Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ...ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher in Chat+/- than in Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.
Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal ...bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.
Abstract only Background: Magnetic resonance imaging (MRI) is a powerful modality for diagnosing stroke. Conventionally, patients must travel to the location of a high-field MRI device. Advances in ...low-field MRI have enabled acquisition of clinically useful images using a portable device at the bedside. The feasibility of using point of care (POC) MRI in a clinical stroke setting is unknown. Objective: To determine the safety and feasibility of portable, bedside, low-field MRI in a clinical setting. Design/Methods: POC MRI exams were performed in Yale’s Neuroscience Intensive Care Unit (NICU) from July 2018 to August 2019. Images were acquired at the bedside using a standard 110V, 15A power outlet. The environment included the bedside vitals monitor, ventilators and intravenous infusion pumps. Exams were performed by research staff trained to operate the POC scanner in the absence of a trained MRI technician. No special precautions were necessary to remove ferrous metals from the room. Scan parameters were controlled using a tablet computer interface, and images were available immediately after acquisition. Results: POC MRI was obtained in 85 stroke cases (46% female, ages 18-96 years, 46% ischemic stroke, 34% intracerebral hemorrhage, 20% subarachnoid hemorrhage). Scans were obtained within 7 days of symptom onset. NIHSS scores ranged from 1 to 29 (median of 7). Of the 85 patients analyzed, 68 underwent T2-weighted imaging, 72 underwent FLAIR imaging, and 39 underwent diffusion weighted imaging (DWI). DWI was only tested in ischemic stroke cases. Patients’ BMI ranged from 20.0 to 46.5 with a median of 26.7. The majority 74 (87%) of patients completed the entire exam. Five patients (6%) were unable to fit in the scanner’s 30 cm opening, while 6 patients (7%) experienced claustrophobia resulting in early termination of the exam. Mean exam time was 28.9 ± 8.4 minutes. The 64 mT static magnetic field, gradient and RF pulses of the POC MRI scanner did not interfere with NICU equipment, and no significant adverse events occurred. Conclusions: We report the first use of a portable, low-field MRI system to image stroke patients at the bedside. This early work suggests our approach is safe and viable in a complex clinical care environment.
Abstract only Background: Radiographic diagnosis of intracranial hemorrhage (ICH) is a critical determinant of stroke care pathways requiring patient transport to a neuroimaging suite. Advances in ...low-field MRI have made it possible to obtain clinically useful imaging at the point of care (POC). Aim: The aim of this study was to obtain preliminary data regarding the ability of a bedside POC MRI scanner to detect ICH. Methods: We studied 36 patients with a diagnosis of ICH (n=18) or ischemic stroke (n=18). Five blinded readers independently evaluated T2W and FLAIR exams acquired prospectively on a 64 mT, portable bedside MRI system (Hyperfine Research, Inc). Kappa coefficients (κ) were calculated to determine inter-rater agreement. Ground truth was obtained from the clinical report of the closest conventional imaging study (17.9 ± 10.4 hours) and verified by a core reader. For each exam, majority consensus among raters was used to determine sensitivity. Results: ICH volume ranged from 4 to 101 cc (median of 13 cc). Exams were acquired within 7 days of symptom onset (51.1 ± 28.8 hours). A pathologic lesion was identified on every exam with 100% sensitivity. Sensitivity for distinguishing any hemorrhage was 89% and specificity was 83%. The mean sensitivity and specificity for individual raters was 79% and 69%, respectively. When limited to supratentorial hemorrhage, consensus sensitivity was 94%. For ICH cases detected by all raters (n=9), there was 100% accuracy for localizing the bleed (lobar vs. non-lobar) with perfect agreement among raters (κ = 1, p <0.0001). There was substantial agreement for identifying intraventricular hemorrhage (IVH) (κ = 0.72, p < 0.0001). Sensitivity for IVH was 100% based on rater consensus. Figure 1 shows a POC exam with an ICH and IVH. Conclusions: These data suggest that low-field, POC MRI may be used to detect hemorrhagic stroke at the bedside. Further work is needed to evaluate this approach in the hyperacute setting and across a wide range of ICH characteristics.
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