Dissecting schizophrenia phenotypic variation:the contribution of genetic variation, environmental exposures, and gene–environment interactions

Schizophrenia is among the leading causes of disability worldwide. Prior studies have conclusively demonstrated that the etiology of schizophrenia contains a strong genetic component. However, the understanding of environmental contributions and gene–environment interactions have remained less well understood. Here, we estimated the genetic and environmental contributions to schizophrenia risk using a unique combination of data sources and mathematical models. We used the administrative health records of 481,657 U.S. individuals organized into 128,989 families. In addition, we employed rich geographically specific measures of air, water, and land quality across the United States. Using models of progressively increasing complexity, we examined both linear and non-linear contributions of genetic variation and environmental exposures to schizophrenia risk. Our results demonstrate that heritability estimates differ significantly when gene–environment interactions are included in the models, dropping from 79% for the simplest model, to 46% in the best-fit model which included the full set of linear and non-linear parameters. Taken together, these findings suggest that environmental factors are an important source of explanatory variance underlying schizophrenia risk. Future studies are warranted to further explore linear and non-linear environmental contributions to schizophrenia risk and investigate the causality of these associations

Adjunct Therapy in Type 1 Diabetes: A Survey to Uncover Unmet Needs and Patient Preferences Beyond HbA1c Measures.

Background: Adjunct therapy can help patients with type 1 diabetes achieve glycemic goals while potentially mitigating some of the side effects of insulin. In this study, we used a patient survey to identify the unmet needs in type 1 diabetes therapy, patient views of treatment benefit-risk trade-offs, and patient preferences for the use of an adjunct therapy. Methods: A quantitative survey was sent to 2084 adults with type 1 diabetes in November 2017. "Jobs-to-be-done" and conjoint analyses were performed on survey responses to identify unmet needs and the importance of treatment-associated benefits and risks to patients. A 5-point Likert scale measured the importance and satisfaction with patients' current therapy, and with gaps relating to unmet needs. In the conjoint analysis, patients were asked to choose between "packages" of attributes of two doses of adjunct therapy (200 and 400 mg) and placebo, based on established benefits and side effects. Results: A total of 1313 patients (63%) responded. The greatest unmet needs identified were simplifying treatment, lowering/maintaining glycated hemoglobin (HbA1c), reducing mental effort, and increasing time in range (TIR). Conjoint analysis showed that reductions in body weight and TIR had the highest attribute importance (25% and 18%, respectively). The majority (93%) of patients had a preference for the adjunct therapy (either dose) over placebo. Conclusions: This survey highlights the importance of measures beyond HbA1c, such as treatment simplification and TIR, and patient preference for adjunct therapies that help address unmet needs in type 1 diabetes treatment

Fetal alcohol exposure leads to abnormal olfactory bulb development and impaired odor discrimination in adult mice

Background: Children whose mothers consumed alcohol during pregnancy exhibit widespread brain abnormalities and a complex array of behavioral disturbances. Here, we used a mouse model of fetal alcohol exposure to investigate relationships between brain abnormalities and specific behavioral alterations during adulthood. Results: Mice drank a 10% ethanol so

Morphological correlates of pyramidal cell axonal myelination in mouse and human neocortex

The axons of neocortical pyramidal neurons are frequently myelinated. Heterogeneity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and caliber are critical local determinants of fast-spiking interneuron myelination. However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy to examine the extent to which axonal morphology is predictive of the topography of myelination along neocortical pyramidal neurons. We identified critical thresholds for axonal caliber and interbranch distance that are necessary, but not sufficient, for myelination of pyramidal cell axons in mouse primary somatosensory cortex (S1). Specifically, we found that pyramidal neuron axonal segments with a caliber &lt; 0.24 μm or interbranch distance &lt; 18.10 μm are rarely myelinated. Moreover, we further confirmed that these findings in mice are similar for human neocortical pyramidal cell myelination (caliber &lt; 0.25 μm, interbranch distance &lt; 19.00 μm), suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is a critical correlate of the topography and cell-type specificity of neocortical myelination.</p

iPSC-derived healthy human astrocytes selectively load miRNAs targeting neuronal genes into extracellular vesicles

Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability in recipient cells. Astrocyte released factors are thought to be involved in neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects of RTT. EVs cross the blood-brain barrier (BBB) and their cargo is found in peripheral blood which may allow non-invasive detection of EV cargo as biomarkers produced by healthy astrocytes. Here we characterize miRNA cargo and sequence motifs in healthy human astrocyte derived EVs (ADEVs). First, human induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor Cells (NPCs) and subsequently into astrocytes using a rapid differentiation protocol. iPSC derived astrocytes expressed specific markers, displayed intracellular calcium transients and secreted ADEVs. miRNAs were identified by RNA-Seq on astrocytes and ADEVs and target gene pathway analysis detected brain and immune related terms. The miRNA profile was consistent with astrocyte identity, and included approximately 80 miRNAs found in astrocytes that were relatively depleted in ADEVs suggestive of passive loading. About 120 miRNAs were relatively enriched in ADEVs and motif analysis discovered binding sites for RNA binding proteins FUS, SRSF7 and CELF5. miR-483-5p was the most significantly enriched in ADEVs. This miRNA regulates MECP2 expression in neurons and has been found differentially expressed in blood samples from RTT patients. Our results identify potential miRNA biomarkers selectively sorted into ADEVs and implicate RNA binding protein sequence dependent mechanisms for miRNA cargo loading.</p

iPSC-derived healthy human astrocytes selectively load miRNAs targeting neuronal genes into extracellular vesicles

Astrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability in recipient cells. Astrocyte released factors are thought to be involved in neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects of RTT. EVs cross the blood-brain barrier (BBB) and their cargo is found in peripheral blood which may allow non-invasive detection of EV cargo as biomarkers produced by healthy astrocytes. Here we characterize miRNA cargo and sequence motifs in healthy human astrocyte derived EVs (ADEVs). First, human induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor Cells (NPCs) and subsequently into astrocytes using a rapid differentiation protocol. iPSC derived astrocytes expressed specific markers, displayed intracellular calcium transients and secreted ADEVs. miRNAs were identified by RNA-Seq on astrocytes and ADEVs and target gene pathway analysis detected brain and immune related terms. The miRNA profile was consistent with astrocyte identity, and included approximately 80 miRNAs found in astrocytes that were relatively depleted in ADEVs suggestive of passive loading. About 120 miRNAs were relatively enriched in ADEVs and motif analysis discovered binding sites for RNA binding proteins FUS, SRSF7 and CELF5. miR-483-5p was the most significantly enriched in ADEVs. This miRNA regulates MECP2 expression in neurons and has been found differentially expressed in blood samples from RTT patients. Our results identify potential miRNA biomarkers selectively sorted into ADEVs and implicate RNA binding protein sequence dependent mechanisms for miRNA cargo loading.</p

Oxytocin moderates the association between testosterone-cortisol ratio and trustworthiness:A randomized placebo-controlled study

Oxytocin has been proposed to enhance feelings of trust, however, these findings have been difficult to replicate. Environmental or hormonal factors might influence this association. We studied whether oxytocin moderates the association between the testosterone-cortisol ratio, which is associated with risk taking behavior and aggression, and trustworthiness, while controlling for the general level of trust. A randomized double-blind placebo-controlled study with 53 healthy males was performed in which 32IU oxytocin (n = 27) or placebo (n = 26) was administered intranasally. Participants subsequently played the Trust Game in which they were allocated to the role of trustee. In the third phase of the Trust Game, we found a positive association between the testosterone-cortisol-ratio and the proportion of the amount that is returned to the investor (P=<0.01). However, administration of oxytocin reduced reciprocity in those with a high testosterone-cortisol ratio after reciprocity restoration (a significant interaction effect between administration of oxytocin and the testosterone-cortisol ratio in the third phase of the Trust Game, P = 0.015). The third phase of the Trust Game represents the restoration of reciprocity and trustworthiness, after this is violated in the second phase. Therefore, our data suggest that oxytocin might hinder the restoration of trustworthiness and diminish risk-taking behavior when trust is violated, especially in those who are hormonally prone to risk-taking behavior by a high testosterone-cortisol ratio

Synthetic Polymers Provide a Robust Substrate for Functional Neuron Culture

Substrates for neuron culture and implantation are required to be both biocompatible and display surface compositions that support cell attachment, growth, differentiation, and neural activity. Laminin, a naturally occurring extracellular matrix protein is the most widely used substrate for neuron culture and fulfills some of these requirements, however, it is expensive, unstable (compared to synthetic materials), and prone to batch-to-batch variation. This study uses a high-throughput polymer screening approach to identify synthetic polymers that supports the in vitro culture of primary mouse cerebellar neurons. This allows the identification of materials that enable primary cell attachment with high viability even under “serum-free” conditions, with materials that support both primary cells and neural progenitor cell attachment with high levels of neuronal biomarker expression, while promoting progenitor cell maturation to neurons.Biomaterials & Tissue Biomechanic

A simplified protocol for the generation of cortical brain organoids

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes

Long-term association of pregnancy and maternal brain structure:the Rotterdam Study

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in women’s lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of pregnancy on maternal brain structure remain unknown. We investigated a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume (β = 0.14, 95% CI = 0.09–0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings suggest that pregnancy and childbirth are associated with robust long-term changes in brain structure involving a larger global gray matter volume that persists for decades. Future studies are warranted to further investigate the mechanism and physiological relevance of these differences in brain morphology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10654-021-00818-5