Hippocampus-Dependent Goal Localization by Head-Fixed Mice in Virtual Reality

Abstract The demonstration of the ability of rodents to navigate in virtual reality (VR) has made it an important behavioral paradigm for studying spatially modulated neuronal activity in these animals. However, their behavior in such simulated environments remains poorly understood. Here, we show that encoding and retrieval of goal location memory in mice head-fixed in VR depends on the postsynaptic scaffolding protein Shank2 and the dorsal hippocampus. In our newly developed virtual cued goal location task, a head-fixed mouse moves from one end of a virtual linear track to seek rewards given at a target location along the track. The mouse needs to visually recognize the target location and stay there for a short period of time to receive the reward. Transient pharmacological blockade of fast glutamatergic synaptic transmission in the dorsal hippocampus dramatically and reversibly impaired performance of this task. Encoding and updating of virtual cued goal location memory was impaired in mice deficient in the postsynaptic scaffolding protein Shank2, a mouse model of autism that exhibits impaired spatial learning in a real environment. These results highlight the crucial roles of the dorsal hippocampus and postsynaptic protein complexes in spatial learning and navigation in VR.

[1]  R M Douglas,et al.  Visual memory task for rats reveals an essential role for hippocampus and perirhinal cortex. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Jeffrey D. Zaremba,et al.  Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding , 2016, Neuron.

[3]  Howard Eichenbaum,et al.  Learning Causes Reorganization of Neuronal Firing Patterns to Represent Related Experiences within a Hippocampal Schema , 2013, The Journal of Neuroscience.

[4]  Mayank R. Mehta,et al.  Multisensory Control of Multimodal Behavior: Do the Legs Know What the Tongue Is Doing? , 2013, PloS one.

[5]  H. Eichenbaum,et al.  Evolution of declarative memory , 2006, Hippocampus.

[6]  Lin Tian,et al.  Functional imaging of hippocampal place cells at cellular resolution during virtual navigation , 2010, Nature Neuroscience.

[7]  J. O’Keefe,et al.  Neuronal computations underlying the firing of place cells and their role in navigation , 1996, Hippocampus.

[8]  Masaaki Sato,et al.  Generation and Imaging of Transgenic Mice that Express G-CaMP7 under a Tetracycline Response Element , 2015, PloS one.

[9]  B. Strowbridge,et al.  Visual landmarks facilitate rodent spatial navigation in virtual reality environments. , 2012, Learning & memory.

[10]  J. Tiago Gonçalves,et al.  Circuit level defects in the developing neocortex of fragile X mice , 2013, Nature Neuroscience.

[11]  Hongkui Zeng,et al.  A Cre-Dependent GCaMP3 Reporter Mouse for Neuronal Imaging In Vivo , 2012, The Journal of Neuroscience.

[12]  E. Save,et al.  Coding for spatial goals in the prelimbic/infralimbic area of the rat frontal cortex. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Bockmann,et al.  Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3′ untranslated region of Shank1 mRNA , 2004, Molecular and Cellular Neuroscience.

[14]  Vikaas S. Sohal,et al.  Putative Microcircuit-Level Substrates for Attention Are Disrupted in Mouse Models of Autism , 2016, Biological Psychiatry.

[15]  M. Stryker,et al.  Distinctive Features of Adult Ocular Dominance Plasticity , 2008, The Journal of Neuroscience.

[16]  Sachin S. Deshmukh,et al.  Influence of local objects on hippocampal representations: Landmark vectors and memory , 2013, Hippocampus.

[17]  S. Commins,et al.  Hippocampal contribution to vector model hypothesis during cue-dependent navigation. , 2013, Learning & memory.

[18]  H. Eichenbaum,et al.  The Hippocampus, Memory, and Place Cells Is It Spatial Memory or a Memory Space? , 1999, Neuron.

[19]  J. O’Neill,et al.  The reorganization and reactivation of hippocampal maps predict spatial memory performance , 2010, Nature Neuroscience.

[20]  E. Tolman.  Cognitive maps in rats and men. , 1948, Psychological review.

[21]  H. Eichenbaum,et al.  Robust Conjunctive Item–Place Coding by Hippocampal Neurons Parallels Learning What Happens Where , 2009, The Journal of Neuroscience.

[22]  Mayank R. Mehta,et al.  Multisensory Control of Hippocampal Spatiotemporal Selectivity , 2013, Science.

[23]  M. Sheng,et al.  The Shank family of scaffold proteins. , 2000, Journal of cell science.

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

[25]  Min Goo Lee,et al.  Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function , 2012, Nature.

[26]  Menno P. Witter,et al.  Place Cells and Place Recognition Maintained by Direct Entorhinal-Hippocampal Circuitry , 2002, Science.

[27]  R. Passingham.  The hippocampus as a cognitive map J. O'Keefe & L. Nadel, Oxford University Press, Oxford (1978). 570 pp., £25.00 , 1979, Neuroscience.

[28]  Anirvan Ghosh,et al.  Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. , 2012, Trends in pharmacological sciences.

[29]  Daniel A. Dombeck,et al.  Calcium transient prevalence across the dendritic arbor predicts place field properties , 2014, Nature.

[30]  S. Molden,et al.  Accumulation of Hippocampal Place Fields at the Goal Location in an Annular Watermaze Task , 2001, The Journal of Neuroscience.

[31]  Michael B. Reiser,et al.  Real neuroscience in virtual worlds , 2012, Current Opinion in Neurobiology.

[32]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[33]  Frances S. Chance,et al.  Erratum: Orthogonal micro-organization of orientation and spatial frequency in primate primary visual cortex , 2013, Nature Neuroscience.

[34]  Georg B. Keller,et al.  Learning Enhances Sensory and Multiple Non-sensory Representations in Primary Visual Cortex , 2015, Neuron.

[35]  M. Stryker,et al.  Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a , 2010, Proceedings of the National Academy of Sciences.

[36]  Emilio Kropff,et al.  Place cells, grid cells, and the brain's spatial representation system. , 2008, Annual review of neuroscience.

[37]  Benjamin R. Arenkiel,et al.  Imaging Neural Activity Using Thy1-GCaMP Transgenic Mice , 2012, Neuron.

[38]  J. Knierim,et al.  Hippocampal place cells: Parallel input streams, subregional processing, and implications for episodic memory , 2006, Hippocampus.

[39]  A Schnee,et al.  Rats are able to navigate in virtual environments , 2005, Journal of Experimental Biology.

[40]  Brad E. Pfeiffer,et al.  Hippocampal place cell sequences depict future paths to remembered goals , 2013, Nature.

[41]  Inah Lee,et al.  The hippocampus is required for visually cued contextual response selection, but not for visual discrimination of contexts , 2012, Front. Behav. Neurosci..

[42]  Conor Liston,et al.  Projections from neocortex mediate top-down control of memory retrieval , 2015, Nature.

[43]  M. Ehlers,et al.  Modeling Autism by SHANK Gene Mutations in Mice , 2013, Neuron.

[44]  M. Moser,et al.  Impaired Recognition of the Goal Location during Spatial Navigation in Rats with Hippocampal Lesions , 2001, The Journal of Neuroscience.

[45]  Howard Eichenbaum,et al.  A cognitive map for object memory in the hippocampus. , 2009, Learning & memory.

[46]  M. Fyhn,et al.  Hippocampal Neurons Responding to First-Time Dislocation of a Target Object , 2002, Neuron.

[47]  Jiangteng Lu,et al.  MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex , 2015, Proceedings of the National Academy of Sciences.

[48]  Bruno Poucet,et al.  Goal-Related Activity in Hippocampal Place Cells , 2007, The Journal of Neuroscience.

[49]  S. J. Martin,et al.  Reversible neural inactivation reveals hippocampal participation in several memory processes , 1999, Nature Neuroscience.

[50]  Ute Moog,et al.  Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation , 2010, Nature Genetics.

[51]  Huilin Li,et al.  The Postsynaptic Density Proteins Homer and Shank Form a Polymeric Network Structure , 2009, Cell.

[52]  John A. King,et al.  How vision and movement combine in the hippocampal place code , 2012, Proceedings of the National Academy of Sciences.

[53]  Michael E. Hasselmo,et al.  A hierarchical model of goal directed navigation selects trajectories in a visual environment , 2015, Neurobiology of Learning and Memory.

[54]  Philippe Gaussier,et al.  The hippocampo-cortical loop: Spatio-temporal learning and goal-oriented planning in navigation , 2013, Neural Networks.

[55]  J. O'Keefe,et al.  The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. , 1971, Brain research.