Juvenile Monkeys Research Articles

Evidence from the Agonadal Juvenile Male Rhesus Monkey (Macaca mulatta) for the View that the Action of Neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor

Human genetics have revealed that kisspeptin signaling and neurokinin B (NKB) signaling are both required for robust pulsatile gonadotropin-releasing hormone (GnRH) release, and therefore for puberty and maintenance of adult gonadal function. How these two peptides interact to affect GnRH pulse generation remains a mystery. To address the hierarchy of the NKB and kisspeptin signaling pathways that are essential for GnRH release, two experiments were conducted using agonadal, juvenile male monkeys. Pituitary responsiveness to GnRH was first heightened by a pulsatile GnRH infusion to use the in situ pituitary as a bioassay for GnRH release. In the first experiment (n = 3), the kisspeptin receptor (KISS1R) was desensitized by a continuous 99-hour i.v. infusion of kisspeptin-10 (100 µg/h). During the last 4 h of continuous kisspeptin-10 infusion, desensitization of KISS1R was confirmed by failure of an i.v. bolus of kisspeptin-10 to elicit GnRH release. Desensitization of KISS1R was associated with a markedly blunted GnRH response to senktide. The response to senktide was progressively restored during the 72 h following termination of continuous kisspeptin-10. An analogous design was employed in the second experiment (n = 2) to desensitize the NKB receptor (neurokinin 3 receptor, NK3R) by administration of a continuous 48-hour i.v. infusion of senktide (200 µg/h). While a bolus of senktide during the last 3 h of continuous senktide administration failed to elicit GnRH release, thus confirming desensitization of NK3R, the ability of kisspeptin to stimulate GnRH was unimpaired. The foregoing findings support the view that NKB stimulation of GnRH release is upstream from KISS1R.

Lymphocyte immunophenotyping and t-dependent antibody response in naïve and KLH-challenged juvenile cynomolgus monkeys

Lymphocyte immunophenotyping and t-dependent antibody response in naïve and KLH-challenged juvenile cynomolgus monkeys

Oscillatory Eye Movements Resembling Pendular Nystagmus in Normal Juvenile Macaques

Juvenile monkeys being trained on smooth-pursuit tasks exhibit ocular oscillations resembling pendular nystagmus. The purpose of this study was to analyze these oscillations, the effects of gabapentin on them, and responses of cerebellar floccular neurons to understand possible neuronal mechanisms. Four monkeys were trained for horizontal and vertical smooth pursuit; in two, saccades were also tested. Frequency, peak-to-peak eye velocity, and amplitude of the ocular oscillations were measured. In one monkey, the effect of gabapentin on the oscillations was measured, and oscillation-related neuronal discharge was recorded in the cerebellar floccular region. Ocular oscillations, with features of pendular nystagmus, appeared early during training of both horizontal and vertical pursuit in all four monkeys. Although these oscillations were observed both in the direction of pursuit and orthogonally, the velocity and amplitude of oscillation were larger in the direction of pursuit, implicating pursuit mechanisms in their generation. Corrective saccades were often superimposed on the oscillations during pursuit and fixation. Gabapentin suppressed oscillations in the monkey tested. Recordings in the floccular region revealed a subset of neurons discharged during both the oscillations and corrective saccades. Many of them exhibited burst-tonic discharge during visually guided saccades, similar to discharge of brain stem burst-tonic neurons, suggesting contributions of the neural integrator to the oscillations. The developmentally transient ocular oscillations occurring in monkeys during pursuit training has properties resembling pendular nystagmus. Both smooth pursuit and a neural integrator may contribute to these ocular oscillations. Analysis using an efference-copy pursuit model supports the interpretation herein.

A cationic lipid/DNA adjuvant enhances the effectiveness of Fluzone® in immunosenescent elderly rhesus macaques. (106.30)

Abstract The decline in immunity in older adult humans results in a reduction of influenza vaccine efficacy. Elderly macaques (> 18 years old) have similar declines in immunity as indicated by significantly lower levels of circulating naïve CD4+ T cells, naïve CD8+ T cells and B cells and declines in pDC function compared to juvenile monkeys. To determine if the adjuvant activity of JVRS-100 can improve the efficacy of the inactivated influenza vaccine, Fluzone®, elderly monkeys were immunized with Fluzone® with or without JVRS-100 and challenged with a human seasonal influenza isolate, A/Memphis/7/2001 (H1N1). On the day of challenge, Fluzone®+JVRS-100 immunized animals had significantly higher plasma anti-influenza IgG (p<0.04) and IgA (p<0.01) titers than the un-adjuvanted immunized monkeys. After virus challenge, only the Fluzone®+JVRS-100 immunized animals had a significantly lower level of virus replication (p<0.05) relative to the unimmunized control animals. There were significant inverse correlations between peak influenza virus replication levels in the respiratory tract and plasma and tracheal anti-influenza IgG and IgA antibody titers prior to challenge. These results demonstrate that JVRS-100 enhances the immunogenicity and efficacy of a licensed inactivated influenza vaccine in an immunosenescent elderly monkey population.

To whom the play signal is directed: A study of headshaking in black-handed spider monkeys (Ateles geoffroyi).

Spider monkeys shake their heads so as to facilitate amicable social contact. This occurs frequently during vigorous play fighting, and so is common during the juvenile period. Occasionally, juvenile spider monkeys use headshakes during nonsocial locomotor play. In this study, head shaking in early infancy and in adulthood was studied in a captive troop of spider monkeys, with a total of 8 infants studied from shortly after birth to just before weaning. Three hypotheses to account for these nonsocial headshakes were tested. The play as the experience of the unexpected hypothesis was found wanting because nonsocial headshakes were most common in early infancy, before the onset of the juvenile peak in play. The immature misdirection of signals hypothesis was also found wanting because the headshakes were correctly directed at other monkeys, but not at inanimate objects that were grabbed and mouthed. Both also failed to predict the occurrence of the observed nonsocial headshakes in adults. The hypothesis best supported by the data is that, under some situations, headshakes are self-directed to promote action when confronting contexts of uncertainty.

Maturation of the hippocampal formation and amygdala in Macaca mulatta: a volumetric magnetic resonance imaging study.

Malformations of the hippocampal formation and amygdala have been implicated in several neurodevelopmental disorders; yet relatively little is known about their normal structural development. The purpose of this study was to characterize the early developmental trajectories of the hippocampus and amygdala in the rhesus macaques (Macaca mulatta) using noninvasive MRI techniques. T1-weighted structural scans of 22 infant and juvenile monkeys (11 male, 11 female) were obtained between 1 week and approximately 2 yrs of age. Ten animals (five males, five females) were scanned multiple times and 12 monkeys (six males, six females) were scanned once between 1 and 4 weeks of age. Both structures exhibited significant age-related changes throughout the first 2 yrs of life that were not explained by overall brain development. The hippocampal formation increased 117.05% in males and 110.86% in females. No sex differences were evident, but the left hemisphere was significantly larger than the right. The amygdala increased 86.49% in males and 72.94% in females with males exhibiting a larger right than left amygdala. For both structures, the most substantial volumetric increases were seen within the first month, but the hippocampal formation appeared to develop more slowly than the amygdala with the rate of hippocampal maturation stabilizing around 11 months and that of amygdala maturation stabilizing around 8 months. Differences in volumetric developmental trajectories of the hippocampal formation and amygdala largely mirror differences in the timing of the functional development of these structures. The current results emphasize the importance of including early postnatal ages when assessing developmental trajectories of neuroanatomical structures and reinforces the utility of nonhuman primates in the assessment of normal developmental patterns.

Effects of Intracranial Trochlear Neurectomy on the Structure of the Primate Superior Oblique Muscle

PURPOSE. Although cyclovertical strabismus in humans is frequently attributed to superior oblique (SO) palsy, anatomic effects of SO denervation have not been studied. Magnetic resonance imaging (MRI) and orbital histology was used to study the effects of acute trochlear (CN4) denervation on the monkey SO. METHODS. Five juvenile macaque monkeys were perfused with formalin for 5 weeks: 15 months after unilateral or bilateral 10-mm intracranial trochlear neurectomy. Denervated and fellow orbits were imaged by MRI, embedded whole in paraffin, serially sectioned at 10-mum thickness, and stained with Masson trichrome. Whole muscle and individual fiber cross sections were quantified in SO muscles throughout the orbit and traced larger fibers in one specimen where they were present. RESULTS. MRI demonstrated marked reduction in midorbital cross section in denervated SO muscles, with anterior shift of SO mass preserving overall volume. Muscle fibers exhibited variable atrophy along their lengths. Denervated orbital layer (OL) fiber cross sections were slightly but significantly reduced from control at most anteroposterior locations, but this reduction was much more profound in global layer (GL) fibers. Intraorbital and intramuscular CN4 were uniformly fibrotic. In one animal, there were scattered clusters of markedly hypertrophic GL fibers that exhibited only sparse myomyous junctions only anteriorly. CONCLUSIONS. CN4 denervation produces predominantly SO GL atrophy with relative OL sparing. Overall midorbital SO atrophy was evident by MRI as early as 5 weeks after denervation, as denervated SO volume shifted anteriorly. Occasional GL fiber hypertrophy suggests that at least some SO fibers extend essentially the full muscle length after trochlear neurectomy.

A chimeric alphavirus replicon particle vaccine expressing the hemagglutinin and fusion proteins protects juvenile and infant rhesus macaques from measles.

Measles remains a major cause of child mortality, in part due to an inability to vaccinate young infants with the current live attenuated virus vaccine (LAV). To explore new approaches to infant vaccination, chimeric Venezuelan equine encephalitis/Sindbis virus (VEE/SIN) replicon particles were used to express the hemagglutinin (H) and fusion (F) proteins of measles virus (MV). Juvenile rhesus macaques vaccinated intradermally with a single dose of VEE/SIN expressing H or H and F proteins (VEE/SIN-H or VEE/SIN-H+F, respectively) developed high titers of MV-specific neutralizing antibody and gamma-interferon (IFN-gamma)-producing T cells. Infant macaques vaccinated with two doses of VEE/SIN-H+F also developed neutralizing antibody and IFN-gamma-producing T cells. Control animals were vaccinated with LAV or with a formalin-inactivated measles vaccine (FIMV). Neutralizing antibody remained above the protective level for more than 1 year after vaccination with VEE/SIN-H, VEE/SIN-H+F, or LAV. When challenged with wild-type MV 12 to 17 months after vaccination, all vaccinated juvenile and infant monkeys vaccinated with VEE/SIN-H, VEE/SIN-H+F, and LAV were protected from rash and viremia, while FIMV-vaccinated monkeys were not. Antibody was boosted by challenge in all groups. T-cell responses to challenge were biphasic, with peaks at 7 to 25 days and at 90 to 110 days in all groups, except for the LAV group. Recrudescent T-cell activity coincided with the presence of MV RNA in peripheral blood mononuclear cells. We conclude that VEE/SIN expressing H or H and F induces durable immune responses that protect from measles and offers a promising new approach for measles vaccination. The viral and immunological factors associated with long-term control of MV replication require further investigation.

Sex and age differences in juvenile social priorities in female philopatric, nondespotic blue monkeys

Juveniles should choose social partners on the basis of both current and future utility. Where one sex is philopatric, one expects members of that sex to develop greater and sex-typical social integration with group-mates over the juvenile period. Where a partner's position in a dominance hierarchy is not associated with services it can provide, one would not expect juveniles to choose partners based on rank, nor sex differences in rank-based preferences. We tested these ideas on 39 wild juvenile (3.2-7.4 years) blue monkeys (Cercopithecus mitis stuhlmanni), cercopithecines with strict female philopatry and muted hierarchies. We made focal animal observations over 6 months, and computed observed:expected amounts of proximity time, approaches and grooming given to various social partners. Overall, our results agree with the hypothesis that juvenile blue monkeys target social partners strategically. Spatial proximity, approaches and active grooming showed similar patterns regarding juvenile social preferences. Females were far more sociable than males, groomed more partners, reciprocated grooming more frequently, and preferred-while males avoided-infants as partners. Older juveniles (5-7 years) spent more time than younger juveniles (3-4 years) near others, and older females were especially attracted to infants. Close kin, especially mothers and less consistently adult sisters, were attractive to both male and female juveniles, regardless of age. Both sexes also preferred same-sex juveniles as social partners while avoiding opposite-sex peers. Juveniles of both sexes and ages generally neither preferred nor avoided nonmaternal adult females, but all juveniles avoided adult males. Partner's rank had no consistent effect on juveniles' preference, as expected for a species in which dominance plays a weak role. Juveniles' social preferences likely reflect both future and current benefits, including having tolerant adult kin to protect them against predators and conspecifics, same-sex play partners, and, for females, infants on which to practice mothering skills. Am. J. Primatol. 72:193-205, 2010. (c) 2009 Wiley-Liss, Inc.

Sex differences in play behavior in juvenile tufted capuchin monkeys (Cebus apella)

Sex differences in play behavior in juvenile tufted capuchin monkeys (Cebus apella)

A history of iron deficiency anemia during infancy alters brain monoamine activity later in juvenile monkeys

Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements. As the infants grew, they were all screened with hematological tests, which documented that 16 (33.3%) became markedly ID between 4 and 8 months of age. During this anemic period and subsequently at 1 year of age, cerebrospinal fluid (CSF) specimens were collected to compare monoamine activity in the ID and iron-sufficient infants. Monoamine neurotransmitters and metabolite levels were normal at 4 and 8 months of age, but by 1 year the formerly anemic monkeys had significantly lower dopamine and significantly higher norepinephrine levels. These findings indicate that ID can affect the developmental trajectory of these two important neurotransmitter systems, which are associated with emotionality and behavioral performance, and further that the impact in the young monkey was most evident during the period of recovery.

Cerebrospinal fluid concentrations of large neutral and basic amino acids in Macaca mulatta: diurnal variations and responses to chronic changes in dietary protein intake

In rats, dietary protein intake influences brain concentrations of tryptophan, tyrosine, and other large neutral amino acids (LNAAs) and the neurotransmitters to which they are linked. Few experiments have examined these dietary protein–amino acid relationships in nonhuman primates, in relation to time of day or dietary protein content. We therefore examined the effect in monkeys of changes in chronic protein intake on 24-hour plasma and cerebrospinal fluid (CSF) concentrations of LNAAs (tyrosine, phenylalanine, branched-chain amino acids) and basic amino acids. Juvenile male monkeys ( Macaca mulatta) consumed for sequential 4-week periods diets differing in protein content (∼23% → ∼16% → ∼10% → ∼6% protein [percentage of energy]). The daily ration was presented as a morning meal of fruit and an afternoon meal of fruit and a commercial diet to mimic feeding patterns in the wild. During week 4 on each diet, blood and CSF were sampled repeatedly over a 48-hour period via indwelling catheters. Plasma and CSF LNAA concentrations varied markedly with time of day and dietary protein content, showing up to 4-fold variations. Diurnal variations in plasma and CSF basic amino acids were smaller in magnitude and generally not strongly linked to dietary protein content. A measure of the competitive transport of LNAAs across the blood-brain barrier, calculated using plasma concentrations of the LNAAs and their blood-brain barrier kinetic constants, predicted the observed CSF concentration of each LNAA examined remarkably well, except for phenylalanine. Based on observations in rats, the variations in the CSF concentrations of the LNAAs in monkeys may be large enough to influence metabolic and signaling pathways in brain to which they have been linked.

Abstract 4950: Infection with Enterovirus Produces Myocarditis in a Non-Human Primate Model

Introduction: We performed a pilot study to establish a non-human primate model of enteroviral infection and myocarditis. Methods: Juvenile cynomolgus monkeys were inoculated via oral (n=1) or intravenous (n=8) routes with a cloned Coxsackievirus B3 (CVB-3) or a CVB-3 /Enterovirus 86 strain (CVB-MCH) isolated from a clinical specimen from a patient with fatal myocarditis. Clinical and echocardiographic assessment was performed at baseline and at days 3, 7, 14, and 28. CVB-3 neutralizing antibody titers were measured. Viral RNA was detected by RT-PCR and culture of plasma and cardiac tissue. Animals were sacrificed at 14 or 28 days and myocardium examined for viral pathology. Results: Infection was achieved by both routes with both CVB-3 strains. Viremia was detected in 6/9, resolving after day 3. All (9/9) generated neutralizing antibody. Two animals infected with 10 7 infectious units (IU) of CVB-3 became moribund and were sacrificed at day 11 and day 14. Subsequent animals received 10 6 IU of CVB-3 and appeared well until sacrificed at day 14 (n=3) or day 28 (n=1). Three infected with 10 6 IU CVB-MCH also appeared well until sacrificed at day 28. Normal ejection fraction was maintained, but four animals had minor wall motion abnormalities. Serum troponin remained normal. Virus was present in myocardium in 5/5 tested. Multiple areas of focal cardiac injury were present in all animals and included lymphocytic or eosinophilic myocarditis (n=6), focal inflammation (n= 3), myocytolysis (n=2), ischemic foci (n=4), contraction band necrosis (n=2), and hypertrophy (n=3). Active myocarditis was present in 4/5 animals at day 14 and 2/4 at day 28. Conclusions: We were able to consistently establish infection with CVB-3 in cynomolgus monkeys resulting in clinically apparent or sub clinical disease, including myocarditis or cardiac injury persisting at 28 days. Despite adequate immune responses to clear viremia, virus persisted in the myocardium. The presence of myocyte hypertrophy and injury at 28 days in this model may provide a basis for experiments aimed at modulating immune or virus induced cardiomyopathy.

Discharge of pursuit-related neurons in the caudal part of the frontal eye fields in juvenile monkeys with up–down pursuit asymmetry

The smooth-pursuit system uses retinal image-slip-velocity information of target motion to match eye velocity to actual target velocity. The caudal part of the frontal eye fields (FEF) contains neurons whose activity is related to direction and velocity of smooth-pursuit eye movements (pursuit neurons), and these neurons are thought to issue a pursuit command. During normal pursuit in well-trained adult monkeys, a pursuit command is usually not differentiable from the actual eye velocity. We examined whether FEF pursuit neurons signaled the actual eye velocity during pursuit in juvenile monkeys that exhibited intrinsic differences between upward and downward pursuit capabilities. Two, head-stabilized Japanese monkeys of 4 years of age were tested for sinusoidal vertical pursuit of target motion at 0.2-1.2 Hz (+/-10 degrees, peak target velocity 12.5-75.0 degrees/s). Gains of downward pursuit were 0.8-0.9 at 0.2-1.0 Hz, and peak downward eye velocity increased up to approximately 60 degrees/s linearly with target velocity, whereas peak upward eye velocity saturated at 15-20 degrees/s. The majority of downward FEF pursuit neurons increased the amplitude of their discharge modulation almost linearly up to 1.2 Hz. The majority of upward FEF pursuit neurons also increased amplitude of modulation nearly linearly as target frequency increased, and the regression slope was similar to that of downward pursuit neurons despite the fact that upward peak eye velocity saturated at approximately 0.5 Hz. These results indicate that the responses of the majority of upward FEF pursuit neurons did not signal the actual eye velocity during pursuit. We suggest that their activity reflected primarily the required eye velocity.

Blood levels and DA transporter occupancy of orally administered methylphenidate in juvenile rhesus monkeys measured by high resolution PET

Blood levels and DA transporter occupancy of orally administered methylphenidate in juvenile rhesus monkeys measured by high resolution PET

Cognitive development in macaques: Attentional set-shifting in juvenile and adult rhesus monkeys

In humans and nonhuman primates, the structure and function of frontal cortical regions of the brain are not completely developed until early adulthood. How this cortical development affects cognitive function continues to be elucidated. To that end, this experiment tested the ability of juvenile and adult rhesus monkeys to perform a cognitive task that is dependent upon intact frontal cortical function for optimal performance. Twenty-four juvenile (mean age 2.3 years) and 16 adult (mean age 10.3 years) rhesus monkeys were tested on the Cambridge Neuropsychological Test Automated Battery intradimensional/extradimensional set-shifting (ID/ED) task. Performance on the ID/ED task has been shown to be dependent upon frontal cortical function in both humans and nonhuman primates. Compared with adults, juveniles were impaired on the reversal of simple discrimination, intradimensional shift, reversal of intradimensional shift, and the extradimensional shift stages of the task. These results indicate juveniles committed more perseverative errors and more errors on the set-formation and set-shifting components of the ID/ED task. The developmental stage of the juvenile monkeys corresponds to roughly 5 to 6-year-old children, and these results are consistent with performance of human children and adults on similar ID/ED tests and on several other tests of attentional set-shifting or attentional flexibility. Furthermore, these results are consistent with the ongoing development of frontal cortical structures relating to ongoing cognitive development in nonhuman primates.

Effects of Prenatal Dexamethasone Treatment on Physical Growth, Pituitary-Adrenal Hormones, and Performance of Motor, Motivational, and Cognitive Tasks in Juvenile and Adolescent Common Marmoset Monkeys

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to prevent respiratory distress syndrome in preterm infants, but there is emerging evidence of subsequent neurobehavioral abnormalities (e.g. problems with inattention/hyperactivity). In the present study, we exposed pregnant common marmosets (Callithrix jacchus, primates) to daily repeated DEX (5 mg/kg by mouth) during either early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 days). Relative to control, and with a longitudinal design, we investigated DEX effects in offspring in terms of physical growth, plasma ACTH and cortisol titers, social and maintenance behaviors, skilled motor reaching, motivation for palatable reward, and learning between infancy and adolescence. Early DEX resulted in reduced sociability in infants and increased motivation for palatable reward in adolescents. Late DEX resulted in a mild transient increase in knee-heel length in infants and enhanced reversal learning of stimulus-reward association in adolescents. There was no effect of either early or late DEX on basal plasma ACTH or cortisol titers. Both treatments resulted in impaired skilled motor reaching in juveniles, which attenuated in early DEX but persisted in late DEX across test sessions. The increased palatable-reward motivation and decreased social motivation observed in early DEX subjects provide experimental support for the clinical reports that prenatal glucocorticoid treatment impairs social development and predisposes to metabolic syndrome. These novel primate findings indicate that fetal glucocorticoid overexposure can lead to abnormal development of motor, affective, and cognitive behaviors. Importantly, the outcome is highly dependent upon the timing of glucocorticoid overexposure.

Two incidents of venomous snakebite on juvenile blue and Sykes monkeys (Cercopithecus mitis stuhlmanni and C. m. albogularis)

Although rarely observed, predation is thought to be an important factor in the evolution of primate life histories and behavior. Here I describe two incidents of snake predation on Cercopithecus mitis guenons from Kenya. The first case involved a juvenile blue monkey (Cercopithecus mitis stuhlmanni) in the Kakamega Forest, which died following a bite by a Gaboon viper (Bitis gabonica gabonica). The snake's attempts to ingest its prey were unsuccessful. In the second incident, a juvenile Sykes monkey (Cercopithecus mitis albogularis) at Gede Ruins National Monument died suddenly after suffering symptoms that are characteristic of bites inflicted by black mambas (Dendroaspis polylepis). In both cases circumstantial evidence suggests that attacks occurred during extended play sessions in dense vegetation on or near the ground. If so, the observations support the hypothesis that play may be a costly activity.

Sex differences in play behavior in juvenile tufted capuchin monkeys (Cebus apella)

According to the motor training hypothesis, play behavior in juvenile primates improves motor skills that are required in later adult life. Sex differences in juvenile play behavior can therefore be expected when adult animals assume distinct sexually dimorphic roles. Tufted capuchin monkeys show sexually dimorphic levels of physical antagonism in both inter- and intra-group encounters. Accordingly, it can be predicted that juvenile capuchins also show sex differences in social play behavior. To test this hypothesis, the play behavior of nine juvenile and two infant capuchins was examined. As predicted, juvenile males showed significantly higher levels of social play (wrestle, chase) than juvenile females, but no differences were found in nonsocial play (arboreal, object). Levels of infant play behavior were comparable to that of juveniles. These results lend support to the motor training hypothesis and highlight the need for more detailed investigations of individual differences in play behavior.

Maturation of Testicular Tissue from Infant Monkeys after Xenografting into Mice

In juvenile monkeys, precocious puberty can be induced by administration of gonadotropins resulting in testicular somatic cell maturation and germ cell differentiation. It is, however, unknown whether testicular maturation can also be induced in younger monkeys. Here we used testis tissue xenografting to investigate whether infant monkey testis tissue will undergo somatic cell maturation and/or spermatogenesis in response to endogenous adult mouse gonadotropins or exogenous gonadotropins. Testicular tissue pieces from 3- and 6-month-old rhesus monkeys were grafted to immunodeficient, castrated mice. Recipient mice were either left untreated or treated with pregnant mare serum gonadotropin and/or human chorionic gonadotropin twice weekly and were killed 28 weeks after grafting. Testicular maturation in grafted tissue was assessed based on morphology and the most advanced germ cell type present and by immunohistochemistry for expression of proliferating cell nuclear antigen, Mullerian-inhibiting substance, and androgen receptor. Testis grafts, irrespective of donor age or treatment, contained fewer germ cells than donor tissue. Grafts from 6-month-old donors showed tubular expansion with increased seminiferous tubule diameter and lumen formation, whereas those harvested from gonadotropin-treated mice contained elongated spermatids. Grafts from 3-month-old donors recovered from gonadotropin-treated mice contained pachytene spermatocytes, whereas those recovered from untreated mice showed only slight tubular expansion. Immunohistochemistry revealed that exposure to exogenous gonadotropins supported Sertoli cell maturation, irrespective of donor age. These results indicate that sustained gonadotropin stimulation of immature (<12 months old) monkey testis supports Sertoli cell maturation, thereby terminating the unresponsive phase of the germinal epithelium and allowing complete spermatogenesis in testis tissue from infant rhesus monkeys.