Exploring the role of substantia nigra dopaminergic neurons in the initiation of self paced actions

RESUMO: Decidir quando nos movemos é essencial para a nossa sobrevivência. A perda de neurónios dopaminérgicos (DANs) na substantia nigra pars compacta (SNc), a alteração patológica característica da doença de Parkinson (PD), causa deficits na iniciação do movimento e lentificação do movimento. A teoria dominante é que o papel dos DANs da SNc no movimento deve-se a mudanças mantidas da atividade destes neurónios (atividade tónica) enquanto as alterações fásicas da atividade estão envolvidas na aprendizagem baseada na recompensa. No entanto, foi demonstrado que a atividade fásica dos DANs da SNc se correlaciona com o início e terminação de uma sequência de ações aprendida. Contudo, continua por esclarecer se esta atividade é ou não necessária para a iniciação ‘self-paced’ de sequências de ações. A maioria dos estudos anteriores que incidiram sobre movimento ou iniciação de ações utilizaram lesões crónicas ou fármacos para manipular a via nigro-estriada. Estes métodos não são ideais para estudar o papel de populações neuronais específicas devido a limitações tais como a baixa resolução temporal e a baixa especificidade destas manipulações. Devido a isto, o papel dos DANs da SNc na iniciação de movimentos/ações ‘self-paced’ continua a ser pouco claro. Para resolver esta questão nós utilizámos uma abordagem optogenética para gravar, visualizar e manipular a atividade de DANs da SNc com uma elevada especificidade neuronal e resolução temporal. Descobrimos que quando murganhos se movimentavam livremente num ‘open field’, os DANs da SNc aumentavam a sua atividade de forma transitória, antes do início do movimento. Para testar se este aumento de atividade era ou não necessário para a iniciação do movimento, expressámos uma opsina inibitória (ArchT) nos DANs da SNc dos murganhos. Utilizando esta estratégia foto-inibimos estes neurónios transitoriamente e descobrimos que conseguíamos perturbar a probabilidade e o vigor das iniciações de movimento mas não conseguíamos modificar a aceleração dos animais quando estes já se encontravam em movimento. Em seguida quisemos saber se uma breve activação destes neurónios era suficiente para promover a iniciação de movimento. Para conseguirmos isto expressámos ChR2 nos DANs da SNc e ativámos transitoriamente estes neurónios enquanto os murganhos se moviam livremente. Ao contrário da experiência de inibição, esta breve ativação promoveu a iniciação do movimento quando os murganhos se encontravam imóveis, e de uma forma semelhante não modificou a aceleração dos murganhos quando estes já se encontravam em movimento. Quando treinámos os murganhos para realizarem uma sequência de acções (recompensando-os se eles pressionassem uma alavanca 8 vezes) descobrimos que os DANs da SNc aumentavam a sua actividade transitoriamente imediatamente antes do início e o final da sequência. Para além disto, estes neurónios na sua maioria correspondiam a uma população que não respondia à recompensa. Quando inibimos transitoriamente os DANs da SNC imediatamente antes do inicio da sequência os murganhos exibiram um aumento da latência para iniciarem a sequência. Contudo, não conseguimos perturbar a execução da sequência quando fizemos a mesma inibição após a sequência ter sido iniciada. Os nossos resultados demonstram que a actividade dos DANs da SNc modulam não apenas a probabilidade mas também o vigor dos movimentos futuros mas não modula o movimento durante a sua execução. Isto sugere que o ‘gating’ de iniciações ‘selfpaced’ acontece através de efeitos permissivos da dopamina nos circuitos estriatais que por sua vez recebem a informação relativa a que ações iniciar de outros ‘inputs’. A depleção de dopamina na PD é crónica. Os estudos sobre o papel da dopamina no movimento utilizando modelos animais de depleção crónica são bastante importantes mas têm uma utilidade limitada para a compreensão do papel dinâmico dos DANs da SNc nos circuitos para os quais projetam. O nosso trabalho, ao demonstrar a relevância da atividade transitória destes neurónios imediatamente antes do início de movimentos ‘self-paced’, sugere que poderá ser benéfico desenvolver terapêuticas que providenciem modulações transitórias dos circuitos dos gânglios da base quando os doentes com PD querem iniciar uma ação (e.g. estimulação cerebral profunda em ‘closed–loop’ despoletada por atividade cortical nas áreas relacionadas com o planeamento motor).ABSTRACT: Deciding if and when to move is critical for survival. Loss of dopamine neurons (DANs) in substantia nigra pars compacta (SNc), the pathological hallmark of Parkinson’s disease (PD), causes deficits in movement initiation and slowness of movement. The dominant theory is that the role of SNc DANs in movement is mainly due to sustained changes in their firing (tonic changes) while phasic changes are involved in rewardbased learning. Nevertheless, phasic activity of SNc DANs has been found to correlate with the start and finish of a learned action sequence. However, it remains unclear whether this activity is necessary for self-paced action initiation. The majority of previous studies on movement/action initiation have used chronic lesions or drugs to manipulate the nigrostriatal pathway. These methods are not ideal to study the role of specific neuron populations due to constraints such as temporal resolution and/or specificity of the manipulations. Thus, the role of SNc DANs in self-paced movement/action initiation remains unsettled. To tackle this question we used an optogenetic approach to record, image and manipulate the activity of genetically identified SNc DANs with high specificity and temporal resolution. We found that when mice were freely moving in an open field SNc DANs transiently increased their activity just before self-paced movements were initiated. To test whether this transient increase in activity was necessary for movement initiation we expressed an inhibitory opsin (ArchT) in SNc DANs of mice. We proceeded to briefly photoinhibit these neurons and found that we could disturb the probability and vigor of movement initiations but we could not change mice's acceleration when they were already moving. Next we wanted to know whether brief activation of SNc DANs was sufficient to promote movement initiation. To achieve this we expressed ChR2 in mice's SNc DANs and briefly activated these neurons while mice were freely moving. Contrary to the inhibition experiment, this brief activation promoted movement initiation when mice were immobile and in a similar way it did not change significantly mice's acceleration when they were already moving. When we trained mice to perform a learned action sequence (by rewarding them if they pressed a lever 8 times) we found that SNc DANs increased their activity transiently just before the start and finish of the action sequence. Furthermore, these neurons were largely non-overlapping with reward related DANs. When we briefly inhibited SNc DANs just before the action sequence, mice increased their latency to initiate the sequence. However, inhibition of these neurons when mice had already started the action sequence did not change their performance. Our results show that the activity of SNc DANs modulates not only the probability but also the vigor of future movements but that it does not modulate movements once they have been initiated. This suggests that the gating of self-paced initiation happens by permissive effects of dopamine on downstream striatal circuits that would receive information about which plans to execute from other inputs. Dopamine depletion in PD is chronic. Studies of the role of dopamine in movement in chronic models of depletion are very valuable, but have limited our understanding of the dynamic role of SNc DAN activity in downstream circuits. Our work, by highlighting the relevance of transient activity of these neurons before self-paced movement initiation, suggests that it could be beneficial to pursue treatments aimed at providing transient modulations of basal ganglia circuitry when patients initiate movements, e.g. via closed-loop deep brain stimulation triggered by activity in cortical areas related to motor planning

Topological analysis of water distribution networks for optimal leak localization

This paper introduces two methodologies to provide an optimum sensor deployment layout, one based on a model-based approach and the other entirely data-driven. The first method is formulated as an integer optimization problem, an optimization criterion consisting of minimizing the average topological distance. The second method is a new methodology to provide an optimum sensor placement regarding how many sensors to install without using hydraulic information but just exploiting the knowledge of the topology of the Water Distribution Networks. The method uses the Girvan-Newman clustering algorithm to ensure complete coverage of the network and the study of the installation of pressure sensors in the central nodes of each group, selected according to different metrics of topological centrality. The approach is illustrated in the Modena network. © 2023 Institute of Physics Publishing. All rights reserved.Postprint (published version

Robust data-driven leak localization in water distribution networks using pressure measurements and topological information

This article presents a new data-driven method for locating leaks in water distribution networks (WDNs). It is triggered after a leak has been detected in the WDN. The proposed approach is based on the use of inlet pressure and flow measurements, other pressure measurements available at some selected inner nodes of the WDN, and the topological information of the network. A reduced-order model structure is used to calculate non-leak pressure estimations at sensed inner nodes. Residuals are generated using the comparison between these estimations and leak pressure measurements. In a leak scenario, it is possible to determine the relative incidence of a leak in a node by using the network topology and what it means to correlate the probable leaking nodes with the available residual information. Topological information and residual information can be integrated into a likelihood index used to determine the most probable leak node in the WDN at a given instant k or, through applying the Bayes’ rule, in a time horizon. The likelihood index is based on a new incidence factor that considers the most probable path of water from reservoirs to pressure sensors and potential leak nodes. In addition, a pressure sensor validation method based on pressure residuals that allows the detection of sensor faults is proposed.This work has been partially funded by SMART Project (ref.num. EFA153/16 Interreg Cooperation Program POCTEFA 2014-2020), L-BEST Project (PID2020-115905RB-C21) funded by MCIN/ AEI /10.13039/501100011033 and AGAUR ACCIO RIS3CAT UTILITIES 4.0–P1 ACTIV 4.0. ref.COMRDI-16-1-0054-03.Peer ReviewedPostprint (published version

Leak detection in water distribution networks based on water demand analysis

This paper deals with the leak detection problem in Water Distribution Networks (WDN). A leak detection method based on the water demand analysis of District Metered Areas (DMAs) is proposed. Historical leak-free data of water demand flow is used to extract minimum, and maximum values, and statistical distributions of differences (errors) between demand flow and predicted values at the different time hours of the day. The concept of sensor fusion is applied to reduce measurement uncertainties. For this, a virtual measurement is generated that considers each hour of the day a feature and, combined, develops a more accurate error analysis capable of detecting leaks and estimating the leak size magnitude. Furthermore, to increase the accuracy of the leak detection method, prediction errors are analyzed in a moving time window. Finally, the performance of the proposed leak detection method is assessed by using actual data of different real DMAs of the Barcelona WDN.Peer ReviewedPostprint (published version

Data-driven leak localization in WDN using pressure sensor and hydraulic information

Maintaining a good quality of service under a wide range of operational management is challenging for water utilities. One of the significant challenges is the location of water leaks in the large-scale water distribution networks (WDN) due to limited data information throughout the system, generally having only flow sensors at the system's entrance and some pressure sensors in some selected nodes. In addition, most systems do not have a network hydraulic model. Therefore, when using the hydraulic model, the presence of model errors, such as nodal demand uncertainty and measurement noise, can interfere with the performance of the leak location method. This work presents a fully data-driven technique to reduce the area of the leak localization in the WDN, using Graph theory to represent the network. To do so, we have developed distance clustering with pre-defined centroids that are the sensor pressure information and some selected nodes. Furthermore, extra pressure information of leak events in the selected centroids is studied to develop a correlation between the pressure measurement and the event. Finally, the approach is evaluated in real-world water systems and discusses graphical results and key performance indicators.Peer ReviewedPostprint (published version

The contribution of somatic items

Funding Information: JO is supported by the NARSAD 2018 Young Investigator Award from the Brain & Behavior Research Foundation , (Grant ID: 27595 ). RL is supported by the 2018 Scientific Employment Stimulus from Fundação para a Ciência e Tecnologia, Portugal (CEECIND/04157/2018). DF, BS and AJO-M are supported by the BOUNCE project (grant agreement number 777167 ), and RL and AJO-M are supported by the FAITH project (grant agreement number 875358 ), both funded by the European Union's Horizon 2020 research and innovation programme. JBB-C and AJO-M are supported by grant FCT-PTDC/MEC-PSQ/30302/2017-IC&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. AJO-M is supported by grant FCT-PTDC/MED-NEU/31331/2017, funded by FCT/MCTES. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Publisher Copyright: © 2022 The AuthorsBackground/Objective: Screening for depression in patients with cancer can be difficult due to overlap between symptoms of depression and cancer. We assessed validity of the Beck Depression Inventory (BDI-II) in this population. Method: Data was obtained in an outpatient neuropsychiatry unit treating patients with and without cancer. Psychometric properties of the BDI-II Portuguese version were assessed separately in 202 patients with cancer, and 376 outpatients with mental health complaints but without cancer. Results: Confirmatory factor analysis suggested a three-factor structure model (cognitive, affective and somatic) provided best fit to data in both samples. Criterion validity was good for detecting depression in oncological patients, with an area under the ROC curve (AUC) of 0.85 (95% confidence interval [CI], 0.76–0.91). A cut-off score of 14 had sensitivity of 87% and specificity of 73%. Excluding somatic items did not significantly change the ROC curve for BDI-II (difference AUCs = 0.002, p=0.9). A good criterion validity for BDI-II was also obtained in the non-oncological population (AUC = 0.87; 95% CI 0.81–0.91), with a cut-off of 18 (sensitivity=84%; specificity=73%). Conclusions: The BDI-II demonstrated good psychometric properties in patients with cancer, comparable to a population without cancer. Exclusion of somatic items did not affect screening accuracy.publishersversionpublishe

Leak localization in water distribution networks using data-driven and model-based approaches

The detection and localization of leaks in water distribution networks (WDNs) is one of the major concerns of water utilities, due to the necessity of an efficient operation that satisfies the worldwide growing demand for water. There exists a wide range of methods, from equipment-based techniques that rely only on hardware devices to software-based methods that exploit models and algorithms as well. Model-based approaches provide an effective performance but rely on the availability of an hydraulic model of the WDN, while data-driven techniques only require measurements from the network operation but may produce less accurate results. This paper proposes two methodologies: a model-based approach that uses the hydraulic model of the network, as well as pressure and demand information; and a fully data-driven method based on graph interpolation and a new candidate selection criteria. Their complementary application was successfully applied to the Battle of the Leakage Detection and Isolation Methods (BattLeDIM) 2020 challenge, and the achieved results are presented in this paper to demonstrate the suitability of the methods.Peer ReviewedPostprint (author's final draft

Postingestive Modulation of Food Seeking Depends on Vagus-Mediated Dopamine Neuron Activity

Postingestive nutrient sensing can induce food preferences. However, much less is known about the ability of postingestive signals to modulate food-seeking behaviors. Here we report a causal connection between postingestive sucrose sensing and vagus-mediated dopamine neuron activity in the ventral tegmental area (VTA), supporting food seeking. The activity of VTA dopamine neurons increases significantly after administration of intragastric sucrose, and deletion of the NMDA receptor in these neurons, which affects bursting and plasticity, abolishes lever pressing for postingestive sucrose delivery. Furthermore, lesions of the hepatic branch of the vagus nerve significantly impair postingestive-dependent VTA dopamine neuron activity and food seeking, whereas optogenetic stimulation of left vagus nerve neurons significantly increases VTA dopamine neuron activity. These data establish a necessary role of vagus-mediated dopamine neuron activity in postingestive-dependent food seeking, which is independent of taste signaling.info:eu-repo/semantics/publishedVersio

Ambiente institucional: construção e estudo exploratório de um questionário em contexto de ensino superior

A literatura sobre ensino superior tem dado destaque ao estudo do ambiente institucional, indicando que as perceções dos estudantes acerca da qualidade dos ambientes institucionais apresentam impacto no seu ajustamento e desenvolvimento. Com este estudo pretendeu-se desenvolver um questionário para avaliar a perceção do estudante sobre o Ambiente Institucional (Questionário do Ambiente Institucional - QAI). Assim, partimos da análise de conteúdo de entrevistas realizadas a 31 estudantes e do seu confronto com a literatura. A versão final do QAI resultou numa solução de dois fatores, com níveis de consistência interna bastante aceitáveis: Estímulo Intelectual (α=.90), Sentimento de Comunidade (α=.88).