Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.     

Two populations of luteinizing hormone-releasing hormone neurons in the forebrain of the rhesus macaque during embryonic development

To investigate the possibility that a second luteinizing hormone-releasing hormone (LHRH) population appears during development in primates, embryos and fetal brains of rhesus monkeys were immunostained with antisera specific to different LHRH forms. Two LHRH cell populations were discernible by immunoreactivity to antisera LR-1 and GF-6. Because one LHRH cell type migrated out from the olfactory placode several days earlier than the other, they were referred to as “early” and “late” LHRH cells, respectively. Although late LHRH neurons were immunoreactive to all anti-mammalian LHRH antisera tested, early LHRH neurons were only detected by antiserum GF-6. Early LHRH neurons (∼10 × 7 μm) were smaller than late LHRH neurons (∼8 × 7 μm). Early LHRH neurons were first found around the olfactory placode, in the nasal mesenchyme, and in the rostroventral forebrain on embryonic day 30 (E30), whereas late LHRH neurons were first seen in the olfactory pit on E32. Early LHRH cells were located throughout the basal forebrain on E32–E42, whereas late LHRH cells were found in the olfactory pit and along the terminal nerve on E34–E36 and were not seen in the forebrain until E38. By E51–E62, late LHRH neurons reached into the basal hypothalamus in a distribution resembling that in the older brain, while early LHRH neurons were found in the septum, preoptic region, stria terminalis, medial amygdala, claustrum, internal capsule, and globus pallidus. Based on the distribution pattern of immunopositive cells with-antiserum LR-1, late LHRH cells are bona fide LHRH neurons that regulate the pituitary-gonadal axis. In contrast, the molecular form of early LHRH cells is unclear, although it is plausible that early LHRH cells may contain the molecule in which the C-terminal epitope of LHRH is modified or absent. It is concluded that in primates there is a second population of LHRH neurons that originates from the embryonic olfactory placode before the origin of mammalian LHRH-like neurons, and that these two populations of LHRH-immunopositive neurons have different morphologic features and different final distributions in the brain. J. Comp. Neurol. 380:293–309, 1997. © 1997 Wiley-Liss, Inc.     

rhIL—11对照射所致骨髓抑制猕猴的治疗作用

本研究观察了rhIL-11对γ线照射后猕猴血小板和白细胞减少症的治疗作用,同时比较了不同时间给药对疗效的影响.用60Coγ射线3.0 Gy照射正常猕猴,造成骨髓抑制模型.照射后当天开始给予rhIL-1130,60或120μg@kg-1@day-1,连续14天皮下注射,可以显著提高给药猴外周血小板数的最低值,虽然白细胞数最低值并未上升,但低于照前值50%的时间明显缩短,这与血小板的变化相似.照射后当天开始给予rhIL-11治疗的动物在照射后开始的2周内红细胞数较对照组略有下降,但第3周即迅速上升并超过对照组.照射后第13天开始给予rhIL-11治疗的4只猴,在照射后前3周内外周血象与对照组相似,此后迅速恢复.骨髓细胞培养结果表明,rhIL-11治疗猴的骨髓细胞在体外形成CFU-Meg,CFU-Mix,CFU-E,BFU-E和CFU-GM能力明显增加.照射后第45天病理组织学检查结果表明,照射对照组动物骨髓腔空虚并有明显出血,治疗组动物骨髓腔中细胞丰富,生长旺盛.这些结果表明,rhIL-11可以促进照射猕猴造血的恢复.     

多基因编辑猪-猴心脏、肝脏、肾脏移植临床前研究初步报道

目的 探讨目前国际上基因改造程度最大的基因编辑猪在临床前异种器官移植中的应用前景.方法 将1只猪内源性逆转录病毒(PERV)敲除联合3种主要异种抗原基因敲除以及抑制补体活化、调节凝血紊乱、抗炎抗吞噬的9种人源化基因转入猪(PERV-KO/3-KO/9-TG)作为供体,获取其心脏、肝脏和肾脏,分别移植给3只恒河猴受体,建...     

酶联免疫法研究天花粉蛋白突变体在猕猴体内的药动学

目的研究猕猴iv天花粉蛋白突变体(MTCS)的药动学。方法猕猴ivMTCS220μg/kg后,采用酶联免疫分析法(ELISA)测定动物血清中的药物质量浓度,血药浓度-时间数据用3P97药动程序拟合分析并计算药动学参数。结果MTCS在猕猴体内消除符合二房室模型。6只猕猴的平均消除半衰期(t1/2β)为(3.82±1.42)h,平均消除速率(CL)为(276.51±118.61)mL/(kg·h),药时曲线下面积(AUC0~24h)为(1124.1±189.5)ng·h/mL。结论用ELISA方法能准确测定动物血清中MTCS质量浓度和研究其药动学。     

Long‐term effects of maternal separation on the responsiveness of the circadian system to melatonin in the diurnal nonhuman primate (Macaca mulatta)

Depression is often linked to early‐life adversity and circadian disturbances. Here, we assessed the long‐term impact of early‐life adversity, particularly preweaning mother–infant separation, on the circadian system's responsiveness to a time giver or synchronizer (Zeitgeber). Mother‐reared (MR) and peer‐reared (PR) rhesus monkeys were subjected to chronic jet‐lag, a forced desynchrony protocol of 22 hr T‐cycles [11:11 hr light:dark (LD) cycles] to destabilize the central circadian organization. MR and PR monkeys subjected to the T‐cycles showed split locomotor activity rhythms with periods of ~22 hr (entrained) and ~24 hr (free‐running), simultaneously. Continuous melatonin treatment in the drinking water (20 μg/mL) gradually increased the amplitude of the entrained rhythm at the expense of the free‐running rhythm, reaching complete entrainment by 1 wk. Upon release into constant dim light, a rearing effect on anticipation for both the predicted light onset and food presentation was observed. In MR monkeys, melatonin did not affect the amplitude of anticipatory behavior. Interestingly, however, PR macaques showed light onset and food anticipatory activities in response to melatonin treatment. These results demonstrate for the first time a rearing‐dependent effect of maternal separation in macaques, imprinting long‐term plastic changes on the circadian system well into late adulthood. These effects could be counteracted by the synchronizer molecule melatonin. We conclude that the melatonergic system is targeted by early‐life adversity of maternal separation and that melatonin supplementation ameliorates the negative impact of stress on the circadian system.