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In recent years, the field of neuroscience has gone through rapid experimental advances and extensive use of quantitative and computational methods. This accelerating growth has created a need for methodological analysis of the role of theory and the modeling approaches currently used in this field. Toward that end, we start from the general view that the primary role of science is to solve empirical problems, and that it does so by developing theories that can account for phenomena within their domain of application. We propose a commonly-used set of terms - descriptive, mechanistic, and normative - as methodological designations that refer to the kind of problem a theory is intended to solve. Further, we find that models of each kind play distinct roles in defining and bridging the multiple levels of abstraction necessary to account for any neuroscientific phenomenon. We then discuss how models play an important role to connect theory and experiment, and note the importance of well-defined translation functions between them. Furthermore, we describe how models themselves can be used as a form of experiment to test and develop theories. This report is the summary of a discussion initiated at the conference Present and Future Theoretical Frameworks in Neuroscience, which we hope will contribute to a much-needed discussion in the neuroscientific community., deposited on: https://arxiv.org/abs/2003.13825

Statement of problem The accuracy of intraoral scanners is a prerequisite for the fabrication of dental restorations in computer-aided design and computer-aided manufacturing (CAD-CAM) dentistry. While the precision of intraoral scanners has been investigated in vitro, clinical data on the accuracy of intraoral scanning (IOS) are limited. Purpose The purpose of this clinical study was to determine the accuracy of intraoral scanning with different devices compared with extraoral scanning. Material and methods An experimental appliance was fabricated for 11 participants and then scanned intraorally and extraorally with 3 different intraoral scanners and a reference scanner. Intraoral and extraoral scans were subdivided into complete-arch and short-span scans and compared with the reference scan to assess trueness. Repeated scans in each group were assessed for precision. Results Precision and trueness were higher for extraoral scans compared with intraoral scans, except for complete-arch scans with 1 intraoral scanner. The median precision of short-span scans was higher (extraoral: 22 to 29 μm, intraoral: 23 to 43 μm) compared with complete-arch scans (extraoral: 81 to 165 μm, intraoral: 80 to 198 μm). The median trueness of short-span scans (extraoral: 28 to 40 μm, intraoral: 38 to 47 μm) was higher than that of complete-arch scans (extraoral: 118 to 581 μm, intraoral: 147 to 433 μm) for intraoral and extraoral scanning. Conclusions Intraoral conditions negatively influenced the accuracy of the scanning devices, which was also reduced for the complete-arch scans.

Background: Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2. Methods: We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients Results: Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P P =0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P =0.14. Conclusions: The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

There are five cloned muscarinic acetylcholine receptors (M1–M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1–M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here, we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration–response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion reduced exploration of salient stimuli, especially under conditions of high novelty, yet had no effect on hedonia assayed using the sucrose preference test or on stress-coping strategy assayed using the forced swim test. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in response to environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is withdrawal from the environment. These data indicate that boosting M5 receptor activity may be a useful therapeutic target for ameliorating these symptoms of depression and anxiety. SIGNIFICANCE STATEMENT The basic physiological and behavioral functions of the muscarinic M5 receptor remain understudied. Furthermore, its presence on dopamine neurons, relatively restricted expression in the brain, and recent crystallization make it an attractive target for therapeutic development. Yet, most preclinical studies of M5 receptor function have primarily focused on substance use disorders in male rodents. Here, we characterized the role of M5 receptors in potentiating dopamine transmission in the nucleus accumbens, finding impaired functioning after stress exposure. Furthermore, we show that M5 receptors can modulate exploratory behavior in a sex-specific manner, without affecting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders.

Contains fulltext : 273922.pdf (Publisher’s version ) (Closed access) Benign peripheral non-cranial nerve sheath tumors are rare lesions, including both schwannomas and neurofibromas. These tumors arise from Schwann cells, and may originate from any peripheral, cranial, or autonomic nerve. Most of them are localized and sporadic but multifocal systemic forms can occur. Cervical sympathetic chain, brachial plexus, cervical plexus and spinal roots and nerves are the major nerve systems commonly affected. Dumbbell-shaped intra- and extradural tumors occur most commonly in the cervical spine, as well as purely extradural and paravertebral tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques and surgical innovations such as endoscopically assisted approaches and robotic surgery. Microsurgical intracapsular excision of the tumor helped by the use of intraoperative fluorescent dyes and intraoperative neurophysiological monitoring minimize postoperative neural deficit, since most schwannomas are encapsulated. Most tumors can be removed with a low rate of complications and recurrence. Radiotherapy should be considered for growing lesions that are not amenable to surgery. In asymptomatic patients, observation and serial scans is an option for elderly infirm patients.

The persistence of negative affect in pain leads to co-morbid symptoms such as anhedonia and depression-major health issues in the United States. The neuronal circuitry and contribution of specific cellular populations underlying these behavioral adaptations remains unknown. A common characteristic of negative affect is a decrease in motivation to initiate and complete goal-directed behavior, known as anhedonia. We report that in rodents, inflammatory pain decreased the activity of ventral tegmental area (VTA) dopamine (DA) neurons, which are critical mediators of motivational states. Pain increased rostromedial tegmental nucleus inhibitory tone onto VTA DA neurons, making them less excitable. Furthermore, the decreased activity of DA neurons was associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA DA neurons was sufficient to restore baseline motivation and hedonic responses to natural rewards. These findings reveal pain-induced adaptations within VTA DA neurons that underlie anhedonia-like behavior.

Introduction: Clostridium septicum (C. septicum) aortitis is a rare condition frequently associated with colon adenocarcinoma and carries a poor prognosis. Case Report: We report the case of an 80-year-old man who was waiting for an elective endovascular repair of an abdominal aortic aneurysm (AAA) with a diameter of 5.8 × 5.4 cm. He underwent a colonoscopy because of a thickening of the colon wall in the preoperatory CT. One week after that, he presented at the emergency with a 48-hour duration of fever and abdominal pain. Abdominal CT imaging revealed an increased aneurysm size to 6.1 × 6.6 cm including gas within the aorta. Treatment consisted of antibiotics, urgent axillar to femoro-femoral bypass, excision and ligation of the infrarenal aorta and right hemicolectomy with end-ileostomy. Aortic cultures were positive for C. septicum. The postoperative was complicated by renal failure and the patient died. Conclusion: C. septicum-infected aortic aneurysm is a rare entity that is strongly associated with colon cancer. The presence of gas within the aorta or emphysematous aortitis is the most common sign of C. septicum infection. Broad-spectrum antibiotics should be initiated and emergency surgical management with excision of the infected aneurysm and grafting is required.

Mutations in Atp2b2, an outer hair cell (OHC) gene, cause dominant hearing loss (HL) in humans. Using a mouse model Atp2b2Obl+, with a dominant HL mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein (RNP) complexes leads to specific editing of the Obl allele. Large deletions encompassing the Obl locus and indels were identified as the result of editing. In vivo genome editing promotes OHC survival and restores OHC function, leading to robust hearing rescue. We further show in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause di-genic genetic HL, RNP delivery targeting both mutations lead to hearing rescue. These findings suggest that liposome-RNP delivery can be used as a strategy to rescue hearing with dominant mutations in OHC genes and with di-genic mutations in the auditory hair cells, expanding therapeutics of gene editing to treat HL.

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition is known to require long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson’s-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiates D1R signaling at the cellular and synaptic level, enhancing alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 are more prone to heavy alcohol drinking and consumption is insensitive to punishment. These findings identify a novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.