The role of T-lymphocytes in central nervous system diseases.

The central nervous system (CNS) has been considered an immunologically privileged site. In the past few decades, research on inflammation in CNS diseases has mostly focused on microglia, innate immune cells that respond rapidly to injury and infection to maintain CNS homeostasis. Discoveries of lymphatic vessels within the dura mater and peripheral immune cells in the meningeal layer indicate that the peripheral immune system can monitor and intervene in the CNS.

C9orf72 poly(PR) aggregation in nucleus induces ALS/FTD-related neurodegeneration in cynomolgus monkeys.

Poly(PR) is a dipeptide repeat protein comprising proline and arginine residues. It is one of the translational product of expanded G4C2 repeats in the C9orf72 gene, and its accumulation is contributing to the neuropathogenesis of C9orf72-associated amyotrophic lateral sclerosis and/or frontotemporal dementia (C9-ALS/FTD). In this study, we demonstrate that poly(PR) protein alone is sufficient to induce neurodegeneration related to ALS/FTD in cynomolgus monkeys.

Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson's disease in animal models.

Although striatal delivery of three critical genes for dopamine synthesis by viruses is a potential clinical approach for treating Parkinson's disease (PD), the approach makes it difficult to finely control dopamine secretion amounts and brings safety concerns. Here, we generate genetically engineered mesenchymal stem cells encoding three critical genes for dopamine synthesis (DOPA-MSCs). DOPA-MSCs retain their MSC identity and stable ability to secrete dopamine during passaging.

Pathological α-synuclein accumulation, CSF metabolites changes and brain microstructures in cynomolgus monkeys treated with 6-hydroxydopamine.

The lack of evidence indicating the accumulation of phosphorylated α-synuclein (P-α-syn), a neuropathological hallmark of Parkinson disease (PD), limits the application of 6-OHDA animal models. In cynomolgus monkeys received unilateral 6-hydroxydopamine (6-OHDA) injection, we identified nigrostriatal dysfunction related behavioral defects, such as the increase of PD score, decrease of locomotor activities, and exhibition of typical rotations. We found the dopaminergic neurons were significantly reduced and had fragmented morphology in substantia nigra (SN).

Spatially resolved gene regulatory and disease-related vulnerability map of the adult Macaque cortex.

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell transcriptomic and chromatin accessibility (single-cell ATAC) data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult female cynomolgus monkey brain, and integrated this dataset with Stereo-seq (spatial enhanced resolution omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity.

Chronic vagus nerve stimulation (VNS) altered IL-6, IL-1β, CXCL-1 and IL-13 levels in the hippocampus of rats with LiCl-pilocarpine-induced epilepsy.

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines.

Longitudinal brain atlases of early developing cynomolgus macaques from birth to 48 months of age.

Longitudinal brain imaging atlases with densely sampled time-points and ancillary anatomical information are of fundamental importance in studying early developmental characteristics of human and non-human primate brains during infancy, which feature extremely dynamic imaging appearance, brain shape and size. However, for non-human primates, which are highly valuable animal models for understanding human brains, the existing brain atlases are mainly developed based on adults or adolescents, denoting a notable lack of temporally densely-sampled atlases covering the dynamic early brain development. To fill this critical gap, in this paper, we construct a comprehensive set of longitudinal brain atlases and associated tissue probability maps (gray matter, white matter, and cerebrospinal fluid) with totally 12 time-points from birth to 4 years of age (i.

The Amygdala Responds Rapidly to Flashes Linked to Direct Retinal Innervation: A Flash-evoked Potential Study Across Cortical and Subcortical Visual Pathways.

Rapid detection and response to visual threats are critical for survival in animals. The amygdala (AMY) is hypothesized to be involved in this process, but how it interacts with the visual system to do this remains unclear. By recording flash-evoked potentials simultaneously from the superior colliculus (SC), lateral posterior nucleus of the thalamus, AMY, lateral geniculate nucleus (LGN) and visual cortex, which belong to the cortical and subcortical pathways for visual fear processing, we investigated the temporal relationship between these regions in visual processing in rats.

Generation of a Hutchinson-Gilford progeria syndrome monkey model by base editing.

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions.

Transcriptomic and open chromatin atlas of high-resolution anatomical regions in the rhesus macaque brain.

The rhesus macaque is a prime model animal in neuroscience. A comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain is key to a deeper understanding of the brain. Here we characterize the transcriptome of 416 brain samples from 52 regions of 8 rhesus macaque brains.

Dissecting primate early post-implantation development using long-term in vitro embryo culture.

The transition from peri-implantation to gastrulation in mammals entails the specification and organization of the lineage progenitors into a body plan. Technical and ethical challenges have limited understanding of the cellular and molecular mechanisms that underlie this transition. We established a culture system that enabled the development of cynomolgus monkey embryos in vitro for up to 20 days.

Threshold for maximal electroshock seizures (MEST) at three developmental stages in young mice.

Early brain development after birth is extremely dynamic, suggesting that potential functional changes occur during this period. In this study, the maximal electroshock seizure threshold (MEST) was used to explore the electrophysiological variation among three developmental stages in young mice (no more than 5 weeks old). The induced electroshock seizure (ES) behavior of early postnatal mice (1-2-weeks old) differed from that during weaning (3 weeks old) and early puberty (4-5-weeks old).

Prepulse Inhibition of Auditory Cortical Responses in the Caudolateral Superior Temporal Gyrus in Macaca mulatta.

Prepulse inhibition (PPI) refers to a decreased response to a startling stimulus when another weaker stimulus precedes it. Most PPI studies have focused on the physiological startle reflex and fewer have reported the PPI of cortical responses. We recorded local field potentials (LFPs) in four monkeys and investigated whether the PPI of auditory cortical responses (alpha, beta, and gamma oscillations and evoked potentials) can be demonstrated in the caudolateral belt of the superior temporal gyrus (STGcb).

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females.

Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons.

[Glaucoma model for stem cell transplantation research in New Zealand white rabbits].

Glaucoma is a typical irreversible blind neurodegenerative disease for which there is no effective treatment for halting visual deterioration. The recent development of neural stem cells studies sheds light on a potential resolution for this disease. As a result, an appropriate glaucoma modeling method for stem cell transplantation study is needed.