We do not perceive the world directly. Rather, our brains must decipher what is out there using the window of information we receive from our senses. The result of this process is referred to as a ‘model’ of the world. Understanding how brains construct and use internal models is a central problem in neuroscience. This problem can be approached by thinking of the brain as a kind of an intuitive scientist, collecting and analysing data, constructing and testing hypotheses based on those data, and revising them in light of new data. Each brain gets different data and produces a different model, making the beliefs that guide our actions subjective and sometimes wrong. Fortunately, like a good scientist, our brains can and do evaluate the quality of the data. This gives us a sense of confidence in our beliefs and decisions, helping us to know when our subjective reality is worth acting on and when to question it. Understanding how all this works in terms of neural circuits is the long-term goal of research in the Systems Neuroscience lab. 

Modulation of cortical circuits and predictive neural coding by serotonin

Serotonin (5-HT) is a central neuromodulator implicated in the regulation of many processes and one of the most important targets for psychoactive drugs. It profoundly impacts decision-making and its dysregulation can contribute to altered perception as well as pathological conditions such as depression, anxiety or obsessive-compulsive disorders. Yet 5-HT’s function is not well understood, hence impeding progress towards better treatments. The broad aim of this work is to understand the involvement of 5-HT in decision-making under conditions of uncertainty. Uncertainty arises whenever partial, ambiguous, or contradictory information is present, a common occurrence in real-world situations. We propose that 5-HT neurons respond to increases in uncertainty caused by unexpected events. . Such effects are hypothesized to modulate behavior at various time-scales. At an immediate time-scale, 5-HT release may promote persistence into ongoing behaviors when outcomes are uncertain. At longer time scales, it may increase behavioral flexibility in response to changes in the environment. Mechanistically, the control exerted by 5HT over these process may be mediated by its ability to modulate the neural representation of prior expectations at different levels of the brain hierarchy. Additionally, to complement our study of 5-HT and uncertainty at the circuit and brain-wide level, we also investigate the inputs and outputs of 5-HT neurons that allow them to exert their behavioral effects.

Funding: ERC

Odors and memory: neural mechanisms for encoding contextual information in olfactory cortex

Olfaction is dynamic and highly associative, and environmental contexts heavily influence olfactory experiences. In addition to odor discrimination, knowing what you have experienced before (odor recognition) is also critical for animals. Despite this, few studies have examined the neural basis for associative features of olfaction and its neuronal bases are poorly understood. We aim to bridge the gap between theory and neurophysiology to provide a mechanism for the encoding of context in olfaction. We use technologies developed in psychophysics, neurophysiology, molecular biology and computational neuroscience to examine interactions between olfactory cortex and the navigational memory system (hippocampus) in a novel spatial context-dependent odor discrimination task. We hypothesize that odor contexts are encoded in olfactory cortex and driven by feedback hippocampal inputs. If successful, we will identify fundamental principles governing holistic sensory percepts in the brain.

Funding: FCT

Cognitive flexibility, cortical excitability and antidepressive effect of psilocybin

Serotonin (5-HT) is a neuromodulator implicated in the regulation of cognitive and behavioural processes, including cognitive flexibility. Conversely, manipulation of 5-HT circuits is a major tool in treatment of depression. Psilocybin, a 5-HT2A agonist, has recently been proposed to have fast and long-lasting antidepressant properties. It is thought to modify cortical excitability, which is altered in depression and modified by antidepressant treatment, namely repetitive transcranial magnetic stimulation. With this project we aim to (i) compare cognitive flexibility and cortical excitability between healthy subjects and depressed patients, (ii) assess antidepressant effects of psilocybin in depressed patients, as well as its impact on cognitive flexibility and cortical excitability and (iii) measure if potential impact of psilocybin on cognitive flexibility and cortical excitability is predictive of its antidepressant effects.

Colaborators: Albino Oliveira Maia

Funding: FCT

Spatial Attention: dissecting the cortical and subcortical circuitry during rapid routing of sensory information

We are constantly inundated with a barrage of sensory information. In an instant, however, a tiny critical fraction of this sensory world is relevant for taking action. Our brains must select out the critical input and use it to guide behavioural response. We often call this selection process attention. Critically, from a human health perspective, deficits in attention is a common characteristic of both neurological (Alzheimer’s & Parkinson’s disease) and neuropsychiatric disorders (ADHD & schizophrenia). It is imperative that we elucidate the fundamental neuroscience underlying the critical function. We aim to understand the neural basis for the modulation of sensory processing by visual spatial attention. By developing the first spatial attention task in the genetically mouse model will will dissect the underlying cortical & subcortical circuitry, and reveal new fundamental principles controlling rapid changes sensory information processing in the brain.

Funding: FCT

The International Brain Laboratory: brain-wide circuits for decision-making

Understanding how the brain works is one of science’s greatest challenges. The key obstacle when attacking this challenge is that we do not understand how neural systems work together to support adaptive behavior. Adaptive behavior requires processing sensory information with focused attention, reaching decisions, acting, and learning from the results of those actions. These require the brain to combine a vast array of information from prior experience, current sensory stimuli, and internal and environmental contexts. These computations involve dynamic interactions between millions of neurons within local circuits and across many brain regions. Understanding these processes is a problem with a scale and complexity that far exceed what can be tackled by any single laboratory and that demands computational theory to be interwoven with experimental design and analysis in a manner not yet achieved. To overcome these challenges, a virtual laboratory has been created, unifying a group of 21 highly experienced neuroscience groups distributed across the world.

Colaborators: https://www.internationalbrainlab.com/

Funding: Wellcome Trust, Simons Foundation, INCF

Zachary Mainen, PhD
Principal Investigator
zmainen@neuro.fchampalimaud.org

Biography

Beatriz Godinho
Research Assistant
beatriz.godinho@research.fchampalimaud.org

Catarina Pimentel, PhD
Lab Manager
catarina.pimentel@research.fchampalimaud.org

Cindy Poo, PhD
Postdoctoral Researcher
cindy.poo@neuro.fchampalimaud.org

Dario Sarra
2016 INDP PhD Student
dario.sarra@neuro.fchampalimaud.org

Eleni Smaragdi
Technician
eleni.smaradgi@research.fchampalimaud.org

Eric Dewitt, PhD
Postdoctoral Researcher
eric.dewitt@neuro.fchampalimaud.org

Fanny Cazettes, PhD
Postdoctoral Researcher
fanny.cazettes@neuro.fchampalimaud.org

Gautam Agarwal, PhD
Postdoctoral Researcher
gautam.agarwal@neuro.fchampalimaud.org

Guido Meijer, PhD
Postdoctoral Researcher
guido.meijer@research.fchampalimaud.org

Hanne Stensola, PhD
Postdoctoral Researcher
hanne.stensola@neuro.fchampalimaud.org

Inês Laranjeira
Research Technician
ines.laranjeira@research.fchampalimaud.org

João Morais
Masters Student
joao.morais@research.fchampalimaud.org

José Miguel Teixeira
Research Technician
jose.teixeira@research.fchampalimaud.org

Julia Huntenburg, PhD
Postdoctoral Researcher
julia.huntenburg@research.fchampalimaud.org

Kcénia Bougrova
2017 INDP PhD Student
kcenia.bougrova@research.fchampalimaud.org

Lucas Soares
Masters Student
lucas.soares@research.fchampalimaud.org

Madalena Fonseca
2013 INDP PhD Student
madalena.fonseca@neuro.fchampalimaud.org

Margarida Duarte, PhD
Research Technician
margarida.duarte@neuro.fchampalimaud.org

Margarida Nunes
Lab Administrator
margarida.nunes@research.fchampalimaud.org

Mattia Bergomi, PhD
Postdoctoral Researcher
mattia.bergomi@neuro.fchampalimaud.org

Megha Patwa
Research Technician
megha.patwa@research.fchampalimaud.org

Niccolò Bonacchi, PhD
Postdoctoral Researcher
niccolo.bonacchi@neuro.fchampalimaud.org

Olivier Winter
Senior Technician
olivier.winter@research.fchampalimaud.org

Pietro Vertechi
2014 INDP PhD Student
pietro.vertechi@neuro.fchampalimaud.org

Romain Ligneul, PhD
Postdoctoral Researcher
romain.ligneul@research.fchampalimaud.org

Solène Sautory
2017 INDP PhD Student
solene.sautory@research.fchampalimaud.org

Tiago Quendera
2017 INDP PhD Student
tiago.quendera@neuro.fchampalimaud.org

Tor Stensola, PhD
Postdoctoral Researcher
tor.stensola@neuro.fchampalimaud.org

Drugowitsch J, Mendonça A, Mainen ZF, Pouget A (2019) Learning optimal decisions with confidence Proc Natl Acad Sci U S A 116 (49) (doi:10.1073/pnas.1906787116)

Pardo-Vazquez JL, Castiñeiras-de Saa JR, Valente M, Damião I, Costa T, Vicente MI, Mendonça AG, Mainen ZF, Renart A (2019) The mechanistic foundation of Weber's law Nat. Neurosci. 22 (9) (doi:10.1038/s41593-019-0439-7)

Rigato J, Rennie SM, Mainen ZF (2019) The overlooked ubiquity of first-person experience in the cognitive sciences Synthese (doi:https://doi.org/10.1007/s11229-019-02136-6)

Iigaya K, Fonseca MS, Murakami M, Mainen ZF, Dayan P (2018) An effect of serotonergic stimulation on learning rates for rewards apparent after long intertrial intervals Nat Commun 9 (1), 2477 (doi:10.1038/s41467-018-04840-2)

Lottem E, Banerjee D, Vertechi P, Sarra D, oude Lohuis M, Mainen ZF (2018) Activation of serotonin neurons promotes active persistence in a probabilistic foraging task Nat Commun (doi:10.1038/s41467-018-03438-y)

Correia, P. A., Matias, S.,p Mainen (2017) Stereotaxic Adeno-associated Virus Injection and Cannula Implantation in the Dorsal Raphe Nucleus of Mice Bio-protocol 7 (18), e2549 (doi:10.21769/BioProtoc.2549)

Murakami M, Shteingart H, Loewenstein Y, Mainen ZF (2017) Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex Neuron 94 (4), 908-919.e7 (doi:10.1016/j.neuron.2017.04.040)

Matias S, Lottem E, Dugué GP, Mainen ZF (2017) Activity patterns of serotonin neurons underlying cognitive flexibility eLife , pii: e20552 (doi:10.7554/eLife.20552)

Correia PA, Lottem E, Banerjee D, Machado AS, Carey MR, Mainen ZF (2017) Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons eLife , pii: e20975 (doi:10.7554/eLife.20975)

Kobak D, Brendel W, Constantinidis C, Feierstein CE, Kepecs A, Mainen ZF, Romo R, Qi XL, Uchida N, Machens CK. (2016) Demixed principal component analysis of neural population data eLife eLife 2016 (5), e10989 (doi:10.7554/eLife.10989)

Gomez-Marin A, Mainen ZF. (2016) Expanding perspectives on cognition in humans, animals, and machines Curr. Opin. Neurobiol. 37 , 85–91 (doi:10.1016/j.conb.2016.01.011)

Lottem E', Lörincz ML', Mainen ZF. (2016) Optogenetic Activation of Dorsal Raphe Serotonin Neurons Rapidly Inhibits Spontaneous But Not Odor-Evoked Activity in Olfactory Cortex. J. Neurosci. 36 (1), 7-18 (doi:10.1523/JNEUROSCI.3008-15.2016)

Meyniel F, Sigman M, Mainen ZF. (2015) Confidence as Bayesian Probability: From Neural Origins to Behavior Neuron 88 (1), 78–92 (doi:10.1016/j.neuron.2015.09.039)

Rigato J, Murakami M, Mainen Z (2015) Spontaneous Decisions and Free Will: Empirical Results and Philosophical Considerations. Cold Spring Harb Symp Quant Biol. (pii: 024810), Epub ahead of print] (doi:10.1101/sqb.2014.79.024810)

Bush PC, Mainen ZF (2015) Columnar architecture improves noise robustness in a model cortical network. PLoS ONE 10 (3), e0119072 (doi:10.1371/journal.pone.0119072)

Murakami M, Mainen ZF. (2015) Preparing and selecting actions with neural populations: toward cortical circuit mechanisms Curr. Opin. Neurobiol. 33 (C), 40–46 (doi:10.1016/j.conb.2015.01.005)

Fonseca MS, Murakami M, Mainen ZF. (2015) Activation of Dorsal Raphe Serotonergic Neurons Promotes Waiting but Is Not Reinforcing Curr. Biol. 25 (3), 306-315 (doi:10.1016/j.cub.2014.12.002)

Gomez-Marin A, Paton JJ, Kampff AR, Costa RM, Mainen ZF. (2014) Big behavioral data: psychology, ethology and the foundations of neuroscience Nat. Neurosci. (17), 1455–1462 (doi: 10.1038/nn.3812)

Murakami M, Vicente MI, Costa GM, Mainen ZF. (2014) Neural antecedents of self-initiated actions in secondary motor cortex Nat. Neurosci. 17 (11), 1455-62 (doi:10.1038/nn.3826)

Lak A, Costa GM, Romberg E, Koulakov AA, Mainen ZF, Kepecs A. (2014) Orbitofrontal Cortex Is Required for Optimal Waiting Based on Decision Confidence Neuron 84 (1), p190–201 (doi:10.1016/j.neuron.2014.08.039)

Dugué GP, Lörincz ML, Lottem E, Audero E, Matias S, Correia PA, Léna C, Mainen ZF. (2014) Optogenetic recruitment of dorsal raphe serotonergic neurons acutely decreases mechanosensory responsivity in behaving mice. PLoS ONE 9 (8), e105941 (doi:10.1371/journal.pone.0105941)

Zachary F. Mainen & Alexandre Pouget (2014) European Commission: Put brain project back on course Nature 511 (534) (doi:10.1038/511534b)

Tecuapetla F, Matias S, Dugue GP, Mainen ZF, Costa RM. (2014) Balanced activity in basal ganglia projection pathways is critical for contraversive movements Nat Commun (5), 4315 (doi: 10.1038/ncomms5315)

Joana Rigato, Masayoshi Murakami and Zachary Mainen (2014) Spontaneous Decisions and Free Will: Empirical Results and Philosophical Considerations Cold Spring Harb Symp Quant Biol. (79), 177-184 (doi:10.1101/sqb.2014.79.024810)

Rennie SM, Moita MM, Mainen ZF. (2013) Social cognition in the rodent: nothing to be sniffed at. Trends Cogn Sci. (doi:10.1016/j.tics.2013.04.011)

Zariwala HA, Kepecs A, Uchida N, Hirokawa J, Mainen ZF. (2013) The Limits of Deliberation in a Perceptual Decision Task. Neuron S0896-6273 (13), 00168-2 (doi:10.1016/j.neuron.2013.02.010)

Miura K, Mainen ZF, Uchida N (2012) Odor Representations in Olfactory Cortex: Distributed Rate Coding and Decorrelated Population Activity Neuron 74 (6), 1087-1098 (doi:10.1016/j.neuron.2012.04.021)

Kepecs A, Mainen ZF. (2012) A computational framework for the study of confidence in humans and animals. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 367 (1594), 1322-1337 (doi:10.1098/rstb.2012.0037)

Felsen G, Mainen ZF. (2012) Midbrain contributions to sensorimotor decision making. J. Neurophysiol. (doi:10.1152/jn.01181.2011)

Vicente MI, Mainen ZF (2011) Convergence in the piriform cortex. Neuron 70 (1), 1-2 (doi:10.1016/j.neuron.2011.03.019)

Vicente MI, Mainen ZF. (2011) Convergence in the piriform cortex. Neuron 70 (1), 1-2 (doi:10.1016/j.neuron.2011.03.019)

Feierstein CE, Mainen ZF (2010) Listening to the crowd: neuronal ensembles rule. Neuron 66 (3), 334-6 (doi:10.1016/j.neuron.2010.04.042)

Ranade SP, Mainen ZF (2009) Transient firing of dorsal raphe neurons encodes diverse and specific sensory, motor, and reward events. J. Neurophysiol. 102 , 3026-3037 (doi:10.1152/jn.00507.2009)

Quirk MC, Sosulski DL, Feierstein CE, Uchida N and Mainen ZF (2009) A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration. Front Syst Neurosci 3 (13) (doi:doi:10.3389/neuro.06.013.2009)

Dugué GP, Mainen ZF (2009) How serotonin gates olfactory information flow. Nat. Neurosci. 12 , 673-675 (doi:10.1038/nn0609-673)

Mainen ZF, Kepecs A (2009) Neural representation of behavioral outcomes in the orbitofrontal cortex. Curr. Opin. Neurobiol. 19 , 84-91 (doi:10.1016/j.conb.2009.03.010)

Vicente MI, Mainen ZF (2008) Towards an image of a memory trace. Front Neurosci 2 (2), 131-132 (doi:10.3389/neuro.01.041.2008)

Felsen G, Mainen ZF (2008) Neural substrates of sensory-guided locomotor decisions in the rat superior colliculus. Neuron 60 (1), 137-148 (doi:10.1016/j.neuron.2008.09.019)

Kepecs A, Uchida N, Zariwala HA, Mainen ZF (2008) Neural correlates, computation and behavioural impact of decision confidence. Nature 455 , 227-231 (doi:10.1038/nature07200)

Huber D, Petreanu L, Ghitani N, Ranade S, Hromádka T, Mainen Z, Svoboda K (2008) Sparse optical microstimulation in barrel cortex drives learned behaviour in freely moving mice. Nature 451 , 61-64 (doi:10.1038/nature06445)

Uchida N, Mainen ZF (2007) Odor concentration invariance by chemical ratio coding. Front Syst Neurosci 1 (3) (doi:10.3389/neuro.06.003.2007)

Mainen ZF (2007) The main olfactory bulb and innate behavior: different perspectives on an olfactory scene. Nat. Neurosci. 10 (12), 1511-1512 (doi:10.1038/nn1207-1511)

Xiao Yun, Donghwi Kim, Stanacevic M., Mainen ZF. (2007) Low-power high-resolution 32-channel neural recording system. Conf Proc IEEE Eng Med Biol Soc , 2373-2376 (doi:10.1109/IEMBS.2007.4352804)

Sato TR, Gray NW, Mainen ZF, Svoboda K (2007) The functional microarchitecture of the mouse barrel cortex. PLoS Biol. 5 (7), e189 (doi:10.1371/journal.pbio.0050189)

Kepecs AC, Uchida N, Mainen ZF (2007) Rapid and precise control of sniffing during olfactory discrimination in rats. J. Neurophysiol. 98 (1), 205-13 (doi:10.1152/jn.00071.2007.)

Gurden H, Uchida N, Mainen ZF (2006) Sensory-evoked intrinsic optical signals in the olfactory bulb are coupled to glutamate release and uptake. Neuron 52 (2), 335-345 (doi:10.1016/j.neuron.2006.07.022)

Feierstein CE, Quirk MC, Uchida N, Sosulski DL, Mainen ZF. (2006) Representation of spatial goals in rat orbitofrontal cortex Neuron 51 (4), 495-507 (doi:10.1016/j.neuron.2006.06.032)

Mainen ZF (2006) Behavioral analysis of olfactory coding and computation in rodents. Curr. Opin. Neurobiol. 16 , 429-423 (doi:10.1016/j.conb.2006.06.003)

Wilson R, Mainen ZF (2006) Early events in olfactory processing. Annu. Rev. Neurosci. 29 , 163-201 (doi:10.1146/annurev.neuro.29.051605.112950)

Uchida N, Kepecs A, Mainen ZF (2006) Seeing at a glance, smelling in a whiff: rapid forms of perceptual decision making. Nat. Rev. Neurosci. 7 , 485-491 (doi:10.1038/nrn1933)

Kepecs A, Uchida N, Mainen ZF (2006) The sniff as a unit of olfactory processing. Chem. Senses 31 , 167-79 (doi:10.1093/chemse/bjj016)

Egger V, Svoboda K, Mainen ZF (2005) Dendrodendritic synaptic signals in olfactory bulb granule cells: local spine boost and global low-threshold spike. J. Neurosci. 25 , 3521-30 (doi:10.1523/JNEUROSCI.4746-04.2005)

Uchida N, Mainen ZF (2003) Speed and accuracy of olfactory discrimination in the rat. Nat. Neurosci. 6 , 1224-1229 (doi:10.1038/nn1142)

Egger V, Svoboda K, Mainen ZF (2003) Mechanisms of lateral inhibition in the olfactory bulb: efficiency and modulation of spike-evoked calcium influx into granule cells. J. Neurosci. 23 (20), 7551-8

Malinow R, Mainen ZF, Hayashi Y (2000) LTP mechanisms: from silence to four-lane traffic. Curr. Opin. Neurobiol. 10 (3), 352-357 (doi:10.1016/S0959-4388(00)00099-4)

Maravall M, Mainen ZF, Sabatini BL, Svoboda K (2000) Estimating intracellular calcium concentrations and buffering without wavelength ratioing. Biophys. J. 78 (5), 2655-2667

Mainen ZF, Maletic-Savatic M, Shi SH, Hayashi Y, Malinow R, Svoboda K (1999) Two-photon imaging in living brain slices. Methods 18 (2), 231-239

Mainen ZF, Malinow R, Svoboda K (1999) Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399 (6732), 151-155 (doi:10.1038/20187)

Svoboda K, Mainen ZF (1999) Synaptic [Ca2+]: intracellular stores spill their guts. Neuron 22 (3), 427-430 (doi:10.1016/S0896-6273(00)80698-4)

Mainen ZF, Jia Z, Roder J, Malinow R (1998) Use-dependent AMPA receptor block in mice lacking GluR2 suggests postsynaptic site for LTP expression. Nat. Neurosci. 1 (7), 579-586 (doi:10.1038/2812)

Mainen ZF, Carnevale NT, Zador AM, Claiborne BJ, Brown TH (1996) Electrotonic architecture of hippocampal CA1 pyramidal neurons based on three-dimensional reconstructions. J. Neurophysiol. 76 (3), 1904-1923

Malinow R, Mainen ZF (1996) Long-term potentiation in the CA1 hippocampus. Science 271 (5255), 1604-1606

Mainen ZF, Sejnowski TJ (1996) Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382 (6589), 363-366 (doi:10.1038/382363a0)

Mainen ZF, Joerges J, Huguenard JR, Sejnowski TJ (1995) A model of spike initiation in neocortical pyramidal neurons. Neuron 15 (6), 1427-1439 (doi:doi:10.1016/0896-6273(95)90020-9)

Mainen ZF, Sejnowski TJ (1995) Reliability of spike timing in neocortical neurons. Science 268 (5216), 1503-1506 (doi:10.1126/science.7770778 )

Destexhe A, Mainen ZF, Sejnowski TJ (1994) Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism. J Comput Neurosci 1 (3), 195-230