Brain,body and encephalization in early primates

Encephalization—the evolution of relatively enlarged brains—was probably a characteristic adaptation in the order Primates from the earliest times. Evidence for this generalization is reviewed by reanalyzing data on brain size and body size in Paleocene, Eocene and Oligocene genera: Plesiadapis, Tetonius, Necrolemur, Smilodectes, Adapis, Rooneyia and Aegyptopithecus. Uncertainties about the generalization are based primarly on problems in the estimation of body size. Mathematical (dimensional) and statistical issues in those estimations are reviewed and the errors-of-estimate are presented quantitatively. These are small enough to suggest that the generalization is correct. Although the early primates were progressive with respect to encephalization, only the omomyids appear to have reached present (tarsiid) grades during the earliest times. Plesiadapis and the adapids appeared to be somewhat below the present strepsorhine grade, and Aegyptopithecus was at a strepsorhine rather than haplorhine grade of encephalization, according to presently available evidence.     

大鼠脑缺血/再灌注后bFGF和GAP-43的表达与神经再生

目的:观察大鼠脑缺血/再灌注后不同时间段碱性成纤维生长因子(bFGF)和生长相关蛋白43(GAP-43)表达与神经元再生的变化,探讨其与神经再生的有关机制。方法:建立大鼠大脑中动脉阻塞模型(MCAO),并分为缺血再灌注3 d、7 d、14 d和28 d四组(n=6)。以神经损伤严重程度评分(NSS),运动评分测试(SMT)评估神经功能缺损程度,Nissl和TUNEL染色法观察不同时段缺血区周边组织神经元存活和凋亡情况,应用蛋白免疫印迹法和免疫荧光双标法检测缺血/再灌注后不同时段缺血区周边组织bFGF和GAP-43的表达水平和神经元再生的变化情况。结果:大鼠脑缺血/再灌注后3 d,大鼠出现了明显的神经功能缺损及运动功能障碍,缺血区周边组织神经元凋亡亦达到高峰,同时bFGF和GAP-43表达增强,7 d达到高峰,以后逐渐减弱,缺血周边组织可见散在的新生神经元,持续到28 d。结论:大鼠脑缺血/再灌注后内源性bFGF和GAP-43表达水平增加,可能与其神经修复和再生有关。     

Evidence of adult neurogenesis in non-human primates and human

Adult neurogenesis in rodents has been extensively studied. Here, we briefly summarize the studies of adult neurogenesis based on non-human primate brains and human postmortem brain samples in recent decades. The differences between rodent, primate and human neurogenesis are discussed. We conclude that these differences may contribute to distinct physiological roles and the self-repair mechanisms in the brain across species.     

Levels of serum brain-derived neurotrophic factor in primates

Brain-derived neurotrophic factor (BDNF) has been reported to exist not only in nervous tissue but also in serum. In contrast to the wealth of knowledge regarding the various physiological functions of BDNF in the nervous system, information about possible roles in other systems is limited. To elucidate the physiological function of serum BDNF in primates, it is first necessary to establish a method to determine the levels of BDNF in serum of primates. In the present study, we established an enzyme-linked immunosorbent assay (ELISA) method which we used to measure levels of serum BDNF in non-human primates. We found that serum BDNF levels were similar among several species of primates. The present results suggest that our BDNF ELISA may be useful in measuring serum BDNF concentration as a physiological marker, and that levels of serum BDNF may be similar among primates including humans. Electronic Publication     

Orexin-1 receptor expression after global ischemia in mice

Orexins are neuropeptides that have a range of physiological effects including the regulation of feeding behavior and the sleep-wakefulness cycle. Recently, we reported that level of orexin A in spinal fluid was decreased in the patients of some neurodegenerative diseases and it is considered that orexin A and the receptors might be related to central nervous system disorders. However, the expression and localization of orexin receptors is not elicited well. Therefore, the purpose of this study is to investigate the time-dependent changes and the cellular localization of orexin receptor focusing on orexin-1 receptor (OX1R) in the mouse brain after transient common carotid artery occlusion (tCCAO) model by using immunohistochemical techniques. OX1R immunoreactivity dramatically increased and peaked in the hippocampus and cortex 2 days after tCCAO, but remained unchanged in the hypothalamus. Using double-immunohistochemistry, the OX1R immunopositive cells at 2 days after tCCAO were co-localized not only with neuronal marker, NeuN-immunoreactivity but also with astroglial and oligodendroglial markers, GFAP- and CNPase-immunoreactivities, respectively. These results suggested that OX1R is induced other cells in addition to the neurons during stress such as ischemia and orexins and its receptor might play an important role for ischemic insult.     

The expression and putative role of brain-derived neurotrophic factor and its receptor in bovine sperm

The neurotrophin family of proteins promote the survival and differentiation of nerve cells and are thought to play an important role in development of reproductive tissues. The objective of the present study was to detect the presence of Brain-derived neurotrophic factor (BDNF) and its receptor TrkB in bovine sperm, and explore the potential role of BDNF in sperm function. We demonstrated that both the neorotrophin BDNF and the tyrosine kinase receptor protein TrkB were expressed in ejaculated bovine sperm. Furthermore, BDNF per se was secreted by sperm. Insulin and leptin secretion by bovine sperm were increased (P < 0.01) when cells were exposed to exogenous BDNF, whereas insulin was decreased by K252a. Therefore, we inferred that BDNF could be a regulator of sperm secretion of insulin and leptin through the TrkB receptor. Sperm viability and mitochondrial activity were both decreased (P < 0.05) when the BDNF/TrkB signaling pathway was blocked with K252a. Furthermore, BDNF promoted apoptosis of bovine sperm through TrkB binding (P < 0.05). In conclusion, these observations provided evidence that BDNF secreted by bovine sperm was important in regulation of insulin and leptin secretion in ejaculated bovine sperm. Furthermore, BDNF may affect sperm mitochondrial activity and apoptosis, as well as their viability.     

Brain corticosteroid receptor gene expression and neuroendocrine dynamics during aging

The present study examined the stress responsiveness of the hypothalamic-pituitary-adrenal axis in relation to the properties of corticosteroid receptors in the brain and pituitary in old (30 months) and young (3 months) male Brown Norway rats. The data demonstrate that circulating ACTH rather than the corticosteroid plasma level was elevated under basal conditions and following stress. Furthermore, a reduction of mineralocorticoid receptor (MR) number in the hippocampus and of glucocorticoid receptor (GR) number in the hypothalamus and the pituitary correspond to increased neuroendocrine responsiveness and negative feedback following stress. The changes in receptor binding do not parallel the changes in the amount of MR and GR mRNA measured with in situ hybridization. This suggests that the processing rather than the receptor gene expression is affected in senescence.     

Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates,in part,the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice

To determine the role of brain-derived neurotrophic factor (BDNF) in the enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), heterozygous BDNF knockout (BDNF +/-) mice and wild-type mice were maintained for 3 months on DR or ad libitum (AL) diets. Mice were then injected with bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF protein in neurons throughout the hippocampus were decreased in BDNF +/- mice, but were increased by DR in wild-type mice and to a lesser amount in BDNF +/- mice. One day after BrdU injection the number of BrdU-labeled cells in the dentate gyrus of the hippocampus was significantly decreased in BDNF +/- mice maintained on the AL diet, suggesting that BDNF signaling is important for proliferation of neural stem cells. DR had no effect on the proliferation of neural stem cells in wild-type or BDNF +/- mice. Four weeks after BrdU injection, numbers of surviving labeled cells were decreased in BDNF +/- mice maintained on either AL or DR diets. DR significantly improved survival of newly generated cells in wild-type mice, and also improved their survival in BDNF +/- mice, albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced neurogenesis in BDNF +/- mice was associated with a significant reduction in the volume of the dentate gyrus. These findings suggest that BDNF plays an important role in the regulation of the basal level of neurogenesis in dentate gyrus of adult mice, and that by promoting the survival of newly generated neurons BDNF contributes to the enhancement of neurogenesis induced by DR.     

Role of delta-opioid receptor function in neurogenesis and neuroprotection

The present study was undertaken to evaluate the implication of delta-opioid receptor function in neurogenesis and neuroprotection. We found that the stimulation of delta-opioid receptors by the selective delta-opioid receptor agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (10 nm) promoted neural differentiation from multipotent neural stem cells obtained from embryonic C3H mouse forebrains. In contrast, either a selective micro-opioid receptor agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), or a specific kappa-opioid receptor agonist, (-)-trans-(1S,2S)-U-50488 hydrochloride (U50,488H), had no such effect. In addition to neural differentiation, the increase in cleaved caspase 3-like immunoreactivity induced by H2O2 (3 microm) was suppressed by treatment with SNC80 in cortical neuron/glia co-cultures. These effects of SNC80 were abolished by a Trk-dependent tyrosine kinase inhibitor: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one (K-252a). The SNC80-induced neural differentiation was also inhibited by treatment with the protein kinase C (PKC) inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitor, mitogen-activated protein kinase kinase (MEK) inhibitor or Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These findings raise the possibility that delta-opioid receptors play a crucial role in neurogenesis and neuroprotection, mainly through the activation of Trk-dependent tyrosine kinase, which could be linked to PI3K, PKC, CaMKII and MEK.     

Brain-derived neurotrophic factor promotes gephyrin protein expression and GABAA receptor clustering in immature cultured hippocampal cells

Fast synaptic inhibition in the adult brain is largely mediated by GABA_A receptors (GABA_AR). GABA_AR are anchored to synaptic sites by gephyrin, a scaffolding protein that appears to be assembled as a hexagonal lattice beneath the plasma membrane. Brain derived neurotrophic factor (BDNF) alters the clustering and synaptic distribution of GABA_AR but mechanisms behind this regulation are just starting to emerge. The current study was aimed to examine if BDNF alters the protein levels and/or clustering of gephyrin and to investigate whether the modulation of gephyrin is accompanied by changes in the distribution and/or clustering of GABA_AR. Exogenous application of BDNF to immature neuronal cultures from rat hippocampus increased the protein levels and clustering of gephyrin. BDNF also augmented the association of gephyrin with GABA_AR and promoted the formation of GABA_AR clusters. Together, these observations indicate that BDNF might regulate the assembly of GABAergic synapses by promoting the association of GABA_AR with gephyrin.     

Prospero and Snail expression during spider neurogenesis

Analysis of early neurogenesis in the spider Cupiennius salei (Chelicerata, Aranea, Ctenidae) has shown that the cells of the central nervous system are recruited from clusters of cells that invaginate from the neuroectoderm. This is in contrast to Drosophila, where only single cells delaminate and become neuroblasts, the stem cells of the nervous system. In order to compare the processes further, we have cloned homologues of the pan-neural Drosophila genes prospero and snail from the spider and have analysed their RNA and protein expression pattern. We find that snail expression is transient and only a subset of neural cells expresses Snail protein at any given time, making it difficult to assess whether it is indeed a pan-neural gene in the spider. Prospero protein expression, on the other hand, is seen in all invaginating cells and continues throughout differentiation of the neurons. In contrast to Drosophila, asymmetric localization cannot be detected, even in cells that still divide. Our results provide no evidence for neuroblasts or stem cells in the spider, although there are a limited number of mitoses in the cells that are derived from the invaginating clusters. These aspects of spider neurogenesis are more similar to the neurogenesis process known from vertebrates.Edited by P. Simpson     

Brain neurotrophic supply in ontogenesis and during development of neurodegenerative diseases

Neurotrophic factors play a key role in ontogenetic changes of the nervous system’s functioning. The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were most completely characterized over six decades of active studies of neurotrophin family protein structure and functions. A complex coordination of synthesis, transport, secretion, and interaction of proneurotrophins and mature neurotrophins, as well as their receptors (Trk tyrosine kinase and p75^NTR receptor family proteins), cause a wide spectrum of their biological activity. In embryogenesis, neurotrophic factors are involved in the nervous system formation regulating both division, differentiation, survival, migration, and growth of neurons and their neurites and apoptosis activation. In the mature brain, neurotrophins are involved in the maintenance of the functional state of neurons and glial cells and synaptic plasticity regulation. It is natural that the development of processes typical for aging and neurodegenerative diseases is closely associated with a change in the brain neurotrophic supply caused both by a damage in neurotrophin metabolism and modification of their availability due to a change in the neuron microenvironment. The restoration of neurotrophic factor balance in the brain is considered as a promising approach to the therapy of neurodegenerative disorders.     

Ciliary neurotrophic factor and its receptor complex

Ciliary neurotrophic factor (CNTF), originally identified for its ability to promote survival of neurons of the ciliary ganglion, is now known to have additional survival and differentiative actions on cells of the nervous system. CNTF is, however, unrelated in structure to the nerve growth factor family of neurotrophic factors. Instead, CNTF is distantly related to, and in fact shares receptor components with, a number of hemopoietic cytokines. This review focuses on the biological actions of CNTF, the shared and unique features of the CNTF receptor complex and signaling pathways, and the distribution of CNTF and its receptor during development, in the adult and in response to injury.     

Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice

Peripheral stimulation and physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. Using a rodent model of whisker-barrel cortex stroke, we have previously demonstrated that whisker activity promotes angiogenesis in the penumbra of the ischemic barrel cortex. This study explored the potential of increased peripheral activity to promote neurogenesis and neural progenitor migration toward the ischemic barrel cortex. Three days after focal barrel cortex ischemia in adult mice, whiskers were manually stimulated (15 min x 3 times/day) to enhance afferent signals to the ischemic barrel cortex. 5-Bromo-2'-deoxyuridine (BrdU, i.p.) was administered once daily to label newborn cells. At 14 days after stroke, whisker stimulation significantly increased vascular endothelial growth factor and stromal-derived factor-1 expression in the penumbra. The whisker stimulation animals showed increased doublecortin (DCX) positive and DCX/BrdU-positive cells in the ipsilateral corpus of the white matter but no increase in BrdU-positive cells in the subventricular zone, suggesting a selective effect on neuroblast migration. Neurogenesis indicated by neuronal nuclear protein and BrdU double staining was also enhanced by whisker stimulation in the penumbra at 30 days after stroke. Local cerebral blood flow was better recovered in mice that received whisker stimulation. It is suggested that the enriched microenvironment created by specific peripheral stimulation increases regenerative responses in the postischemic brain and may benefit long-term functional recovery from ischemic stroke.     

Evolution of a pigmentation gene,the melanocortin-1 receptor,in primates

The melanocortin-1 receptor (MC1R) forms a critical switch in the production of orange/red pheomelanin and black/brown eumelanin pigments during hair development in mammals. The molecular evolution of the melanocortin-1 receptor gene was investigated in a broad range of primate species, including several groups with large differences in distribution of orange/red and black hairs. Primate MC1R has been subject to purifying selection throughout most of its evolution, with small changes in selective constraint being detected early in primate evolution. In contrast to the situation in humans and domestic mammals, many intraspecific and intrageneric differences in primate coat color cannot be attributed to changes in the MC1R coding sequence. Nevertheless, important changes in the biochemical function of MC1R are suggested by mutations in sites of known functional importance, particularly in New World monkeys and lemurs. The evolution of the MC1R in lion tamarins is anomalous, with a combination of a high nonsynonymous to synonymous substitution rate (dN/dS) ratio, deletions, and substitutions.     

Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates

Background

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs.

Materials/Methodology

Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.

Results

Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.

Conclusion

We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.     

Structure,diversity, and evolution of the T-cell receptor VB gene repertoire in primates

AB T-cell receptors (TCR) that recognize major histocompatibility complex (MHC)/peptide antigen complexes regulate humoral and cellular arms of the adaptive immune response. Antigen binding sites of MHC and immunoglobulin heavy chain variable regions(Igh-V) are subject to diversity enhancing selection. We sought to establish whether positive Darwinian selection has driven diversity of TCRBV chains in the primate lineage by sequencing rearranged TCR from rhesus monkeys and chimpanzees and comparing them with those of humans. Rates of synonymous (silent) and nonsynonymous (replacement) substitutions indicate selection against amino acid replacements in TCRBV frameworks, and relaxation of these constraints in putative MHC/peptide contact sites. The lack of positive selection for variability in likely ligand contact sites suggests that mechanisms generating somatic diversity in TCR junctional regions have relaxed the pressure for selection of variability in the TCR V region encoded in the germline.