RNA-programmable cell type monitoring and manipulation in the human cortex with CellREADR.

Reliable and systematic experimental access to diverse cell types is necessary for understanding the neural circuit organization, function, and pathophysiology of the human brain. Methods for targeting human neural populations are scarce and currently center around identifying and engineering transcriptional enhancers and viral capsids. Here we demonstrate the utility of CellREADR, a programmable RNA sensor-effector technology that couples cellular RNA sensing to effector protein translation, for accessing, monitoring, and manipulating specific neuron types in human cortical tissues.

Pathogenic variants associated with speech/cognitive delay and seizures affect genes with expression biases in excitatory neurons and microglia in developing human cortex.

Background & Objective: Congenital brain malformations and neurodevelopmental disorders (NDDs) are common pediatric neurological disorders and result in chronic disability. With the expansion of genetic testing, new etiologies for NDDs are continually uncovered, with as many as one third attributable to single-gene pathogenic variants. While our ability to identify pathogenic variants has continually improved, we have little understanding of the underlying cellular pathophysiology in the nervous system that results from these variants.

Clinical and Imaging Findings in Children with Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD): From Presentation to Relapse.

Background And Purpose: Myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) is an increasingly recognized cause of demyelinating disease in children. The purpose of this study is to characterize the CNS imaging manifestations of pediatric MOGAD and identify clinical and imaging variables associated with relapse.

Materials And Methods: We retrospectively identified children with serum antibody-positive MOGAD evaluated at our institution between 1997 and 2020.

Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.

Background: The association between childhood cancer risk and maternal prenatal substance use/abuse remains uncertain due to modest sample sizes and heterogeneous study designs.

Methods: We surveyed parents of children with cancer regarding maternal gestational use of tobacco, alcohol, and illicit drugs, using a Likert-type scale, and demographic, perinatal, and clinical variables. Multivariable log-Poisson regression assessed differences in frequency of prenatal substance use across fifteen childhood cancer subtypes, adjusting for birthweight, gestational age, and demographic factors.

Acquired Brain Injuries Across the Perinatal Spectrum: Pathophysiology and Emerging Therapies.

The development of the central nervous system can be directly disrupted by a variety of acquired factors, including infectious, inflammatory, hypoxic-ischemic, and toxic insults. Influences external to the fetus also impact neurodevelopment, including placental health, maternal comorbidities, adverse experiences, environmental exposures, and social determinants of health. Acquired perinatal brain insults tend to affect the developing brain in a stage-specific manner that reflects the susceptible cell types, developmental processes, and risk factors present at the time of the insult.

The association of placental pathology and neurodevelopmental outcomes in patients with neonatal encephalopathy.

Background: Studies conflict on how acute versus chronic placental pathology impacts outcomes after neonatal encephalopathy from presumed hypoxic-ischemic encephalopathy (HIE). We examine how outcomes after presumed HIE vary by placental pathology categories.

Methods: We performed retrospective chart review for neonates with presumed HIE, regardless of severity, focusing on 50 triads for whom placental specimens were available for re-review.

The progenitor basis of cortical projection neuron diversity.

Diverse glutamatergic projection neurons (PNs) mediate myriad processing streams and output channels of the cerebral cortex. Yet, how different types of neural progenitors, such as radial glia (RGs) and intermediate progenitors (IPs), produce PN diversity, and hierarchical organization remains unclear. A fundamental issue is whether RGs constitute a homogeneous, multipotent lineage capable of generating all major PN types through a temporally regulated developmental program, or whether RGs comprise multiple transcriptionally heterogenous pools, each fated to generate a subset of PNs.

Child Neurology: Infantile Biotin Thiamine Responsive Basal Ganglia Disease: Case Report and Brief Review.

Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier. It is considered a treatable condition if vitamin supplementation, most commonly with thiamine and biotin, is initiated early. BTRBGD can present as an infantile form, classical childhood form, or adult Wernicke-like encephalopathy.

Neonatal Encephalopathy: Beyond Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy is a clinical syndrome of neurologic dysfunction that encompasses a broad spectrum of symptoms and severity, from mild irritability and feeding difficulties to coma and seizures. It is vital for providers to understand that the term "neonatal encephalopathy" is simply a description of the neonate's neurologic status that is agnostic to the underlying etiology. Unfortunately, hypoxic-ischemic encephalopathy (HIE) has become common vernacular to describe any neonate with encephalopathy, but this can be misleading.

The Arginase Pathway in Neonatal Brain Hypoxia-Ischemia.

Brain damage after hypoxia-ischemia (HI) occurs in an age-dependent manner. Neuroprotective strategies assumed to be effective in adults might have deleterious effects in the immature brain. In order to create effective therapies, the complex pathophysiology of HI in the developing brain requires exploring new mechanisms.

Management of Pediatric Movement Disorders: Present and Future.

Management of movement disorders in children is an evolving field. This article outlines the major categories of treatment options for pediatric movement disorders and general guidelines for their use. We review the evidence for existing therapies, which continue to lack large-scale controlled trials to guide treatment decisions.

A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry.

Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions.

Misexpression of ptf1a in cortical pyramidal cells in vivo promotes an inhibitory peptidergic identity.

The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al.

From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity.

Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics.

Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord.

During perinatal development, corticospinal tract (CST) projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit.

An identity crisis: the need for core competencies in undergraduate medical education.

A medical student perspective on the role of core competencies in undergraduate medical education in light of medical education reform associated with recent Flexner II.