Developmental Changes In Response Research Articles

LOB Domain Proteins: Beyond Lateral Organ Boundaries.

LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins defined by a conserved LATERAL ORGAN BOUNDARIES (LOB) domain are key regulators of plant organ development. Recent studies have expanded their functional diversity beyond the definition of lateral organ boundaries to pollen development, plant regeneration, photomorphogenesis, pathogen response, and specific developmental functions in non-model plants, such as poplar and legumes. The identification of a range of upstream regulators, protein partners, and downstream targets of LBD family members has unraveled the molecular networks of LBD-dependent processes. Moreover, it has been demonstrated that LBD proteins have essential roles in integrating developmental changes in response to phytohormone signaling or environmental cues. As we discuss here, these novel discoveries of LBD functions and their molecular contexts promote a better understanding of this plant-specific transcription factor family.

Prenatal stress puzzle, the oxytocin piece: Prenatal stress alters the behaviour and autonomic regulation in piglets, insights from oxytocin

Developmental changes in response to prenatal stressors (PNS) can result in anxiety and abnormal social development in the offspring. Oxytocin (OT) reduces anxiety, whereas OT deficiencies are associated with social behaviour deficits. Hence, we hypothesized that OT could reverse some of the PNS effects. Female offspring from three socially stressed (PNS 35–56 days of gestation) and three control sows were tested at 18 days of age. In each litter, two piglets received 24IU of OT intranasally and two piglets received saline as a control treatment. After 45min, each piglet was isolated for 15min in a separate room. The PNS piglets displayed fewer alert behaviours during social isolation than control piglets (saline-control: 93.6±0.2, OT-control: 82.5±0.2, saline-PNS: 52.0±0.2, and OT-PNS piglets: 67.8±0.2). All other behavioural differences were the result of the administration of OT to PNS piglets, which reestablished a few behavioural changes such as the time spent standing in PNS piglets, with OT-PNS piglets standing more than saline-PNS piglets (77.8±6.7s vs. 57.1±6.7s respectively), and as much as saline- and OT-controls (76.7±6.7s and 70.0±6.7s respectively). Furthermore, saline-PNS piglets spent more time sitting than control piglets, and OT reversed this effect in OT-PNS piglets, with OT-PNS piglets sitting no more than controls. Prenatal stress and the administration of OT interacted in their effect on the heart rate, with OT-control and PNS piglets (saline or OT) having lower mean heart rate than saline-control piglets (saline-control: 168±4, OT-control: 159±4, saline-PNS: 146±5, and OT-PNS piglets: 149±5). Neither PNS nor OT administration influenced the RMSSD of the heart rate. In conclusion, these preliminary results suggest that social stress in mid-gestation results in some behavioural differences and alters the development of the autonomic nervous system in the sow's offspring, in this case female offspring. Exogenous OT administration reversed some behavioural changes, suggesting a common physiological basis.

Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus

Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/−) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/− mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/− mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/− mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

Changes in responsiveness of rat spiral ganglion neurons to neurotrophins across age: differential regulation of survival and neuritogenesis

Developmental changes in responsiveness of rat spiral ganglion neurons (SGNs) to neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were examined using an explant culture system. Spiral ganglion (SG) explants at embryonic Day 18 (E18), postnatal Day 0 (P0), P5, P10 and P20 were cultured with the addition of either NT-3 or BDNF at various concentrations (0.1–100 ng/ml) and analyzed the dose-response characteristics of three parameters: SGN survival, the number of neurites emanating from the explants and the length of neurite extension. In E18 cultures, SGN survival and neurite number were enhanced more strongly by NT-3 than by the BDNF. As the explants became more mature, the effects of NT-3 decreased, whereas those of BDNF increased, peaking at P0. Although the intrinsic capacity of SGNs to produce and extend neurites declined considerably by P20, they still retained the capacity to respond to both NT-3 and BDNF. These temporal patterns in responsiveness of SGNs to neurotrophins correspond well to the expression pattern of the two neurotrophins in cochlear sensory epithelium in vivo and also correlate with the time course of developmental events in SGNs such as cell death and the establishment of mature hair cell innervation patterns.

Cardiovascular and metabolic influences of fetal smoke exposure

Many epidemiological studies showed associations of low birth weight with cardiovascular disease, type 2 diabetes and obesity. The associations seem to be consistent and stronger among subjects with a postnatal catch up growth. It has been suggested that developmental changes in response to adverse fetal exposures might lead to changes in the fetal anatomy and physiology. These adaptations may be beneficial for short term, but may lead to common diseases in adulthood. Maternal smoking during pregnancy is one of the most important adverse fetal exposures in Western countries, and is known to be associated with a 150–200 g lower birth weight. An accumulating body of evidence suggests that maternal smoking during pregnancy might be involved in pathways leading to both low birth weight and common diseases, including cardiovascular disease, type 2 diabetes and obesity, in adulthood. In this review, we discuss epidemiological studies focused on the associations of maternal smoking with fetal growth and development and cardiovascular and metabolic disease in later life. We also discuss potential biological mechanisms, and challenges for future epidemiological studies.

Changes in responsiveness of appetite, leptin and hypothalamic IL-1β and TNF-α to lipopolysaccharide in developing rats

In addition to its role as a regulator of energy homeostasis, leptin plays a pivotal role in some immune/inflammatory responses. Synthesis and secretion of leptin are increased under immune stress conditions, and increased leptin may participate in the development of anorexia and fever. These actions are partially mediated by up-regulation of hypothalamic IL-1β. Leptin also protects against immune stress-induced lethality. On the other hand, the response and roles of leptin to immune stress conditions in the neonatal period have scarcely been examined. We hypothesized that 1. the response of leptin to immune stress would be suppressed in the early neonatal period, 2. hyporesponse of leptin in the early neonatal period would attenuate the anorectic response and increase the lethal rate under immune stress conditions and 3. supplementation of leptin in the early neonatal period would increase the anorectic response, whereas it would decrease the lethal rate under immune stress conditions. To test these hypotheses, we first examined the developmental changes in the responses of leptin and hypothalamic proinflammatory cytokines, i.e., IL-1β and TNF-α, to LPS-induced immune stress in female rats. We also examined the developmental changes in the anorectic response and lethality rate under LPS-induced immune stress conditions. Five- and 15-day-old rats showed no leptin response and a weak hypothalamic IL-1β response to LPS when compared with 25- and 42-day-old rats. Fifteen-day-old rats showed low anorectic responses and high lethality rates when compared with 25- and 42-day-old rats under LPS-induced immune stress conditions. We then examined whether administration of leptin affected the response to the anorectic and lethal effects of LPS in 15-day-old rats. Administration of leptin further attenuated body weight after LPS injection, but not after saline injection. On the other hand, administration of leptin did not affect survival rate. In addition, hypothalamic IL-1β mRNA levels were not affected by leptin administration. In conclusion, the absence of a leptin response may act to prevent immune stress-induced anorexia during the early neonatal period.

Age-related physiological responses to emotion anticipation and exposure

Although there is accumulating evidence for physiological and behavioral changes in response to emotion with age, little is known about developmental changes in response to emotion anticipation. Here, we investigated brain activations related to emotion anticipation and exposure, in participants aged between 19 and 54 years. During the anticipation of negative stimuli, a linear decrease of activation with age was detected in the rostral anterior cingulate cortex and brainstem; whereas exposure to negative stimuli revealed decreasing activation in a network of regions implicated in emotion processing and salience detection. The observed results might reflect reduced focusing on negative future events with age, and are in line with an age-related shift of motivational priorities for the pursuit of emotional satisfaction and well being.

Light-regulated transcriptional networks in higher plants

Plants have evolved complex and sophisticated transcriptional networks that mediate developmental changes in response to light. These light-regulated processes include seedling photomorphogenesis, seed germination and the shade-avoidance and photoperiod responses. Understanding the components and hierarchical structure of the transcriptional networks that are activated during these processes has long been of great interest to plant scientists. Traditional genetic and molecular approaches have proved powerful in identifying key regulatory factors and their positions within these networks. Recent genomic studies have further revealed that light induces massive reprogramming of the plant transcriptome, and that the early light-responsive genes are enriched in transcription factors. These combined approaches provide new insights into light-regulated transcriptional networks.

Developmental changes in responsiveness to parents and unfamiliar adults in a monogamous monkey (Callicebus moloch)

Titi monkeys (Callicebus moloch) are monogamous New World primates that are characteristically found in family-type groups consisting of a mated adult pair and one or two young. The factors maintaining the small size of these groups are not known. Based on observations of free-ranging and captive families, parental aggression toward older offspring seems unlikely to play a significant role. Maturing individuals themselves, however, could undergo behavioral changes that weaken ties to their natal group. These might include waning of affiliative relations with parents, or subtle forms of aversion. Independent of such changes, increasing interest in unfamiliar conspecifics could be a factor. We examined these possibilities in the present study by assessing changes in social behavior and social preferences from initial ambulatory independence (6 months) through reproductive maturity (24 months) in a combined cross-sectional/longitudinal study of 21 captive titi monkeys living with their parents. Responses to both parents and to an unfamiliar adult heterosexual pair, a single unfamiliar adult male, and a single unfamiliar adult female were observed when subjects were given a choice between parents and strangers presented simultaneously or as the only social incentive. Social stimuli were at opposite ends of a 16.8-m-long test corridor. Subjects could move freely about the corridor for 5 min with each configuration of social stimuli. They stayed closer to parents than to strangers at all ages. Responsiveness to strangers increased with age and suggested growing ambivalence, particularly toward the male stranger. As they approached 24 months of age, male subjects showed a dramatic increase in the frequency and intensity of agonistic behaviors toward male strangers, behaviors that were rarely directed toward female strangers or parents. Waning of attraction to parents may be less important in dispersal from the natal group than changing reactions to strangers.

Developmental Changes in Interrenal Responsiveness in Anuran Amphibians

Basal activity of the hypothalamo-pituitary-interrenal (HPI) axis changes over development in larval amphibians, but development of the responsiveness of this axis to an external stressor has not been studied. We compared developmental changes in whole-body corticosterone content of two anuran amphibian species, Rana pipiens (family Ranidae) and Xenopus laevis (family Pipidae). We also examined developmental changes in the responsiveness of the HPI axis by subjecting tadpoles of different developmental stages to a laboratory shaking/confinement stress and to ACTH injection. We measured whole-body corticosterone content as an indicator of the activity of the HPI axis. Whole-body corticosterone content of R. pipiens remained low during premetamorphosis and prometamorphosis but increased dramatically at metamorphic climax and remained elevated in juvenile frogs. By contrast, whole-body corticosterone content of X. laevis was highest during premetamorphosis, declined at the onset of prometamorphosis, increased at metamorphic climax and remained at climax levels in juvenile frogs. Premetamorphic and prometamorphic tadpoles of both species showed strong corticosterone responses to both shaking stress and ACTH injection. The magnitude and pattern of response differed among developmental stages, with premetamorphic tadpoles of both species showing greater responsiveness to stress and ACTH. Our results show that interrenal responsiveness is developed in premetamorphic tadpoles, suggesting that at these stages tadpoles are capable of mounting an increase in stress hormone production in response to changes in the external environment. Our results also highlight the importance of comparative studies in understanding the development of the stress axis.

AGE-RELATED CHANGES IN CONTRACTILE RESPONSES OF RABBIT LOWER URINARY TRACT TO ENDOTHELIN

AGE-RELATED CHANGES IN CONTRACTILE RESPONSES OF RABBIT LOWER URINARY TRACT TO ENDOTHELIN

Developmental changes in the response of trigeminal neurons to neurotrophins: influence of birthdate and the ganglion environment.

Previous studies have shown that most neurons in cultures established during the early stages of neurogenesis in the embryonic mouse trigeminal ganglion are supported by BDNF whereas most neurons cultured from older ganglia survive with NGF. To ascertain to what extent these developmental changes in neurotrophin responsiveness result from separate phases of generation of BDNF- and NGF-responsive neurons or from a developmental switch in the response of neurons from BDNF to NGF, we administered BrdU to pregnant mice at different stages of gestation to identify neurons born at different times and studied the survival of labelled neurons in dissociated cultures established shortly after BrdU administration. Most early-generated neurons responded to BDNF, neurons generated at intermediate times responded to both factors and late-generated neurons responded to NGF, indicating that there are overlapping phases in the generation of BDNF- and NGF-responsive neurons and that late-generated neurons do not switch responsiveness from BDNF to NGF. To ascertain if early-generated neurons do switch their response to neurotrophins during development, we used repeated BrdU injection to label all neurons generated after an early stage in neurogenesis and studied the neurotrophin responsiveness of the unlabelled neurons in cultures established after neurogenesis had ceased. The response of these early-generated neurons had decreased to BDNF and increased to NGF, indicating that at least a proportion of early-generated neurons switch responsiveness to neurotrophins in vivo. Because early-generated neurons do not switch responsiveness from BDNF to NGF in long-term dissociated cultures, we cultured early trigeminal ganglion explants with and without their targets for 24 hours before establishing dissociated cultures. This period of explant culture was sufficient to enable many early-generated neurons to switch their response from BDNF to NGF and this switch occurred irrespective of presence of target tissue. Our findings conclusively demonstrate for the first time that individual neurons switch their neurotrophin requirements during development and that this switch depends on cell interactions within the ganglion. In addition, we show that there are overlapping phases in the generation of BDNF- and NGF-responsive neurons in the trigeminal ganglion.

Developmental changes in response to subatmospheric pressure loading of the upper airway.

Children snore less than adults and have fewer obstructive apneas, suggesting a less collapsible upper airway. We therefore hypothesized that the compensatory upper airway responses to subatmospheric pressure loading decrease with age because of changes in upper airway structure and ventilatory drive. We measured upper airway upstream pressure-flow relationships during sleep in 20 nonsnoring, nonobese children and adults. Measurements were made by correlating maximal inspiratory airflow with the level of nasal pressure applied via a mask. The slope of the upstream pressure-flow curve (S(PF)) was used to characterize upper airway function. We found that S(PF) was flatter in children than in adults (8 +/- 5 vs. 30 +/- 18 ml x s(-1). cmH(2)O(-1), P < 0.002) and that S(PF) correlated with age (r = 0.62, P < 0.01) and body mass index (r = 0. 63, P < 0.01). The occlusion pressure in 100 ms during sleep was measured in six children and two adults; it correlated inversely with S(PF) (r = -0.80, P < 0.02). We conclude that the upper airway compensatory responses to subatmospheric pressure loading decrease with age. This is associated with increased body mass index, even in nonsnoring, nonobese subjects. Ventilatory drive during sleep plays a role in modulating upper airway responses.

Development of responsiveness to novel objects in the titi monkey,Callicebus moloch

Adult titi monkeys react to novelty more strongly and cautiously than other New World primates. Developmental changes in responsiveness were assessed by presenting complex novel objects to family groups consisting of 11 male-female pairs and their adult (31–33 months), subadult (20–23 months), and juvenile offspring (10–16 months). Food and a simple block were included as control conditions. Differences in attraction to novel objects were inversely related to age. Juveniles approached more objects, more quickly, and spent more time near them than older subjects. Parents, the least responsive age-group, seemed more indifferent than cautious. Age-effects were smaller with the block, and negligible with food. Even in the most responsive age-group, investigatory behavior appeared subdued as compared to other primate species.

Response of preimplantation murine embryos to heat shock as modified by developmental stage and glutathione status.

Objectives were to characterize developmental changes in response to heat shock in the preimplantation mouse embryo and to evaluate whether ability to synthesize glutathione is important for thermal resistance in mouse embryos. Heat shock (41 degrees C for 1 or 2 h) was most effective at disrupting development to the blastocyst stage when applied to embryos at the 2-cell stage that were delayed in development. Effects of heat shock on ability of embryos to undergo hatching were similar for 2-cell, 4-cell, and morula stage embryos. The phenomenon of induced thermotolerance, for which exposure to a mild heat shock increases resistance to a more severe heat shock, depended upon stage of development and whether embryos developed in vitro or in vivo. In particular, induced thermotolerance was observed for morulae derived from development in vivo but not for 2-cell embryos or morulae that developed in culture. Administration of buthionine sulfoximine to inhibit glutathione synthesis did not increase thermal sensitivity of 2-cell embryos or morulae but did reduce subsequent development of 2-cell embryos at both 37 degrees and 41 degrees C. In summary, changes in the ability of 2-cell through morula stages to continue to develop following a single heat shock were generally minimal. However, 2-cell embryos delayed in development had reduced thermal resistance, and therefore, maternal heat stress may be more likely to cause mortality of embryos that are already compromised in development. There were also developmental changes in the capacity of embryos to undergo induced thermotolerance. Glutathione synthesis was important for development of embryos but inhibition of glutathione synthesis did not make embryos more susceptible to heat shock.

Impairment of Kit-dependent development of interstitial cells alters contractile responses of murine intestinal tract.

We examined developmental changes in responses of the isolated segment of the ileum of BALB/c mice treated with a monoclonal antibody (ACK2) to the receptor tyrosine kinase (Kit) for 4 days postnatally to pharmacological agents in vitro. Rhythmic contraction and relaxation of the isolated ileum started to appear on day 4 postpartum, and the sensitivity to acetylcholine (ACh) decreased gradually after birth. Treatment with ACK2 induced augmentation of contractile responses and receptor sensitivity of the longitudinal muscle of the ileum to ACh, bradykinin, and prostaglandin F2 alpha. ACh induced larger depolarization in smooth muscle cells of the ileum in the ACK2-treated mice than in the control. Circular muscle responses to these substances, as measured by changes in intraluminal pressure, were not altered by ACK2 treatment. Results suggest that interstitial cells play an important role not only in the development of the pacemaking system of the small intestine but also in the functional development of the contractile properties of the intestinal smooth muscle.

Photoperiod Sensitivity during Flower Development of Opium Poppy (Papaver somniferum L.)

Flower development in opium poppy (Papaver somniferum L. `album DC') is enhanced by long photoperiods (PP ≥ 16-hours). Predicting time to flower in field-grown opium poppy requires knowledge of which developmental stages are sensitive to PP and how the rate of flower development is changed by changes in PP. The objective of this work was to determine when poppy plants first demonstrated developmental changes in response to PP and how long PP continued to influence the time to first flower under consistent temperature conditions. Plants were grown in artificially lit growth chambers with either a 16- (inductive) or a 9-hour PP (noninductive). Plants were transferred at 1 to 3-day intervals from a 16- to a 9-hour PP and vice versa. All chambers were maintained at a 12-hour thermoperiod of 25/20°C. Poppy plants demonstrated developmental changes in response to PP four days after emergence and required a minimum of four inductive cycles before the plant flowered. Additional inductive cycles, up to of a maximum of nine, hastened flowering. After 13 inductive cycles, flowering time was no longer influenced by PP. These results indicate four phases between emergence and first flower: 1) a photoperiod-insensitive juvenile phase (JP); 2) a photoperiod-sensitive inductive phase (PSP); 3) a photoperiod-sensitive post-inductive phase (PSPP); and 4) a photoperiod-insensitive post-inductive phase (PIPP). The minimum durations (days) of these phases under the conditions of our experiment were JP = 4, PSP = 4, PSPP = 9, and PIPP = 14.

Developmental changes in response to endothelins and receptor subtypes of isolated rat duodenum

The response of isolated duodenum to endothelin-1, -3 and IRL 1620 (Suc-[Glu 9, Ala 11,15]endothelin-1 (8–21)), a selective endothelin ET B receptor agonist, was studied in both neonatal (1-week-old) and adult rats by recording mechanical activity isotonically. Endothelin-1, -3 and IRL 1620 (1–100 nM) elicited sustained contraction of neonatal duodenum, in a concentration-dependent manner, with a potency order of endothelin-1 = endothelin-3 > IRL 1620. The response to endothelin-1 and -3 (10–1000 nM) of adult duodenum was biphasic, i.e., transient relaxation followed by contraction, with a potency order of endothelin-1 > endothelin-3. The contractile response to endothelin-1 of adult but not neonatal duodenum was significantly antagonized by pretreatment with FR139317 (1 μM), an endothelin ET A receptor antagonist. An endothelin ET B receptor antagonist, RES-701-1 (3 μM), weakly antagonized the IRL 1620-induced contraction of neonatal duodenum. However, RES-701-1 (10 μM) did not affect the response to endothelin-1 of either adult or neonatal duodenum. These results indicate that the duodenal response to endothelins changes from a sustained contraction in neonates to a biphasic response in adults. The contractile response to endothelins of neonatal duodenum is suggested to be mediated through endothelin ET B receptors or possibly RES-701-1 -resistant ET B receptor subtypes and contraction of adult duodenum through endothelin ET A receptors. The mechanism of the endothelin-induced response of duodenum was also studied.

Maternal dietary glucose-lipid interactions modulate embryological development in vivo and in embryo culture.

To examine the dietary interrelationships of glucose and lipid on embryological growth and development, two levels of glucose (0% and 24%) and two types of lipid--soybean oil (SBO; 44.5% 18:2[n-6]) or oleic acid (OL; 6.7% 18:2[n-6])--were fed to pregnant rat dams until Day 12.5 of gestation, when developing embryos and maternal tissues were collected for analysis. In addition, Day 9.5 embryos were obtained from the dietary treatment groups and cultured in vitro until Day 12.5 to ascertain whether or not the embryos showed developmental changes in response to dietary treatment in the absence of maternal and placental factors. Differences in energy intake and macronutrient composition explained differences in early placental weight; macronutrient composition, but not energy intake, accounted for differences in weight of in vivo embryos and in morphological scores of cultured embryos. With food intake as a covariate in the statistical analysis, the results showed that only the level of maternal dietary glucose influenced the number of live embryos and resorptions per litter. Both the level of carbohydrate and the type of lipid in the maternal diet, however, independently and interactively affected both embryonic growth and development in vivo and in culture. To evaluate the biological significance of this dietary interaction, concentrations of essential fatty acids in the embryonic and maternal tissues were measured. A striking result of this study was the rapidity of the diet-induced changes in tissue fatty acid composition. By gestational Day 12.5, the lack of glucose in the OL-based diet was associated with a raised 18:2 (n-6)/20:4 (n-6) ratio and a lowered 20:4 (n-6) content in the embryo and the maternal liver. We suggest that a carbohydrate-free maternal diet with apparently adequate levels of essential fatty acid can contribute to embryonic growth retardation both in vivo and in vitro by perturbing embryonic essential fatty acid metabolism.

A longitudinal assessment of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys

Twenty-two rhesus macaques were studied longitudinally from infancy to early adolescence in order to assess the effects of developmental change, experimental history, gender, and individual variation on the response of the catecholaminergic, serotonergic, and adrenocortical systems to separation-induced stress. Experimental effects were assessed by comparing subjects reared for the first 6 months of life either with their mothers or in peer groups. Developmental changes in response to repeated separation stress were assessed by subjecting the monkeys to four sequential 4-day social separations when they were 6 and 18 months old. At both ages, prior to, and on the last day of the first and fourth separations, cerebrospinal fluid (CSF) was obtained from the cisterna magna to assess monoamine metabolite concentrations, and blood samples were collected to assess plasma cortisol concentrations. Blood samples were also obtained on the first day of each separation at each age. Age-related declines were found in both homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations for all subjects. Social separation consistently increased CSF 3-methoxy-4-hydroxyphenolglycol (MHPG) over baseline levels, but decreased HVA concentrations, whereas 5-HIAA levels increased following the first, but not the fourth separation. Plasma cortisol increased rapidly immediately after separation and remained higher than baseline on day 4 of both the first and fourth separation. Independent of age and experimental condition, peer-rearing increased CSF MHPG and plasma cortisol concentrations. During year 1, peer-rearing also produced diminished CSF 5-HIAA concentrations in female monkeys relative to female mother-reared monkeys, but increased male peer-reared monkeys' concentrations relative to mother-reared males. Interindividual differences were highly stable, with significant correlations both within and between years for each of the three metabolites and cortisol.