Gestational immune activation disrupts hypothalamic neurocircuits of maternal care behaviorZambon, Alice; Rico, Laura Cuenca; Herman, Mathieu; Gundacker, Anna; Telalovic, Amina; Hartenberger, Lisa-Marie; Kuehn, Rebekka; Romanov, Roman A.; Hussaini, S. Abid; Harkany, Tibor; Pollak, Daniela D.
doi: 10.1038/s41380-022-01602-xpmid: 35581295
Immune activation is one of the most common complications during pregnancy, predominantly evoked by viral infections. Nevertheless, how immune activation affects mother–offspring relationships postpartum remains unknown. Here, by using the polyinosinic-polycytidylic acid (Poly I:C) model of gestational infection we show that viral-like immune activation at mid-gestation persistently changes hypothalamic neurocircuit parameters in mouse dams and, consequently, is adverse to parenting behavior. Poly I:C-exposed dams favor non-pup-directed exploratory behavior at the expense of pup retrieval. These behavioral deficits are underlain by dendrite pruning and lesser immediate early gene activation in Galanin (Gal)+ neurons with dam-specific transcriptional signatures that reside in the medial preoptic area (mPOA). Reduced activation of an exclusively inhibitory contingent of these distal-projecting Gal+ neurons allows for increased feed-forward inhibition onto putative dopaminergic neurons in the ventral tegmental area (VTA) in Poly I:C-exposed dams. Notably, destabilized VTA output specifically accompanies post-pup retrieval epochs. We suggest that gestational immunogenic insults bias both threat processing and reward perception, manifesting as disfavored infant caregiving.
Techniques for investigating lncRNA transcript functions in neurodevelopmentSrinivas, Tara; Siqueira, Edilene; Guil, Sonia
doi: 10.1038/s41380-023-02377-5pmid: 38145986
Long noncoding RNAs (lncRNAs) are sequences of 200 nucleotides or more that are transcribed from a large portion of the mammalian genome. While hypothesized to have a variety of biological roles, many lncRNAs remain largely functionally uncharacterized due to unique challenges associated with their investigation. For example, some lncRNAs overlap with other genomic loci, are expressed in a cell-type-specific manner, and/or are differentially processed at the post-transcriptional level. The mammalian CNS contains a vast diversity of lncRNAs, and lncRNAs are highly abundant in the mammalian brain. However, interrogating lncRNA function in models of the CNS, particularly in vivo, can be complex and challenging. Here we review the breadth of methods used to investigate lncRNAs in the CNS, their merits, and the understanding they can provide with respect to neurodevelopment and pathophysiology. We discuss remaining challenges in the field and provide recommendations to assay lncRNAs based on current methods.
Genetic factors associated with suicidal behaviors and alcohol use disorders in an American Indian populationPeng, Qian; Gilder, David A.; Bernert, Rebecca A.; Karriker-Jaffe, Katherine J.; Ehlers, Cindy L.
doi: 10.1038/s41380-023-02379-3pmid: 38177348
American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low-frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0–4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1, ANK1, and FBXO11. Nonsynonymous rare and low-frequency mutations in four genes including SERPINF1 (PEDF), ZNF30, CD34, and SLC5A9, and non-intronic rare and low-frequency mutations in genes OPRD1, HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare and low-frequency variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare and low-frequency variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention.
Roles of the medial and lateral orbitofrontal cortex in major depression and its treatmentZhang, Bei; Rolls, Edmund T.; Wang, Xiang; Xie, Chao; Cheng, Wei; Feng, Jianfeng
doi: 10.1038/s41380-023-02380-wpmid: 38212376
We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.
Examining intergenerational risk factors for conduct problems using polygenic scores in the Norwegian Mother, Father and Child Cohort StudyFrach, Leonard; Barkhuizen, Wikus; Allegrini, Andrea G.; Ask, Helga; Hannigan, Laurie J.; Corfield, Elizabeth C.; Andreassen, Ole A.; Dudbridge, Frank; Ystrom, Eivind; Havdahl, Alexandra; Pingault, Jean-Baptiste
doi: 10.1038/s41380-023-02383-7pmid: 38225381
The aetiology of conduct problems involves a combination of genetic and environmental factors, many of which are inherently linked to parental characteristics given parents’ central role in children’s lives across development. It is important to disentangle to what extent links between parental heritable characteristics and children’s behaviour are due to transmission of genetic risk or due to parental indirect genetic influences via the environment (i.e., genetic nurture). We used 31,290 genotyped mother-father-child trios from the Norwegian Mother, Father and Child Cohort Study (MoBa), testing genetic transmission and genetic nurture effects on conduct problems using 13 polygenic scores (PGS) spanning psychiatric conditions, substance use, education-related factors, and other risk factors. Maternal or self-reports of conduct problems at ages 8 and 14 years were available for up to 15,477 children. We found significant genetic transmission effects on conduct problems for 12 out of 13 PGS at age 8 years (strongest association: PGS for smoking, β = 0.07, 95% confidence interval = [0.05, 0.08]) and for 4 out of 13 PGS at age 14 years (strongest association: PGS for externalising problems, β = 0.08, 95% confidence interval = [0.05, 0.11]). Conversely, we did not find genetic nurture effects for conduct problems using our selection of PGS. Our findings provide evidence for genetic transmission in the association between parental characteristics and child conduct problems. Our results may also indicate that genetic nurture via traits indexed by our polygenic scores is of limited aetiological importance for conduct problems—though effects of small magnitude or effects via parental traits not captured by the included PGS remain a possibility.
Blood extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brainSmirnova, Lena; Modafferi, Sergio; Schlett, Charlotte; Osborne, Lauren M.; Payne, Jennifer L.; Sabunciyan, Sarven
doi: 10.1038/s41380-023-02384-6pmid: 38212371
The absence of non-invasive tests that can monitor the status of the brain is a major obstacle for psychiatric care. In order to address this need, we assessed the feasibility of using tissue-specific gene expression to determine the origin of extracellular vesicle (EV) mRNAs in peripheral blood. Using the placenta as a model, we discovered that 26 messenger RNAs that are specifically expressed in the placenta are present in EVs circulating in maternal blood. Twenty-three of these transcripts were either exclusively or highly expressed in maternal blood during pregnancy only and not in the postpartum period, verifying the feasibility of using tissue-specific gene expression to infer the tissue of origin for EV mRNAs. Using the same bioinformatic approach, which provides better specificity than isolating L1 cell-adhesion molecule containing EVs, we discovered that 181 mRNAs that are specifically expressed in the female brain are also present in EVs circulating in maternal blood. Gene set enrichment analysis revealed that these transcripts, which are involved in synaptic functions and myelination, are enriched for genes implicated in mood disorders, schizophrenia, and substance use disorders. The EV mRNA levels of 13 of these female brain-specific transcripts are associated with postpartum depression (adjusted p-vals = 3 × 10−5 to 0.08), raising the possibility that they can be used to infer the state of the brain. In order to determine the extent to which EV mRNAs reflect transcription in the brain, we compared mRNAs isolated from cells and EVs in an iPSC-derived brain microphysiological system differentiated for 3 and 9 weeks. We discovered that, although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular RNA expression changes in the brain via EV mRNA levels. Our findings bring EV mRNAs to the forefront of peripheral biomarker development efforts in psychiatric diseases by demonstrating the feasibility of inferring transcriptional changes in the brain via blood EV mRNA levels.
Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biologyShchelochkov, Oleg A.; Farmer, Cristan A.; Chlebowski, Colby; Adedipe, Dee; Ferry, Susan; Manoli, Irini; Pass, Alexandra; McCoy, Samantha; Van Ryzin, Carol; Sloan, Jennifer; Thurm, Audrey; Venditti, Charles P.
doi: 10.1038/s41380-023-02385-5pmid: 38200289
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.