Evidence for two distinct thalamocortical circuits in retrosplenial cortex

Spatial navigation forms one of the core components of an animal’s behavioural repertoire. Good navigational skills boost survival by allowing one to avoid predators, to search successfully for food in an unpredictable world, and to be able to find a mating partner. As a consequence, the brain has dedicated many of its resources to the processing of spatial information. Decades of seminal work has revealed how the brain is able to form detailed representations of one’s current position, and use an internal cognitive map of the environment to traverse the local space. However, what is much less understood is how neural computations of position depend on distance information of salient external locations such as landmarks, and how these distal places are encoded in the brain. The work in this thesis explores the role of one brain region in particular, the retrosplenial cortex (RSC), as a key area to implement distance computations in relation to distal landmarks. Previous research has shown that damage to the RSC results in losses of spatial memory and navigation ability, but its exact role in spatial cognition remains unclear. Initial electrophysiological recordings of single cells in the RSC during free exploration behaviour of the animal resulted in the discovery of a new population of neurons that robustly encode distance information towards nearby walls throughout the environment. Activity of these border cells was characterized by high firing rates near all boundaries of the arena that were available to the animal, and sensory manipulation experiments revealed that this activity persisted in the absence of direct visual or somatosensory detection of the wall. It quickly became apparent that border cell activity was not only modulated by the distance to walls, but was contingent on the direction the animal was facing relative to the boundary. Approximately 40% of neurons displayed significant selectivity to the direction of walls, mostly in the hemifield contra-lateral to the recorded hemisphere, such that a neuron in left RSC is active whenever a wall occupies proximal space on the right side of the animal. Using a cue-rotation paradigm, experiments initially showed that this egocentric direction information was invariant to the physical rotation of the arena. Yet this rotation elicited a corresponding shift in the preferred direction of local head-direction cells, as well as a rotation in the firing fields of spatially-tuned cells in RSC. As a consequence, position and direction encoding in RSC must be bound together, rotating in unison during the environmental manipulations, as information about allocentric boundary locations is integrated with head-direction signals to form egocentric border representations. It is known that the RSC forms many anatomical connections with other parts of the brain that encode spatial information, like the hippocampus and para-hippocampal areas. The next step was to establish the circuit mechanisms in place for RSC neurons to generate their activity in respect to the distance and direction of walls. A series of inactivation experiments revealed how RSC activity is inter-dependent with one of its communication partners, the medial entorhinal cortex (MEC). Together they form a wider functional network that encodes precise spatial information of borders, with information flowing from the MEC to RSC but not vice versa. While the conjunction between distance and heading direction relative to the outer walls was the main driver of neural activity in RSC, border cells displayed further behavioural correlates related to movement trajectories. Spiking activity in either hemisphere tended to precede turning behaviour on a short time-scale in a way that border cells in the right RSC anticipated right-way turns ~300 ms into the future. The interpretation of these results is that the RSC’s primary role in spatial cognition is not necessarily on the early sensory processing stage as suggested by previous studies. Instead, it is involved in computations related to the generation of motion plans, using spatial information that is processed in other brain areas to plan and execute future actions. One potential function of the RSC’s role in this process could be to act correctly in relation to the nearby perimeter, such that border cells in one hemisphere are involved in the encoding of walls in the contralateral hemifield, after which the animal makes an ipsilateral turn to avoid collision. Together this supports the idea that the MEC→RSC pathway links the encoding of space and position in the hippocampal system with the brain’s motor action systems, allowing animals to use walls as prominent landmarks to navigate the room.

The retrosplenial cortex (RSC) integrates sensory and mnemonic information to support spatial orientation and navigation, yet how visuospatial processing differs across its subregions remains unclear. Here, we combined cellular imaging in navigating mice with brain-wide anatomical input tracing to characterize how multimodal sensory and positional signals are integrated along the anterior–posterior axis of dorsal RSC. We identified consistent differences between anterior and posterior subregions in both functional response properties and long-range connectivity. Anterior RSC neurons displayed sharper and more reliable position tuning during tactile-cued navigation and preferential sensitivity to fast, low–spatial-frequency visual motion. In contrast, posterior RSC neurons showed broader position selectivity, stronger responses to slow, high–spatial-frequency visual patterns, and enhanced tuning in visually immersive virtual environments. Consistent with these differences, anterior RSC received denser projections from motor, somatosensory, and parietal areas, whereas posterior RSC received stronger input from primary and posteromedial visual cortices. Together, these findings identify an anterior–posterior functional gradient in RSC, with subregions differing in how they integrate sensory and positional signals during navigation.

From visual perception to language, sensory stimuli change their meaning depending on previous experience. Recurrent neural dynamics can interpret stimuli based on externally cued context, but it is unknown whether they can compute and employ internal hypotheses to resolve ambiguities. Here we show that mouse retrosplenial cortex (RSC) can form several hypotheses over time and perform spatial reasoning through recurrent dynamics. In our task, mice navigated using ambiguous landmarks that are identified through their mutual spatial relationship, requiring sequential refinement of hypotheses. Neurons in RSC and in artificial neural networks encoded mixtures of hypotheses, location and sensory information, and were constrained by robust low-dimensional dynamics. RSC encoded hypotheses as locations in activity space with divergent trajectories for identical sensory inputs, enabling their correct interpretation. Our results indicate that interactions between internal hypotheses and external sensory data in recurrent circuits can provide a substrate for complex sequential cognitive reasoning.

NMDA receptor-dependent oscillatory signal outputs from the retrosplenial cortex triggered by a non-NMDA receptor-dependent signal input from the visual cortex

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).

In everyday life, mammals navigate through environments composed of multiple interconnected spaces. Understanding how the brain encodes space in such complex settings is essential to uncover the mechanisms that support flexible navigation in the real world. In this study, we investigated how the retrosplenial cortex (RSC) and the hippocampus (HPC) encode spatial information in multi-room environments by recording neuronal activity in rats exploring environments composed of two or four connected rooms. These environments varied both in their structural layout and in their sensory features, allowing us to disentangle the influence of environmental geometry from that of local sensory cues. We found that two types of directional coding coexist within the RSC: classical head direction cells maintained a stable preferred firing direction across all rooms, while multidirectional cells expressed room-specific directional tuning that followed the geometric structure of the environment (e.g., 180° or 90° rotations). In addition, non-directional RSC neurons displayed room-specific spatial firing patterns that repeated across rooms following geometric transformations, similar to the activity observed in multidirectional cells. In contrast, hippocampal place cells either remapped between rooms or showed simple translational repetition, without preserving any geometric alignment. Taken together, these findings reveal a functional dissociation between retrosplenial and hippocampal spatial codes. The RSC supports a structured, multi-scale representation of space, segmenting the environment into locally anchored reference frames embedded within a coherent global geometry. The HPC, by contrast, encodes room-specific representations independently for each compartment. This division may support flexible navigation in complex environments by integrating geometry-based spatial segmentation and unification in the RSC with context-specific encoding in the HPC, thereby enabling multi-level spatial coding across interconnected spaces.

In everyday life, mammals navigate through environments composed of multiple interconnected spaces. Understanding how the brain encodes space in such complex settings is essential to uncover the mechanisms that support flexible navigation in the real world. In this study, we investigated how the retrosplenial cortex (RSC) and the hippocampus (HPC) encode spatial information in multi-room environments by recording neuronal activity in rats exploring environments composed of two or four connected rooms. These environments varied both in their structural layout and in their sensory features, allowing us to disentangle the influence of environmental geometry from that of local sensory cues. We found that two types of directional coding coexist within the RSC: classical head direction cells maintained a stable preferred firing direction across all rooms, while multidirectional cells expressed room-specific directional tuning that followed the geometric structure of the environment (e.g., 180° or 90° rotations). In addition, non-directional RSC neurons displayed room-specific spatial firing patterns that repeated across rooms following geometric transformations, similar to the activity observed in multidirectional cells. In contrast, hippocampal place cells either remapped between rooms or showed simple translational repetition, without preserving any geometric alignment. Taken together, these findings reveal a functional dissociation between retrosplenial and hippocampal spatial codes. The RSC supports a structured, multi-scale representation of space, segmenting the environment into locally anchored reference frames embedded within a coherent global geometry. The HPC, by contrast, encodes room-specific representations independently for each compartment. This division may support flexible navigation in complex environments by integrating geometry-based spatial segmentation and unification in the RSC with context-specific encoding in the HPC, thereby enabling multi-level spatial coding across interconnected spaces.

The retrosplenial cortex is reciprocally connected with multiple structures implicated in spatial cognition, and damage to the region itself produces numerous spatial impairments. Here, we sought to characterize spatial correlates of neurons within the region during free exploration in two-dimensional environments. We report that a large percentage of retrosplenial cortex neurons have spatial receptive fields that are active when environmental boundaries are positioned at a specific orientation and distance relative to the animal itself. We demonstrate that this vector-based location signal is encoded in egocentric coordinates, is localized to the dysgranular retrosplenial subregion, is independent of self-motion, and is context invariant. Further, we identify a subpopulation of neurons with this response property that are synchronized with the hippocampal theta oscillation. Accordingly, the current work identifies a robust egocentric spatial code in retrosplenial cortex that can facilitate spatial coordinate system transformations and support the anchoring, generation, and utilization of allocentric representations.

The formation and recall of sensory, motor, and cognitive representations require coordinated fast communication among multiple cortical areas. Interareal projections are mainly mediated by glutamatergic pyramidal cell projections; only few long-range GABAergic connections have been reported. Using in vivo recording and labeling of single cells and retrograde axonal tracing, we demonstrate novel long-range GABAergic projection neurons in the rat hippocampus: (1) somatostatin- and predominantly mGluR1alpha-positive neurons in stratum oriens project to the subiculum, other cortical areas, and the medial septum; (2) neurons in stratum oriens, including somatostatin-negative ones; and (3) trilaminar cells project to the subiculum and/or other cortical areas but not the septum. These three populations strongly increase their firing during sharp wave-associated ripple oscillations, communicating this network state to the septotemporal system. Finally, a large population of somatostatin-negative GABAergic cells in stratum radiatum project to the molecular layers of the subiculum, presubiculum, retrosplenial cortex, and indusium griseum and fire rhythmically at high rates during theta oscillations but do not increase their firing during ripples. The GABAergic projection axons have a larger diameter and thicker myelin sheet than those of CA1 pyramidal cells. Therefore, rhythmic IPSCs are likely to precede the arrival of excitation in cortical areas (e.g., subiculum) that receive both glutamatergic and GABAergic projections from the CA1 area. Other areas, including the retrosplenial cortex, receive only rhythmic GABAergic CA1 input. We conclude that direct GABAergic projections from the hippocampus to other cortical areas and the septum contribute to coordinating oscillatory timing across structures.

Rapid eye movement (REM) sleep is a sleep state characterized by skeletal muscle paralysis and cerebral cortical activation. Yet, global cortical dynamics and their role in regulating REM sleep remain unclear. Here we show that in mice, REM sleep is accompanied by highly patterned cortical activity waves, with the retrosplenial cortex (RSC) as a major initiation site. Two-photon imaging of layer 2/3 pyramidal neurons of the RSC revealed two distinct patterns of population activities during REM sleep. These activities encoded two sequential REM sleep substages, characterized by contrasting facial movement and autonomic activity and by distinguishable electroencephalogram theta oscillations. Closed-loop optogenetic inactivation of RSC during REM sleep altered cortical activity dynamics and shortened REM sleep duration via inhibition of the REM substage transition. These results highlight an important role for the RSC in dictating cortical dynamics and regulating REM sleep progression.

Recent advances in the understanding of spatial cognition are reviewed, focusing on memory for locations in large-scale space and on those advances inspired by single-unit recording and lesion studies in animals. Spatial memory appears to be supported by multiple parallel representations, including egocentric and allocentric representations, and those updated to accommodate self-motion. The effects of these representations can be dissociated behaviorally, developmentally, and in terms of their neural bases. It is now becoming possible to construct a mechanistic neural-level model of at least some aspects of spatial memory and imagery, with the hippocampus and medial temporal lobe providing allocentric environmental representations, the parietal lobe egocentric representations, and the retrosplenial cortex and parieto-occipital sulcus allowing both types of representation to interact. Insights from this model include a common mechanism for the construction of spatial scenes in the service of both imagery and episodic retrieval and a role for the remainder of Papez's circuit in orienting the viewpoint used. In addition, it appears that hippocampal and striatal systems process different aspects of environmental layout (boundaries and local landmarks, respectively) and do so using different learning rules (incidental learning and associative reinforcement, respectively).

Binge-like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal-diencephalic-cingulate memory network. This is mediated, in part, by reduced Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors followed by a decrease in the activation of pro-survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch-clamp electrophysiological techniques in acute slices from postnatal day 6-8mice to test the effect of the positive allosteric modulator GNE-9278 on ethanol-induced inhibition of NMDA receptor function. GNE-9278 dose-dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5μmol L-1 , GNE-9278 significantly reduced the 90 mmol L-1 ethanol-induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current-clamp experiments showed that 5μmol L-1 GNE-9278 ameliorated the 90 mmol L-1 ethanol-induced inhibition of synaptically-evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol-induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro-apoptotic effects during the late stages of fetal development.

Spatial context and the functional role of the postrhinal cortex

Distinctive cortico-striatal circuits that serve motor and cognitive functions have been recently mapped based on resting state connectivity. It has been reported that age differences in cortico-striatal connectivity relate to cognitive declines in aging. Moreover, children in their early teens (i.e., youth) already show mature motor network patterns while their cognitive networks are still developing. In the current study, we examined age differences in the frontal-striatal "cognitive" and "motor" circuits in children and adolescence, young adults (YAs), and older adults (OAs). We predicted that the strength of the "cognitive" frontal-striatal circuits would follow an inverted "U" pattern across age; children and OAs would have weaker connectivity than YAs. However, we predicted that the "motor" circuits would show less variation in connectivity strength across the lifespan. We found that most areas in both the "cognitive" and "motor" circuits showed higher connectivity in YAs than children and OAs, suggesting general inverted "U"-shaped changes across the lifespan for both the cognitive and motor frontal-striatal networks.

Neural oscillations are important for memory formation in the brain. The desynchronization of alpha (10 Hz) oscillations in the neocortex has been shown to predict successful memory encoding and retrieval. However, when engaging in learning, it has been found that the hippocampus synchronizes in theta (4 Hz) oscillations, and that learning is dependent on the phase of theta. This inconsistency as to whether synchronization is "good" for memory formation leads to confusion over which oscillations we should expect to see and where during learning paradigm experiments. This paper seeks to respond to this inconsistency by presenting a neural network model of how a well functioning learning system could exhibit both of these phenomena, i.e., desynchronization of alpha and synchronization of theta during successful memory encoding.We present a spiking neural network (the Sync/deSync model) of the neocortical and hippocampal system. The simulated hippocampus learns through an adapted spike-time dependent plasticity rule, in which weight change is modulated by the phase of an extrinsically generated theta oscillation. Additionally, a global passive weight decay is incorporated, which is also modulated by theta phase. In this way, the Sync/deSync model exhibits theta phase-dependent long-term potentiation and long-term depression. We simulated a learning paradigm experiment and compared the oscillatory dynamics of our model with those observed in single-cell and scalp-EEG studies of the medial temporal lobe. Our Sync/deSync model suggests that both the desynchronization of neocortical alpha and the synchronization of hippocampal theta are necessary for successful memory encoding and retrieval.SIGNIFICANCE STATEMENT A fundamental question is the role of rhythmic activation of neurons, i.e., how and why their firing oscillates between high and low rates. A particularly important question is how oscillatory dynamics between the neocortex and hippocampus support memory formation. We present a spiking neural-network model of such memory formation, with the central ideas that (1) in neocortex, neurons need to break out of an alpha oscillation to represent a stimulus (i.e., alpha desynchronizes), whereas (2) in hippocampus, the firing of neurons at theta facilitates formation of memories (i.e., theta synchronizes). Accordingly, successful memory formation is marked by reduced neocortical alpha and increased hippocampal theta. This pattern has been observed experimentally and gives our model its name-the Sync/deSync model.