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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.

The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction.

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.

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 agonist oxotremorine, we revealed a unique concentration response curve and a sensitivity to repeated stressor 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. We conclude that M5 receptors are critical for both engaging with the environment and updating behavioral output in responses to the environment cues, specifically in male mice. A cardinal feature of mood and anxiety disorders is a 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 StatementThe 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 impacting hedonic behavior. These findings further illustrate the therapeutic potential of the M5 receptor, warranting further research in the context of treating mood disorders.

Summary: Background: Radiation-induced carotid artery disease (RICAD) is an important issue in head and neck cancer (HNC) survivors after radiotherapy (RT). The risk of cerebrovascular disease in these patients is doubled. The aim of this study was to assess the effect of RT on carotid artery stiffness in HNC patients. Patients and methods: Conventional arterial stiffness parameters were measured in a total of 50 HNC survivors treated with RT for at least 5 years and compared to 50 unirradiated HNC patients. Elastic modulus (Ep) and Beta stiffness index (β) were measured in proximal, mid and distal common carotid artery (CCA). Results: The mean age of the subjects was 68±9 years (range: 44–84) in the irradiated group and 67±10 years (range: 45–85) in the control group. The RT group was treated with a mean radiation exposure of 60.3±6.7 Gy (range: 44–72) in the neck. Carotid stiffness parameters showed significant group differences: Ep in the RT group was 2.329±1.222 vs 1.742±828 in the non-RT group (p=0.006) and β index in the RT group was 23±11 vs 15±8 in the non-RT group (p

Background: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a commo...

Dopamine modulation of nucleus accumbens (NAc) circuitry is central to theories of reward seeking and reinforcement learning. Despite decades of effort, the acute dopamine actions on the NAc microcircuitry remain puzzling. Here, we dissect out the direct actions of dopamine on lateral inhibition between medium spiny neurons (MSNs) in mouse brain slices and find that dopamine’s acute actions on NAc lateral inhibition are pathway-specific. Dopamine potently and selectively depresses GABAergic transmission from presynaptic dopamine D2 receptor-expressing MSNs (D2-MSNs), while it potentiates transmission from presynaptic dopamine D1 receptor-expressing MSNs. To our surprise, presynaptic D2 receptors mediate only half of the depression induced by either dopamine neuron stimulation or dopamine application. Presynaptic serotonin 5-HT1b receptors are responsible for a significant component of dopamine-induced synaptic depression. Thus, this study clarifies the mechanistic understanding of dopamine actions in the NAc by showing pathway-specific modulation of lateral inhibition and the involvement of both D2 and 5-HT1b receptors in dopamine depression of D2-MSN synapses.

Age-related macular degeneration (AMD) is the leading cause of central blindness in developed countries. It affects people mainly over the age of 50 years. It is a disease of the macula, an area of the retina responsible for sharp central vision. It particularly affects the Bruch’s membrane (BM); a layer in the retina that acts as the basement upon which retinal pigment epithelial cells (RPE) attach and survive. The pathology of AMD is not fully understood, but age is considered the main risk factor. There are two forms; nonexudative, leading to the end-stage of the disease, called nonexudative (or dry) AMD (90% of cases) where fatty deposits called drusen form under the RPE on top of the BM lifting off the RPE, and neovascular (or wet) AMD (10% of cases) where abnormal new blood vessels grow and push through the BM, bleeding in and disrupting the RPE. Neovascular AMD is well controlled with regular antiangiogenic drug injections of anti-vascular endothelial growth factor (anti-VEGF) into the eye, whereas there is no current treatment for nonexudative AMD. Many research groups across the world are working on a treatment for nonexudative AMD. This review discusses the research currently being conducted including cell therapies, development of cell transplantation membranes, targeting other disease structures in affected retina (i.e. drusen), and drug delivery to the retina using nanoparticles. Finally, we include our research contributing to the field; developing a bioactive membrane intended to function two-fold: target diseased structures and transplant healthy RPE to the desired area.

Serotonin plays a central role in cognition and is the target of most pharmaceuticals for psychiatric disorders. Existing drugs have limited efficacy; creation of improved versions will require better understanding of serotonergic circuitry, which has been hampered by our inability to monitor serotonin release and transport with high spatial and temporal resolution. We developed and applied a binding-pocket redesign strategy, guided by machine learning, to create a high-performance, soluble, fluorescent serotonin sensor (iSeroSnFR), enabling optical detection of millisecond-scale serotonin transients. We demonstrate that iSeroSnFR can be used to detect serotonin release in freely behaving mice during fear conditioning, social interaction, and sleep/wake transitions. We also developed a robust assay of serotonin transporter function and modulation by drugs. We expect that both machine-learning-guided binding-pocket redesign and iSeroSnFR will have broad utility for the development of other sensors and invitro and invivo serotonin detection, respectively.

Dopamine (DA) signals in the striatum are critical for a variety of vital processes, including motivation, motor learning, and reinforcement learning. Striatal DA signals can be evoked by direct activation of inputs from midbrain DA neurons (DANs) as well as cortical and thalamic inputs to the striatum. In this study, we show that in vivo optogenetic stimulation of prelimbic (PrL) and infralimbic (IL) cortical afferents to the striatum triggers an increase in extracellular DA concentration, which coincides with elevation of striatal acetylcholine (ACh) levels. This increase is blocked by a nicotinic ACh receptor (nAChR) antagonist. Using single or dual optogenetic stimulation in brain slices from male and female mice, we compared the properties of these PrL/IL-evoked DA signals with those evoked by stimulation from midbrain DAN axonal projections. PrL/IL-evoked DA signals are undistinguishable from DAN evoked DA signals in their amplitudes and electrochemical properties. However, PrL/IL-evoked DA signals are spatially restricted and preferentially recorded in the dorsomedial striatum. PrL/IL-evoked DA signals also differ in their pharmacological properties, requiring activation of glutamate and nicotinic ACh receptors. Thus, both in vivo and in vitro results indicate that cortical evoked DA signals rely on recruitment of cholinergic interneurons, which renders DA signals less able to summate during trains of stimulation and more sensitive to both cholinergic drugs and temperature. In conclusion, cortical and midbrain inputs to the striatum evoke DA signals with unique spatial and pharmacological properties that likely shape their functional roles and behavioral relevance. SIGNIFICANCE STATEMENT Dopamine signals in the striatum play a critical role in basal ganglia function, such as reinforcement and motor learning. Different afferents to the striatum can trigger dopamine signals, but their release properties are not well understood. Further, these input-specific dopamine signals have only been studied in separate animals. Here we show that optogenetic stimulation of cortical glutamatergic afferents to the striatum triggers dopamine signals both in vivo and in vitro. These afferents engage cholinergic interneurons, which drive dopamine release from dopamine neuron axons by activation of nicotinic acetylcholine receptors. We also show that cortically evoked dopamine signals have other unique properties, including spatial restriction and sensitivity to temperature changes than dopamine signals evoked by stimulation of midbrain dopamine neuron axons.

Fyn kinase in the dorsomedial striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised of medium spiny neurons (MSNs) that project directly (dMSNs) or indirectly (iMSNs) to the substantia nigra. Here, we examined the cell-type specificity of Fyn’s actions in alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake. D1Rs are coupled to Gαs/olf, which activate cAMP signaling. To examine whether Fyn’s actions are mediated through cAMP signaling, DMS dMSNs were infected with GαsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. In contract, remote activation of GαsDREADD in DLS dMSNs did not alter Fyn signaling. We then tested whether activation of GαsDREADD in DMS dMSNs or iMSNs alters alcohol intake and observed that CNO-dependent activation of GαsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake. Finally, we examined the contribution of Fyn to GαsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GαsDREADD-dependent increase in alcohol consumption. Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption. Fil: Ehinger, Yann. University of California San Francisco; Estados Unidos Fil: Morisot, Nadege. Nkarta Therapeutics; Estados Unidos. University of California San Francisco; Estados Unidos Fil: Phamluong, Khanhky. University of California San Francisco; Estados Unidos Fil: Sakhai, Samuel A.. Sage Therapeutics; Estados Unidos. University of California San Francisco; Estados Unidos Fil: Soneja, Drishti. University of California San Francisco; Estados Unidos Fil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. University Of California San Francisco (ucsf); Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Alvarez, Veronica A.. National Institutes of Health; Estados Unidos Fil: Ron, Dorit. University of California San Francisco; Estados Unidos

Long-lasting plastic changes in the striatum play a central role in driving the transition from hedonic to compulsive alcohol drinking, a hallmark of alcohol use disorders. It is known that the propensity to undergo this transition varies with the individual, yet the underlying molecular mechanisms are not well understood. Here, we report that the Parkinson’s-related protein Leucine-rich repeat kinase 2 (LRRK2) plays a role in in this transition to compulsive alcohol drinking by modulating the function of dopamine D1 receptors within the striatonigral pathway. We find that alcohol decreases LRRK2 kinase activity in the dorsal striatum and that deletion of the Lrrk2 gene specifically from D1-expressing striatal neurons promotes compulsive-like alcohol drinking in mice by strengthening D1 receptor signaling and function. These findings identify a novel role for Lrrk2 in the striatum and suggest that Lrrk2 function promotes resilience for compulsive alcohol drinking and the development of alcohol use disorders.

Objetivo: Revisar las herramientas utilizadas en las investigaciones de e-salud en cuidados paliativos durante los últimos cinco años Método: se realizó una revisión bibliográfica en las bases de datos PubMed, Scopus y Bireme sobre el tema de cuidados paliativos, e-salud y costos en los últimos cinco años. Resultados: El uso de las tecnologías de la información es favorable para usuarios que reciben cuidados paliativos, ya que facilita su seguimiento y el manejo de sus síntomas, además de mejorar la comunicación entre profesionales y pacientes, disminuyendo en algunos casos los desplazamientos geográficos y reduciendo los costos asociados a la atención de estos pacientes. Conclusión: la e-salud implementada a través de diferentes herramientas de intervención ha demostrado ser valiosa para los pacientes con enfermedad avanzada en cuidados paliativos, ofreciendo potenciales beneficios educativos y de optimización de recursos y tiempo para pacientes, cuidadores, que les permite mejorar su contacto con profesionales de la salud.

Background: Changes in motor development provide children with new learning opportunities to interact with objects, their environment, and with caregivers. Previous research finds that both gross and fine motor skills are predictive of later language outcomes across early infancy and childhood. However, gross and fine motor skills afford different types of interactions. Thus, gross and fine motor skills may potentially differ in the developmental trajectories through which cascading changes in language may occur. The aim of the present study was to investigate whether there are differences in the predictive capacities of gross and fine motor skills toward language outcomes across infancy and early childhood in typical development. Method: A systematic review of existing literature on motor-language cascades was conducted in across studies measuring gross and/or fine motor and language development in children from 0 to 5 years old. Searches were conducted in PsycINFO, PubMed, and MEDLINE. Keywords used were a combination of "gross motor," "fine motor," "motor performance," "motor development," or "psychomotor development" along with "language," "language development," or "communication skills." Two independent reviewers screened abstracts and full texts based on inclusion and exclusion criteria. Results: A total of 23 articles were retained. Of these, seven studies measured only gross motor skills, four studies measured only fine motor skills, and 12 studies measured both gross and fine motor skills in the same study. Studies used a variety of measures to assess gross motor skills, fine motor skills, and language development (e.g., parent report, in lab observations, standardized assessment), and findings varied based on analyses used. Results demonstrated that both gross and fine motor skills are related to language outcomes, but due to a smaller amount of studies testing fine motor skills, conclusions regarding whether one is more important for language outcomes cannot be drawn. Conclusions: We conclude that both gross and fine motor skills help foster language development from infancy to early childhood. Limitations regarding current knowledge regarding the mechanisms that underlie motor-language cascades are discussed, as well as the need for more studies on fine motor skills.

espanolEl objetivo del trabajo que se presenta es la identificacion de innovaciones y nuevos procesos en carnaza como subproducto de la curticion. Para esto se realizo un proceso de vigilancia tecnologica a traves de una busqueda de informacion, referente a juguetes caninos, tecnologias de proceso, normatividad, y tendencias. Se aplico la metodologia de analisis del ciclo de vida de la tecnologia a traves de curvas en S. Entre los documentos mas importantes se encontraron dos nuevos procesos de elaboracion para la fabricacion de juguetes caninos descritos en dos patentes de Estados Unidos. Ademas, para la harina de carnaza su punto de inflexion en articulos se presento en el periodo 2016-2018 lo cual representa una oportunidad para continuar investigando sobre esta tecnologia. EnglishThe objective of the work presented in this paper is the identification of innovations and new processes in split leather. For this, a process of technological surveillance was done through the search of information referred to canine toys, process technologies, normativity, and trends. Life cycle analysis of the technologies through S curves was applied. Among the most important documents found were two new processes for the manufacture of canine toys described in two patents in the United States. Also, for split leather flour its inflection point in articles was presented in the period 2016-2018, which represents an opportunity to continue research on this technology.

The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.

Brain circuits that include the cortex and basal ganglia make up the bulk of the forebrain, and influence behaviors related to almost all aspects of affective, cognitive and sensorimotor functions. The learning of new actions as well as association of existing action repertoires with environmental events are key functions of this circuitry. Unfortunately, the cortico-basal ganglia circuitry is also the target for all drugs of abuse, including alcohol. This makes the circuitry susceptible to the actions of chronic alcohol exposure that impairs circuit function in ways that contribute to cognitive dysfunction and drug use disorders. In the present review, we describe the connectivity and functions of the associative, limbic and sensorimotor cortico-basal ganglia circuits. We then review the effects of acute and chronic alcohol exposure on circuit function. Finally, we review studies examining the roles of the different circuits and circuit elements in alcohol use and abuse. We attempt to synthesize information from a variety of studies in laboratory animals and humans to generate hypotheses about how the three circuits interact with each other and with the other brain circuits during exposure to alcohol and during the development of alcohol use disorders. This article is part of the Special Issue entitled "Alcoholism".

Alcohol operant self-administration paradigms are critical tools for studying the neural circuits implicated in both alcohol-seeking and consummatory behaviors and for understanding the neural basis underlying alcohol-use disorders. In this study, we investigate the predictive value of two operant models of oral alcohol self-administration in mice, one in which alcohol is delivered into a cup following nose-poke responses with no accurate measurement of consumed alcohol solution, and another paradigm that provides access to alcohol via a sipper tube following lever presses and where lick rate and consumed alcohol volume can be measured. The goal was to identify a paradigm where operant behaviors such as lever presses and nose pokes, as well as other tracked behavior such as licks and head entries, can be used to reliably predict blood alcohol concentration (BAC). All mice were first exposed to alcohol in the home cage using the "drinking in the dark" (DID) procedure for 3 weeks and then were trained in alcohol self-administration using either of the operant paradigms for several weeks. Even without sucrose fading or food pre-training, mice acquired alcohol self-administration with both paradigms. However, neither lever press nor nose-poke rates were good predictors of alcohol intake or BAC. Only the lick rate and consumed alcohol were consistently and significantly correlated with BAC. Using this paradigm that accurately measures alcohol intake, unsupervised cluster analysis revealed three groups of mice: high-drinking (43%), low-drinking (37%), and non-drinking mice (20%). High-drinking mice showed faster acquisition of operant responding and achieved higher BACs than low-drinking mice. Lick rate and volume consumed varied with the alcohol concentration made available only for high- and low-drinking mice, but not for non-drinking mice. In addition, high- and low-drinking mice showed similar patterns during extinction and significant cue-induced reinstatement of seeking. Only high-drinking mice showed insensitivity to quinine adulteration, indicating a willingness to drink alcohol despite pairing with aversive stimuli. Thus, this study shows that relying on active presses is not an accurate determination of drinking behavior in mice. Only paradigms that allow for accurate measurements of consumed alcohol and/or lick rate are valid models of operant alcohol self-administration, where compulsive-like drinking could be accurately determined based on changes in alcohol intake when paired with bitter-tasting stimuli.

Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity. To investigate this, we quantified multiple aspects of dopamine signaling in lean and obese mice. We found that D2-type receptor (D2R) binding in the striatum, but not D1-type receptor binding or dopamine levels, was reduced in obese mice. Genetically removing D2Rs from striatal medium spiny neurons was sufficient to reduce motor activity in lean mice, whereas restoring Gi signaling in these neurons increased activity in obese mice. Surprisingly, although mice with low D2Rs were less active, they were not more vulnerable to diet-induced weight gain than control mice. We conclude that deficits in striatal D2R signaling contribute to physical inactivity in obesity, but inactivity is more a consequence than a cause of obesity. Fil: Friend, Danielle M.. National Institutes of Health; Estados Unidos Fil: Devarakonda, Kavya. National Institutes of Health; Estados Unidos Fil: O'Neal, Timothy J.. National Institutes of Health; Estados Unidos Fil: Skirzewski, Miguel. National Institutes of Health; Estados Unidos Fil: Papageorgiou, Ioannis. National Institutes of Health; Estados Unidos Fil: Kaplan, Alanna R.. National Institutes of Health; Estados Unidos Fil: Liow, Jeih San. National Institutes of Health; Estados Unidos Fil: Guo, Juen. National Institutes of Health; Estados Unidos Fil: Rane, Sushil G.. National Institutes of Health; Estados Unidos Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina. University of Michigan; Estados Unidos Fil: Alvarez, Verónica A.. National Institutes of Health; Estados Unidos Fil: Hall, Kevin D.. National Institutes of Health; Estados Unidos Fil: Kravitz, Alexxai V.. National Institutes of Health; Estados Unidos

SUMMARY Alcohol produces both stimulant and sedative effects in humans and rodents. In humans, alcohol abuse disorder is associated with a higher stimulant and lower sedative responses to alcohol. Here, we show that this association is conserved in mice and demonstrate a causal link with another liability factor: low expression of striatal dopamine D2 receptors (D2Rs). Using transgenic mouse lines, we find that the selective loss of D2Rs on striatal medium spiny neurons enhances sensitivity to ethanol stimulation and generates resilience to ethanol sedation. These mice also display higher preference and escalation of ethanol drinking, which continues despite adverse outcomes. We find that striatal D1R activation is required for ethanol stimulation and that this signaling is enhanced in mice with low striatal D2Rs. These data demonstrate a link between two vulnerability factors for alcohol abuse and offer evidence for a mechanism in which low striatal D2Rs trigger D1R hypersensitivity, ultimately leading to compulsive-like drinking., In Brief Phenotypes associated with alcohol abuse are well established. Bocarsly et al. identify the upregulation of D1R functioning as an underlying mechanism. We provide direct evidence that low levels of D2Rs on striatal projection neurons heighten ethanol stimulation and drinking, despite adverse outcomes contributing to abuse liability via enhanced D1R signaling., Graphical Abstract

Background A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA). Methods We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor–expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA. Results Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor–expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing. Conclusions These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

As data becomes more accessible, visualization methods are needed to help make sense of the information. Analyzing and visualizing data helps the public to better recognize the patterns and connections between different datasets. By using visual elements such as graphs, charts, and maps, it is easier to see and understand the trends and outliers in data. This project aims to study the correlation between environmental factors and public health. Large sets of data pertaining to the environment and health were gathered from open data sources. The tool used to analyze and visualize the collected data is Tableau, which is a software program that is used to transform data into dashboards and visuals such as treemaps, histograms, or area charts. For this project, the data will be displayed through charts and interactive maps that will be created through this software.

Serotonin is involved in numerous critical physiologic and cognitive processes. Drugs that modulate serotonin transport are among the most widely used medications to treat pervasive mental disorders. Both a deeper understanding of serotoninergic circuitry and design of improved treatments will require the ability to measure serotonin release and transport with high spatial and temporal resolution. Here we developed and applied a binding-pocket redesign strategy guided by machine learning to create a high-performance soluble, fluorescent serotonin sensor (iSeroSnFR). This sensor has requisite selectivity and sensitivity needed for direct detection of serotonin transients in various biological systems, especially permits detection of subsecond-scale serotonin release events during fear conditioning and sleep-to-wakefulness transitions. Furthermore, the solubility of iSeroSnFR allowed us to develop a rapid, cytoplasmic sensor-based assay of serotonin transporter activity in the presence of pharmacological manipulations.

Striatal medium spiny neurons (MSNs) form inhibitory synapses on neighboring striatal neurons through axon collaterals. The functional relevance of this lateral inhibition and its regulation by dopamine remains elusive. We show that synchronized stimulation of collateral transmission from multiple indirect-pathway MSNs (iMSNs) potently inhibits action potentials in direct-pathway MSNs (dMSNs) in the nucleus accumbens. Dopamine D2 receptors (D2Rs) suppress lateral inhibition from iMSNs to disinhibit dMSNs, which are known to facilitate locomotion. Surprisingly, D2R inhibition of synaptic transmission was larger at axon collaterals from iMSNs than their projections to the ventral pallidum. Targeted deletion of D2Rs from iMSNs impaired cocaine's ability to suppress lateral inhibition and increase locomotion. These impairments were rescued by chemogenetic activation of Gi-signaling in iMSNs. These findings shed light on the functional significance of lateral inhibition between MSNs and offer a novel synaptic mechanism by which dopamine gates locomotion and cocaine exerts its canonical stimulant response. Fil: Dobbs, Lauren K.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unidos Fil: Kaplan, Alanna R.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unidos Fil: Lemos, Julia C.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unidos Fil: Matsui, Aya. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unidos Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Michigan State University; Estados Unidos Fil: Alvarez, Veronica A.. National Institute on Alcohol Abuse and Alcoholism. Bethesda; Estados Unidos

Bradykinesia is a prominent phenotype of Parkinson's disease, depression, and other neurological conditions. Disruption of dopamine (DA) transmission plays an important role, but progress in understanding the exact mechanisms driving slowness of movement has been impeded due to the heterogeneity of DA receptor distribution on multiple cell types within the striatum. Here we show that selective deletion of DA D2 receptors (D2Rs) from indirect-pathway medium spiny neurons (iMSNs) is sufficient to impair locomotor activity, phenocopying DA depletion models of Parkinson's disease, despite this mouse model having intact DA transmission. There was a robust enhancement of GABAergic transmission and a reduction of in vivo firing in striatal and pallidal neurons. Mimicking D2R signaling in iMSNs with Gi-DREADDs restored the level of tonic GABAergic transmission and rescued the motor deficit. These findings indicate that DA, through D2R activation in iMSNs, regulates motor output by constraining the strength of GABAergic transmission. Lemos et al. find that targeted deletion of dopamine D2 receptors from indirect-pathway medium spiny neurons (iMSNs) leads to enhanced GABAergic transmission downstream of iMSNs. This enhanced GABAergic tone causes a Parkinsonian-like motor deficit similar to dopamine depletion models. Fil: Lemos, Julia C.. National Institutes of Health; Estados Unidos Fil: Friend, Danielle M.. National Institutes of Health; Estados Unidos Fil: Kaplan, Alanna R.. National Institutes of Health; Estados Unidos Fil: Shin, Jung Hoon. National Institutes of Health; Estados Unidos Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Kravitz, Alexxai V.. National Institutes of Health; Estados Unidos Fil: Alvarez, Veronica A.. National Institutes of Health; Estados Unidos