Biology subjects

Mainen, Z. F.

Publications and source records attributed to Mainen, Z. F..

12 recordsLinked to original sources

bioRxiv2026

Serotonin induces DOWN states across the anesthetized mouse forebrain

Serotonergic neurons in the dorsal raphe nucleus (DRN) project extensively throughout the forebrain, yet their influence on global network states remains controversial. Serotonin is implicated in regulating slow-oscillations, so-called UP and DOWN states, which occur during sleep and light anesthesia. While optogenetic fMRI suggests that serotonin (5-HT) suppresses brain-wide activity, classical electrical stimulation studies report the induction of cortical UP states. To resolve this discrepancy, we combined optogenetic 5-HT stimulation with large-scale Neuropixel recordings across the forebrain of lightly anesthetized mice. We demonstrate that selective 5-HT release consistently induces DOWN states across the cortex and striatum, while leaving midbrain dynamics largely unaffected. A multi-area computational model constrained by biologically plausible connectivity, indicates that in certain regions the transitions arises from network-level synchronization rather than direct DRN input.

neuroscience↗

bioRxiv2025

Serotonin modulates neural dynamics in a subspace orthogonal to the choice space

Serotonin (5-HT) is a central neuromodulator which is implicated in, amongst other functions, cognitive flexibility. 5-HT is released from the dorsal raphe nucleus (DRN) throughout nearly the entire forebrain. Little is known, however, about how serotonin affects downstream populations of neurons and how this modulation might support its cognitive functions. Here, we optogenetically stimulated serotonergic neurons in the DRN while recording large parts of the brain with Neuropixels during quiet wakefulness and performance of a perceptual decision-making task. During quiet wakefulness, 5-HT stimulation induced a rapid switch in internal state, as indicated by dilation of the pupil, suppression of hippocampal sharp wave ripples, and increased exploratory behaviors, such as whisking. To elucidate the brain-wide effect of serotonin release we performed acute Neuropixel recordings in seven target locations, a total of 7,478 neurons were recorded across 17 mice. We found that 5-HT stimulation significantly modulated neural activity in all the recorded brain regions, both during quiet wakefulness and task performance. During task performance, however, we observed no change in behavior when stimulating 5-HT. We found that the 5-HT modulation of high-dimensional neural dynamics is confined to a subspace which is orthogonal relative to the choice axis. These observations describe a possible mechanism for the induction of state-dependent stimulus representations, suggesting a neural basis for neuromodulatory effects on brain-wide circuits to flexible decision-making.

neuroscience↗

bioRxiv2023

A Brain-Wide Map of Neural Activity during Complex Behaviour

A key challenge in neuroscience is understanding how neurons in hundreds of interconnected brain regions integrate sensory inputs with prior expectations to initiate movements and thereby make decisions. It is difficult to meet this challenge if different laboratories apply different analyses to different recordings in different regions during different behaviours. Here, we report a comprehensive set of recordings from 621733 neurons across 139 mice in 12 labs performing a decision-making task with sensory, motor, and cognitive components, obtained with 699 Neuropixels probe insertions covering 279 brain areas in the left forebrain and midbrain and the right hindbrain and cerebellum. We provide an initial appraisal of this brain-wide map, assessing how neural activity encoded key task variables. Representations of visual stimuli appeared transiently in classical visual areas after stimulus onset and then spread to ramp-like activity in a collection of mid- and hindbrain regions that also encoded choices. Neural responses correlated with motor action almost everywhere in the brain. Responses to reward delivery and consumption versus negative feedback were also widespread. This publicly available dataset represents an unprecedented resource for understanding how computations distributed across and within brain areas drive behaviour.

neuroscience↗

bioRxiv2020

Phasic activation of dorsal raphe serotonergic neurons increases pupil-linked arousal

Variations in pupil size under constant luminance are closely coupled to changes in arousal state [1-5]. It is assumed that such fluctuations are primarily controlled by the noradrenergic system [6-9]. Phasic activity of noradrenergic axons precedes pupil dilations associated with rapid changes in arousal [7,9], and is believed to be driven by unexpected uncertainty [1,10-16]. However, the role of other modulatory pathways in the control of pupil-linked arousal has not been as thoroughly investigated, but evidence suggests that noradrenaline may not be alone [7,17,18]. Administration of serotonergic drugs seems to affect pupil size [19-23], but these effects have not been investigated in detail. Here, we show that transient serotonin (5-HT) activation, like noradrenaline, causes pupil-size changes. We used phasic optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) in head-fixed mice locomoting in a foraging task. 5-HT-driven modulations of pupil size were maintained throughout the photostimulation period and sustained for several seconds after the end of the stimulation. The activation of 5-HT neurons increased pupil size additively with locomotor speed, suggesting that 5-HT transients affect pupil-linked arousal independently from locomotor states. We found that the effect of 5-HT on pupil size depended on the level of environmental uncertainty, consistent with the idea that 5-HT may report a salience or surprise signal [24]. Together, these results challenge the classic view of the neuromodulatory control of pupil-linked arousal, revealing a tight relationship between the activation of 5-HT neurons and changes in pupil size.

neuroscience↗

bioRxiv2020

Functional MRI of large scale activity in behaving mice

Behaviour involves complex dynamic interactions across many brain regions. Detecting whole-brain activity in mice performing sophisticated behavioural tasks could facilitate insights into distributed processing underlying behaviour, guide local targeting, and help bridge the disparate spatial scales between rodent and human studies. Here, we present a comprehensive approach for recording brain-wide activity with functional magnetic resonance imaging (fMRI) compatible with a wide range of behavioural paradigms and neuroscience questions. We introduce hardware and procedural advances to allow multi-sensory, multi-action behavioural paradigms in the scanner. We identify signal artefacts arising from task-related body movements and propose novel strategies to reduce them. We validate and explore our approach in a 4-odour classical conditioning and a visually-guided operant task, illustrating how it can be used to extract information so far inaccessible to rodent behaviour studies. Our work paves the way for future studies combining fMRI and local circuit techniques during complex behaviour to tackle multi-scale behavioural neuroscience questions.

neuroscience↗

bioRxiv2020

Citric Acid water as an alternative to water scheduling in behaving mice

AO_SCPLOWBSTRACTC_SCPLOWPowerful neural measurement and perturbation tools have positioned mice as an ideal species for probing the neural circuit mechanisms of cognition. Crucial to this success is the ability to motivate animals to perform specific behaviors. One successful strategy is to restrict their water intake, rewarding them with water during a behavioral task. However, water restriction requires rigorous monitoring of animals health and hydration status and can be challenging for some mice. We present an alternative that allows mice more control over their water intake: free home-cage access to water, made slightly sour by a small amount of citric acid (CA). In a previous study, rats with free access to CA water readily performed a behavioral task for water rewards, although completing fewer trials than under water restriction (Reinagel, 2018). We here extend this approach to mice and confirm its robustness across multiple laboratories. Mice reduced their intake of CA water while maintaining healthy weights. Continuous home-cage access to CA water only subtly impacted their willingness to perform a decision-making task, in which they were rewarded with sweetened water. When free CA water was used instead of water restriction only on weekends, learning and decision-making behavior were unaffected. CA water is thus a promising alternative to water restriction, allowing animals more control over their water intake without interfering with behavioral performance. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWHigh-throughput, reliable behavioral training is a key requirement for the use of mice in behavioral and systems neuroscience, but depends crucially on ability to motivate animals to perform specific behaviors. Here, we present an alternative method to commonly used methods of water restriction: free home-cage access to water, made slightly sour by a small amount of citric acid. This non-labor-intensive, low-error option benefits animal health without hindering behavioral training progress. Citric acid water can serve as a reliable and standardized strategy to achieve high quality task behavior, further facilitating the use of mice in high-throughput behavioral studies.

neuroscience↗

bioRxiv2020

Spatial maps in olfactory cortex during olfactory navigation

Odors are a fundamental part of the sensory environment used by animals to inform behaviors such as foraging and navigation1, 2. Primary olfactory (piriform) cortex is thought to be dedicated to encoding odor identity3-8. Here, using neural ensemble recordings in freely moving rats performing a novel odor-cued spatial choice task, we show that posterior piriform cortex neurons also carry a robust spatial map of the environment. Piriform spatial maps were stable across behavioral contexts independent of olfactory drive or reward availability, and the accuracy of spatial information carried by individual neurons depended on the strength of their functional coupling to the hippocampal theta rhythm. Ensembles of piriform neurons concurrently represented odor identity as well as spatial locations of animals, forming an "olfactory-place map". Our results reveal a previously unknown function for piriform cortex in spatial cognition and suggest that it is well-suited to form odor-place associations and guide olfactory cued spatial navigation.

neuroscience↗

bioRxiv2019

Inference based decisions in a hidden state foraging task: differential contributions of prefrontal cortical areas

Essential features of the world are often hidden and must be inferred by constructing internal models based on indirect evidence. Here, to study the mechanisms of inference we established a foraging task that is naturalistic and easily learned, yet can distinguish inference from simpler strategies such as the direct integration of sensory data. We show that both mice and humans learn a strategy consistent with optimal inference of a hidden state. However, humans acquire this strategy more than an order of magnitude faster than mice. Using optogenetics in mice we show that orbitofrontal and anterior cingulate cortex inactivation impact task performance, but only orbitofrontal inactivation reverts mice from an inference-based to a stimulus-bound decision strategy. These results establish a cross-species paradigm for studying the problem of inference-based decision-making and begin to dissect the network of brain regions crucial for its performance.

neuroscience↗

bioRxiv2018

The impact of learning on perceptual decisions and its implication for speed-accuracy tradeoffs

In standard models of perceptual decision-making, noisy sensory evidence is considered to be the primary source of choice errors and the accumulation of evidence needed to overcome this noise gives rise to speed-accuracy tradeoffs. Here, we investigated how the history of recent choices and their outcomes interacts with these processes using a combination of theory and experiment. We found that the speed and accuracy of performance of rats on olfactory decision tasks could be best explained by a Bayesian model that combines reinforcement-based learning with accumulation of uncertain sensory evidence. This model predicted the specific pattern of trial history effects that were found in the data. The results suggest that learning is a critical factor contributing to speed-accuracy tradeoffs in decision-making and that task history effects are not simply biases but rather the signatures of an optimal learning strategy.

neuroscience↗

bioRxiv2017

The Long and the Short of Serotonergic Stimulation: Optogenetic activation of dorsal raphe serotonergic neurons changes the learning rate for rewards

Serotonin plays an influential, but computationally obscure, modulatory role in many aspects of normal and dysfunctional learning and cognition. Here, we studied the impact of optogenetic stimulation of dorsal raphe serotonin neurons in mice performing a non-stationary, reward-driven, foraging task. We report that activation of serotonin neurons significantly boosted learning rates for choices following long inter-trial-intervals that were driven by the recent history of reinforcement.

neuroscience↗

bioRxiv2017

Activation of serotonin neurons promotes active exploitation in a probabilistic foraging task

The neuromodulator serotonin (5-HT) has been implicated in a variety of functions that involve patience or impulse control. For example, activation of 5-HT neurons promotes waiting for delayed rewards. Many of these effects are consistent with a long-standing theory that 5-HT promotes behavioral inhibition, a motivational bias favoring passive over active behaviors. To further test this idea, we studied the impact of 5-HT in a probabilistic foraging task, in which mice must learn the statistics of the environment and infer when to leave a depleted foraging site for the next. Critically, mice were required to actively nose poke in order to exploit a given site. We found that optogenetic activation of 5-HT neurons in the dorsal raphe nucleus increased the willingness of mice to actively attempt to exploit a reward site before giving up. These results indicate that behavioral inhibition is not an adequate description of 5-HT function and suggest that a unified account must be based on a higher-order function.

neuroscience↗

bioRxiv2016

Distinct sources of deterministic and stochastic components of action timing decisions in rodent frontal cortex

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.

neuroscience↗