We are interested in understanding the principles underlying the complex adaptive behavior of organisms. Starting with quantitative observations of animal behavior, we aim to integrate quantitative cellular and systems level experimental analysis of underlying neural mechanisms with theoretical, ecological and evolutionary contexts. Rats and mice provide flexible animal models that allow us monitor and manipulate neural circuits using electrophysiological, optical and molecular techniques. We have made progress using highly-controlled studies of a simple learned odor-cued decision task and are extending our focus toward more complex behaviors. Projects in the lab are wide-ranging and continually evolving. Current topics include (i) olfactory sensory decision-making, (ii) the function of the serotonin system, (iii) the role of uncertainty in brain function and behavior. 

Watch a recent video about Mainen’s Lab research. 

Optogenetic identification and control of serotonin neurons in behaving animals

Serotonin is an important neurotransmitter implicated in a wide variety of physiological functions and pathophysiologies but whose function is not well understood. Critically, very little is known about the activity of serotonin-releasing neurons in the brain. This problem is greatly exacerbated by the difficulty in their identification during physiological recordings. To address these problems we are using a combination of behavioral analysis, electrophysiological recording and optical-genetic probes targeted through specific promoters to this class of cells. By selectively activating serotonin neurons with light delivered through implanted fiber optics, we will be able to positively identify them during recordings and to specifically activate them, allowing us to test specific hypotheses concerning the role of serotonin in brain function and behavior.

Funding: ERC

Olfactory objects and decisions: From psychophysics to neural computation

Object recognition is an important and difficult problem solved by the nervous system. Although visual recognition is far more familiar to us, it is through the chemical senses that object recognition occurs for most organisms. Neural computations within the olfactory system enable faithful recognition and tracking of meaningful odor sources, even when they comprise complex chemical blends embedded in a sea of background odors. The overall aim of this line of work is to understand the neural computations that make olfactory object recognition possible. According to theoretical accounts, object recognition can be understood as a process of probabilistic inference. Under this hypothesis, complex odor stimuli are represented using a probabilistic population code and processed in a Bayesian optimal fashion by the nervous system. To link these normative ideas to specific neurophysiological and behavioral predictions, we are formalizing them using computational models. Experimentally, our main goal is to monitor and perturb object representations in the functioning, computing brain. To this end, we deploy psychophysical tasks in rats which formalize complex real-world olfactory problems and also allow us to operationalize cognitive processes such as attention and memory. By combining such quantitative paradigms with large-scale neural ensemble recordings in the olfactory cortex, we can study how populations of neurons encode and process complex odor scenes, attempt to account for behavioral performance, and test the predictions of theoretical models. At the level of neural circuits and their physiology, we are particularly interested in the origin of neuronal variability, the nature of inter-neuronal correlations, the properties of inter-areal brain communication and the action of neuromodulators.

Colaborators: Alex Pouget (U. Rochester), Matthieu Luis (CRG, Barcelona)

Funding: HFSP

Evaluating the reliability of knowledge: Neural mechanisms of confidence estimation

Humans and other animals must often make decisions on the basis of imperfect evidence. What is the neural basis for such judgments? How does the brain compute confidence estimates about predictions, memories and judgments? Previously, we found that a population of neurons in the orbitofrontal cortex (OFC) tracks the confidence in decision outcomes. We are seeking to extend these observations by testing whether confidence-related neural activity in the OFC is causally related to confidence judgments. We are also addressing how the uncertainty about a stimulus in the course of decision-making is computed in olfactory sensory cortex. These experiments will give us further insights into the nature of the neural processes underlying confidence estimation.

Colaborators: Adam Kepecs (CSHL)

Frontal cortex and the control of impulsive action

Inhibition of behaviour is as important as its generation, and failure to inhibit inappropriate actions—impulsivity—is a central feature of pathologies including attention deficit hyperactivity disorder, drug addiction and obsessive compulsive disorder. Previous work has identified the frontal cortex as a central component in the control of inhibiting impulsive actions. The goal of this project is to understand how this brain area performs this function. Two current specific aims are to reveal the activity of frontal cortical neurons while rats are engaged in impulse control task and to examine the effect of inactivating subregions of frontal cortex on impulse control behavior. Recording from large ensembles of neurons in the medial prefrontal cortex (mPFC) and the secondary motor cortex (M2) of rats during performance of the impulse control task allows us to characterize in detail the neural activity in these areas in relationship to behavior. We find that the activity of subpopulations of mPFC and M2 neurons predict the impulse control performance of rats on a trial-by-trial basis. Preliminary results show that reversible inactivation of the mPFC also impairs the ability of rats to inhibit impulsive action. We are now seeking to understand in more detail the nature of the neural representations underlying impulse control.

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

Biography

Ana Fonseca
2008 INDP PhD Student
rita.fonseca@neuro.fchampalimaud.org

Ana Nunes, PhD
Lab Manager
ana.nunes@neuro.fchampalimaud.org

André Mendonça
2008 INDP PhD Student
andre.mendonca@neuro.fchampalimaud.org

Artur Silva
Programmer
artur.silva@neuro.fchampalimaud.org

Bassam Atallah, PhD
Postdoctoral Fellow
bassam.atallah@neuro.fchampalimaud.org

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

Dhruba Banerjee
PhD Student
dhruba.banerjee@neuro.fchampalimaud.org

Eran Lottem, PhD
Postdoctoral Fellow
eran.lottem@neuro.fchampalimaud.org

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

Eva Kobak, PhD
Postdoctoral Fellow
eva.kobak@neuro.fchampalimaud.org

Filipe Carvalho
Hardware Developer
filipe.carvalho@neuro.fchampalimaud.org

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

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

Maria Vicente
2007 INDP PhD Student
maria.vicente@neuro.fchampalimaud.org

Masayoshi Murakami, PhD
Postdoctoral Fellow
masayoshi.murakami@neuro.fchampalimaud.org

Niccolò Bonacchi
2009 INDP PhD Student
niccolo.bonacchi@neuro.fchampalimaud.org

Patrícia Correia
2007 INDP PhD Student
patricia.correia@neuro.fchampalimaud.org

Paul Bush, PhD
Visiting Faculty
paul.bush@neuro.fchampalimaud.org

Rita Venturini, PhD
Visiting Faculty
rita.venturini@neuro.fchampalimaud.org

Samuel Viana
PhD Student
samuel.viana@neuro.fchampalimaud.org

Sara Matias
MIT PhD Student
sara.matias@neuro.fchampalimaud.org

Madalena S. Fonseca, Masayoshi Murakami, Zachary F. Mainen (2015) Activation of Dorsal Raphe Serotonergic Neurons Promotes Waiting but Is Not Reinforcing Curr. Biol. , In Press. (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. , [Epub ahead of print] (doi:10.1038/nn.3826)

Armin Lak, Gil M. Costa, Erin Romberg, Alexei A. Koulakov, Zachary F. Mainen, Adam Kepecs (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)

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) Spatial goal representations in 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