CF - Champalimaud Foundation
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The Champalimaud Foundation is a private, non-profit organization, which focuses on cutting-edge research and strives to stimulate new discoveries and knowledge that can improve the health and well-being of people around the world. The Champalimaud Centre for the Unknown, based in Lisbon, Portugal, hosts the Foundation’s activities in the fields of neuroscience and cancer by means of research programmes and the provision of clinical care of excellence. The Foundation also supports the fight against blindness through a focused outreach programme.
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- Activation of Dorsal Raphe Serotonergic Neurons Promotes Waiting but Is Not ReinforcingPublication . Fonseca, Madalena S.; Murakami, Masayoshi; Mainen, Zachary F.The central neuromodulator serotonin (5-HT) has been implicated in a wide range of behaviors and affective disorders, but the principles underlying its function remain elusive. One influential line of research has implicated 5-HT in response inhibition and impulse control. Another has suggested a role in affective processing. However, whether and how these effects relate to each other is still unclear.
- Activity patterns of serotonin neurons underlying cognitive flexibilityPublication . Matias, Sara; Lottem, Eran; Dugué, Guillaume P; Mainen, Zachary FSerotonin 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.
- An effect of serotonergic stimulation on learning rates for rewards apparent after long intertrial intervalsPublication . Iigaya, Kiyohito; Fonseca, Madalena S.; Murakami, Masayoshi; Mainen, Zachary F.; Dayan, PeterSerotonin has widespread, but computationally obscure, modulatory effects on learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven decision-making task. Animals showed two distinct choice strategies. Choices after short inter-trial-intervals (ITIs) depended only on the last trial outcome and followed a win-stay-lose-switch pattern. In contrast, choices after long ITIs reflected outcome history over multiple trials, as described by reinforcement learning models. We found that optogenetic stimulation during a trial significantly boosted the rate of learning that occurred due to the outcome of that trial, but these effects were only exhibited on choices after long ITIs. This suggests that serotonin neurons modulate reinforcement learning rates, and that this influence is masked by alternate, unaffected, decision mechanisms. These results provide insight into the role of serotonin in treating psychiatric disorders, particularly its modulation of neural plasticity and learning.
- Confidence as Bayesian Probability: From Neural Origins to BehaviorPublication . Meyniel, Florent; Sigman, Mariano; Mainen, Zachary F.Research on confidence spreads across several sub-fields of psychology and neuroscience. Here, we explore how a definition of confidence as Bayesian probability can unify these viewpoints. This computational view entails that there are distinct forms in which confidence is represented and used in the brain, including distributional confidence, pertaining to neural representations of probability distributions, and summary confidence, pertaining to scalar summaries of those distributions. Summary confidence is, normatively, derived or "read out" from distributional confidence. Neural implementations of readout will trade off optimality versus flexibility of routing across brain systems, allowing confidence to serve diverse cognitive functions.
- Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal CortexPublication . Murakami, Masayoshi; Shteingart, Hanan; Loewenstein, Yonatan; Mainen, Zachary F.The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals.
- Explicit knowledge of task structure is a primary determinant of human model-based actionPublication . Castro-Rodrigues, Pedro; Akam, Thomas; Snorasson, Ivar; Camacho, Marta; Paixão, Vitor; Maia, Ana; Barahona-Corrêa, J. Bernardo; Dayan, Peter; Simpson, H. Blair; Costa, Rui M.; Oliveira-Maia, Albino J.Explicit information obtained through instruction profoundly shapes human choice behaviour. However, this has been studied in computationally simple tasks, and it is unknown how model-based and model-free systems, respectively generating goal-directed and habitual actions, are affected by the absence or presence of instructions. We assessed behaviour in a variant of a computationally more complex decision-making task, before and after providing information about task structure, both in healthy volunteers and in individuals suffering from obsessive-compulsive or other disorders. Initial behaviour was model-free, with rewards directly reinforcing preceding actions. Model-based control, employing predictions of states resulting from each action, emerged with experience in a minority of participants, and less in those with obsessive-compulsive disorder. Providing task structure information strongly increased model-based control, similarly across all groups. Thus, in humans, explicit task structural knowledge is a primary determinant of model-based reinforcement learning and is most readily acquired from instruction rather than experience.
- Metastable attractors explain the variable timing of stable behavioral action sequencesPublication . Recanatesi, S; Pereira-Obilinovic, U; Murakami, M; Mainen, ZF; Mazucatto, L
- Neural antecedents of self-initiated actions in secondary motor cortexPublication . Murakami, Masayoshi; Vicente, M Inês; Costa, Gil M; Mainen, Zachary FThe neural origins of spontaneous or self-initiated actions are not well understood and their interpretation is controversial. To address these issues, we used a task in which rats decide when to abort waiting for a delayed tone. We recorded neurons in the secondary motor cortex (M2) and interpreted our findings in light of an integration-to-bound decision model. A first population of M2 neurons ramped to a constant threshold at rates proportional to waiting time, strongly resembling integrator output. A second population, which we propose provide input to the integrator, fired in sequences and showed trial-to-trial rate fluctuations correlated with waiting times. An integration model fit to these data also quantitatively predicted the observed inter-neuronal correlations. Together, these results reinforce the generality of the integration-to-bound model of decision-making. These models identify the initial intention to act as the moment of threshold crossing while explaining how antecedent subthreshold neural activity can influence an action without implying a decision.
- Optogenetic Activation of Dorsal Raphe Serotonin Neurons Rapidly Inhibits Spontaneous But Not Odor-Evoked Activity in Olfactory CortexPublication . Lottem, E.; Lorincz, M. L.; Mainen, Z. F.Serotonin (5-hydroxytriptamine; 5-HT) is implicated in a variety of brain functions including not only the regulation of mood and control of behavior but also the modulation of perception. 5-HT neurons in the dorsal raphe nucleus (DRN) often fire locked to sensory stimuli, but little is known about how 5-HT affects sensory processing, especially on this timescale. Here, we used an optogenetic approach to study the effect of 5-HT on single-unit activity in the mouse primary olfactory (anterior piriform) cortex. We show that activation of DRN 5-HT neurons rapidly inhibits the spontaneous firing of olfactory cortical neurons, acting in a divisive manner, but entirely spares sensory-driven firing. These results identify a new role for serotonergic modulation in dynamically regulating the balance between different sources of neural activity in sensory systems, suggesting a possible role for 5-HT in perceptual inference.
- Optogenetic Recruitment of Dorsal Raphe Serotonergic Neurons Acutely Decreases Mechanosensory Responsivity in Behaving MicePublication . Dugué, Guillaume P.; Lörincz, Magor L.; Lottem, Eran; Audero, Enrica; Matias, Sara; Correia, Patricia A.; Léna, Clément; Mainen, Zachary F.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.