Betina Elfving

Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human induced pluripotent stem-cell derived neurons. We found that inhibition of a human-specific microRNA, miR-1229-3p, alters the trajectory of human neuronal maturation and enhances excitatory synaptic transmission. Transcriptome analysis following miR-1229 knockdown revealed a downregulation of mitochondrial DNA (mtDNA) encoded genes. We further show that miR-1229 regulates mitochondrial morphology, mtDNA abundance as well as mitophagy, and that stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Accordingly, miR-1229 directly targets an entire network of genes involved in mitochondrial function and ER-associated protein homeostasis. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.

Serotonin (5-hydroxytryptamine, 5-HT) is a multifaceted neuromodulator involved in processes from early embryogenesis to postnatal brain maturation. During pregnancy, 5-HT plays critical roles not only in maternal mood and behavior but also in placental function and fetal brain development. Beyond its classical role in mood regulation, 5-HT acts as a developmental signal influencing neuronal proliferation, migration, and synaptic organization within precisely timed critical windows. This narrative review provides an integrative framework linking molecular, cellular, and systems-level 5-HT mechanisms to neurodevelopmental outcomes, emphasizing how maternal, placental, and fetal sources of 5-HT dynamically interact with genetic, environmental, and pharmacological factors during gestation. By considering recent advances from developmental neurobiology, genetics, and psychopharmacology, we propose that disrupted 5-HTergic homeostasis represents a convergent mechanism underlying neurodevelopmental risk, particularly in autism spectrum disorder (ASD). We further highlight emerging evidence for sex-dependent 5-HTergic signaling and its role in differential susceptibility across offspring. These results collectively indicate the key role of 5-HT in neurodevelopment and highlight its promise as a biomarker and therapeutic target in neurodevelopmental disorders.

Here, we report that long-term stored human brain samples, formalin-fixed paraffin-embedded (FFPE) from The Brain Collection, University of Southern Denmark, Denmark (https://www.sdu.dk/en/forskning/bridge/the-brain-collection), can be used for in situ hybridization (ISH) analysis of selected microRNAs (miRNAs). The Human Brain Collection consists of brains from 9479 subjects who died at a Danish State Mental Hospital in the period of 1945–1982. In the present study we included tissue specimens from prefrontal cortex (PFC) and hippocampus (HIP) from 163 patients diagnosed with schizophrenia, bipolar disorder, or major depressive disorder. Initially, the Nanostring nCounter platform was used to identify miRNA candidates for ISH analysis using the miRNAscope technology. Based on the Nanostring nCounter quantifications with bulk tissue, we identified and selected 10 miRNAs from PFC (miR-9-5p, miR-29b-3p, miR-30c-5p, miR-124-3p, miR-125b-5p, miR-138-5p, miR-181a-5p, miR-224-5p, miR-302d-3p, and miR-432-5p) and 6 miRNAs from HIP (let-7a-5p, miR-7-5p, miR-124-3p, miR-127-3p, miR-145-5p and miR-149-5p). miRNAscope ISH analysis was then performed with the respective probes on 30 PFC and 30 HIP samples, respectively. In the PFC six miRNAs (miR-9-5p, miR-29b-3p, miR-124-3p, miR-125b-5p, miR-138-5p, and miR-181a-5p) were detected and four (miR-145-5p, let-7a-5p, miR-124-3p and miR-7-5p) in the HIP samples. In both brain regions miR-124-3p was the most abundantly expressed. We conclude, that the combination of the Nanostring nCounter technology and the miRNAscope analysis is a valid approach to study spatial expression of specific miRNAs in these up to 76 years old FFPE blocks. This opens a new avenue of possibilities for studying the underlying epigenetic mechanisms in mental disorders.

Circadian rhythm (CR) disturbances are among the most commonly observed symptoms during major depressive disorder, mostly in the form of disrupted sleeping patterns. However, several other measurable parameters, such as plasma hormone rhythms and differential expression of circadian clock genes (ccgs), are also present, often referred to as circadian phase markers. In the recent years, CR disturbances have been recognized as an essential aspect of depression; however, most of the known animal models of depression have yet to be evaluated for their eligibility to model CR disturbances. In this study, we investigate the potential of adrenocorticotropic hormone (ACTH)‐treated animals as a disease model for research in CR disturbances in treatment‐resistant depression. For this purpose, we evaluate the changes in several circadian phase markers, including plasma concentrations of corticosterone, ACTH, and melatonin, as well as gene expression patterns of 13 selected ccgs at 3 different time points, in both peripheral and central tissues. We observed no impact on plasma corticosterone and melatonin concentrations in the ACTH rats compared to vehicle. However, the expression pattern of several ccgs was affected in the ACTH rats compared to vehicle. In the hippocampus, 10 ccgs were affected by ACTH treatment, whereas in the adrenal glands, 5 ccgs were affected and in the prefrontal cortex, hypothalamus and liver 4 ccgs were regulated. In the blood, only 1 gene was affected. Individual tissues showed changes in different ccgs, but the expression of Bmal1, Per1, and Per2 were most generally affected. Collectively, the results presented here indicate that the ACTH animal model displays dysregulation of a number of phase markers suggesting the model may be appropriate for future studies into CR disturbances. image

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.