Via Ca 2+ -imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, for each day the ensemble representation of this environment involved a unique subset of cells. Yet, cells within the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.CA1 place cells are considered crucial for spatial memory, but data is limited regarding whether their representations of space evolve over time scales of weeks or more 1 . Some theories suggest place cells should retain stable place fields for long-term retention of familiar environments 1 . Alternatively, dynamic aspects of place coding may facilitate distinct memory traces of different events occurring in the same environment 2 .Due to technical limitations, it has been only partially explored if CA1 representations of familiar environments are stable or evolve over time. Electrical recordings from many tens of cells are feasible 3 , but it is challenging to record from the same cells longer than a few days. Data on place fields' stability has largely been from small numbers of cells recorded over at most a week [4][5][6][7][8][9][10] . These studies have demonstrated cells with stable place fields, but the data have been too sparse to assess how coding evolves at the ensemble level.To study long-term coding dynamics, we combined (Fig. 1a): a viral vector (AAV2/5-CamKIIα-GCaMP3) to express the Ca 2+ -indicator GCaMP3 11 in pyramidal cells; a chronic mouse preparation for time-lapse imaging of CA1 over weeks 12 ; and a miniaturized (<2 g) microscope for Ca 2+ -imaging in hundreds of cells in freely behaving mice 13 . We thereby tracked somatic Ca 2+ dynamics of 515-1040 pyramidal cells in individual mice as they repeatedly visited a familiar track over 45 days.

The brain’s ability to associate different stimuli is vital to long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala (BLA) encode associations between conditioned and unconditioned stimuli (CS, US). Using a miniature fluorescence microscope, we tracked BLA ensemble neural Ca2+ dynamics during fear learning and extinction over six days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning and reshaped the CS ensemble neural representation to gain similarity to the US-representation. During extinction training with repetitive CS presentations, the CS-representation became more distinctive without reverting to its original form. Throughout, the strength of the ensemble-encoded CS-US association predicted each mouse’s level of behavioral conditioning. These findings support a supervised learning model in which activation of the US-representation guides the transformation of the CS-representation.

Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions, but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory.

Fluorescence Ca2+ imaging enables large-scale recordings of neural activity, but collective dynamics across mammalian brain regions are generally inaccessible within single fields of view. Here we introduce a two-photon microscope possessing two articulated arms that can simultaneously image two brain areas (~0.38 mm2 each), either nearby or distal, using microendoscopes. Concurrent Ca2+ imaging of ~100–300 neurons in primary visual cortex (V1) and lateromedial (LM) visual area in behaving mice revealed that the variability in LM neurons’ visual responses was strongly dependent on that in V1, suggesting that fluctuations in sensory responses propagate through extended cortical networks.

Entorhinal-hippocampal circuits in the mammalian brain are crucial for an animal's spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca 2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope. We found that both oceans and islands contain grid cells in similar proportions, but island cell activity, including activity in a proportion of grid cells, is significantly more speed modulated than ocean cell activity. We speculate that this differential property reflects island cells' and ocean cells' contribution to different downstream functions: island cells may contribute more to spatial path integration, whereas ocean cells may facilitate contextual representation in downstream circuits.speed | grid cell | calcium imaging | entorhinal | hippocampus

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The convergence of internal path integration with sensory information from external landmarks generates a cognitive spatial map in the hippocampus. We have recorded the activity of cells in CA1 during a virtual navigation task to examine how mice represent, recognize and employ sparse olfactory landmarks to estimate their location. We observe that the presence of odor landmarks at multiple locations in a virtual environment greatly enriches the place cell representation and dramatically improves navigation. Presentation of the same odor at different locations generates distinct place cell representations, indicating that path integration can disambiguate two identical cues on the basis of location. The enhanced place cell representation at one cue location led to the formation of place cells at locations beyond that cue and, ultimately recognition of a second odor cue as a distinct landmark. This suggests an iterative mechanism for extending place cell representations into unknown territory.These results reveal how odor cues can serve as landmarks to guide navigation and suggest a model to explain how the convergence of landmarks and path integration participates in an iterative process that generates a cognitive spatial map.Fischler, et al. 3Hippocampal representations of an animal's environment reflect both external sensory landmarks and internal path integration of the animal's movement in space 1 .These two sources of a cognitive spatial map, path integration and landmarks, are mutually dependent 2-7 . Path integration uses idiothetic signals generated by self-motion to define an organism's position relative to fixed points or landmarks [8][9][10] . Such landmarks are valuable only if they are recognized as fixed in space, and this determination may require path integration 11 . Sensory landmarks and internal path integration signals are likely to converge in the hippocampus. We examined hippocampal activity in mice performing a navigational task that relies solely on path integration and sparse olfactory cues. These observations provide a new model that explains how the convergence of sensory and idiothetic signals drive the development of a hippocampal spatial map. Our results suggest that the extension of a spatial map into previously unexplored territory is an iterative process in which path integration from existing landmarks identifies new landmarks that then provide a basis for further path integration.Olfactory cues are a primary source of sensory information in mice and can serve as landmarks when fixed in space. The hippocampus receives olfactory information from the lateral entorhinal cortex (LEC) [12][13][14][15] . The LEC receives input directly from the olfactory bulb and piriform cortex 16,17 , two structures that encode odor identity.The influence of odors on hippocampal activity has been shown in both spatial and nonspatial contexts 18-21 . Grid 22 , head direction 23 , boundary 24 , and speed cells 25 in the medial entorhinal cortex (MEC) 26 provide information to the hippocampus about locat...

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