There is growing clinical and experimental evidence to suggest that maternal obesity increases children's susceptibility to neurodevelopmental and neuropsychiatric disorders. Given the worldwide ...obesity epidemic, it is crucial that we acquire a thorough understanding of the available evidence, identify gaps in knowledge, and develop an agenda for intervention. This review synthesizes human and animal studies investigating the association between maternal obesity and offspring brain health. It also highlights key mechanisms underlying these effects, including maternal and fetal inflammation, alterations to the microbiome, epigenetic modifications of neurotrophic genes, and impaired dopaminergic and serotonergic signaling. Lastly, this review highlights several proposed interventions and priorities for future investigation.
Regulation of gene expression is primarily controlled by changes in the proteins that occupy genes' regulatory elements. We developed genomic locus proteomics (GLoPro), in which we combine ...CRISPR-based genome targeting, proximity labeling, and quantitative proteomics to discover proteins associated with a specific genomic locus in native cellular contexts.
Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this ...epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.
Children who require surgery in the newborn period are at risk for long-term neurodevelopmental impairment (NDI). There is growing evidence that surgery during this critical window of ...neurodevelopment gives rise to an increased risk of brain injury, predisposing to neurodevelopmental challenges including motor delays, learning disabilities, executive function impairments, and behavioral disorders. These impairments can have a significant impact on the quality of life of these children and their families. This review explores the current literature surrounding the effect of neonatal surgery on neurodevelopment, as well as the spectrum of proposed mechanisms that may impact neurodevelopmental outcomes. The goal is to identify modifiable risk factors and patients who may benefit from close neurodevelopmental follow-up and early referral to therapy.
Auditory experience drives neural circuit refinement during windows of heightened brain plasticity, but little is known about the genetic regulation of this developmental process. The primary ...auditory cortex (A1) of mice exhibits a critical period for thalamocortical connectivity between postnatal days P12 and P15, during which tone exposure alters the tonotopic topography of A1. We hypothesized that a coordinated, multicellular transcriptional program governs this window for patterning of the auditory cortex. To generate a robust multicellular map of gene expression, we performed droplet-based, single-nucleus RNA sequencing (snRNA-seq) of A1 across three developmental time points (P10, P15, and P20) spanning the tonotopic critical period. We also tone-reared mice (7 kHz pips) during the 3-d critical period and collected A1 at P15 and P20. We identified and profiled both neuronal (glutamatergic and GABAergic) and nonneuronal (oligodendrocytes, microglia, astrocytes, and endothelial) cell types. By comparing normal- and tone-reared mice, we found hundreds of genes across cell types showing altered expression as a result of sensory manipulation during the critical period. Functional voltage-sensitive dye imaging confirmed GABA circuit function determines critical period onset, while Nogo receptor signaling is required for its closure. We further uncovered previously unknown effects of developmental tone exposure on trajectories of gene expression in interneurons, as well as candidate genes that might execute tonotopic plasticity. Our single-nucleus transcriptomic resource of developing auditory cortex is thus a powerful discovery platform with which to identify mediators of tonotopic plasticity.
Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later ...stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.
The mammalian central nervous system coordinates a network of signaling pathways and cellular interactions, which enable a myriad of complex cognitive and physiological functions. While traditional ...efforts to understand the molecular basis of brain function have focused on well-characterized proteins, recent advances in high-throughput translatome profiling have revealed a staggering number of proteins translated from non-canonical open reading frames (ncORFs) such as 5' and 3' untranslated regions of annotated proteins, out-of-frame internal ORFs, and previously annotated non-coding RNAs. Of note, microproteins < 100 amino acids (AA) that are translated from such ncORFs have often been neglected due to computational and biochemical challenges. Thousands of putative microproteins have been identified in cell lines and tissues including the brain, with some serving critical biological functions. In this perspective, we highlight the recent discovery of microproteins in the brain and describe several hypotheses that have emerged concerning microprotein function in the developing and mature nervous system.
In fetuses with Ebstein anomaly or tricuspid valve dysplasia (EA/TVD), poor hemodynamic status is associated with worse neonatal outcome. It is not known whether EA/TVD fetuses with more favorable ...physiology earlier in gestation progress to more severe disease in the third trimester. We evaluated if echocardiographic indexes in EA/TVD fetuses presenting <24 weeks of gestation are reliable indicators of physiologic status later in pregnancy. This multicenter, retrospective study included 51 fetuses presenting at <24 weeks of gestation with EA/TVD and serial fetal echocardiograms ≥4 weeks apart. We designated the following as markers of poor outcome: absence of anterograde flow across the pulmonary valve, pulmonary valve regurgitation, cardiothoracic area ratio >0.48, left ventricular (LV) dysfunction, or tricuspid valve (TV) annulus Z-score >5.6. Median gestational age at diagnosis was 21 weeks (range, 18 to 24). Eighteen fetuses (35%) had no markers for poor hemodynamic status initially, whereas only 7 of these continued to have no markers of poor outcome in the third trimester. Nine of 27 fetuses (33%) with anterograde pulmonary blood flow on the first echocardiogram developed pulmonary atresia; 7 of 39 (18%) developed new pulmonary valve regurgitation. LV dysfunction was present in 2 (4%) patients at <24 weeks but in 14 (37%) later (p <0.001). The TV annulus Z-score and cardiothoracic area both increased from diagnosis to follow-up. In conclusion, progressive hemodynamic compromise was common in this cohort. Our study highlights that care must be taken in counseling before 24 weeks, as the absence of factors associated with poor outcome early in pregnancy may be falsely reassuring.
Weight drop models in rodents have been used for several decades to advance our understanding of the pathophysiology of traumatic brain injury. Weight drop models have been used to replicate focal ...cerebral contusion as well as diffuse brain injury characterized by axonal damage. More recently, closed head injury models with free head rotation have been developed to model sports concussions, which feature functional disturbances in the absence of overt brain damage assessed by conventional imaging techniques. Here, we describe the history of development of closed head injury models in the first part of the chapter. In the second part, we describe the development of our own weight drop closed head injury model that features impact plus rapid downward head rotation, no structural brain injury, and long-term cognitive deficits in the case of multiple injuries. This rodent model was developed to reproduce key aspects of sports concussion so that a mechanistic understanding of how long-term cognitive deficits might develop will eventually follow. Such knowledge is hoped to impact athletes and war fighters and others who suffer concussive head injuries by leading to targeted therapies aimed at preventing cognitive and other neurological sequelae in these high-risk groups.
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