High-throughput automatic training system for odor-based cognitive behaviors in head-fixed mice

Understanding neuronal mechanisms of cognitive behaviors requires efficient behavioral assays. We designed a high-throughput automatic training system (HATS) for olfactory behaviors in head-fixed mice. The hardware and software were constructed to enable automatic training with minimal human intervention. The integrated system was composed of customized 3D-printing supporting components, an odor-delivery unit with fast response, Arduino based hardware-controlling and data-acquisition unit. Furthermore, the customized software was designed to enable automatic training in all training phases, including lick-teaching, shaping, and learning. Using HATS, we trained mice to perform delayed non-match to sample (DNMS), delayed paired association (DPA), Go/No-go (GNG), and GNG reversal tasks. These tasks probed cognitive functions including sensory discrimination, working memory, decision making, and cognitive flexibility. Mice reached stable levels of performance within several days in the tasks. HATS enabled an experimenter to train eight mice simultaneously, therefore greatly enhanced the experimental efficiency. Combined with causal perturbation and activity recording techniques, HATS can greatly facilitate our understanding of the neural-circuitry mechanisms underlying cognitive behaviors.

[1]  George H. Denfield,et al.  Pupil Fluctuations Track Fast Switching of Cortical States during Quiet Wakefulness , 2014, Neuron.

[2]  D. Tank,et al.  Intracellular dynamics of hippocampal place cells during virtual navigation , 2009, Nature.

[3]  Adam Kepecs,et al.  Rapid and precise control of sniffing during olfactory discrimination in rats. , 2007, Journal of neurophysiology.

[4]  Jeffrey C. Erlich,et al.  A Cortical Substrate for Memory-Guided Orienting in the Rat , 2011, Neuron.

[5]  Brigitte L. Kieffer,et al.  New automated procedure to assess context recognition memory in mice , 2014, Psychopharmacology.

[6]  Adam Claridge‐Chang,et al.  The surveillance state of behavioral automation , 2012, Current Opinion in Neurobiology.

[7]  Yumiko Umino,et al.  A system to measure the pupil response to steady lights in freely behaving mice , 2016, Journal of Neuroscience Methods.

[8]  A. Baddeley Working memory: theories, models, and controversies. , 2012, Annual review of psychology.

[9]  Bingni W. Brunton,et al.  Rats and Humans Can Optimally Accumulate Evidence for Decision-Making , 2013, Science.

[10]  B. Ache,et al.  Olfaction: Diverse Species, Conserved Principles , 2005, Neuron.

[11]  D. McCormick,et al.  Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex , 2016, Nature Communications.

[12]  Andreas T. Schaefer,et al.  Two Distinct Channels of Olfactory Bulb Output , 2012, Neuron.

[13]  Emmeke Aarts,et al.  A 1-night operant learning task without food-restriction differentiates among mouse strains in an automated home-cage environment , 2015, Behavioural Brain Research.

[14]  Jeffry S. Isaacson,et al.  Cortical Feedback Control of Olfactory Bulb Circuits , 2012, Neuron.

[15]  Robert L. Heilbronner,et al.  The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe, Second Edition , 1989 .

[16]  Emmeke Aarts,et al.  The light spot test: Measuring anxiety in mice in an automated home-cage environment , 2015, Behavioural Brain Research.

[17]  Howard Eichenbaum,et al.  Olfactory Memory , 2009, Annals of the New York Academy of Sciences.

[18]  C R Gallistel,et al.  Automated, quantitative cognitive/behavioral screening of mice: for genetics, pharmacology, animal cognition and undergraduate instruction. , 2014, Journal of visualized experiments : JoVE.

[19]  Karel Svoboda,et al.  Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice , 2010, Nature.

[20]  Olaf Riess,et al.  Automated behavioral phenotyping reveals presymptomatic alterations in a SCA3 genetrap mouse model. , 2012, Journal of genetics and genomics = Yi chuan xue bao.

[21]  Joseph J. Paton,et al.  Big behavioral data: psychology, ethology and the foundations of neuroscience , 2014, Nature Neuroscience.

[22]  Z. Mainen,et al.  Speed and accuracy of olfactory discrimination in the rat , 2003, Nature Neuroscience.

[23]  Bingni W. Brunton,et al.  Distinct relationships of parietal and prefrontal cortices to evidence accumulation , 2014, Nature.

[24]  A. Pouget,et al.  Context- and Output Layer-Dependent Long-Term Ensemble Plasticity in a Sensory Circuit , 2017, Neuron.

[25]  Limei Ma,et al.  Automated Analyses of Innate Olfactory Behaviors in Rodents , 2014, PloS one.

[26]  J. Roughan,et al.  Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice , 2009, Laboratory animals.

[27]  J. White,et al.  Sniffing controls an adaptive filter of sensory input to the olfactory bulb , 2007, Nature Neuroscience.

[28]  Marion Mutter,et al.  Characterizing visual performance in mice: an objective and automated system based on the optokinetic reflex. , 2013, Behavioral neuroscience.

[29]  Burton M. Slotnick,et al.  Odor matching and odor memory in the rat , 1993, Physiology & Behavior.

[30]  Burton M. Slotnick,et al.  Olfactory learning and odor memory in the rat , 1991, Physiology & Behavior.

[31]  Takaki Komiyama,et al.  Broadcasting of cortical activity to the olfactory bulb. , 2015, Cell reports.

[32]  Russell G. Port,et al.  High-Throughput Automated Phenotyping of Two Genetic Mouse Models of Huntington's Disease , 2013, PLoS currents.

[33]  Thomas A. Cleland,et al.  Behavioral models of odor similarity. , 2002, Behavioral neuroscience.

[34]  D. Tank,et al.  Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice , 2007, Neuron.

[35]  David Kleinfeld,et al.  Hierarchy of orofacial rhythms revealed through whisking and breathing , 2013, Nature.

[36]  H. Seo,et al.  Neural basis of reinforcement learning and decision making. , 2012, Annual review of neuroscience.

[37]  R. Doty,et al.  Odor-guided behavior in mammals , 1986, Experientia.

[38]  Thomas Serre,et al.  Automated home-cage behavioural phenotyping of mice. , 2010, Nature communications.

[39]  B. Roth,et al.  Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand , 2007, Proceedings of the National Academy of Sciences.

[40]  J. Fuster The Prefrontal Cortex , 1997 .

[41]  David Kleinfeld,et al.  Sniffing and whisking in rodents , 2012, Current Opinion in Neurobiology.

[42]  S. Hyman,et al.  Animal models of neuropsychiatric disorders , 2010, Nature Neuroscience.

[43]  O. Feinerman,et al.  Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment , 2013, Nature Communications.

[44]  A. Gelperin,et al.  Speed-Accuracy Tradeoff in Olfaction , 2006, Neuron.

[45]  Matthew C Smear,et al.  Precise olfactory responses tile the sniff cycle , 2011, Nature Neuroscience.

[46]  J. Gold,et al.  The neural basis of decision making. , 2007, Annual review of neuroscience.

[47]  Wenjun Yan,et al.  Medial prefrontal activity during delay period contributes to learning of a working memory task , 2014, Science.

[48]  J. Langlois,et al.  An olfactory discrimination procedure for mice. , 2000, Journal of the experimental analysis of behavior.

[49]  K. Deisseroth,et al.  Engineering Approaches to Illuminating Brain Structure and Dynamics , 2013, Neuron.

[50]  Jutta Kretzberg,et al.  OMR-Arena: Automated Measurement and Stimulation System to Determine Mouse Visual Thresholds Based on Optomotor Responses , 2013, PloS one.

[51]  Joseph E. LeDoux,et al.  A robust automated method to analyze rodent motion during fear conditioning , 2007, Neuropharmacology.

[52]  Martin Vinck,et al.  Arousal and Locomotion Make Distinct Contributions to Cortical Activity Patterns and Visual Encoding , 2014, Neuron.

[53]  Lin Tian,et al.  Activity in motor-sensory projections reveals distributed coding in somatosensation , 2012, Nature.

[54]  Andreas T. Schaefer,et al.  Maintaining Accuracy at the Expense of Speed Stimulus Similarity Defines Odor Discrimination Time in Mice , 2004, Neuron.

[55]  Neil A. Macmillan,et al.  Detection Theory: A User's Guide , 1991 .

[56]  D J Davis,et al.  A rapid automatic technique for generating operant key-press behavior in rats. , 1971, Journal of the experimental analysis of behavior.

[57]  Lisa M. Saksida,et al.  A touch screen-automated cognitive test battery reveals impaired attention, memory abnormalities, and increased response inhibition in the TgCRND8 mouse model of Alzheimer's disease , 2013, Neurobiology of Aging.

[58]  A. Grinvald,et al.  Optical mapping of electrical activity in rat somatosensory and visual cortex , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[59]  J. Wallis,et al.  Neuroscience of Rule-Guided Behavior , 2007 .

[60]  Joseph H. Solomon,et al.  Biomechanical models for radial distance determination by the rat vibrissal system. , 2007, Journal of neurophysiology.

[61]  M. Laska,et al.  A two-choice discrimination method to assess olfactory performance in pigtailed macaques, Macaca nemestrina , 2001, Physiology & Behavior.

[62]  Tatiana M Kazdoba,et al.  Automated evaluation of sensitivity to foot shock in mice: inbred strain differences and pharmacological validation , 2007, Behavioural pharmacology.

[63]  Alan Carleton,et al.  Similar Odor Discrimination Behavior in Head-Restrained and Freely Moving Mice , 2012, PloS one.

[64]  April M. Becker,et al.  An automated task for the training and assessment of distal forelimb function in a mouse model of ischemic stroke , 2016, Journal of Neuroscience Methods.

[65]  M. Dubocovich,et al.  Automated video analysis system reveals distinct diurnal behaviors in C57BL/6 and C3H/HeN mice , 2013, Behavioural Brain Research.

[66]  J. C. Walker,et al.  Odor psychophysics in vertebrates , 1985, Neuroscience & Biobehavioral Reviews.

[67]  D. Cai,et al.  Behavioral Neuroscience , 2022 .

[68]  D. Wesson,et al.  The Olfactory Tubercle Encodes Odor Valence in Behaving Mice , 2015, The Journal of Neuroscience.

[69]  D. McCormick,et al.  Waking State: Rapid Variations Modulate Neural and Behavioral Responses , 2015, Neuron.

[70]  Hongkui Zeng,et al.  Olfactory cortical neurons read out a relative time code in the olfactory bulb , 2013, Nature Neuroscience.

[71]  A. Calvin Olfactory Discrimination. , 1960, Science.

[72]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[73]  Nathan P Cramer,et al.  Anticipatory activity of motor cortex in relation to rhythmic whisking. , 2006, Journal of neurophysiology.

[74]  T. Komiyama,et al.  Parvalbumin-Expressing Interneurons Linearly Control Olfactory Bulb Output , 2013, Neuron.

[75]  Risa Kawai,et al.  A Fully Automated High-Throughput Training System for Rodents , 2013, PloS one.

[76]  Nathan G. Clack,et al.  Vibrissa-Based Object Localization in Head-Fixed Mice , 2010, The Journal of Neuroscience.

[77]  P. Perona,et al.  utomated multi-day tracking of marked mice for the analysis of ocial behaviour , 2013 .

[78]  Detlef H. Heck,et al.  Minimally invasive highly precise monitoring of respiratory rhythm in the mouse using an epithelial temperature probe , 2016, Journal of Neuroscience Methods.

[79]  Takaki Komiyama,et al.  Balancing the Robustness and Efficiency of Odor Representations during Learning , 2016, Neuron.

[80]  Donald A Wilson,et al.  Olfactory perceptual stability and discrimination , 2008, Nature Neuroscience.

[81]  F. Baumgartner,et al.  What is "minimally invasive"? , 1998, The Annals of thoracic surgery.

[82]  Ryan M Carey,et al.  Rapid Encoding and Perception of Novel Odors in the Rat , 2008, PLoS biology.

[83]  David J. Anderson,et al.  Automated measurement of mouse social behaviors using depth sensing, video tracking, and machine learning , 2015, Proceedings of the National Academy of Sciences.

[84]  Zengcai V. Guo,et al.  Procedures for Behavioral Experiments in Head-Fixed Mice , 2014, PloS one.

[85]  J. Götz,et al.  Animal models of Alzheimer's disease and frontotemporal dementia , 2008, Nature Reviews Neuroscience.