The role of prospective contingency in the control of behavior and dopamine signals during associative learning.

Associative learning depends on contingency, the degree to which a stimulus predicts an outcome. Despite its importance, the neural mechanisms linking contingency to behavior remain elusive. Here we examined the dopamine activity in the ventral striatum - a signal implicated in associative learning - in a Pavlovian contingency degradation task in mice. We show that both anticipatory licking and dopamine responses to a conditioned stimulus decreased when additional rewards were delivered uncued, but remained unchanged if additional rewards were cued. These results conflict with contingency-based accounts using a traditional definition of contingency or a novel causal learning model (ANCCR), but can be explained by temporal difference (TD) learning models equipped with an appropriate inter-trial-interval (ITI) state representation. Recurrent neural networks trained within a TD framework develop state representations like our best 'handcrafted' model. Our findings suggest that the TD error can be a measure that describes both contingency and dopaminergic activity.

An opponent striatal circuit for distributional reinforcement learning.

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards - an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons - D1 and D2 MSNs - contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5-15 to reap the computational benefits of distributional RL.

Interpretable deep learning for deconvolutional analysis of neural signals.

The widespread adoption of deep learning to build models that capture the dynamics of neural populations is typically based on "black-box" approaches that lack an interpretable link between neural activity and function. Here, we propose to apply algorithm unrolling, a method for interpretable deep learning, to design the architecture of sparse deconvolutional neural networks and obtain a direct interpretation of network weights in relation to stimulus-driven single-neuron activity through a generative model. We characterize our method, referred to as deconvolutional unrolled neural learning (DUNL), and show its versatility by applying it to deconvolve single-trial local signals across multiple brain areas and recording modalities. To exemplify use cases of our decomposition method, we uncover multiplexed salience and reward prediction error signals from midbrain dopamine neurons in an unbiased manner, perform simultaneous event detection and characterization in somatosensory thalamus recordings, and characterize the responses of neurons in the piriform cortex. Our work leverages the advances in interpretable deep learning to gain a mechanistic understanding of neural dynamics.

Intervenções de enfermagem promotoras da adaptação dos pais (de primeira viagem) na transição para a parentalidade: Relatório de Estágio III / Nursing interventions promoting the adaptation of (first-time) parents in the transition to parenthood: Practicum Report III

O presente relatório reporta-se ao estágio de natureza profissional desenvolvido na Unidade de Saúde Familiar Rainha D. Leonor de Caldas da Rainha, no período de 13 de setembro de 2021 a 28 de janeiro de 2022. Objetivo: Descrever e refletir sobre o percurso desenvolvido no contexto da prática clínica na aquisição de competências específicas em Enfermagem de Saúde Familiar. Assim como, apresentar uma revisão sistemática de literatura com o título "Intervenções de enfermagem promotoras da adaptação dos pais (de primeira viagem) na transição para a parentalidade ", desenvolvida em contexto de estágio. Com o objetivo de conhecer quais as intervenções de enfermagem promotoras da adaptação dos pais de primeira viagem na transição para a parentalidade. Metodologia: Revisão sistemática de literatura com metodologia: PICo para dar resposta à questão: Quais as intervenções de enfermagem promotoras da adaptação dos pais de primeira viagem na transição para a parentalidade? Como critérios de inclusão foram definidos estudos qualitativos de pais pela primeira vez com filhos até aos três anos de idade. Os motores de busca, através do acesso do IPL e da OE, e as bases de dados consultadas foram: B-On, PubMed, BVS, EBSCO (CINAHL complete), ScienceDirect., WoS., SciÉLO, SciÉLO Portugal, RCAAP e RIA. A pesquisa foi efetuada entre novembro de 2021 e abril de 2022, tendo sido encontrados 535 artigos. Os artigos foram analisados segundo os critérios de inclusão e exclusão estabelecidos e de acordo com o diagrama PRISMA. Resultados: Após seleção foram incluídos três artigos específicos para responder à problemática identificada. Os estudos apontam para intervenções de enfermagem baseadas em pressupostos teóricos e uma abordagem interativa e de parceria. Durante a transição para a parentalidade é fundamental tomar a família como unidade de cuidados, mas também focar-se na individualidade de cada progenitor e ajudar a gerir as expectativas, emoções, dúvidas e papéis e a reconhecer suas forças e recursos, promovendo uma adequada adaptação dos pais de primeira viagem. Conclusões: Este trabalho expôs o percurso em contexto de estágio na aquisição das competências exigidas e demonstrou que os objetivos propostos foram alcançados. Os resultados obtidos pela investigação desenvolvida permitiram conhecer quais as intervenções de enfermagem na transição para a parentalidade em pais pela primeira vez e evidenciar o papel do enfermeiro de família na capacitação destes durante esta transição e dar um contributo científico à Enfermagem nas intervenções de enfermagem a implementar na parentalidade em pais de primeira viagem.

This report reports on the internship of a professional nature developed in the Family Health Unit Rainha D. Leonor of Caldas da Rainha, in the period from 13 September 2021 to 28 January 2022. Objetivo: Descrever e refletir sobre o percurso desenvolvido no contexto da prática clínica na aquisição de competências específicas em Enfermagem de Saúde Familiar. Assim como, apresentar uma revisão sistemática de literatura com título "Intervenções de enfermagem promotoras da adaptação dos pais (de primeira viagem) na transição para a parentalidade", desenvolvida no contexto de estágio. The purpose of this study was to identify which nursing interventions promote the adaptation of first-time parents in the transition to parenthood. Metodologia: Revisão sistemática de literatura com metodologia: PICo para dar resposta à questão: Quais as intervenções de enfermagem promotoras da adaptação dos pais de primeira viagem na transição para a parentalidade? Qualitative studies of first-time parents with children up to three years of age were defined as inclusion criteria. The search engines, through IPL and OE access, and the databases consulted were: B-On, PubMed, BVS, EBSCO (CINAHL complete), ScienceDirect, WoS, SciÉLO, SciÉLO Portugal, RCAAP, and RIA. The search was performed between November 2021 and April 2022, and 535 articles were found. The articles were analysed according to the established inclusion and exclusion criteria and according to the PRISMA diagram. Results: After selection, three specific articles were included to answer the identified problematic. The studies point to nursing interventions based on theoretical assumptions and an interactive and partnership approach. During the transition to parenthood, it is essential to take the family as a unit of care, but also to focus on each parent's individuality and help them manage their expectations, emotions, doubts and roles and recognise their strengths and resources, thus promoting an adequate adaptation of first-time parents. Conclusions: This study exposed the journey in the internship context in the acquisition of the required skills and showed that the proposed objectives were met. The results obtained through the research made it possible to identify the nursing interventions in the transition to parenthood among first-time parents and highlight the role of the family nurse in empowering these parents during this transition and provide a scientific contribution to Nursing in the nursing interventions to be implemented in parenthood among first-time parents.

A gradual temporal shift of dopamine responses mirrors the progression of temporal difference error in machine learning.

A large body of evidence has indicated that the phasic responses of midbrain dopamine neurons show a remarkable similarity to a type of teaching signal (temporal difference (TD) error) used in machine learning. However, previous studies failed to observe a key prediction of this algorithm: that when an agent associates a cue and a reward that are separated in time, the timing of dopamine signals should gradually move backward in time from the time of the reward to the time of the cue over multiple trials. Here we demonstrate that such a gradual shift occurs both at the level of dopaminergic cellular activity and dopamine release in the ventral striatum in mice. Our results establish a long-sought link between dopaminergic activity and the TD learning algorithm, providing fundamental insights into how the brain associates cues and rewards that are separated in time.

Bioelectricity generation using long-term operated biocathode: RFLP based microbial diversity analysis.

In the present work, power generation and substrate removal efficiencies of long-term operated microbial fuel cells, containing abiotic cathodes and biocathodes, were evaluated for 220 days. Among the two microbial fuel cell (MFC) types, the one containing biocathode showed higher power density (54 mW/m2), current density (122 mA/m2) coulombic efficiency (33%), and substrate removal efficiency (94%) than the abiotic cathode containing MFC. Voltammetric analysis also witnessed higher and sustainable electron discharge for the MFC with biocathode, when compared with the abiotic cathode MFC. Over the tested period, both MFC have shown a cell voltage drop, after 150 and 165, days, for the MFC with biocathode and abiotic cathodes, respectively. Polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) analysis identified 281 clones. Bacteria belonging to Acinetobacter, Acidovorax, Pseudomonas and Burkholderia were observed in the abiotic cathode MFC. Bacteria belonging to Geobacter, Cupriavidus and Acidobacteria were observed in the biocathode MFC. Almost similar types of archaea (Methanosarcinales, Methanolinea, Nitrososphaera and Methanomicrobiales) were observed in both MFCs.

Distributional Reinforcement Learning in the Brain.

Learning about rewards and punishments is critical for survival. Classical studies have demonstrated an impressive correspondence between the firing of dopamine neurons in the mammalian midbrain and the reward prediction errors of reinforcement learning algorithms, which express the difference between actual reward and predicted mean reward. However, it may be advantageous to learn not only the mean but also the complete distribution of potential rewards. Recent advances in machine learning have revealed a biologically plausible set of algorithms for reconstructing this reward distribution from experience. Here, we review the mathematical foundations of these algorithms as well as initial evidence for their neurobiological implementation. We conclude by highlighting outstanding questions regarding the circuit computation and behavioral readout of these distributional codes.

Stereotaxic Adeno-associated Virus Injection and Cannula Implantation in the Dorsal Raphe Nucleus of Mice.

Optogenetic methods are now widespread in neuroscience research. Here we present a detailed surgical procedure to inject adeno-associated viruses and implant optic fiber cannulas in the dorsal raphe nucleus (DRN) of living mice. Combined with transgenic mouse lines, this protocol allows specific targeting of serotonin-producing neurons in the brain. It includes fixing a mouse in a stereotaxic frame, performing a craniotomy, virus injection and fiber implantation. Animals can be later used in behavioral experiments, combined with optogenetic manipulations (Dugué et al., 2014; Correia et al., 2017) or monitoring of neuronal activity (Matias et al., 2017). The described procedure is a fundamental step in both optogenetic and fiber photometry experiments of deep brain areas. It is optimized for serotonin neurons in the DRN, but it can be applied to any other cell type and brain region. When using transgenic mouse lines that express functionally relevant levels of optogenetic tools or reporter lines, the virus injection step can be skipped and the protocol is reduced to the cannula implantation procedure.

Activity patterns of serotonin neurons underlying cognitive flexibility.

Serotonin is implicated in mood and affective disorders. However, growing evidence suggests that a core endogenous role is to promote flexible adaptation to changes in the causal structure of the environment, through behavioral inhibition and enhanced plasticity. We used long-term photometric recordings in mice to study a population of dorsal raphe serotonin neurons, whose activity we could link to normal reversal learning using pharmacogenetics. We found that these neurons are activated by both positive and negative prediction errors, and thus report signals similar to those proposed to promote learning in conditions of uncertainty. Furthermore, by comparing the cue responses of serotonin and dopamine neurons, we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Our findings show how the activity patterns of serotonin neurons support a role in cognitive flexibility, and suggest a revised model of dopamine-serotonin opponency with potential clinical implications.

Bonsai: an event-based framework for processing and controlling data streams.

The design of modern scientific experiments requires the control and monitoring of many different data streams. However, the serial execution of programming instructions in a computer makes it a challenge to develop software that can deal with the asynchronous, parallel nature of scientific data. Here we present Bonsai, a modular, high-performance, open-source visual programming framework for the acquisition and online processing of data streams. We describe Bonsai's core principles and architecture and demonstrate how it allows for the rapid and flexible prototyping of integrated experimental designs in neuroscience. We specifically highlight some applications that require the combination of many different hardware and software components, including video tracking of behavior, electrophysiology and closed-loop control of stimulation.

Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice.

The inhibition of sensory responsivity is considered a core serotonin function, yet this hypothesis lacks direct support due to methodological obstacles. We adapted an optogenetic approach to induce acute, robust and specific firing of dorsal raphe serotonergic neurons. In vitro, the responsiveness of individual dorsal raphe serotonergic neurons to trains of light pulses varied with frequency and intensity as well as between cells, and the photostimulation protocol was therefore adjusted to maximize their overall output rate. In vivo, the photoactivation of dorsal raphe serotonergic neurons gave rise to a prominent light-evoked field response that displayed some sensitivity to a 5-HT1A agonist, consistent with autoreceptor inhibition of raphe neurons. In behaving mice, the photostimulation of dorsal raphe serotonergic neurons produced a rapid and reversible decrease in the animals' responses to plantar stimulation, providing a new level of evidence that serotonin gates sensory-driven responses.

Primary care monitoring of patients under oral anticoagulation.

INTRODUCTION AND OBJECTIVES: With the advent of new oral anticoagulants that do not require regular laboratory control but are significantly more expensive, there has been renewed interest in the quality of the classic agents and the monitoring of patients taking them. We set out to analyze time in therapeutic range of patients under oral anticoagulation monitored in our health unit, to determine whether primary care monitoring is comparable to that in anticoagulation clinics. At the same time, we aimed to ascertain whether there was any association between the dosing method (unit protocol vs. computer-assisted) and the time in therapeutic range achieved.Methods We analyzed all INR values determined in our health unit during the first six months of 2012, using Excel 2007 and SPSS version 17.0, and applying the Student's t test for a level of significance of 0.05. RESULTS: All INR assessments during the first six months of 2012 were recorded, a total of 320 tests; mean patient age was 69.9±11.25 years, 63% male. Dose adjustments were made according to the unit protocol in 77% of cases. Atrial fibrillation was the most prevalent indication. Most values (65.3%) were within the target therapeutic range; 24.1% were subtherapeutic and 10.6% supratherapeutic. Computer-assisted dosing achieved better control than the protocol (72.5% vs. 62.9%), without statistical significance. CONCLUSIONS: Primary care monitoring of oral anticoagulation appears to be comparable to that in anticoagulation clinics, while affording better access and cost reductions.

Balanced activity in basal ganglia projection pathways is critical for contraversive movements.

The basal ganglia, and the striatum in particular, have been implicated in the generation of contraversive movements. The striatum projects to downstream basal ganglia nuclei through two main circuits, originating in striatonigral and striatopallidal neurons, and different models postulate that the two pathways can work in opposition or synergistically. Here we show striatonigral and striatopallidal neurons are concurrently active during spontaneous contraversive movements. Furthermore, we show that unilateral optogenetic inhibition of either or both projection pathways disrupts contraversive movements. Consistently, simultaneous activation of both neuron types produces contraversive movements. Still, we also show that imbalanced activity between the pathways can result in opposing movements being driven by each projection pathway. These data show that balanced activity in both striatal projection pathways is critical for the generation of contraversive movements and highlights that imbalanced activity between the two projection pathways can result in opposing motor output.