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Deciphering the Neural Code of Head Direction and Spatial Location

Grid cells and path integration

My team is investigating entorhinal grid cells, which are implicated in encoding spatial position through a grid-like mapping predicated on movement. Grids cells are known to aide a process called path integration, an innate ability to maintain knowledge of your position in space based on the integration or memory of your prior movements. Our research demonstrated the necessity of medial septum input for grid cell operation. Our current explorations are directed at determining how specific subcircuits within the medial septum—namely cholinergic, GABAergic, and glutamatergic— influence this representation. Initial experiments utilizing cell-specific optogenetic inactivation have underscored the significance of septal GABAergic inputs to the entorhinal cortex in the grid cell paradigm. This is further elucidated in our recent work (Robinson et al., biorxiv 2023), where we used optogenetics to inhibit MS-GABAergic neurons and found that this inhibition disrupts grid cell spatial periodicity and temporal coding, including theta phase precession. The effects persisted during short recovery periods, suggesting these neurons are crucial for maintaining grid cell functionality. 

Alignment of head direction system

Our research has a keen emphasis on the head direction system, encompassing pathways from the vestibular nuclei through the thalamus to cortical regions processing spatial data. Notably, our recent findings on thalamic head direction cells (Ajabi et al., 2023 Nature), elucidate the correctional mechanisms whereby the system realigns itself upon an animal’s forced reorientation. This is achieved by a rotational activity across the head direction network, independent of the animal’s own movement, facilitated by a global inhibition across the network. The computational model we introduced posits that such direct and global inhibitory inputs enable the observed dynamism. My laboratory is committed to extending this research to identify the source of global inhibition and to further comprehend the system’s adaptability to navigational challenges like path integration and goal-directed behavior. We are pursuing experiments and computational modeling to elucidate how the spatial navigation system executes reorientation tasks, with early evidence indicating a mental rotation of two-dimensional spatial maps within the hippocampal CA1 region (unpublished, presented at SfN 2023).

Mapping the circuits of the navigation system 

It is posited that the medial entorhinal cortex (MEC) receives its head direction (HD) coding primarily from the subicular complex due to the scarcity of direct thalamic projections to the MEC. Our research, utilizing rabies-mediated retrograde tracing in mice, reveals that axons from the anterodorsal nucleus (ADN) specifically connect to interneurons within the MEC. Notably, ADN axons demonstrate a preferential connection to Vasoactive Intestinal Peptide (VIP) interneurons—a class of cells whose involvement in the MEC's spatial processing has not been previously acknowledged (unpublished, presented at SfN 2023). These VIP interneurons also integrate signals from the hippocampus, subiculum, and retrosplenial cortex, highlighting their potential significance in spatial memory. By integrating behavioral analysis with cFos imaging and pharmacogenetic manipulation of VIP interneurons, we uncover their indispensable role in spatial memory processes, particularly in the context of detecting novel environments (unpublished, presented at SfN 2023).

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Grid cell disruption in a mouse model of early Alzheimer’s disease reflects reduced integration of self-motion cues

Population dynamics of head-direction neurons during drift and reorientation

Disruption of the grid cell network in a mouse model of early Alzheimer’s disease

Path integration in normal aging and Alzheimer's disease

Skipping ahead: A circuit for representing the past, present, and future

A Characterization of the Electrophysiological and Morphological Properties of Vasoactive Intestinal Peptide (VIP) Interneurons in the Medial Entorhinal Cortex (MEC)

DG–CA3 circuitry mediates hippocampal representations of latent information

A zero-inflated gamma model for post deconvolved calcium imaging traces

Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies

Multiple Running Speed Signals in Medial Entorhinal Cortex

During running in place, grid cells integrate elapsed time and distance run

Head direction is coded more strongly than movement direction in a population of entorhinal neurons

Related publications 

Grid cells and path integration

Alignment of head direction system

Mapping the circuits of the navigation system 

My team is investigating entorhinal grid cells, which are implicated in encoding spatial position through a grid-like mapping predicated on movement. Grids cells are known to aide a process called path integration, an innate ability to maintain knowledge of your position in space based on the integration or memory of your prior movements. Our research demonstrated the necessity of medial septum input for grid cell operation. Our current explorations are directed at determining how specific subcircuits within the medial septum—namely cholinergic, GABAergic, and glutamatergic— influence this representation. Initial experiments utilizing cell-specific optogenetic inactivation have underscored the significance of septal GABAergic inputs to the entorhinal cortex in the grid cell paradigm. This is further elucidated in our recent work (Robinson et al., biorxiv 2023), where we used optogenetics to inhibit MS-GABAergic neurons and found that this inhibition disrupts grid cell spatial periodicity and temporal coding, including theta phase precession. The effects persisted during short recovery periods, suggesting these neurons are crucial for maintaining grid cell functionality.

Our research has a keen emphasis on the head direction system, encompassing pathways from the vestibular nuclei through the thalamus to cortical regions processing spatial data. Notably, our recent findings on thalamic head direction cells (Ajabi et al., 2023 Nature), elucidate the correctional mechanisms whereby the system realigns itself upon an animal’s forced reorientation. This is achieved by a rotational activity across the head direction network, independent of the animal’s own movement, facilitated by a global inhibition across the network. The computational model we introduced posits that such direct and global inhibitory inputs enable the observed dynamism. My laboratory is committed to extending this research to identify the source of global inhibition and to further comprehend the system’s adaptability to navigational challenges like path integration and goal-directed behavior. We are pursuing experiments and computational modeling to elucidate how the spatial navigation system executes reorientation tasks, with early evidence indicating a mental rotation of two-dimensional spatial maps within the hippocampal CA1 region (unpublished, presented at SfN 2023).

It is posited that the medial entorhinal cortex (MEC) receives its head direction (HD) coding primarily from the subicular complex due to the scarcity of direct thalamic projections to the MEC. Our research, utilizing rabies-mediated retrograde tracing in mice, reveals that axons from the anterodorsal nucleus (ADN) specifically connect to interneurons within the MEC. Notably, ADN axons demonstrate a preferential connection to Vasoactive Intestinal Peptide (VIP) interneurons—a class of cells whose involvement in the MEC's spatial processing has not been previously acknowledged (unpublished, presented at SfN 2023). These VIP interneurons also integrate signals from the hippocampus, subiculum, and retrosplenial cortex, highlighting their potential significance in spatial memory. By integrating behavioral analysis with cFos imaging and pharmacogenetic manipulation of VIP interneurons, we uncover their indispensable role in spatial memory processes, particularly in the context of detecting novel environments (unpublished, presented at SfN 2023).

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