RESUMO
When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.
RESUMO
Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-enriched astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses; conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep-layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.
Assuntos
Astrócitos , Proteínas Hedgehog , Astrócitos/metabolismo , Proteínas Hedgehog/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Sinapses/metabolismoRESUMO
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of hypoxic respiratory failure that results from ventilation and perfusion mismatching. Inhaled epoprostenol induces relaxation of smooth muscle in pulmonary vasculature, leading to improved oxygenation. OBJECTIVE: To determine if the use of inhaled epoprostenol produced a 10% or greater increase in the ratio of arterial partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) in ARDS patients and to review adverse events and medication errors. METHODS: An observational chart review was performed based on a report generated from the electronic medical record system. Patients who received at least 1 dose of inhaled epoprostenol from January 1, 2008, to December 31, 2010, at any hospital within the Florida Hospital Health System were considered for inclusion. Demographics, dose, duration of therapy, adverse effects, medication errors, and outcomes data were collected. RESULTS: Sixteen patients were included in the study. Oxygenation improved by 10% or more in 62.5% (10/16) of the patients, with an initial (within the first 4 hours) median increase of 44.5% in PaO2/FiO2. The mean (SD) starting dose was 30 (10) ng/kg/min. Medication errors were observed in 25% (4/16) of patients. Hypotension was the most frequently observed adverse event, with a rate of 18.8% (3/16). CONCLUSIONS: Based on study findings, inhaled epoprostenol may improve oxygenation in patients with ARDS, with findings suggesting a 62.5% response to therapy. The significance of these effects on improving survival remains unknown. The frequency of medication errors observed in this study poses a significant concern regarding the administration of epoprostenol. Further controlled prospective studies are needed to determine the role of inhaled epoprostenol in improving survival in patients with ARDS.