Cytogenesis in the adult monkey motor cortex: perivascular NG2 cells are the major adult born cell type.

We used confocal microscopy and immunohistochemistry (IHC) to look for new cells in the motor cortex of adult macaque monkeys that might form the cellular bases of improved brain function from exercise. Twenty-four female Macaca fascicularis monkeys divided into groups by age (10-12 years, 15-17 years), postexercise survival periods, and controls, received 10 weekly injections of the thymidine analog, bromodeoxyuridine (BrdU) to mark new cells. Sixteen monkeys survived 15 weeks (5 weeks postexercise) and 8 monkeys survived 27 weeks (12 weeks postexercise) after initial BrdU injections. Additionally, five Macaca mulatta female monkeys (∼5.5-7 years) received single injections of BrdU and survived 2 days, 2 weeks, and 6 weeks after BrdU injections. Neural and glial antibodies were used to identify new cell phenotypes and to look for changes in proportions of these cells with respect to time and experimental conditions. No BrdU(+) /DCx(+) cells were found but about 7.5% of new cells were calretinin-positive (Cr(+) ). BrdU(+) /GABA(+) (gamma-aminobutyric acid) cells were also found but no new Cr(+) or GABA(+) cells colabeled with a mature neuron marker, NeuN or chondroitin sulfate antibody, NG2. The proportion of new cells that were NG2(+) was about 85% for short and long survival monkeys of which two, newly described perivascular phenotypes (Pldv and Elu) and a small percentage of pericytes (2.5%) comprised 44% and 51% of the new NG2(+) cells, respectively. Proportions of NG2(+) phenotypes were affected by post-BrdU survival periods, monkey age, and possibly a postexercise sedentary period but no direct effect of exercise was found.

Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months.

We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis in the dentate gyrus of the hippocampus. In the first group, six adult monkeys (Macaca mulatta) received a single injection of the thymidine analog BrdU (75 mg/kg), which is incorporated into replicating DNA and serves as a marker for new cell birth. Brain tissue was collected 48 h, 2 wk, and 6 wk after BrdU injection to examine the initial stages of neurogenesis. Because mature neurons were not evident at 6 wk, we examined tissue collected over a longer time course in a second study. In this study, eight monkeys (Macaca fascicularis) who were subjects in a separate exercise study received 10 weekly injections of BrdU (75 mg/kg), and brain tissue was collected at 16 and 28 wk from the first injection. Based on the timing of expression of neuronal cell markers (ßIII-tubulin, doublecortin, NeuN), the extent of dendritic arborization, and acquisition of mature cell body morphology, we show that granule cell maturation in the dentate gyrus of a nonhuman primate is protracted over a minimum of a 6-mo time period, more than 6 times longer than in rodents. The lengthened time course for new cell maturation in nonhuman primates may be appropriate for preservation of neural plasticity over their longer life span and is relevant to our understanding of antidepressant and other therapies that have been linked to neurogenesis in humans.

Molecular correlates of spontaneous activity in non-human primates.

In our monkey model, cortical ARC and BDNF expressions were strongly correlated with spontaneous physical activity. The expressions of ARC and BDNF were inversely correlated with serum CRP levels, suggesting that CRP could be a putative peripheral marker of brain resiliency.

Selected neurotrophins, neuropeptides, and cytokines: developmental trajectory and concentrations in neonatal blood of children with autism or Down syndrome.

Using a double-antibody immunoaffinity assay (Luminex) and ELISA technology, we measured concentrations of certain neurotrophins, neuropeptides, and cytokines in pooled samples (one to three subjects per sample) eluted from archived neonatal blood of children with later-diagnosed autism, Down syndrome, very preterm birth, or term control infants. We also measured analytes in blood from healthy adult controls. Case or control status for infant subjects was ascertained by retrospective review of service agency medical records. We observed inhibitory substances in eluates from archived bloodspots, especially marked for measurement of BDNF. Concentrations in control subjects differed by age: BDNF rose markedly with age, while NT-3 and NT-4/5 concentrations were lower in adults than in newborn infants. IL-8 concentrations were higher in newborn infants, preterm and term, than in adults. Considered by diagnostic group, total protein was higher in Down syndrome than in either autism or control subjects. In infants with Down syndrome, concentrations of IL-8 levels were higher than in controls, whether or not corrected for total protein; NT-3 and CGRP were lower and VIP higher. In samples from autistic subjects, NT-3 levels were significantly lower than controls and an increase in VIP approached statistical significance. Concentrations of NT-4/5 and CGRP were correlated in infants with autism but not in Down syndrome or controls. Some of these results differ from earlier findings using a single-antibody recycling immunoaffinity chromatography (RIC) system. We discuss interrelationships of VIP, NT-3 and IL-8 and their potential relevance to features of the neuropathology of autism or Down syndrome.

Neonatal cytokines and cerebral palsy in very preterm infants.

To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of 11 cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-alpha, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children.