High-throughput single-cell omics of non-human primate brain tissue provides a powerful platform to investigate the molecular basis of brain aging. Here, we present a comprehensive transcriptomic and chromatin accessibility atlas of 2,955,873 nuclei from eight brain regions of 23 female cynomolgus macaques spanning the adult lifespan, including exceptionally old individuals. Our analyses reveal dynamic, cell-subtype- and region-specific age-related changes in core brain functions, including synaptic communication and axon myelination. We identify multicellular networks in the pons and medulla as a previously unrecognized hotspot of primate brain aging, highlighting white matter vulnerability as a central feature of aging. Integration with human brain aging and neurodegeneration datasets reveals both shared and divergent molecular mechanisms. We further define transcription factors and age-related chromatin remodeling programs linked to longevity and neurodegeneration. This spatiotemporal atlas establishes a foundational framework for understanding the cellular and regulatory architecture of primate brain aging and its links to disease.

Individuals who have experienced early life stress (ELS) are more vulnerable to later life stress induced depression, which might attribute to ELS potentiated impact of later life stress. The presumption and neurobiological mechanisms involved require further validation and elucidation. To investigate impact of pre-weaning maternal separation (MS) on post-weaning social isolation (SI) in inducing depressive-like behavior, and involvement of central oxidative stress, glutamatergic and brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling in the process. Male offspring were exposed to MS, SI or maternal separation and social isolation (MSSI) stress, respectively. Subjects were treated with saline, antioxidant diallyl disulfide (DADS) (30 mg/kg, i.g.) or antidepressant fluoxetine (10 mg/kg, i.p.), for two weeks before behavioral tests in adolescents or adults. Depressive-like behavior was assessed with sucrose preference, forced swim and tail suspension tests. Concentrations of 4-hydroxynonenal (4-HNE), glutathione and superoxide dismutase in hippocampus and serum, and hippocampal protein expressions of glutamate transporter 1 (GLT-1), BDNF and TrkB were assessed by western blotting analysis. MSSI, rather than MS or SI, induced significant depressive-like behavior, in adults but not adolescents. Consistently, only MSSI significantly elevated 4-HNE, whereas inhibited GLT-1, BDNF and TrkB in adult hippocampus. MSSI induced behavioral and biochemical abnormalities in adults were reversed by DADS or fluoxetine treatment. Early MS age-dependently potentiates later SI impact in inducing depressive-like behavior in male rats, through elevating oxidative stress and interrupting glutamatergic and BDNF/TrkB signaling in the brain. Results further suggest antioxidant treatment as a promising anti-depressant avenue.

Motor learning (ML), which plays a fundamental role in growth and physical rehabilitation, involves different stages of learning and memory processes through different brain regions. However, the neural mechanisms that underlie ML are not sufficiently understood. Here, a previously unreported neuronal projection from the dorsal hippocampus (dHPC) to the zona incerta (ZI) involved in the regulation of ML behaviors is identified. Using recombinant adeno-associated virus, the projections to the ZI are surprisingly identified as originating from the dorsal dentate gyrus (DG) and CA1 subregions of the dHPC. Furthermore, projection-specific chemogenetic and optogenetic manipulation reveals that the projections from the dorsal CA1 to the ZI play key roles in the acquisition and consolidation of ML behaviors, whereas the projections from the dorsal DG to the ZI mediate the retrieval/retention of ML behaviors. The results reveal new projections from the dorsal DG and dorsal CA1 to the ZI involved in the regulation of ML and provide insight into the stages over which this regulation occurs.

The neural mechanisms underlying the natural and maladaptive forgetting of established memory remain largely unknown. Brain disease states might hijack the physiological forgetting mechanisms, resulting in maladaptive forgetting such as accelerated forgetting that contributes to cognitive decline in various neurologic conditions including epilepsy. Based on the key role of the integrated stress response (ISR) in memory storage and maintenance, we determined whether the ISR underpins natural and accelerated forgetting. Here, based on the object location recognition (OLR) and novel object recognition (NOR) paradigms in mice, we found that the ISR was activated while an established memory was naturally forgotten, which was denoted by increased levels of phosphorylated eukaryotic translation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4), and reduced general protein synthesis. Multiple administrations of ISRIB, a small molecule ISR inhibitor, during the memory retention interval attenuated the ISR activation, and prevented the natural forgetting of established OLR and NOR memories. At the same time, a single injection of ISRIB has no effect on natural forgetting and memory retrieval. Moreover, administration of pentylenetetrazole (PTZ), an inducer of epileptic seizures, during the memory retention interval provoked the ISR activation and accelerated forgetting, which was corrected by ISRIB treatment. Together, our findings suggest that the ISR is critically involved in natural forgetting and accelerated forgetting associated with epilepsy, and pharmacological inhibition of the ISR may emerge as a novel intervention strategy for accelerated forgetting in patients with epilepsy.

Lactate acts as an important metabolic substrate and signalling molecule modulating neural activities in the brain, and recent preclinical and clinical studies have revealed its antidepressant effect after acute or chronic peripheral administration. However, the neural mechanism underlying the antidepressant effect of lactate, in particular when lactate is acutely administered remains largely unknown. In the current study, we focused on forced swimming test (FST) to elucidate the neural mechanisms through which acute intracerebroventricular (ICV) infusion of lactate exerts antidepressant-like effect. A total of 238 male Sprague Dawley rats were used as experimental subjects. Results showed lactate produced antidepressant-like effect, as indicated by reduced immobility, in a dose- and time-dependent manner. Moreover, the antidepressant-like effect of lactate was dependent of new protein synthesis but not new gene expression, lactate’s metabolic effect or hydroxy-carboxylic acid receptor 1 (HCAR1) activation. Furthermore, lactate rapidly promoted dephosphorylation of eukaryotic elongation factor 2 (eEF2) and increased brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus in a cyclic adenosine monophosphate (cAMP)-dependent manner. Finally, inhibition of cAMP production blocked the antidepressant-like effect of lactate. These findings suggest that acute administration of lactate exerts antidepressant-like effect through cAMP-dependent protein synthesis.

The ability to rapidly recognize basic facial emotions (e.g. fear) is crucial for social interactions and adaptive functioning. To date, the origin of facial-emotion-recognition ability remains equivocal. Using a classical twin design in humans, we found a clear dissection of low and high spatial frequencies (LSF and HSF) in facial emotion perception: whereas genetic factors contributed to individual variation in LSF processing, HSF processing is largely shaped by environmental effects. Furthermore, the ability to recognize facial emotions of LSF content genetically correlated with the function of the amygdala. Crucially, single-unit recording of the amygdala in macaques further revealed the dissociation between LSF and HSF processing in facial emotion perception, indicating the existence of an evolutionarily conserved mechanism. This cross-species study enhances insights into the neurobiological dual-route model (subcortical vs. cortical) of emotion perception and illuminates the origin and the functional development of the emotional brain in primates.

抑郁症是影响范围广、人数多的精神/心境障碍,其经典致病机制假说包括HPA(hypothalamic-pituitary-adrenocortical axis)轴功能异常、单胺类和神经可塑性缺陷等.要充分阐明抑郁症多种致病因素,及不同病因之间复杂的相互作用关系,仍需更加深入的研究.慢性应激是抑郁症主要临床诱因,利用此动物模型可充分揭示发病过程中复杂的病理机制及其变化趋势,且利于将转化医学研究结果快速有效地向临床转化,对疾病预防和治疗有重要意义.目前现有相关综述主要围绕经典的HPA轴异常、单胺类和神经可塑性缺陷、大脑神经元结构功能、中枢神经递质和因子及其受体等方面异常展开.本文综述了近年抑郁症研究热点和新发现,包括基因变异和表观遗传修饰、神经胶质细胞(星形胶质细胞和小胶质细胞)结构功能异常、线粒体功能障碍、机体系统水平异常(氧化应激、免疫炎症反应和微生物-肠-脑轴),旨在系统呈现慢性应激诱导动物抑郁样行为机制研究进展,为后续有针对性地深入研究致病机制,及其临床预防和治疗提供新思路.

The ability to decipher biological motion information is an essential brain function that develops early in life and is evolutionarily conserved across many species. However, the neuronal encoding of biological motion information remains unclear due to the scarce electrophysiological evidence. In the current study, we tackled this issue by examining whether and how neurons in the monkey medial superior temporal cortex (MST) extract form from biological motion and encode spatial transformations in biological motion. Results revealed that MST neurons are capable of encoding form information and discriminating the horizontal and the vertical mirror transformations of biological motion. More importantly, BM information is dynamically encoded in the modulation strength of evoked spike trains rather than the average firing rate during stimulus presentation. Furthermore, the ability of MST neurons to detect various biological motion features is closely linked with the neuronal selectivity for optic flow patterns.

Integrating multisensory inputs to generate accurate perception and guide behavior is among the most critical functions of the brain. Subcortical regions such as the amygdala are involved in sensory processing including vision and audition, yet their roles in multisensory integration remain unclear. In this study, we systematically investigated the function of neurons in the amygdala and adjacent regions in integrating audiovisual sensory inputs using a semi-chronic multi-electrode array and multiple combinations of audiovisual stimuli. From a sample of 332 neurons, we showed the diverse response patterns to audiovisual stimuli and the neural characteristics of bimodal over unimodal modulation, which could be classified into four types with differentiated regional origins. Using the hierarchical clustering method, neurons were further clustered into five groups and associated with different integrating functions and sub-regions. Finally, regions distinguishing congruent and incongruent bimodal sensory inputs were identified. Overall, visual processing dominates audiovisual integration in the amygdala and adjacent regions. Our findings shed new light on the neural mechanisms of multisensory integration in the primate brain.

Iron accumulates in the brain with age and catalyzes free radical damage to neurons, thus playing a pathogenic role in Alzheimer's disease (AD). To decrease the incidence of AD, we synthesized the iron-affinitive peptide 5YHEDA to scavenge the excess iron in the senile brain. However, the blood-brain barrier (BBB) blocks the entrance of macromolecules into the brain, thus decreasing the therapeutic effects. To facilitate the entrance of the 5YHEDA peptide, we linked the low-density lipoprotein receptor (LDLR)-binding segment of ApoB-100 to 5YHEDA (named "bs-YHEDA "). The results of intravenous injections of bs-5YHEDA into senescent mice demonstrated that bs-YHEDA entered the brain, increased ferriportin levels, reduced iron and free radical levels, decreased the consequences of neuronal necrosis and ameliorated cognitive disfunction without kidney or liver damage. bs-5YHEDA is a safe iron and free radical remover that potentially alleviates aging and Alzheimer's disease.

In addition to the antidepressant properties of ketamine at subanesthetic doses, studies have revealed ketamine's influence on memory acquisition, consolidation, and reconsolidation. The effects of acute low-dose ketamine administration on conditioned memory have been investigated extensively in rodents through conditioned fear memory and morphine-induced conditioned place preference. In contrast to conditioned memory, the novel object recognition (NOR) task assesses the natural format of memory by exploiting the rodents' natural preference for novelty. Acute low-dose ketamine administration impairs NOR acquisition and consolidation, but its influence on reconsolidation remains unclear. We investigated the issue as well as the involvement of BDNF/TrkB pathway in this process by administering ketamine (i.p., 10 mg/kg, immediately or 6 h after reactivation, or without reactivation) and ANA-12 (i.p., 0.5 mg/kg, 5 min after ketamine/vehicle administration). ANA-12 is a selective antagonist for the BDNF TrkB receptor. Ketamine administration, immediately after (rather than without) reactivation, significantly increased the NOR preference index, thus suggesting an enhanced memory reconsolidation rather than consolidation. Ketamine exerted no significant effect when administered 6 h after reactivation, thereby suggesting 6 h to be an effective time window. ANA-12 administration significantly reduced the ketamine-induced NOR preference index increase, thus suggesting that the blockage of ketamine improves NOR reconsolidation. However, this blockage had no significant effect on the ketamine-induced hippocampal BDNF level increase. In conclusion, acute low-dose ketamine administration improves NOR memory reconsolidation by increasing hippocampal BDNF levels and subsequent BDNF binding to the TrkB receptor.

As advanced cognitive activities, it is poorly understood if visual weakening affects auditory fear conditioning. Here we investigated the responses in auditory Pavlovian fear conditioning, using mutant rd/rd, cl/cl mice as visual weakening group. Freezing behaviors were recorded during fear conditioning, fear extinction, and extinction recall phases. The results indicated that mice with shape vision deprivation are more conducive to auditory fear conditioning. We discuss the possible neuro-mechanism of visual-auditory system interactions.

Studies have shown that both aging and dopaminergic dysfunction affected spatial learning and memory. Systematic dopaminergic inhibition, by dopamine receptor (DR) antagonist treatment, impaired spatial delayed-response (SDR) performance, which mostly requires self/body centered egocentric reference frame, in rhesus monkeys. However, the influence of DR blocking on large scale maze learning, which mainly involves world centered allocentric reference frame, remains unclear. Moreover, the effects of aging on the process also remain unknown. Present study investigated the issues, using large scale mazes composed of 8 maze units. Maze No. 1 was used for adaptation and training. Mazes No. 2-4 were used to investigate influence of aging, by comparing learning performance between young and aged rhesus monkeys. Mazes No. 5-8 were used to investigate the effects of DR antagonist treatment, SKF-83566 (0.02, 0.2 mg/kg) and haloperidol (0.001, 0.01 mg/kg). The result showed similar learning performance between young and aged monkeys in mazes No. 2-4. In mazes No. 5-8, we also found similar learning performance after acute DR antagonist injection, compared with pre-treatment baseline performance in mazes No. 2-4, in both young and aged groups. The result showed similar maze learning performance between young and aged monkeys in mazes (No. 2-4), suggesting no significant influence of aging on allocentric spatial learning. We also found similar maze performance in both groups, after dopamine receptor antagonist treatment in mazes (No. 5-8) compared with pre-treatment baseline performance in mazes (No. 2-4), suggesting no significant influence of dopaminergic inhibition on allocentric spatial learning. Together, the present study potentially suggested insensitivity of allocentric spatial learning to cognitive aging and acute systematic dopaminergic inhibition.

Previous studies have revealed faster detection of snake images in humans and non-human primates (NHPs), suggesting automatic detection of evolutionary fear-relevant stimuli. Furthermore, human studies have indicated that general fear-relevance rather than evolutionary relevance is more effective at capturing attention. However, the issue remains unclarified in NHPs. Thus, in the present study, we explored the attentional features of laboratory-reared monkeys to evolutionary and general fear-relevant stimuli (e.g., images of snakes, capturing gloves). Eye-tracking technology was utilized to assess attentional features as it can provide more accurate latency and variables of viewing duration and frequency compared with visual search task (VST) and response latency adopted in previous studies. In addition, those with autism spectrum disorder (ASD) show abnormal attention to threatening stimuli, including snake images. Rett syndrome (RTT) is considered a subcategory of ASD due to the display of autistic features. However, the attentional features of RTT patients or animal models to such stimuli remain unclear. Therefore, we also investigated the issue in MECP2 gene-edited RTT monkeys. The influence of different cognitive loads on attention was further explored by presenting one, two, or four images to increase stimulus complexity. The eye-tracking results revealed no significant differences between RTT and control monkeys, who all presented increased viewing (duration and frequency) of snake images but not of aversive stimuli compared with control images, thus suggesting attentional preference for evolutionary rather than general fear-relevant visual stimuli. Moreover, the preference was only revealed in visual tasks composed of two or four images, suggesting its cognitive-load dependency.

基因编辑技术的开创性进展使得利用CRISPR技术建立猴模型并开展病变基因校正成为目前基因治疗研究领域的热点.非人灵长类与人类在进化关系上最为接近,在模型构建、疾病机制研究以及药物研发方面优势突出.随着基因修饰技术在非人灵长类上的逐步应用,目前已经构建出多种与临床患者病症高度吻合的疾病模型,为开展遗传疾病的基因治疗打下了坚实基础.然而,目前基因递送和基因修复系统面临巨大挑战,能否安全、高效、精确地修复致病基因是基因治疗临床转化的关键问题,现将综述基于猴模型开展基因治疗研究的前景及挑战.

The cognitive phenotypes of Rett syndrome (RTT) remain unclarified compared with the well‐defined genetic etiology. Recent clinical studies suggest the eye‐tracking method as a promising avenue to quantify the visual phenotypes of the syndrome. The present study explored various aspects of visual attention of the methyl‐CpG‐binding protein 2 gene mutant RTT monkeys with the eye‐tracking procedure. Comprehensive testing paradigms, including social valence comparison (SVC), visual paired comparison (VPC), and social recognition memory (SRM), were utilized to investigate their attentional features to social stimuli with differential valence, the novelty preferences, and short‐term recognition memory, respectively. To explore the neurobiological mechanisms underlying the eye‐tracking findings, we assessed changes of the brain subregion volumes and neurotransmitter concentrations. Compared with control monkeys, RTT monkeys demonstrated increased viewing on the more salient stare faces than profile faces in the SVC test, and increased viewing on the whole presented images composed of monkey faces in the VPC and SRM tests. Brain imaging revealed reduced bilateral occipital gyrus in RTT monkeys. The exploratory neurotransmitter analyses revealed no significant changes of various neurotransmitter concentrations in the cerebrospinal fluid and blood of RTT monkeys. The eye‐tracking results suggested social‐valence‐related increased attention in RTT monkeys, supplementing the cognitive phenotypes associated with the syndrome. Further investigations from broader perspectives are required to uncover the underlying neurobiological mechanisms. Autism Res 2019 , 00: 1–13. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay summary Altered expressions of the methyl‐CpG‐binding protein 2 ( MECP2 ) gene are usually associated with neurodevelopmental disorders, such as autism spectrum disorders, Rett syndrome (RTT), and so forth. The present eye‐tracking study found social‐valence‐related increased attention in our firstly established MECP2 mutant RTT monkeys. The novel findings supplement the cognitive phenotypes and potentially benefit the behavioral interventions of the RTT syndrome.

RATIONALE:Phencyclidine (PCP) could induce schizophrenia (Sz) like behavior in both humans and animals, therefore, has been widely utilized to establish Sz animal models. It induced cognitive deficits, the core symptom of Sz, mainly through influencing frontal dopaminergic function. Nonhuman primate (NHP) studies demonstrated impaired object retrieval detour (ORD) and spatial delayed response (SDR) task performance by acute or chronic PCP treatment. However, NHP investigations, continually monitoring SDR performance before, during and after PCP treatment, are lacking.OBJECTIVES:Present study investigated the long-term influence of chronic PCP treatment on SDR performance and the possible increase of SDR deficit severity and duration by the incremental dosing procedure in rhesus monkeys.METHODS:SDR task was performed repeatedly up to eight weeks after constant dosing procedure (i.m., 0.3 mg/kg, day 12-25), during which drug effects on locomotor activity and blood cortisol concentration were assessed. Incremental dosing procedure (starting dose 0.3 mg/kg, day 6-19) began five months later.RESULTS:Constant dosing procedure induced differential level of hyperactivity across testing days, without significant influence on blood cortisol concentration. It reduced SDR performance, until occurrence of the first and worst impairment on day 15 and 23 respectively. The impaired performance recovered to pretreatment level over one week after drug cessation. In contrast, incremental dosing procedure impaired SDR performance on the first treatment day, which recovered within treatment period.CONCLUSION:Results suggested increase of SDR deficit severity by repeated PCP administrations, whereas the incremental dosing procedure did not increase SDR deficit severity and duration.

Early rearing experiences are important in one's whole life, whereas early adverse rearing experience(EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate(NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors(including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments(including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal(HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed.

Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction.

A common pattern in dominance hierarchies is that some ranks result in higher levels of psychosocial stress than others. Such stress can lead to negative health outcomes, possibly through altered levels of stress hormones. The dominance rank-stress physiology relationship is known to vary between species; sometimes dominants show higher levels of glucocorticoid stress hormones, whereas in other cases subordinates show higher levels. It is less clear how this relationship varies between groups of different ages or cultures. In this study, we used long-term cortisol measurement methods to compare the effect of rank on cortisol levels in adult and adolescent male rhesus macaques. In the adult groups, subordinates had significantly higher cortisol levels. In the adolescents, no significant correlation between cortisol and status was found. Further analysis demonstrated that the adult hierarchy was stricter than that of the adolescents. Adult subordinates received extreme aggression more frequently than dominants and this class of behavior was positively correlated with cortisol; by contrast, adolescents showed neither trend. Together, these findings provide evidence for a cortisol-rank relationship determined by social factors, namely, despotism of the group and highlight the importance of group-specific social analysis when comparing or combining results obtained from different groups of animals.