Oxford open neuroscience最新文献

PRDM16 is a dynamic transcriptional regulator of various stem cell niches, including adipocytic, hematopoietic, cardiac progenitors, and neural stem cells. PRDM16 has been suggested to contribute to 1p36 deletion syndrome, one of the most prevalent subtelomeric microdeletion syndromes. We report a patient with a de novo nonsense mutation in the PRDM16 coding sequence, accompanied by lissencephaly and microcephaly features. Human stem cells were genetically modified to mimic this mutation, generating cortical organoids that exhibited altered cell cycle dynamics. RNA sequencing of cortical organoids at day 32 unveiled changes in cell adhesion and WNT-signaling pathways. ChIP-seq of PRDM16 identified binding sites in postmortem human fetal cortex, indicating the conservation of PRDM16 binding to developmental genes in mice and humans, potentially at enhancer sites. A shared motif between PRDM16 and LHX2 was identified and further examined through comparison with LHX2 ChIP-seq data from mice. These results suggested a collaborative partnership between PRDM16 and LHX2 in regulating a common set of genes and pathways in cortical radial glia cells, possibly via their synergistic involvement in cortical development.

A child's social world is complex and rich, but has traditionally been assessed with conventional experiments where children are presented with repeated stimuli on a screen. These assessments are impoverished relative to the dynamics of social interactions in real life, and can be challenging to implement with preschoolers, who struggle to comply with strict lab rules. The current work meets the need to develop new platforms to assess preschoolers' social development, by presenting a unique virtual-reality set-up combined with wearable functional near-infrared spectroscopy (fNIRS). As a proof-of-principle, we validated this platform by measuring brain activity during self-guided social interaction in 3-to-5-year-olds, which is under-investigated, yet crucial to understand the basis of social interactions in preschoolers. 37 preschoolers chose an interaction partner from one of 4 human-like avatars of different gender and age. We recorded spontaneous brain fluctuations from the frontal and temporoparietal regions (notably engaged in social-categorization and preference) while children played a bubble-popping game with a preferred and an assigned avatar. 60% of the participants chose to play with the same-gender and same-age avatar. However, this result was driven by females (>80% vs. 50% in males). Different fronto-temporoparietal connectivity patterns when playing with the two avatars were observed, especially in females. We showed the feasibility of using a novel set-up to naturalistically assess social preference in preschoolers, which was assessed at the behavioural and functional connectivity level. This work provides a first proof-of-principle for using cutting-edge technologies and naturalistic experiments to study social development, opening new avenues of research.

Human brain development is spatially and temporally complex. Insufficient access to human brain tissue and inadequacy of animal models has limited the study of brain development and neurodegenerative diseases. Recent advancements of brain organoid technology have created novel opportunities to model human-specific neurodevelopment and brain diseases. In this review, we discuss the use of brain organoids to model the midbrain and Parkinson's disease. We critically evaluate the extent of recapitulation of PD pathology by organoids and discuss areas of future development that may lead to the model to become a next-generation, personalized therapeutic strategy for PD and beyond.

Glioblastoma (GBM) is the most aggressive adult primary brain tumor with nearly universal treatment resistance and recurrence. The mainstay of therapy remains maximal safe surgical resection followed by concurrent radiation therapy and temozolomide chemotherapy. Despite intensive investigation, alternative treatment options, such as immunotherapy or targeted molecular therapy, have yielded limited success to achieve long-term remission. This difficulty is partly due to the lack of pre-clinical models that fully recapitulate the intratumoral and intertumoral heterogeneity of GBM and the complex tumor microenvironment. Recently, GBM 3D organoids originating from resected patient tumors, genetic manipulation of induced pluripotent stem cell (iPSC)-derived brain organoids and bio-printing or fusion with non-malignant tissues have emerged as novel culture systems to portray the biology of GBM. Here, we highlight several methodologies for generating GBM organoids and discuss insights gained using such organoid models compared to classic modeling approaches using cell lines and xenografts. We also outline limitations of current GBM 3D organoids, most notably the difficulty retaining the tumor microenvironment, and discuss current efforts for improvements. Finally, we propose potential applications of organoid models for a deeper mechanistic understanding of GBM and therapeutic development.

Interpersonal brain synchronization (IBS) has been observed during social interactions and involves various factors, such as familiarity with the partner and type of social activity. A previous study has shown that face-to-face (FF) interactions in pairs of strangers increase IBS. However, it is unclear whether this can be observed when the nature of the interacting partners is different. Herein, we aimed to extend these findings to pairs of acquaintances. Neural activity in the frontal and temporal regions was recorded using functional near-infrared spectroscopy hyperscanning. Participants played an ultimatum game that required virtual economic exchange in two experimental settings: face-to-face and face-blocked conditions. Random pair analysis confirmed whether IBS was induced by social interaction. Contrary to the aforementioned study, our results did not show any cooperative behavior or task-induced IBS increase. Conversely, the random pair analysis results revealed that the pair-specific IBS was significant only in the task condition at the left and right superior frontal, middle frontal, orbital superior frontal, right superior temporal, precentral and postcentral gyri. Our results tentatively suggested that FF interaction in acquainted pairs did not increase IBS and supported the idea that IBS is affected by 'with whom we interact and how'.

Neuronal development and function are known to be among the most energy-demanding functions of the body. Constant energetic support is therefore crucial at all stages of a neuron's life. The two main adenosine triphosphate (ATP)-producing pathways in cells are glycolysis and oxidative phosphorylation. Glycolysis has a relatively low yield but provides fast ATP and enables the metabolic versatility needed in dividing neuronal stem cells. Oxidative phosphorylation, on the other hand, is highly efficient and therefore thought to provide most or all ATP in differentiated neurons. However, it has recently become clear that due to their distinct properties, both pathways are required to fully satisfy neuronal energy demands during development and function. Here, we provide an overview of how glycolysis and oxidative phosphorylation are used in neurons during development and function.

Ambiguous relationships between events may be established using interference procedures such as latent inhibition, extinction or counterconditioning. Under these conditions, the retrieval of individual associations between a stimulus and outcome is affected by contextual cues. To examine the roles of the dorsal (prelimbic) and ventral (infralimbic) medial prefrontal cortex in the contextual modulation of such associations, we investigated the context specificity of latent inhibition. Male Lister hooded rats were pre-exposed to two separate stimuli, one in each of two distinct contexts. Both stimuli were then paired with the delivery of mild foot-shock in the same one of these contexts. Finally, the strength of the resultant conditioned emotional response (CER) to each stimulus was assessed in each context. For the sham-operated control rats, the CER was attenuated for each stimulus when it was tested in the context in which it had been pre-exposed. Rats who had received lesions to the infralimbic cortex showed this effect only in the conditioning context, whereas rats with lesions to the prelimbic cortex showed the effect only in the context in which conditioning had not taken place. These findings indicate that infralimbic and prelimbic cortices play distinct, and competing, roles in the contextual modulation of initial and later learning.

α-Synuclein is a pleiotropic protein underlying a group of progressive neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. Together, these are known as synucleinopathies. Like all neurological diseases, understanding of disease mechanisms is hampered by the lack of access to biopsy tissues, precluding a real-time view of disease progression in the human body. This has driven researchers to devise various experimental models ranging from yeast to flies to human brain organoids, aiming to recapitulate aspects of synucleinopathies. Studies of these models have uncovered numerous genetic modifiers of α-synuclein, most of which are evolutionarily conserved. This review discusses what we have learned about disease mechanisms from these modifiers, and ways in which the study of modifiers have supported ongoing efforts to engineer disease-modifying interventions for synucleinopathies.

[This corrects the article DOI: 10.1093/oons/kvac001.].