A case of abnormally dilated and tortuous arc of Buhler and pancreaticoduodenal arteries in the absence of celiac trunk stenosis.

INTRODUCTION: The Arc of Buhler is a rare vascular variant describing a persistent remnant of the embryologic ventral anastomosis between the celiac trunk (CT) and superior mesenteric artery (SMA), invariably reported in the context of CT stenosis. PURPOSE: To report a case of (1) a large and tortuous pancreaticoduodenal arcade and (2) a large and tortuous Arc of Buhler in the absence of celiac axis stenosis. METHODS: The variant was discovered during routine cadaver dissection. We acquired transverse biopsies of variant vessels and evaluated their wall thickness. RESULTS: The donor's anterior PDA, posterior PDA, and Arc of Buhler had larger diameters, and the common hepatic artery had a smaller diameter than the literature-reported values of a standard human body. The posterior PDA had significantly increased wall thickness compared to the other investigated vessels. CONCLUSIONS: The Arc of Buhler is a rare remnant of the embryologic ventral anastomosis that is estimated to be hemodynamically active in only half of cases. Previous reports have documented hemodynamically active Arcs of Buhler only in cases of CT stenosis. To the best of the authors' knowledge, this is a unique case of a persistent and hemodynamically active Arc of Buhler in the absence of CT stenosis. Clinicians should be aware of this variant as its abnormal position may increase risk of herniation and surgical complications, and its tortuosity may increase risk of clot formation.

Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.

DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations. Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy. Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout mice exhibit seizures and neuronal mTORC1 hyperactivation. It is not known if Depdc5cc+ mice have a hyperactivity/anxiety phenotype, die early from terminal seizures or whether mTOR inhibitors rescue DEPDC5-related seizures and associated comorbidities. Herein, we report that Depdc5cc+ mice were hyperactive in open-field testing but did not display anxiety-like behaviors on the elevated-plus maze. Unlike many other mTOR-related models, Depdc5cc+ mice had minimal epileptiform activity and rare seizures prior to seizure-induced death, as confirmed by video-EEG monitoring. Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity. Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size. Loss of Depdc5 led to a decrease in the other GATOR1 protein levels (NPRL2 and NPRL3). Rapamycin failed to rescue GATOR1 protein levels but rather rescued downstream mTORC1 hyperactivity as measured by phosphorylation of S6. Collectively, our data provide the first evidence of behavioral alterations in mice with Depdc5 loss and support mTOR inhibition as a rational therapeutic strategy for DEPDC5-related epilepsy in humans.

Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases.

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.

Electrographic spikes are common in wildtype mice.

High-voltage rhythmic electroencephalographic (EEG) spikes have been recorded in wildtype (WT) rats during periods of light slow-wave sleep and passive wakefulness. The source of this activity is unclear but has been attributed to either an inherent form of absence epilepsy or a normal feature of rodent sleep EEG. In contrast, little is known about epileptiform spikes in WT mice. We thus characterize and quantify epileptiform discharges in WT mice for the first time. Thirty-six male WT C57 mice with 24-h wireless telemetry video-EEG recordings were manually scored by blinded reviewers to mark individual spikes and spike trains. Epileptiform spikes were detected in 100% of the recorded WT mice, and spike trains of at least three spikes were recorded in 90% of mice. The spikes were more frequent during the day than at night and were inversely correlated to each animal's locomotor activity. However, the discharges were not absent during active nighttime periods. These discharges may indicate a baseline tendency toward epileptic seizures or perhaps are benign variants of normal rodent background EEG. Nevertheless, a better understanding of baseline WT EEG activity will aid in differentiating pathological and normal EEG activity in mouse epilepsy models.

Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy. METHODS: In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1. RESULTS: Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development. INTERPRETATION: Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC.

"In Class We Were All One." A Qualitative Exploration of Yoga and Educational Interventions for Predominantly Low-Income and Minority Adults with Chronic Low Back Pain.

Introduction: Chronic low back pain (cLBP) can be physically and psychologically debilitating and disproportionally afflicts vulnerable populations. Yoga and education are increasingly common interventions for cLBP yet are understudied in low-income and minority adults. The objective of this qualitative study was to understand the yoga and self-care experience of adults with cLBP from urban, underserved communities who were enrolled in a randomized controlled trial that included these treatments. Methods: We interviewed 26 (18 yoga and 8 education) participants. Interviews were transcribed verbatim and analyzed using thematic analysis with codes developed inductively from data. Results: Participants from both yoga and education groups reported initial apprehension and ambivalence toward their respective intervention. However, physical and psychological benefits were noted, mainly in the form of improved pain self-management. Communal support and camaraderie reported by the yoga group was absent and desired by education participants. Social factors impeding the ability to sustain yoga practice included transportation, access, and cost, whereas education participants described literacy and language challenges and a general lack of motivation to read the book. Conclusion: Yoga and education are viable treatments for adults with cLBP who live in underserved neighborhoods. However, social stigma and socioeconomic barriers may hinder their uptake. Communal support in group-based nonpharmacological treatments is valued and may contribute to participation and clinical outcomes. ClinicalTrials.gov Identifier: NCT01343927.