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The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task., (© 2024. The Author(s).)

Throughout development, neuronal identity is controlled by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 regulates VIP-positive cortical interneuron migration, survival, and connectivity. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early postnatal life. Synaptic in vitro electrophysiology in male and female mice shows that postnatal Prox1 removal differentially affects the dynamics of excitatory inputs onto VIP bipolar and multipolar subtypes. RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Further genetic, pharmacological, and electrophysiological experiments demonstrate that removing Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Finally, overexpression experiments and analysis of native Elfn1 mRNA expression reveal that Elfn1 levels are differentially controlled at the post-transcriptional stage. Thus, in addition to activity-dependent processes that contribute to the developmental trajectory of VIP cells, genetic programs engaged by Prox1 control the final differentiation of multipolar and bipolar subtypes. SIGNIFICANCE STATEMENT The transcription factor Prox1 generates functional diversification of cortical VIP interneuron subtypes in early postnatal life, thus expanding the inhibitory repertoire of the cortex., (Copyright © 2021 Stachniak, Kastli et al.)

Vital motor functions, such as respiration and locomotion, rely on the ability of spinal motor neurons (MNs) to acquire stereotypical positions in the ventral spinal cord and to project with high precision to their peripheral targets. These key properties of MNs emerge during development through transcriptional programs that dictate their subtype identity and connectivity; however, the molecular mechanisms that establish the transcriptional landscape necessary for MN specification are not fully understood. Here, we show that the enzyme topoisomerase IIβ (Top2β) controls MN migration and connectivity. Surprisingly, Top2β is not required for MN generation or survival but has a selective role in columnar specification. In the absence of Top2β , phrenic MN identity is eroded, while other motor columns are partially preserved but fail to cluster to their proper position. In Top2β -/- mice, peripheral connectivity is impaired as MNs exhibit a profound deficit in terminal branching. These defects likely result from the insufficient activation of Hox/Pbx-dependent transcriptional programs as Hox and Pbx genes are downregulated in the absence of Top2β . Top2β mutants recapitulate many aspects of Pbx mutant mice, such as MN disorganization and defects in medial motor column (MMC) specification. Our findings indicate that Top2β , a gene implicated in neurodevelopmental diseases such as autism spectrum disorders, plays a critical, cell-specific role in the assembly of motor circuits.

Objectives: Studies have found that recommendations for additional imaging (RAI) accompany up to 31% of index computed tomography (CT) scans. In this study we assessed the frequency with which recommendations are accepted by the referring physician and the impact of AI on case management., Methods: We performed a cross-sectional study of all index CT scans of the chest, abdomen, and pelvis performed on adult inpatients during a 1-month period at a tertiary medical center. Each radiology report was examined for mention of RAI. We used a standardized abstraction tool to review medical records for the indication for the RAI (related to original diagnosis vs incidental finding), the clinician's rationale for pursuing or discarding the RAI, and the impact of the AI on the inpatient treatment plan., Results: Among the 430 scans reviewed, most (57.7%) were of the abdomen/pelvis. RAI was recommended in 67 cases (odds ratio [OR] 15.6%; 95% confidence interval [CI] 12.4-19.3) and AI was completed in 24 of 67 cases (35.8%). Factors associated with a recommendation for AI were the presence of an incidental finding (OR 3.5, 95% CI 1.7-6.8) and verbal communication of the result to the ordering provider (OR 2.09, 95% CI 1.23-3.5). When performed, AI altered the treatment plan 75% (18/24) of the time. Among the 43 cases in which AI was not performed, 34.1% were deferred to outpatient, 13.6% underwent alternative clinical intervention, and 13.6% were judged unnecessary by the primary team. No rationale was documented in the chart for the remaining 38.6%., Conclusions: Despite concerns about autoreferral by radiologists for AI studies, we found a lower rate than in many prior studies, which may reflect a change in clinical practice. One-third of these recommendations were implemented and verbal communication was strongly associated with the likelihood of second image ordering. In the majority of the cases, the AI affected patient management. Based on these findings, radiologists should consider calling the ordering provider to increase the likelihood that the primary team will follow their recommendations.

The clustering of neurons sharing similar functional properties and connectivity is a common organizational feature of vertebrate nervous systems. Within motor networks, spinal motor neurons (MNs) segregate into longitudinally arrayed subtypes, establishing a central somatotopic map of peripheral target innervation. MN organization and connectivity relies on Hox transcription factors expressed along the rostrocaudal axis; however, the developmental mechanisms governing the orderly arrangement of MNs are largely unknown. We show that Pbx genes, which encode Hox cofactors, are essential for the segregation and clustering of neurons within motor columns. In the absence of Pbx1 and Pbx3 function, Hox-dependent programs are lost and the remaining MN subtypes are unclustered and disordered. Identification of Pbx gene targets revealed an unexpected and apparently Hox-independent role in defining molecular features of dorsally projecting medial motor column (MMC) neurons. These results indicate Pbx genes act in parallel genetic pathways to orchestrate neuronal subtype differentiation, connectivity, and organization., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The emergence of limb-driven locomotor behaviors was a key event in the evolution of vertebrates and fostered the transition from aquatic to terrestrial life. We show that the generation of limb-projecting lateral motor column (LMC) neurons in mice relies on a transcriptional autoregulatory module initiated via transient activity of multiple genes within the HoxA and HoxC clusters. Repression of this module at thoracic levels restricts expression of LMC determinants, thus dictating LMC position relative to the limbs. This suppression is mediated by a key regulatory domain that is specifically found in the Hoxc9 proteins of appendage-bearing vertebrates. The profile of Hoxc9 expression inversely correlates with LMC position in land vertebrates and likely accounts for the absence of LMC neurons in limbless species such as snakes. Thus, modulation of both Hoxc9 protein function and Hoxc9 gene expression likely contributed to evolutionary transitions between undulatory and ambulatory motor circuit connectivity programs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5-Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The study aimed to determine the prevalence of chronic illness and chronic pain in emergency department (ED) patients across demographic backgrounds., Methods: This was a cross-sectional study at an urban, level I trauma center with 98,000 annual visits. This was a prospective sample of adult patients presenting to the ED during a randomized distribution of daily 8-hour periods between June 4 and August 26, 2007. Prevalence of chronic illness was compared to subject demographics using logistic regression, and prevalence of chronic pain was compared using ordinal logistic regression., Results: Six thousand nine hundred sixty-one patients presented during the data collection periods; 3882 were eligible, and 3132 (82%) were enrolled (51.7% male; age, 41.1 ± 15.8 years; range, 18-98 years). Chronic illness was reported in 36.3% of patients and chronic pain in 34.9% of patients. Chronic illness was associated with homelessness (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.17-2.61), family income less than $25,000 (OR, 2.27; 95% CI, 1.60-3.22), and lack of access to primary care facilities (OR, 2.68; 95% CI, 2.25-3.21). Chronic pain was associated with homelessness (OR, 2.56; 95% CI, 1.79-3.64), family income less than $25,000 (OR, 2.54; 95% CI, 1.91-3.39), and lack of access to primary care facilities (OR, 1.47; 95% CI, 1.26-1.70)., Conclusions: Patient housing situation, family income, and perceived access to primary care medical facilities were associated with higher self-reported rates of chronic illness and chronic pain., (Copyright © 2011 Elsevier Inc. All rights reserved.)

An advisory reference level of 200 Bq m(-3) and a statutory reference level of 400 Bq m(-3) apply to radon exposure in Irish schools. Following the results of a national survey of radon in Irish schools, several hundred classrooms were identified in which the reference levels were exceeded and a remediation program was put in place. This paper provides an initial analysis of the effectiveness of that remediation program. All remediation techniques proved successful in reducing radon concentrations. Active systems such as radon sumps and fan assisted under-floor ventilation were generally applied in rooms with radon concentrations above 400 Bq m(-3). These proved most effective with average radon reduction factors of 9 to 34 being achieved for radon sumps and 13 to 57 for fan assisted under-floor ventilation. Both of these techniques achieved maximum radon reduction factors in excess of 100. The highest average reduction factors were associated with the highest initial radon concentrations. Passive remediation systems such as wall and window vents were used to increase background ventilation in rooms with radon concentrations below 400 Bq m(-3) and achieved average radon reductions of approximately 55%. Following the installation of active remediation systems, the radon concentration in adjacent rooms, i.e., rooms in which the radon concentration was already below 200 Bq m(-3) and therefore did not require remediation, was further reduced by an average of 25%. The long-term effectiveness of a number of radon sump systems with at least three years operation showed no evidence of fan failures. This study showed an apparent increase in sump effectiveness with time as indicated by an increase in radon reduction factors during this period.