Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3ß, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3ß, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.

Brain organoids for hypoxic-ischemic studies: from bench to bedside.

Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females.

The parabrachial nucleus elicits a vigorous corticosterone feedback response to the pro-inflammatory cytokine IL-1ß.

The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS), the release of which is controlled in the hypothalamus by the paraventricular nucleus (PVN), is a potent negative regulator of immune responses. Using the mouse model, we report that the parabrachial nucleus (PB), an important hub linking interoceptive afferent information to autonomic and behavioral responses, also integrates the pro-inflammatory cytokine IL-1ß signal to induce the CS response. A subpopulation of PB neurons, directly projecting to the PVN and receiving inputs from the vagal complex (VC), responds to IL-1ß to drive the CS response. Pharmacogenetic reactivation of these IL-1ß-activated PB neurons is sufficient to induce CS-mediated systemic immunosuppression. Our findings demonstrate an efficient brainstem-encoded modality for the central sensing of cytokines and the regulation of systemic immune responses.