Abstract: “The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors. ”
Park G-H et al: Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia. Nature Neurosci. 23(11): 1352-1364 (2020).
Summary: ”The neuropeptide oxytocin is an important regulator of social behavior and is widely considered to reduce anxiety-related behaviors. However, growing evidence suggests that sometimes oxytocin increases anxiety. How can the same molecule have such different effects on behavior? Here we provide evidence that oxytocin produced outside of the hypothalamus is necessary and sufficient for stress-induced social anxiety behaviors. This suggests that the diverse effects of oxytocin on anxiety-related behaviors are mediated by circuit-specific oxytocin action.”
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Liotta EM et al: Frequent neurologic manifestations and encephalopathy‐associated morbidity in Covid‐19 patients. Annals of Clinical and Translational Neurology [Epub ahead of print, Oct. 5, 2020;https://doi.org/10.1002/acn3.51210 ]
Abstract: “Parkinson’s disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.”
Marshall LL, Killinger BA, Ensink E, Li P et al: Epigenetic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective. Nature Neurosci. 23(10): 1203-1214 (2020).
Abstract: “‘Dysbiosis’ of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.”
Vuong, H.E., Pronovost, G.N., Williams, D.W. et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature (2020). https://doi.org/10.1038/s41586-020-2745-3.
“Our results show that the experience of being alone has immediate consequences on brain gene activity. Clearly this is important for the human context, where loneliness (i.e., perceived social isolation) is a risk factor for psychological and neurodegenerative disorders. As the response occurs in brain areas involved in higher-order cognition and perception, these changes in gene activity may influence the ongoing processing of experience. Prior studies in humans have measured effects of social isolation in circulating leukocytes, but not in brain, and studies in mammalian models have typically focused on effects of much longer isolation periods (weeks or more). The results also bear on interpretation of animal experiments where short-term isolation is used to establish the baseline reference condition.”
George JM et al: Acute social isolation alters neurogenomic state in songbird forebrain. Proc. Natl. Acad. Sci. USA 117 (38): 23311-23316 (2020).
“Parkinson’s disease or parkinsonism have been described after infections by viruses, such as influenza A, Epstein-Barr virus, varicella zoster, hepatitis C virus, HIV, Japanese encephalitis virus, or West Nile virus. We report a patient with probable Parkinson’s disease, who was diagnosed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection….”
Cohen ME et al: A case of probable Parkinson’s disease after SARS-CoV-2 infection. Lancet Neurology 19(10): 804-805, 2020.
ESSAYS ON SCIENCE AND SOCIETY NEUROMODULATION
Hong G: Seeing the sound. Science 369(6504): 638 (2020).