Subicular neurons encode concave and convex geometries.

Animals in the natural world constantly encounter geometrically complex landscapes. Successful navigation requires that they understand geometric features of these landscapes, including boundaries, landmarks, corners and curved areas, all of which collectively define the geometry of the environment1-12. Crucial to the reconstruction of the geometric layout of natural environments are concave and convex features, such as corners and protrusions. However, the neural substrates that could underlie the perception of concavity and convexity in the environment remain elusive. Here we show that the dorsal subiculum contains neurons that encode corners across environmental geometries in an allocentric reference frame. Using longitudinal calcium imaging in freely behaving mice, we find that corner cells tune their activity to reflect the geometric properties of corners, including corner angles, wall height and the degree of wall intersection. A separate population of subicular neurons encode convex corners of both larger environments and discrete objects. Both corner cells are non-overlapping with the population of subicular neurons that encode environmental boundaries. Furthermore, corner cells that encode concave or convex corners generalize their activity such that they respond, respectively, to concave or convex curvatures within an environment. Together, our findings suggest that the subiculum contains the geometric information needed to reconstruct the shape and layout of naturalistic spatial environments.

Anatomical organization of temporally correlated neural calcium activity in the hippocampal CA1 region.

Hippocampal CA1 neuronal ensembles generate sequential patterns of firing activity that contribute to episodic memory formation and spatial cognition. Here we used in vivo calcium imaging to record neural ensemble activities in mouse hippocampal CA1 and identified CA1 excitatory neuron sub-populations whose members are active across the same second-long period of time. We identified groups of hippocampal neurons sharing temporally correlated neural calcium activity during behavioral exploration and found that they also organized as clusters in anatomical space. Such clusters vary in membership and activity dynamics with respect to movement in different environments, but also appear during immobility in the dark suggesting an internal dynamic. The strong covariance between dynamics and anatomical location within the CA1 sub-region reveals a previously unrecognized form of topographic representation in hippocampus that may guide generation of hippocampal sequences across time and therefore organize the content of episodic memory.

Rethinking retrosplenial cortex: Perspectives and predictions.

The last decade has produced exciting new ideas about retrosplenial cortex (RSC) and its role in integrating diverse inputs. Here, we review the diversity in forms of spatial and directional tuning of RSC activity, temporal organization of RSC activity, and features of RSC interconnectivity with other brain structures. We find that RSC anatomy and dynamics are more consistent with roles in multiple sensorimotor and cognitive processes than with any isolated function. However, two more generalized categories of function may best characterize roles for RSC in complex cognitive processes: (1) shifting and relating perspectives for spatial cognition and (2) prediction and error correction for current sensory states with internal representations of the environment. Both functions likely take advantage of RSC's capacity to encode conjunctions among sensory, motor, and spatial mapping information streams. Together, these functions provide the scaffold for intelligent actions, such as navigation, perspective taking, interaction with others, and error detection.

Degenerate mapping of environmental location presages deficits in object-location encoding and memory in the 5xFAD mouse model for Alzheimer's disease.

A key challenge in developing diagnosis and treatments for Alzheimer's disease (AD) is to detect abnormal network activity at as early a stage as possible. To date, behavioral and neurophysiological investigations in AD model mice have yet to conduct a longitudinal assessment of cellular pathology, memory deficits, and neurophysiological correlates of neuronal activity. We therefore examined the temporal relationships between pathology, neuronal activities and spatial representation of environments, as well as object location memory deficits across multiple stages of development in the 5xFAD mice model and compared these results to those observed in wild-type mice. We performed longitudinal in vivo calcium imaging with miniscope on hippocampal CA1 neurons in behaving mice. We find that 5xFAD mice show amyloid plaque accumulation, depressed neuronal calcium activity during immobile states, and degenerate and unreliable hippocampal neuron spatial tuning to environmental location at early stages by 4 months of age while their object location memory (OLM) is comparable to WT mice. By 8 months of age, 5xFAD mice show deficits of OLM, which are accompanied by progressive degradation of spatial encoding and, eventually, impaired CA1 neural tuning to object-location pairings. Furthermore, depressed neuronal activity and unreliable spatial encoding at early stage are correlated with impaired performance in OLM at 8-month-old. Our results indicate the close connection between impaired hippocampal tuning to object-location and the presence of OLM deficits. The results also highlight that depressed baseline firing rates in hippocampal neurons during immobile states and unreliable spatial representation precede object memory deficits and predict memory deficits at older age, suggesting potential early opportunities for AD detecting.

Linking global top-down views to first-person views in the brain.

Humans and other animals have a remarkable capacity to translate their position from one spatial frame of reference to another. The ability to seamlessly move between top-down and first-person views is important for navigation, memory formation, and other cognitive tasks. Evidence suggests that the medial temporal lobe and other cortical regions contribute to this function. To understand how a neural system might carry out these computations, we used variational autoencoders (VAEs) to reconstruct the first-person view from the top-down view of a robot simulation, and vice versa. Many latent variables in the VAEs had similar responses to those seen in neuron recordings, including location-specific activity, head direction tuning, and encoding of distance to local objects. Place-specific responses were prominent when reconstructing a first-person view from a top-down view, but head direction-specific responses were prominent when reconstructing a top-down view from a first-person view. In both cases, the model could recover from perturbations without retraining, but rather through remapping. These results could advance our understanding of how brain regions support viewpoint linkages and transformations.

Adaptive integration of self-motion and goals in posterior parietal cortex.

Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.

Cortical and hippocampal dynamics under logical fragmentation of environmental space.

Navigation is often constrained to pathways, and a recurring problem concerns whether to turn left or right when approaching an intersection. We examined this problem during T-maze performance in which the maze location in the recording environment varied over five-trial blocks and analyzed the associated positional firing patterns of hippocampal CA1 and posterior parietal cortex neurons. An arbitrary partitioning of the environmental space determined the left versus right turning rule for T-maze behavior. Under these conditions, rats learned the logical fragmentation of allocentric space into left turn and right turn sub-regions. Paradoxically, under these conditions, the spatial tuning of both posterior parietal cortex and hippocampal CA1 neurons followed the frame of reference given by the T-maze, as opposed to the location in the environment. Moreover, first trials within each block were associated with distinct firing rate changes for both posterior parietal cortex and hippocampal CA1 neurons. These data support a model where spatial tuning by hippocampus and cortex can interact to guide choice behavior in complex, path-based environments where a correct turn choice varies across environmental locations, and as a function of recent experience.

Spatial coding defects of hippocampal neural ensemble calcium activities in the triple-transgenic Alzheimer's disease mouse model.

Alzheimer's disease (AD) causes progressive age-related defects in memory and cognitive function and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Here we examine large-scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer's disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes ("miniscopes") on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3-6.5 months old) and old (18-21 months old) ages. During open-field exploration, 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. The spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotor speed significantly modulates the amplitude of hippocampal neural calcium ensemble activities to a greater extent in 3xTg-AD mice during open field exploration. Our data offer new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model and provide strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway.

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

Locomotor action sequences impact the scale of representation in hippocampus and posterior parietal cortex.

The hippocampus and posterior parietal cortex are implicated in both episodic memory and encoding of position in an environment. In the present study, we examine the impact of locomotor behaviors associated with movement in both the horizontal and vertical dimensions on population activity patterns in these two brain structures. We utilized a five-looped, squared spiral track containing stair segments, ramp segments, and flat segments. In addition to encoding locations along the full route, posterior parietal cortex population activity demonstrates strong pattern recurrence for similar action types at different locations in the environment. Additionally, posterior parietal and hippocampal neurons exhibit parallel modulation in the scale of representation that follows behavioral dynamics required for track traversal. These findings build on prior work examining spatial mapping in the vertical dimension and provide a better understanding of how a series of actions and visited locations can be coordinated in the generation of episodic memory.

Cognitive Maps: Distortions of the Hippocampal Space Map Define Neighborhoods.

In place of continuous overhead satellite views of an environment, the brain often relies on first-person experiences to estimate spatial relationships between locations. Using new methods, a recent study has found the spatial metric observed in hippocampal activity adapts to encode local environmental terrain.

Secondary Motor Cortex Transforms Spatial Information into Planned Action during Navigation.

Fluid navigation requires constant updating of planned movements to adapt to evolving obstacles and goals. For that reason, a neural substrate for navigation demands spatial and environmental information and the ability to effect actions through efferents. The secondary motor cortex (M2) is a prime candidate for this role given its interconnectivity with association cortices that encode spatial relationships and its projection to the primary motor cortex. Here, we report that M2 neurons robustly encode both planned and current left/right turning actions across multiple turn locations in a multi-route navigational task. Comparisons within a common statistical framework reveal that M2 neurons differentiate contextual factors, including environmental position, route, action sequence, orientation, and choice availability. Despite significant modulation by environmental factors, action planning, and execution are the dominant output signals of M2 neurons. These results identify the M2 as a structure integrating spatial information toward the updating of planned movements.

CA1-projecting subiculum neurons facilitate object-place learning.

Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is biased by inputs from CA1 inhibitory neurons and the visual cortex, but lacks input from the entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target the perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. Our findings also implicate this circuitry in the formation of complex spatial representations and learning of object-place associations.

Neurophysiological signatures of temporal coordination between retrosplenial cortex and the hippocampal formation.

Retrosplenial cortex (RSC) is heavily interconnected with a multitude of cortical regions and is directly connected with the hippocampal formation. As such, it is a likely coordinator of information transfer between the hippocampus (HPC) and cortex in the service of spatial cognition and episodic memory. The current work examined three potential temporal frameworks for retrosplenial-hippocampal communication, namely, theta frequency oscillations (6-12 Hz), sharp-wave/ripple events, and repeating, theta phase-locked shifts from low (30-65 Hz) to high (120-160 Hz) gamma frequency oscillations. From simultaneous recordings of single units and local field potentials (LFPs) in RSC and HPC, we report the presence of prominent theta, low-gamma, and high-gamma oscillations in the retrosplenial LFP. Retrosplenial and hippocampal theta rhythms were strongly coherent and subgroups of retrosplenial neurons exhibited either spiking at theta frequencies and/or spike-phase-locking to theta. Retrosplenial neurons were also phase-locked to local low- and high-gamma rhythms, and power in these frequency bands was coupled in a sequential fashion to specific phases of hippocampal and retrosplenial theta rhythms. Coordinated activity between the two regions also occurred during hippocampal sharp-wave/ripple events, where retrosplenial neuron populations were modulated in their spiking and retrosplenial LFPs exhibited sharp-wave-like events that co-occurred with those observed in HPC. These results identify several temporal windows of synchronization between RSC and HPC that may mediate cortico-hippocampal processes related to learning, memory, and spatial representation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Conjunctive coding in an evolved spiking model of retrosplenial cortex.

Retrosplenial cortex (RSC) is an association cortex supporting spatial navigation and memory. However, critical issues remain concerning the forms by which its ensemble spiking patterns register spatial relationships that are difficult for experimental techniques to fully address. We therefore applied an evolutionary algorithmic optimization technique to create spiking neural network models that matched electrophysiologically observed spiking dynamics in rat RSC neuronal ensembles. Virtual experiments conducted on the evolved networks revealed a mixed selectivity coding capability that was not built into the optimization method, but instead emerged as a consequence of replicating biological firing patterns. The experiments reveal several important outcomes of mixed selectivity that may subserve flexible navigation and spatial representation: (a) robustness to loss of specific inputs, (b) immediate and stable encoding of novel routes and route locations, (c) automatic resolution of input variable conflicts, and (d) dynamic coding that allows rapid adaptation to changing task demands without retraining. These findings suggest that biological retrosplenial cortex can generate unique, first-trial, conjunctive encodings of spatial positions and actions that can be used by downstream brain regions for navigation and path integration. Moreover, these results are consistent with the proposed role for the RSC in the transformation of representations between reference frames and navigation strategy deployment. Finally, the specific modeling framework used for evolving synthetic retrosplenial networks represents an important advance for computational modeling by which synthetic neural networks can encapsulate, describe, and predict the behavior of neural circuits at multiple levels of function. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Opposing and Complementary Topographic Connectivity Gradients Revealed by Quantitative Analysis of Canonical and Noncanonical Hippocampal CA1 Inputs.

Physiological studies suggest spatial representation gradients along the CA1 proximodistal axis. To determine the underlying anatomical basis, we quantitatively mapped canonical and noncanonical inputs to excitatory neurons in dorsal hippocampal CA1 along the proximal-distal axis in mice of both sexes using monosynaptic rabies tracing. Our quantitative analyses show comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Noncanonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum-CA1 input strength systematically increases but the presubiculum-CA1 input strength decreases along the proximal-distal axis. The subiculum input strength cotracks that of the lateral EC, known to be less spatially selective than the medial EC. The functional significance of this organization is verified physiologically for subiculum-to-CA1 inputs. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 representations.

Spatially Periodic Activation Patterns of Retrosplenial Cortex Encode Route Sub-spaces and Distance Traveled.

Traversal of a complicated route is often facilitated by considering it as a set of related sub-spaces. Such compartmentalization processes could occur within retrosplenial cortex, a structure whose neurons simultaneously encode position within routes and other spatial coordinate systems. Here, retrosplenial cortex neurons were recorded as rats traversed a track having recurrent structure at multiple scales. Consistent with a major role in compartmentalization of complex routes, individual retrosplenial cortex (RSC) neurons exhibited periodic activation patterns that repeated across route segments having the same shape. Concurrently, a larger population of RSC neurons exhibited single-cycle periodicity over the full route, effectively defining a framework for encoding of sub-route positions relative to the whole. The same population simultaneously provides a novel metric for distance from each route position to all others. Together, the findings implicate retrosplenial cortex in the extraction of path sub-spaces, the encoding of their spatial relationships to each other, and path integration.

Subiculum neurons map the current axis of travel.

Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180° apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context.

Retrosplenial cortex maps the conjunction of internal and external spaces.

Intelligent behavior demands not only multiple forms of spatial representation, but also coordination among the brain regions mediating those representations. Retrosplenial cortex is densely interconnected with the majority of cortical and subcortical brain structures that register an animal's position in multiple internal and external spatial frames of reference. This unique anatomy suggests that it functions to integrate distinct forms of spatial information and provides an interface for transformations between them. Evidence for this was found in rats traversing two different routes placed at different environmental locations. Retrosplenial ensembles robustly encoded conjunctions of progress through the current route, position in the larger environment and the left versus right turning behavior of the animal. Thus, the retrosplenial cortex has the requisite dynamics to serve as an intermediary between brain regions generating different forms of spatial mapping, a result that is consistent with navigational and episodic memory impairments following damage to this region in humans.

Cell assemblies of the basal forebrain.

The basal forebrain comprises several heterogeneous neuronal subgroupings having modular projection patterns to discrete sets of cortical subregions. Each cortical region forms recurrent projections, via prefrontal cortex, that reach the specific basal forebrain subgroups from which they receive afferents. This architecture enables the basal forebrain to selectively modulate cortical responsiveness according to current processing demands. Theoretically, optimal functioning of this distributed network would be enhanced by temporal coordination among coactive basal forebrain neurons, or the emergence of "cell assemblies." The present work demonstrates assembly formation in rat basal forebrain neuronal populations during a selective attention task. Neuron pairs exhibited coactivation patterns organized within beta-frequency time windows (55 ms), regardless of their membership within distinct bursting versus nonbursting basal forebrain subpopulations. Thus, the results reveal a specific temporal framework for integration of information within basal forebrain networks and for the modulation of cortical responsiveness.