Contribution of the idiothetic and the allothetic information to the hippocampal place code

Hippocampal cells exhibit preference to be active at a specific place in a familiar environment, enabling them to encode the representation of space within the brain at the population level (J. O’Keefe and Dostrovsky 1971). These cells rely on the external sensory inputs and self-motion cues, however, it is still not known how exactly these inputs interact to build a stable representation of a certain location (“place field”). Existing studies suggest that both proprioceptive and other idiothetic types of information are continuously integrated to update the self-position (e.g. implementing “path integration”) while other stable sensory cues provide references to update the allocentric position of self and correct it for the collected integration-related errors. It was shown that both allocentric and idiothetic types of information influence positional cell firing, however in most of the studies these inputs were firmly coupled. The use of virtual reality setups (Thurley and Ayaz 2016) made it possible to separate the influence of vision and proprioception for the price of not keeping natural conditions - the animal is usually head- or body-fixed (Hölscher et al. 2005; Ravassard A. 2013; Jayakumar et al. 2018a; Haas et al. 2019), which introduces vestibular motor- and visual- conflicts, providing a bias for space encoding. Here we use the novel CAVE Virtual Reality system for freely-moving rodents (Del Grosso 2018) that allows to investigate the effect of visual- and positional- (vestibular) manipulation on the hippocampal space code while keeping natural behaving conditions. In this study, we focus on the dynamic representation of space when the visual- cue-defined and physical-boundary-defined reference frames are in conflict. We confirm the dominance of one reference frame over the other on the level of place fields, when the information about one reference frame is absent (Gothard et al. 2001). We show that the hippocampal cells form adjacent categories by their input preference - surprisingly, not only that they are being driven either by visual / allocentric information or by the distance to the physical boundaries and path integration, but also by a specific combination of both. We found a large category of units integrating inputs from both allocentric and idiothetic pathways that are able to represent an intermediate position between two reference frames, when they are in conflict. This experimental evidence suggests that most of the place cells are involved in representing both reference frames using a weighted combination of sensory inputs. In line with the studies showing dominance of the more reliable sensory modality (Kathryn J. Jeffery and J. M. O’Keefe 1999; Gothard et al. 2001), our data is consistent (although not proving it) with CA1 cells implementing an optimal Bayesian coding given the idiothetic and allocentric inputs with weights inversely proportional to the availability of the input, as proposed for other sensory systems (Kate J. Jeffery, Page, and Simon M. Stringer 2016). This mechanism of weighted sensory integration, consistent with recent dynamic loop models of the hippocampal-entorhinal network (Li, Arleo, and Sheynikhovich 2020), can contribute to the physiological explanation of Bayesian inference and optimal combination of spatial cues for localization (Cheng et al. 2007)

New Behavioral Insights Into Home Range Orientation of the House Mouse (Mus musculus)

Home-range orientation is a necessity for an animal that maintains an area of daily activity. The ability to navigate efficiently among goals not perceived at the starting point requires the animal to rely on place recognition and vector knowledge. These two components of navigation allow the animal to dynamically update its current position and link that position with the locomotor distance and direction needed to reach a goal. In order to use place knowledge and vector knowledge the animal must learn and remember relevant spatial information obtained from the environment and from internal feedback. The research in this dissertation focuses on behavioral components of topographic orientation, using the house mouse as a model species. Specifically, this research made important discoveries in three main areas: 1) locomotor exploration behavior, 2) the use of learned spatial information for compass orientation, and 3) testable hypotheses based on the controversial cognitive map. In Chapter 1, I used a radial arm maze to find a systematic locomotor component to exploration behavior, which is typically described as random movement. Exploration refers to the learning process that occurs as an animal acquires relevant spatial information for home-range orientation. I predicted that this process must have a systematic component; and the results revealed that in a radial arm maze, mice avoided exploring a place explored one and two visits prior. Therefore, locomotor exploration does have a systematic component. In Chapter 2, I trained mice to navigate to their home within a circular arena, with access to a visual beacon and an enriched visual background. The mice showed that to navigate home, they preferred to rely on the extra-arena (background) cues for compass direction. However, when these extra-arena cues became unreliable, the mice showed flexibility in their preference by ignoring the visual background and instead relying on the visual beacon to locate home. This flexibility in cue use negates a popular theory, called the snapshot theory, which does not allow for such flexibility in navigation. To further study the use of compass cues in mice, in Chapter 3, I utilized a plus-maze to manipulate both allothetic (environmental) and idiothetic (internal) cues. The purpose was to determine which cue type predominated the directional choice of mice at the maze intersection while both leaving and returning home. Previous studies have ignored the potential difference in cue use during the complete roundtrip an animal would make within its home range. The results show that mice relied on different cues for the outward path and the homing path of a familiar complex roundtrip. Finally, I developed two testable hypotheses and a valid experimental design that can be used to test house mice, and other animals, for the so-called cognitive map. An animal that has a cognitive map would be able to compute a novel shortcut to a goal relying exclusively on the flexibility of such a map, and not from the other two options of novel shortcutting: guidance orientation or path integration. Thus by designing my experiments to eliminate the potential for the mice to rely on a guiding cue to direct them home, and by eliminating the ability to compute a shortcut by summing the vectors previously walked, I was able to test mice for a truly novel, map-based shortcut home. These two hypotheses were named viewpoint extrapolation and viewpoint interpolation and require pure visual exploration to acquire the necessary place and vector knowledge. Both experiments showed that mice were not capable of using pure visual exploration and therefore these studies provide no evidence that mice have a cognitive map. Overall, my research provides evidence that mice do have a mental route-based map and to build such a mental map, locomotor exploration is necessary and sufficient for acquiring relevant spatial knowledge to later use to efficiently navigate

Exteroceptive and interoceptive cue control of hippocampal place cells

Place cells in the hippocampal formation form the cornerstone of the rat’s navigational system and together with head direction cells in the postsubiculum and grid cells in the entorhinal cortex are the key elements of what O’Keefe and Nadel (1978) postulate to be a “cognitive map”. The hippocampal formation is ideally positioned anatomically to receive highly processed inputs from almost all brain regions. Previous research has focused on the cues that determine and contribute to place cell selectivity. Such cues include information about the external world that the rat perceives through its senses (“exteroceptive cues”) as well as cues internal to the body such as proprioception or somatosensation (“interoceptive cues”). This thesis uses a novel experimental paradigm in which the rat runs on a moving-treadmill linear track to investigate the relative contribution of interoceptive and exteroceptive cues for determining place cell spatial selectivity. The major finding is that place fields shift in the direction of the moving treadmill, both when the animal runs along with or against the motion of the treadmill, indicating that self-motion information is a key input to place cells. Furthermore, place fields in the middle of the track shift more than fields closer to the end walls suggesting that exteroceptive information interacts with interoceptive information to assist in accurate navigation. This conclusion is further supported by experiments performed in complete darkness where two populations of cells are observed: the first are cells which become quiescent or remap, presumably under strong exteroceptive control, while the second are cells that maintain similar firing characteristics under both lighting conditions, putatively under the influence of interoceptive inputs

A Tale of Two Direction Codes in Rat Retrosplenial Cortex: Uncovering the Neural Basis of Spatial Orientation in Complex Space

Head direction (HD) cells only become active whenever a rat faces one direction and stay inactive when it faces others, producing a unimodal activity distribution. Working together in a network, HD cells are considered the neural basis supporting a sense of direction. The retrosplenial cortex (RSC) is part of the HD circuit and contains neurons that express multiple spatial signals, including a pattern of bipolar directional tuning – as recently reported in rats exploring a rotationally symmetric two-compartment space. This suggests an unexplored mechanism of the neural compass. In this thesis, I investigated whether the association between the two-way firing symmetry and twofold environment symmetry reveals a general environment symmetry-encoding property of these RSC neurons. I recorded RSC neurons in environments having onefold, twofold and fourfold symmetry. The current study showed that RSC HD cells maintained a consistent global signal, whereas other RSC directional cells showed multi-fold symmetric firing patterns that reflected environment symmetry, not just globally (across all sub-compartments) but also locally (within each sub-compartment). The analyses also showed that the pattern was independent of egocentric boundary vector coding but represented an allocentric spatial code. It means that these RSC cells use environmental cues to organise multiple singular tuning curves which sometimes are combined to form a multidirectional pattern, likely via an interaction with the global HD signal. Thus, both local and global environment symmetry are encoded by local firing patterns in subspaces. This interestingly suggests cognitive mapping and abstraction of space beyond immediate perceptual bounds in RSC. The data generated from this study provides important insights for modelling of direction computation. Taken together, I discuss how having two types of direction codes in RSC may help us to orient more accurately and flexibly in complex and ambiguous space

Contribution of Cerebellar Sensorimotor Adaptation to Hippocampal Spatial Memory

Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation

Developing a System to Investigate Age-Related Differences in the Real-Time Utilization of Dynamically Changing External Cues during Navigation

Successful navigation depends critically upon two broad categories of sensory information, environmental (allothetic) and self-motion (idiothetic). Both the hippocampus and the medial portion of the entorhinal cortex (MEC) are critical for spatial navigation and contain functionally distinct sub-networks of spatially-modulated cells. These cells are characterized by their tuning to different spatial sensory-perceptual features of the environment and all utilize both allothetic and idiothetic cues to anchor and update their spatial firing to generate a comprehensive and dynamic representation of space. As with older adults, aged rats show pronounced impairments on a number of different spatial navigation tasks and these impairments are accompanied by a bias toward relying on egocentric over allocentric navigation strategies. Similarly, the hippocampus and MEC are also highly susceptible to age-associated changes. The influence visual allothetic cues exert on hippocampal place cell spatial tuning is diminished and delayed in aged animals. Two plausible and non-exclusive explanations that could account for these age-related alterations in allothetic processing are 1) circuit disruptions caused by known age-related functional and anatomical changes in the entorhinal-hippocampal processing pathway or 2) degraded sensory-perceptual information resulting from well-established age-related deficits across multiple sensory domains. Either of these possibilities could have the effect of either slowing allothetic cue processing or weakening the ability of these cues to influence firing field alignment. Within this context, this thesis was conceived with the aim of investigating the degree and timing with which young and aged animals utilize allothetic and idiothetic feedback to update their internal representation of space and calibrate their behavioral output. A large focus of this thesis is given to the incremental design and piloting of a number of novel technologies. Foremost among the methodological contributions of this study is the development of an augmented reality behavioral apparatus, termed the Instantaneous Cue Rotation (ICR) arena, which utilizes projected visual cues to allow for rapid remote control of all symmetry breaking visual features in the environment as rats actively engage in a visual-cue based goal navigation task. The results of extensive behavioral piloting of old and young rats validate both the ICR rotation manipulation as well as the mobile reward delivery system. This system traverses the track in tandem with the rat, enabling food based spatial reinforcement while preventing food-related olfactory cues from becoming associated with any specific location. In parallel with this work, microdrive technology was developed to enable simultaneous recording from both MEC and CA1 which is discussed along with results from single-region hippocampal and MEC implanted rats assessed in the context of a cue rotation manipulation conceptually similar to the that of the ICR. Finally, the results of the behavioral study suggest that in young rats the cue rotation exerts reliable but incomplete control over running behavior. In aged rats, by comparison, the cues exert an overall less pronounced influence on running behavior, consistent with known age-related deficits in allothetic processing. When assessed on a lap-by-lap basis, it was found that the behavior of both young and aged rats became progressively more aligned with the cues over the first few laps following cue rotation. These findings suggest a progressive realignment of behavior from an egocentric to an allocentric reference frame which is reminiscent of the reported progressive realignment of place field firing in response to conflicting spatial feedback

Learning cognitive maps: Finding useful structure in an uncertain world

In this chapter we will describe the central mechanisms that influence how people learn about large-scale space. We will focus particularly on how these mechanisms enable people to effectively cope with both the uncertainty inherent in a constantly changing world and also with the high information content of natural environments. The major lessons are that humans get by with a less is more approach to building structure, and that they are able to quickly adapt to environmental changes thanks to a range of general purpose mechanisms. By looking at abstract principles, instead of concrete implementation details, it is shown that the study of human learning can provide valuable lessons for robotics. Finally, these issues are discussed in the context of an implementation on a mobile robot. © 2007 Springer-Verlag Berlin Heidelberg

Landmark processing by head direction cells

Head direction (HD) cells are neurons that increase their firing rate whenever a rat faces within a range of heading directions, irrespective of its location within the environment. Their direction-specific firing is multisensory, where visual cues have a dominant role in controlling the preferred firing direction (PFD) to which an HD cell fires. Many studies have examined the role of visual cues in controlling the firing of HD and other spatially modulated cells, however, little is known about how visual information is integrated with a spatial navigation signal. Therefore, the aim of this thesis is to investigate what properties of the visual environment are detected and used by the navigation system. To investigate this question, HD cells were recorded in the retrosplenial cortex (RSC) and the postsubiculum (PoS) of rats as they explored an arena with two oppositely positioned cards that varied in contrast, or the orientation, height and lateral position of a bar. The cue cards were rotated together to test the hypothesis that HD cells use differences in the visual properties of local cues to align their PFD. A second experiment tested the hypothesis that PoS HD cells process the configuration of landmarks, examining changes in the PFD when the spatial relation between multiple local cues was altered. The main finding from these experiments is that contrast and orientation were reliably used as landmarks, while height and lateral position had a weaker effect in controlling the activity of HD cells. The second finding is that PoS HD cells were sensitive to changes in the spatial arrangement of familiar cues, selecting the cues that changed their position over those that remained stationary. Overall, these results show that HD cells process fine-grained visual form which might be used for complex image analysis and landmark processing

Spatial-memory control of defensive actions

Adapting anti-predatory defensive strategies to the properties of the environment is critical for survival. Here, I investigated the dependence of mouse instinctive defensive behaviours on memory of the spatial environment, and the neural mechanisms responsible for accurate escape towards refuge. First, using behavioural assays, I show that the choice and execution of defensive behaviours rely on rapidly acquired memory and are promptly updated following acute changes in the environment. In the presence of a known refuge mice escape directly to it, even if this requires approaching the source of threat. Escape is initiated by a memory- guided, accurate head-rotation movement towards the location of the refuge, indicating knowledge of the spatial goal prior to flight start. Second, I demonstrate that the superior colliculus (SC) is essential to accurately orient to shelter during escape, in agreement with its known role in both sensory- and memory- guided head orientation. To identify which upstream areas provide information about refuge location to the SC, I retrogradely traced the SC afferents and performed loss-of- function experiments in candidate areas, which showed that the retrosplenial cortex (RSC) plays a critical role in escape accuracy. Furthermore, channelrhodopsin-2-assisted connectivity studies showed a functional connection between RSC and SC, and chemogenetic inactivation of this projection impaired accurate orientation to refuge during escape. To understand how the RSC and SC control orientation to shelter during escape, I performed simultaneous single-unit recordings from the RSC and SC with Neuropixels probes. Both RSC and SC were found to encode the angular offset between the mouse’s heading and the shelter, at the single-neuron and population levels. Chemogenetic inactivation of SC-projecting RSC neurons disrupts encoding of head-shelter offset in both regions, but it does not compromise the SC motor function during a sensory- orientation task. In summary, I show that escape is a flexible behaviour and its accuracy critically depends on a monosynaptic projection from the RSC to SC. In addition, I show RSC-dependent egocentric encoding of goal direction at SC, an area critical for orientation during escape, providing a possible mechanism for controlling ethologically relevant goal-directed navigation.Boehringer Ingelheim Fellowshi