in responses of macaques to transport cage training.

Corticosteroid values in response to brief confinement in a transport cage were compared between rhesus, bonnet, and crabeating macaques before and after they were trained to enter the cage. Behavioral data were collected to assess performance during training. Species differences were found both in training measures and in corticosteroid response to confinement in the transport cage after training. Bonnets took longer to train than rhesus or crabeaters. Rhesus showed the smallest adrenocortical response to cage confinement after training and crabeaters the greatest, suggesting that this group habituated more slowly to confinement than the other two groups. The results have implications for choice of experimental subject species and for management and husbandry of laboratory primates.

Brief communication: Morphometric data for adult lion-tailed macaques (Macaca silenus).

Basic morphometric data were collected from 22 adult lion-tailed macaques (M. silenus) of both sexes. M. silenus is a rare primate species from which adequate morphometric data have not heretofore been available for comparative purposes. Data collected include measures of gross body size (weight; crown-rump and rump-heel length), and for males, measures of secondary sexual characteristics (canine tooth and testes size). Degree of sexual dimorphism was marked, with males significantly larger and heavier than females. The three body size measures were correlated for males but not for females. There was substantial variation among individual males in secondary sex characteristics measurements. The data indicate than lion-tailed macaque morphometrics are consonant with the general pattern of positive allometry for body size and sexual dimorphism characteristic of the primate order.

A novel structural variant of the human beta 4 integrin cDNA.

The ability of the alpha 6 beta 4 integrin to function as a laminin receptor appears to be cell-type dependent. We reported that this integrin functions as a laminin receptor on clone A cells, a colon carcinoma cell line (Lee et al., J. Cell Biol., 117:671-678), but this integrin may not function as a laminin receptor on all cell types in which it is expressed. One potential mode of alpha 6 beta 4 regulation resides in the beta 4 cytoplasmic domain because structural variants of this domain exist. We isolated beta 4 clones from a clone A cDNA library and identified a 21 bp (7aa), in-frame deletion not previously reported. This 7aa variant is located within a region that exhibits a relatively high degree of homology (42%) with the 70aa insert previously reported by Tamura et al. (J. Cell Biol., 111:1593-1604). One major difference between these two regions is that the region we have highlighted does not contain the four potential serine/threonine phosphorylation sites that are present in the 210 bp (70aa) insert. PCR analysis revealed that the 7aa variant is also expressed in RNA obtained from normal colon and placenta.