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Projeto de investigação
Viscerosensorial patwhays in nutrient postingestive signalling
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Publicações
Nutrient postingestive signalling : the asymmetry of the response of dopaminergic neuronal circuits
Publication . Quadrado, Carolina; Fernandes, Ana B.
Feeding behaviour encompasses any action an animal performs to obtain and consume food. This
complex process is affected by pre and postingestive (PI) signals. The former occurs prior and during food
consumption, while the latter are related to the mechanisms that occur once food is swallowed. Both these
signals shape food-seeking behaviour and convey important information to the central nervous system (CNS).
Currently, it is known that both homeostatic and non-homeostatic circuits, within the CNS, respond to PI
stimuli. Homeostatic circuits are controlled by several hypothalamic nuclei. Non-homeostatic circuits are mostly
related to the rewarding properties of food and involve dopamine activation and consequent release in the
striatum. In fact, several authors have shown that dopamine release in the nucleus accumbens (NAc), a nucleus
from the ventral striatum, increases upon PI carbohydrate detection. Additionally, there is robust evidence that
PI stimuli from carbohydrates increases neuronal dopaminergic activity in the ventral tegmental area (VTA).
Recently, it was described that gut infusions of fat increased dopamine release in the dorsal striatum, However,
much less is known about central nervous responses to PI stimuli from other nutrients, such as fat or proteins.
On the other hand, the usage of different nutrients to understand PI feedback in feeding behaviour has
been extensively studied using classical associative learning. There is clear evidence that animals prefer flavours
paired with calories, carbohydrates, fat or proteins, to flavours paired with non-nutritive solutions. This indicates
that the reinforcing properties of PI stimuli could be associated, mostly, to the caloric content of food.
Therefore, the hypothesis for this work is that dopaminergic neurons increase their activity when caloric
solutions are infused directly into the stomach. More specifically, it is postulated that ventral areas of
dopaminergic neurons will increase their activity when carbohydrates are infused, while intragastric (IG) lipids
infusion will activate a more dorsal area of dopaminergic neurons activating substantia nigra dopaminergic
neurons and dopamine release in dorsal striatum.
To test this hypothesis, this work focused on how dopaminergic neurons respond to different IG nutrient
infusions and how PI feedback affects dopamine response in ventral and dorsal striatal and dopaminergic
regions. Thus, calcium imaging and fibre photometry experiments were carried out in dopaminergic regions -
VTA and substantia nigra pars compacta (SNc) - and striatal regions - NAc and dorsal-lateral striatum (DLS) -,
respectively, while isocaloric solutions of fat and sucrose were infused directly into the stomach. Additionally,
how PI stimuli impacts a reinforcement learning (RL) probabilistic behavioural task was also studied. For this, a
novel two-action probabilistic instrumental task was developed to better asses how PI feedback modulates
learning based on IG infusions of sucrose (caloric carbohydrate) or sucralose (non-caloric artificial sweetener)
and how different reward probabilities can affect this type of behaviour.
Calcium imaging recordings revealed that the VTA responds specifically to sucrose, when compared to
corn oil or a non-caloric artificial sweetener - sucralose. SNc responses were not nutrient-specific, since
dopaminergic activity in this nucleus showed similar patterns of response for all the reinforcers tested.
Evaluation of dopamine release in ventral and the dorsal striatum, simultaneously and in the same animal,
corroborated previous evidence that dopamine release in the NAc increases when sucrose is infused. In
opposition, DLS did not respond to any of the reinforcers administered. Additionally, preliminary data showed
that dopaminergic SNc responses did not depend on the lipid administered since response to isocaloric SMOF
lipid solution, composed of several types of fatty acids, was similar to corn oil response. Interestingly, NAc
response to SMOF lipid was similar to sucrose response, which could mean that ventral response depends on
lipid constitution.
The development of the instrumental two-action probabilistic task showed that, when given the choice,
between a lever associated to IG infusion of a caloric solution and a lever associated to IG infusion of a non caloric solution, mice develop a clear preference for the lever associated with caloric content. This preference
was independent of the probability of delivering the reward associated with each lever.
Altogether, results from this work shed light on the postulated asymmetry of dopaminergic responses
between mesolimbic (VTA to ventral striatum) and nigrostriatal (SNc to dorsal striatum) neuronal pathways,
according to the type of postingestive stimuli. Results from the development of the two-action task inferred
important parameters in decision making and RL based on PI stimuli.
Blinding the ear: rethinking the control for transcutaneous auricular vagus nerve stimulation
Publication . Santos, Bruna Filipa; Fernandes, Ana Barbosa de Matos Abreu
Resumo: A estimulação transcutânea auricular do nervo vago (taVNS) é uma técnica não invasiva de neuromodulação que aplica impulsos elétricos em regiões da orelha inervadas pelo ramo auricular do nervo vago, nomeadamente a concha cimba (CC). Dada a participação do nervo vago em múltiplas funções fisiológicas – regulação autonómica, comportamento alimentar, motivação e processamento de recompensa – a taVNS tem sido proposta como uma intervenção promissora em várias condições neurológicas e psiquiátricas. Contudo, a evidência tem revelado resultados inconsistentes ou até contraditórios, o que poderá resultar da variabilidade dos protocolos experimentais utilizados. No entanto, a maioria dos estudos publicados careceu de uma avaliação adequada do efeito placebo e de marcadores biológicos específicos, o que põe em causa a interpretabilidade dos resultados, o que poderá explicar a variabilidade de resultados observada na literatura.
Para clarificar estas questões, realizámos uma sequência de experiências com o objetivo de testar a eficácia do efeito placebo de condições de controlo habitualmente utilizadas na investigação em taVNS, avaliando sistematicamente se os participantes conseguiam diferenciar taVNS real (estimulação ativa da CC) de várias condições controlo. As condições de controlo foram inicialmente aplicadas separadamente na escafa e no lóbulo da orelha, regiões não inervadas pelo nervo vago. Numa segunda experiência, não foi administrada estimulação na CC na condição de controlo. Numa terceira abordagem experimental, utilizou-se como controlo a diminuição gradual da intensidade de estimulação até cessar, na CC. Medidas fisiológicas foram recolhidas em todas as sessões. Os resultados indicam que os participantes conseguiram distinguir entre locais de estimulação e identificar de forma fiável a taVNS real em comparação com condições de controlo sem estimulação elétrica. A utilização da abordagem de diminuição gradual da intensidade contribuiu para um controlo do efeito placebo eficaz entre sujeitos, mas não intra-sujeitos. Nenhuma das medidas fisiológicas analisadas – nomeadamente frequência cardíaca, variabilidade da frequência cardíaca, e níveis salivares de amilase e cortisol – revelou diferenças significativas que refletissem manipulação da atividade vagal.
Esta investigação representa um contributo relevante para o aperfeiçoamento dos protocolos de taVNS, aumentando a fiabilidade dos resultados e apoiando a utilização futura desta técnica sem enviesamentos decorrentes de expectativas.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/SAU-NUT/3507/2021