Chronic alcohol exposure differentially alters calcium activity of striatal cell populations during actions.

Alcohol Use Disorder (AUD) can induce long lasting alterations to executive function. This includes altered action control, which can manifest as dysfunctional goal-directed control. Cortical and striatal circuits mediate goal-directed control over behavior, and prior research has found chronic alcohol disrupts these circuits. In particular, prior in vivo and ex vivo work have identified alterations to function and activity of dorsal medial striatum (DMS), which is necessary for goal-directed control. However, unknown is whether these alterations manifest as altered activity of select DMS populations during behavior. Here we examine effects of prior chronic alcohol exposure on calcium activity modulation during action-related behaviors via fiber photometry of genetically-identified DMS populations including the direct and indirect output pathways, and fast-spiking interneurons. We find that prior chronic alcohol exposure leads to increased calcium modulation of the direct pathway during action related behavior. In contrast, prior chronic alcohol exposure led to decreased calcium activity modulation of the indirect pathway and the fast-spiking interneuron population around action-related events. Together, our findings suggest an imbalance in striatal activity during action control. This disruption may contribute to the altered goal-directed control previously reported.

The Prognostic Significance of HALP Index for Colon Cancer Patients in a Hispanic-Based Population.

Background: Survival and recurrence rates following locoregional colon cancer surgical resection are highly variable. Currently used tools to assess patient risk are still imperfect. In the present work, we evaluate, for the first time, the prognostic value of the recently developed HALP (hemoglobin, albumin, lymphocyte, and platelet) index in Hispanic colon cancer patients. Patients and Methods. We conducted a retrospective cohort study in Mexican patients with a nonmetastatic colon cancer diagnosis who underwent surgical resection. We determined the preoperative HALP score optimal cut-off value by using the X-tile software. We plotted survival curves using the Kaplan-Meier method and performed a multivariate Cox regression analysis to explore the association of preoperative HALP score with two primary endpoints: overall survival (OS) and disease-free survival (DFS). Results: We included 640 patients (49.8% female). The optimal HALP cut-off value was 15.0. A low HALP index was statistically significantly associated with a higher TNM stage. Low HALP score was statistically significantly associated with shorter median OS in the Kaplan-Meier analysis (73.5 vs. 84.8 months) and in the multivariate Cox regression analysis (HR = 1.942, 95% CI = 1.647-2.875). There was no significant association between the HALP score and DFS. Conclusions: Our findings show that the HALP index is an independent factor associated with survival in Hispanic patients, despite recurrence. It seems to reflect both the anatomical extent of the disease and traditionally unaccounted nutritional and inflammatory factors that are significant for prognosis.

Information normally considered task-irrelevant drives decision-making and affects premotor circuit recruitment.

Decision-making is a continuous and dynamic process with prior experience reflected in and used by the brain to guide adaptive behavior. However, most neurobiological studies constrain behavior and/or analyses to task-related variables, not accounting for the continuous internal and temporal space in which they occur. We show mice rely on information learned through recent and longer-term experience beyond just prior actions and reward - including checking behavior and the passage of time - to guide self-initiated, self-paced, and self-generated actions. These experiences are represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrates this information to bias strategy-level decision-making, and DMS projections reflect specific aspects of this recent experience to guide actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.

Use of discrete event simulation and genetic algorithms to estimate the necessary resources to respond in a timely manner in the Medical Emergency System in Bogotá. / Uso de simulación de eventos discretos y algoritmos genéticos para estimar los recursos necesarios para responder oportunamente en el sistema de emergencias médicas en Bogotá.

Introduction: Bogotá has a Medical Emergency System of public and private ambulances that respond to health incidents. However, its sufficiency in quantity, type and location of the resources demanded is not known. Objective: Based on the data from the Medical Emergency System of Bogotá, Colombia, we first sought to characterize the prehospital re- sponse in cardiac arrest and determine with the model which is the least number of resources necessary to respond within eight minutes, taking into account their location, number, and type. Methods: A database of incidents reported in administrative records of the district health authority of Bogotá (2014 to 2017) was obtained. Based on this information, a hybrid model based on discrete event simulation and genetic algorithms was designed to establish the amount, type and geographic location of resources according to the frequencies and typology of the events. Results: From the database, Bogotá presented 938 671 ambulances dispatches in the period. 47.4% high priority, 18.9% medium and 33.74% low. 92% of these corresponded to 15 of 43 medical emergency codes. The response times recorded were longer than expected, especially in out-of-hospital cardiac arrest (median 19 minutes). In the proposed model, the best scenario required at least 281 ambulances, medicalized and basic in a 3:1 ratio, respectively, to respond in adequate time. Conclusions: Results suggest the need for an increase in the resources that respond to these incidents to bring these response times to the needs of our population.

Introducción: Bogotá cuenta con un sistema de emergencias médicas de ambulancias públicas y privadas que responden a incidentes de salud. No se conoce, sin embargo, su suficiencia en cantidad, tipo y ubicación de recursos demandados. Objetivos: A partir de los datos del sistema de emergencias médicas de Bogotá, Colombia, se buscó primero caracterizar la respuesta pre hospitalaria en paro cardiaco. Luego, con el modelo se buscó determinar cuál sería el menor número de recursos necesarios para responder antes de ocho minutos, teniendo en cuenta su ubicación, número y tipo. Métodos: Se obtuvo una base de datos de incidentes reportados en registros administrativos de la autoridad sanitaria distrital de Bogotá (de 2014 a 2017). A partir de esa información, se diseñó un modelo híbrido basado en la simulación de eventos discretos y algoritmos genéticos para establecer la cantidad, tipo y ubicación geográfica de recursos, conforme a frecuencias y tipología de los eventos. Resultados: De la base de datos, Bogotá presentó 938 671 envíos de ambulancias en el período. El 47,4% de prioridad alta, 18,9% media y 33,74% baja. El 92% de estos correspondieron a 15 de 43 códigos de emergencias médicas. Los tiempos de respuesta registrados fueron mayores a lo esperado, especialmente en paro cardiaco extra hospitalario (mediana de 19 minutos). En el modelo planteado, el mejor escenario requirió al menos 281 ambulancias, medicalizadas y básicas en proporción de 3:1 respectivamente para responder en tiempos adecuados. Conclusiones: Los resultados sugieren la necesidad de incrementar los recursos que responden a estos incidentes para acercar estos tiempos de respuesta a las necesidades de nuestra población.

Uso de simulación de eventos discretos y algoritmos genéticos para estimar los recursos necesarios para responder oportunamente en el sistema de emergencias médicas en Bogotá / Use of discrete event simulation and genetic algorithms to estimate the necessary resources to respond in a timely manner in the Medical Emergency System in Bogotá

INTRODUCCIÓN: Bogotá cuenta con un sistema de emergencias médicas de ambulancias públicas y privadas que responden a incidentes de salud. No se conoce, sin embargo, su suficiencia en cantidad, tipo y ubicación de recursos demandados. OBJETIVOS: A partir de los datos del sistema de emergencias médicas de Bogotá, Colombia, se buscó primero caracterizar la respuesta pre hospitalaria en paro cardiaco. Luego, con el modelo se buscó determinar cuál sería el menor número de recursos necesarios para responder antes de ocho minutos, teniendo en cuenta su ubicación, número y tipo. MÉTODOS: Se obtuvo una base de datos de incidentes reportados en registros administrativos de la autoridad sanitaria distrital de Bogotá (de 2014 a 2017). A partir de esa información, se diseñó un modelo híbrido basado en la simulación de eventos discretos y algoritmos genéticos para establecer la cantidad, tipo y ubicación geográfica de recursos, conforme a frecuencias y tipología de los eventos. RESULTADOS: De la base de datos, Bogotá presentó 938 671 envíos de ambulancias en el período. El 47,4% de prioridad alta, 18,9% media y 33,74% baja. El 92% de estos correspondieron a 15 de 43 códigos de emergencias médicas. Los tiempos de respuesta registrados fueron mayores a lo esperado, especialmente en paro cardiaco extra hospitalario (mediana de 19 minutos). En el modelo planteado, el mejor escenario requirió al menos 281 ambulancias, medicalizadas y básicas en proporción de 3:1 respectivamente para responder en tiempos adecuados. CONCLUSIONES: Los resultados sugieren la necesidad de incrementar los recursos que responden a estos incidentes para acercar estos tiempos de respuesta a las necesidades de nuestra población.

INTRODUCTION: Bogotá has a Medical Emergency System of public and private ambulances that respond to health incidents. However, its sufficiency in quantity, type and location of the resources demanded is not known. OBJECTIVE: Based on the data from the Medical Emergency System of Bogotá, Colombia, we first sought to characterize the prehospital response in cardiac arrest and determine with the model which is the least number of resources necessary to respond within eight minutes, taking into account their location, number, and type. METHODS: A database of incidents reported in administrative records of the district health authority of Bogotá (2014 to 2017) was obtained. Based on this information, a hybrid model based on discrete event simulation and genetic algorithms was designed to establish the amount, type and geographic location of resources according to the frequencies and typology of the events. RESULTS: From the database, Bogotá presented 938 671 ambulances dispatches in the period. 47.4% high priority, 18.9% medium and 33.74% low. 92% of these corresponded to 15 of 43 medical emergency codes. The response times recorded were longer than expected, especially in out-of-hospital cardiac arrest (median 19 minutes). In the proposed model, the best scenario required at least 281 ambulances, medicalized and basic in a 3:1 ratio, respectively, to respond in adequate time. CONCLUSIONS: Results suggest the need for an increase in the resources that respond to these incidents to bring these response times to the needs of our population.

Precisión de la calculadora de riesgo quirúrgico ACS NSQIP para predecir morbilidad y mortalidad en pacientes mexicanos.

BACKGROUND: American College of Surgeons (ACS) developed the ACS NSQIP surgical risk calculator that predicts the results of elective and emergency surgical procedures. This tool has been useful improving the morbidity and mortality in hospitals in the United States and Canada. OBJECTIVE: To evaluate the usefulness of the ACS NSQIP risk calculator for predicting postoperative complications in Mexican population. METHOD: Prospective, observational, analytical study. Patients undergoing abdominal surgery were recorded, 21 preoperative variables were captured and entered into the calculator. They were followed up to 30 days postoperatively, identifying 14 types of postoperative complications. RESULTS: 109 patients were registered. A comparison was made between the calculated and observed complications, obtaining a good correlation in the complications of cardiac arrest, surgical site infection, reoperation, sepsis and mortality (p < 0.05). CONCLUSIONS: ACS NSQIP risk calculator is useful in the Mexican population, since the score obtained predicts most postoperative complications including mortality. The use of this tool offers an opportunity to improve decision-making in the care of the surgical patient.

ANTECEDENTES: El American College of Surgeons (ACS) desarrolló la calculadora de riesgo quirúrgico ACS NSQIP que predice los resultados de las cirugías electivas y de urgencia. Dicha herramienta ha sido útil para mejorar las cifras de morbilidad y mortalidad en hospitales de los Estados Unidos y Canadá. OBJETIVO: Evaluar la utilidad de la calculadora de riesgo ACS NSQIP para predecir complicaciones posquirúrgicas en pacientes mexicanos. MÉTODO: Estudio prospectivo, observacional y analítico. Se registraron los pacientes sometidos a cirugía abdominal, se capturaron 21 variables preoperatorias y se ingresaron en la calculadora. Se vigilaron hasta cumplir 30 días de posoperatorio y se identificaron 14 tipos de complicaciones posoperatorias. RESULTADOS: Se registraron 109 pacientes y se hizo una comparación entre las probabilidades de complicaciones calculadas y observadas, obteniendo una buena correlación en las complicaciones de paro cardiaco, infección de sitio quirúrgico, reintervención quirúrgica, sepsis y mortalidad (p < 0.05). CONCLUSIONES: La calculadora de riesgo ACS NSQIP es útil en la población mexicana, ya que el puntaje obtenido predice la mayoría de las complicaciones posoperatorias, incluida la mortalidad. El uso de esta herramienta ofrece una oportunidad para mejorar la toma de decisiones en la atención del paciente quirúrgico.

Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation-specific mechanism gating OFC activity in alcohol-exposed mice.

Habitual Ethanol Seeking and Licking Microstructure of Enhanced Ethanol Self-Administration in Ethanol-Dependent Mice.

BACKGROUND: A significant component of ethanol (EtOH) dependence is the disruption to decision-making processes. Prior work has shown EtOH dependence biases habitual seeking of EtOH and disrupts neural mechanisms supporting decision-making. This has contributed to the hypothesis that habitual EtOH seeking in EtOH dependence may promote excessive habitual or compulsive EtOH consumption. However, decision-making and behavioral processes underlying seeking and consummatory behaviors differ. Here, we examine the microstructure of EtOH consummatory behavior in the context of habitual EtOH seeking. METHODS: Following home cage pre-exposure to EtOH, C57Bl/6J mice underwent 4 rounds of chronic intermittent EtOH (CIE) or air exposure. Following acute withdrawal, mice began training for operant self-administration of 15% EtOH. Training consisted of 16-hour sessions in which mice were trained in a random ratio (RR) schedule of reinforcement for 30-second access to the EtOH sipper. To test for CIE-induced changes in action control, we used sensory-specific satiation and assessed the effect of outcome devaluation on EtOH seeking. Importantly, the use of a lickometer during operant training allowed us to measure the microstructure of lick behavior. RESULTS: Prior induction of EtOH dependence led to increased EtOH seeking, consumption, and an insensitivity to outcome devaluation, the latter indicative of habitual EtOH seeking. We also found altered consummatory lick patterns in CIE-exposed mice compared to Air controls. While CIE mice had significantly more licks in a burst and a longer burst duration, there were no differences in the total number of bursts compared to Air controls. Furthermore, these EtOH consummatory behaviors correlated with blood EtOH concentrations (BECs), while EtOH-seeking responses did not. CONCLUSIONS: Our results confirm that EtOH dependence can produce habitual EtOH seeking and suggests the increased EtOH consummatory behaviors following EtOH dependence are separable from decision-making processes controlling EtOH seeking.

Fractionating the all-or-nothing definition of goal-directed and habitual decision-making.

Goal-directed and habitual decision-making are fundamental processes that support the ongoing adaptive behavior. There is a growing interest in examining their disruption in psychiatric disease, often with a focus on a disease shifting control from one process to the other, usually a shift from goal-directed to habitual control. However, several different experimental procedures can be used to probe whether decision-making is under goal-directed or habitual control, including outcome devaluation and contingency degradation. These different experimental procedures may recruit diverse behavioral and neural processes. Thus, there are potentially many opportunities for these disease phenotypes to manifest as alterations to both goal-directed and habitual controls. In this review, we highlight the examples of behavioral and neural circuit divergence and similarity, and suggest that interpretation based on behavioral processes recruited during testing may leave more room for goal-directed and habitual decision-making to coexist. Furthermore, this may improve our understanding of precisely what the involved neural mechanisms underlying aspects of goal-directed and habitual behavior are, as well as how disease affects behavior and these circuits.

Orbital frontal cortex updates state-induced value change for decision-making.

Recent hypotheses have posited that orbital frontal cortex (OFC) is important for using inferred consequences to guide behavior. Less clear is OFC's contribution to goal-directed or model-based behavior, where the decision to act is controlled by previous experience with the consequence or outcome. Investigating OFC's role in learning about changed outcomes separate from decision-making is not trivial and often the two are confounded. Here we adapted an incentive learning task to mice, where we investigated processes controlling experience-based outcome updating independent from inferred action control. We found chemogenetic OFC attenuation did not alter the ability to perceive motivational state-induced changes in outcome value but did prevent the experience-based updating of this change. Optogenetic inhibition of OFC excitatory neuron activity selectively when experiencing an outcome change disrupted the ability to update, leaving mice unable to infer the appropriate behavior. Our findings support a role for OFC in learning that controls decision-making.

Chronic alcohol exposure disrupts top-down control over basal ganglia action selection to produce habits.

Addiction involves a predominance of habitual control mediated through action selection processes in dorsal striatum. Research has largely focused on neural mechanisms mediating a proposed progression from ventral to dorsal lateral striatal control in addiction. However, over reliance on habit striatal processes may also arise from reduced cortical input to striatum, thereby disrupting executive control over action selection. Here, we identify novel mechanisms through which chronic intermittent ethanol exposure and withdrawal (CIE) disrupts top-down control over goal-directed action selection processes to produce habits. We find CIE results in decreased excitability of orbital frontal cortex (OFC) excitatory circuits supporting goal-directed control, and, strikingly, selectively reduces OFC output to the direct output pathway in dorsal medial striatum. Increasing the activity of OFC circuits restores goal-directed control in CIE-exposed mice. Our findings show habitual control in alcohol dependence can arise through disrupted communication between top-down, goal-directed processes onto basal ganglia pathways controlling action selection.

Long-term subregion-specific encoding of enhanced ethanol intake by D1DR medium spiny neurons of the nucleus accumbens.

The nucleus accumbens (NAc) is a critical component of the mesocorticolimbic system and is involved in mediating the motivational and reinforcing aspects of ethanol consumption. Chronic intermittent ethanol (CIE) exposure is a reliable model to induce ethanol dependence and increase volitional ethanol consumption in mice. Following a CIE-induced escalation of ethanol consumption, NMDAR (N-methyl-D-aspartate receptor)-dependent long-term depression in D1 dopamine receptor expressing medium spiny neurons of the NAc shell was markedly altered with no changes in plasticity in D1 dopamine receptor medium spiny neurons from the NAc core. This disruption of plasticity persisted for up to 2 weeks after cessation of ethanol access. To determine if changes in AMPA receptor (AMPAR) composition contribute to this ethanol-induced neuroadaptation, we monitored the rectification of AMPAR excitatory postsynaptic currents (EPSCs). We observed a marked decrease in the rectification index in the NAc shell, suggesting the presence of GluA2-lacking AMPARs. There was no change in the amplitude of spontaneous EPSCs (sEPSCs), but there was a transient increase in sEPSC frequency in the NAc shell. Using the paired pulse ratio, we detected a similar transient increase in the probability of neurotransmitter release. With no change in sEPSC amplitude, the change in the rectification index suggests that GluA2-containing AMPARs are removed and replaced with GluA2-lacking AMPARs in the NAc shell. This CIE-induced alteration in AMPAR subunit composition may contribute to the loss of NMDAR-dependent long-term depression in the NAc shell and therefore may constitute a critical neuroadaptive response underlying the escalation of ethanol intake in the CIE model.

Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure.

A major mouse model widely adopted in recent years to induce pronounced ethanol intake is the ethanol vapor model known as "CIE" or "Chronic Intermittent Ethanol." One critical question concerning this model is whether the rapid induction of high blood ethanol levels for such short time periods is sufficient to induce alterations in N-methyl-d-aspartate receptor (NMDAR) function which may contribute to excessive ethanol intake. In this study, we determined whether such short term intermittent ethanol exposure modulates NMDAR function as well as other prominent electrophysiological properties and the expression of plasticity in both D1 (D1+) and D2 (D1-) dopamine receptor expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell. To distinguish between the two subtypes of MSNs in the NAc we treated Drd1a-TdTomato transgenic mice with CIE vapor and electrophysiological recordings were conducted 24 h after the last vapor exposure. To investigate CIE induced alterations in plasticity, long-term depression (LTD) was induced by pairing low frequency stimulation (LFS) with post synaptic depolarization. In ethanol naïve mice, LFS induced synaptic depression (LTD) was apparent exclusively in D1+ MSNs. Whereas in slices prepared from CIE treated mice, LFS induced synaptic potentiation (LTP) in D1+ MSNs. Furthermore, following CIE exposure, LFS now produced LTD in D1- MSNs. We found that CIE exposure induced an increase in excitability in D1+ MSNs with no change in D1- MSNs. After CIE, we found a significant increase in spontaneous EPSCs (sEPSCs) frequency in D1+ but not D1- MSNs suggesting alterations in baseline α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated signaling. CIE induced changes in NMDAR function were measured using the NMDA/AMPA ratio and input-output curves of isolated NMDAR currents. We observed a significant increase in NMDAR function in D1+ MSNs and a decrease in D1- MSNs after ethanol vapor exposure. The reversal of NMDAR function may account for the CIE induced alterations in the expression of plasticity. The cell type specific alterations in excitatory signaling in the NAc shell may constitute an important neuroadaptation necessary for the expression of increased ethanol consumption induced by intermittent ethanol vapor exposure. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

El reto de la cronicidad en España: mejor transformar que racionar / The challenge of chronicity in Spain: better transform rather than ration

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Ethanol attenuation of long-term depression in the nucleus accumbens can be overcome by activation of TRPV1 receptors.

BACKGROUND: Altered expression of synaptic plasticity within the nucleus accumbens (NAc) constitutes a critical neuroadaptive response to ethanol (EtOH) and other drugs of abuse. We have previously reported that N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) is markedly affected by chronic intermittent ethanol exposure in vivo; however, endocannabinoid (eCB)-dependent synaptic depression, despite being very well-documented in the dorsal striatum, is much less well understood in the NAc. METHODS: Whole cell patch clamp electrophysiology was used to investigate interactions between these different plasticity-induction systems. Excitatory postsynaptic currents (EPSCs) were measured in the NAc shell and NMDAR-LTD was induced by a pairing protocol (500 stimuli at 1 Hz stimulation [low-frequency stimulation (LFS)] paired with postsynaptic depolarization to -50 mV). AM251, a CB1 receptor antagonist, was used to determine whether this form of LTD is modulated by eCBs. To determine the effect of EtOH on a purely eCB-dependent response in the NAc, depolarization-induced suppression of excitation (DSE) was used in the presence of 40 mM EtOH. Finally, we determined whether the enhancement of eCB signaling with URB597, a fatty acid amide hydrolase inhibitor, and AM404, an anandamide re-uptake inhibitor would also modulate LFS LTD in the presence of NMDAR blockade or EtOH. RESULTS: In the presence of AM251, the LFS pairing protocol resulted in NMDAR-dependent long-term potentiation that was blocked with either EtOH or DL-APV. We also found that DSE in the NAc shell was blocked by AM251 and suppressed by EtOH. Enhanced eCB signaling rescued NAc-LTD expression in the presence of EtOH through a distinct mechanism requiring activation of TRPV1 receptors. CONCLUSIONS: EtOH modulation of synaptic plasticity in the NAc is dependent upon a complex interplay between NMDARs, eCBs, and TRPV1 receptors. These findings demonstrate a novel form of TRPV1-dependent LTD in the NAc shell that may be critical for EtOH dependence.