Cf - Neuroscience
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- 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.
- 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.
- Orbitofrontal Cortex Is Required for Optimal Waiting Based on Decision ConfidencePublication . Lak, Armin; Costa, Gil M.; Romberg, Erin; Koulakov, Alexei A.; Mainen, Zachary F.; Kepecs, AdamConfidence judgments are a central example of metacognition-knowledge about one's own cognitive processes. According to this metacognitive view, confidence reports are generated by a second-order monitoring process based on the quality of internal representations about beliefs. Although neural correlates of decision confidence have been recently identified in humans and other animals, it is not well understood whether there are brain areas specifically important for confidence monitoring. To address this issue, we designed a postdecision temporal wagering task in which rats expressed choice confidence by the amount of time they were willing to wait for reward. We found that orbitofrontal cortex inactivation disrupts waiting-based confidence reports without affecting decision accuracy. Furthermore, we show that a normative model can quantitatively account for waiting times based on the computation of decision confidence. These results establish an anatomical locus for a metacognitive report, confidence judgment, distinct from the processes required for perceptual decisions.
- 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.
- Preparing and selecting actions with neural populations: toward cortical circuit mechanismsPublication . Murakami, Masayoshi; Mainen, Zachary FHow the brain selects one action among multiple alternatives is a central question of neuroscience. An influential model is that action preparation and selection arise from subthreshold activation of the very neurons encoding the action. Recent work, however, shows a much greater diversity of decision-related and action-related signals coexisting with other signals in populations of motor and parietal cortical neurons. We discuss how such distributed signals might be decoded by biologically plausible mechanisms. We also discuss how neurons within cortical circuits might interact with each other during action selection and preparation and how recurrent network models can help to reveal dynamical principles underlying cortical computation.
- 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.
- 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.
- Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neuronsPublication . Correia, Patrícia A; Lottem, Eran; Banerjee, Dhruba; Machado, Ana S; Carey, Megan R; Mainen, Zachary FSerotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions.
- 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.
- 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.