@article{pmid39579760,

title = {Identifying representational structure in CA1 to benchmark theoretical models of cognitive mapping},

author = {J Quinn Lee and Alexandra T Keinath and Erica Cianfarano and Mark P Brandon},

doi = {10.1016/j.neuron.2024.10.027},

issn = {1097-4199},

year  = {2025},

date = {2025-01-01},

journal = {Neuron},

volume = {113},

number = {2},

pages = {307--320.e5},

abstract = {Decades of theoretical and empirical work have suggested the hippocampus instantiates some form of a cognitive map. Yet, tests of competing theories have been limited in scope and largely qualitative in nature. Here, we develop a novel framework to benchmark model predictions against observed neuronal population dynamics as animals navigate a series of geometrically distinct environments. In this task space, we show a representational structure in the dynamics of hippocampal remapping that generalizes across brains, discriminates between competing theoretical models, and effectively constrains biologically viable model parameters. With this approach, we find that accurate models capture the correspondence in spatial coding of a changing environment. The present dataset and framework thus serve to empirically evaluate and advance theories of cognitive mapping in the brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39163200,

title = {Optogenetic silencing of medial septal GABAergic neurons disrupts grid cell spatial and temporal coding in the medial entorhinal cortex},

author = {Jennifer C Robinson and Johnson Ying and Michael E Hasselmo and Mark P Brandon},

doi = {10.1016/j.celrep.2024.114590},

issn = {2211-1247},

year  = {2024},

date = {2024-08-01},

journal = {Cell Rep},

volume = {43},

number = {8},

pages = {114590},

abstract = {The hippocampus and medial entorhinal cortex (MEC) form a cognitive map that facilitates spatial navigation. As part of this map, MEC grid cells fire in a repeating hexagonal pattern across an environment. This grid pattern relies on inputs from the medial septum (MS). The MS, and specifically GABAergic neurons, are essential for theta rhythm oscillations in the entorhinal-hippocampal network; however, the role of this population in grid cell function is unclear. To investigate this, we use optogenetics to inhibit MS-GABAergic neurons and observe that MS-GABAergic inhibition disrupts grid cell spatial periodicity. Grid cell spatial periodicity is disrupted during both optogenetic inhibition periods and short inter-stimulus intervals. In contrast, longer inter-stimulus intervals allow for the recovery of grid cell spatial firing. In addition, grid cell phase precession is also disrupted. These findings highlight the critical role of MS-GABAergic neurons in maintaining grid cell spatial and temporal coding in the MEC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37536286,

title = {Time and experience are independent determinants of representational drift in CA1},

author = {J Quinn Lee and Mark P Brandon},

doi = {10.1016/j.neuron.2023.07.001},

issn = {1097-4199},

year  = {2023},

date = {2023-08-01},

journal = {Neuron},

volume = {111},

number = {15},

pages = {2275--2277},

abstract = {In this issue of Neuron, Khatib et al. and Geva et al. present complementary and breakthrough discoveries demonstrating that elapsed time and active experience independently affect unique aspects of representational drift in the hippocampus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37220744,

title = {Grid cell disruption in a mouse model of early Alzheimer's disease reflects reduced integration of self-motion cues},

author = {Johnson Ying and Antonio Reboreda and Motoharu Yoshida and Mark P Brandon},

doi = {10.1016/j.cub.2023.04.065},

issn = {1879-0445},

year  = {2023},

date = {2023-06-01},

journal = {Curr Biol},

volume = {33},

number = {12},

pages = {2425--2437.e5},

abstract = {Converging evidence from human and rodent studies suggests that disrupted grid cell coding in the medial entorhinal cortex (MEC) underlies path integration behavioral deficits during early Alzheimer's disease (AD). However, grid cell firing relies on both self-motion cues and environmental features, and it remains unclear whether disrupted grid coding can account for specific path integration deficits reported during early AD. Here, we report in the J20 transgenic amyloid beta (Aβ) mouse model of early AD that grid cells were spatially unstable toward the center of the arena, had qualitatively different spatial components that aligned parallel to the borders of the environment, and exhibited impaired integration of distance traveled via reduced theta phase precession. Our results suggest that disrupted early AD grid coding reflects reduced integration of self-motion cues but not environmental information via geometric boundaries, providing evidence that grid cell impairments underlie path integration deficits during early AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36949190,

title = {Population dynamics of head-direction neurons during drift and reorientation},

author = {Zaki Ajabi and Alexandra T Keinath and Xue-Xin Wei and Mark P Brandon},

doi = {10.1038/s41586-023-05813-2},

issn = {1476-4687},

year  = {2023},

date = {2023-03-01},

journal = {Nature},

volume = {615},

number = {7954},

pages = {892--899},

abstract = {The head direction (HD) system functions as the brain's internal compass, classically formalized as a one-dimensional ring attractor network. In contrast to a globally consistent magnetic compass, the HD system does not have a universal reference frame. Instead, it anchors to local cues, maintaining a stable offset when cues rotate and drifting in the absence of referents. However, questions about the mechanisms that underlie anchoring and drift remain unresolved and are best addressed at the population level. For example, the extent to which the one-dimensional description of population activity holds under conditions of reorientation and drift is unclear. Here we performed population recordings of thalamic HD cells using calcium imaging during controlled rotations of a visual landmark. Across experiments, population activity varied along a second dimension, which we refer to as network gain, especially under circumstances of cue conflict and ambiguity. Activity along this dimension predicted realignment and drift dynamics, including the speed of network realignment. In the dark, network gain maintained a 'memory trace' of the previously displayed landmark. Further experiments demonstrated that the HD network returned to its baseline orientation after brief, but not longer, exposures to a rotated cue. This experience dependence suggests that memory of previous associations between HD neurons and allocentric cues is maintained and influences the internal HD representation. Building on these results, we show that continuous rotation of a visual landmark induced rotation of the HD representation that persisted in darkness, demonstrating experience-dependent recalibration of the HD system. Finally, we propose a computational model to formalize how the neural compass flexibly adapts to changing environmental cues to maintain a reliable representation of HD. These results challenge classical one-dimensional interpretations of the HD system and provide insights into the interactions between this system and the cues to which it anchors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35504915,

title = {The representation of context in mouse hippocampus is preserved despite neural drift},

author = {Alexandra T Keinath and Coralie-Anne Mosser and Mark P Brandon},

doi = {10.1038/s41467-022-30198-7},

issn = {2041-1723},

year  = {2022},

date = {2022-05-01},

journal = {Nat Commun},

volume = {13},

number = {1},

pages = {2415},

abstract = {The hippocampus is thought to mediate episodic memory through the instantiation and reinstatement of context-specific cognitive maps. However, recent longitudinal experiments have challenged this view, reporting that most hippocampal cells change their tuning properties over days even in the same environment. Often referred to as neural or representational drift, these dynamics raise questions about the capacity and content of the hippocampal code. One such question is whether and how these long-term dynamics impact the hippocampal code for context. To address this, we image large CA1 populations over more than a month of daily experience as freely behaving mice participate in an extended geometric morph paradigm. We find that long-timescale changes in population activity occur orthogonally to the representation of context in network space, allowing for consistent readout of contextual information across weeks. This population-level structure is supported by heterogeneous patterns of activity at the level of individual cells, where we observe evidence of a positive relationship between interpretable contextual coding and long-term stability. Together, these results demonstrate that long-timescale changes to the CA1 spatial code preserve the relative structure of contextual representation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35173173,

title = {Disruption of the grid cell network in a mouse model of early Alzheimer's disease},

author = {Johnson Ying and Alexandra T Keinath and Raphael Lavoie and Erika Vigneault and Salah El Mestikawy and Mark P Brandon},

doi = {10.1038/s41467-022-28551-x},

issn = {2041-1723},

year  = {2022},

date = {2022-02-01},

journal = {Nat Commun},

volume = {13},

number = {1},

pages = {886},

abstract = {Early-onset familial Alzheimer's disease (AD) is marked by an aggressive buildup of amyloid beta (Aβ) proteins, yet the neural circuit operations impacted during the initial stages of Aβ pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aβ throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aβ fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aβ-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34872838,

title = {Path integration in normal aging and Alzheimer's disease},

author = {Vladislava Segen and Johnson Ying and Erik Morgan and Mark Brandon and Thomas Wolbers},

doi = {10.1016/j.tics.2021.11.001},

issn = {1879-307X},

year  = {2022},

date = {2022-02-01},

journal = {Trends Cogn Sci},

volume = {26},

number = {2},

pages = {142--158},

abstract = {In this review we discuss converging evidence from human and rodent research demonstrating how path integration (PI) is impaired in healthy aging and Alzheimer's disease (AD), and point to the neural mechanisms that underlie these deficits. Importantly, we highlight that (i) the grid cell network in the entorhinal cortex is crucial for PI in both humans and rodents, (ii) PI deficits are present in healthy aging and are significantly more pronounced in patients with early-stage AD, (iii) compromised entorhinal grid cell computations in healthy older adults and in young adults at risk of AD are linked to PI deficits, and (iv) PI and grid cell deficits may serve as sensitive markers for pathological decline in early AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34647521,

title = {Skipping ahead: A circuit for representing the past, present, and future},

author = {Jennifer C Robinson and Mark P Brandon},

doi = {10.7554/eLife.68795},

issn = {2050-084X},

year  = {2021},

date = {2021-10-01},

journal = {Elife},

volume = {10},

abstract = {Envisioning the future is intuitively linked to our ability to remember the past. Within the memory system, substantial work has demonstrated the involvement of the prefrontal cortex and the hippocampus in representing the past and present. Recent data shows that both the prefrontal cortex and the hippocampus encode future trajectories, which are segregated in time by alternating cycles of the theta rhythm. Here, we discuss how information is temporally organized by these brain regions supported by the medial septum, nucleus reuniens, and parahippocampal regions. Finally, we highlight a brain circuit that we predict is essential for the temporal segregation of future scenarios.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34421547,

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

author = {Saishree Badrinarayanan and Frédéric Manseau and Sylvain Williams and Mark P Brandon},

doi = {10.3389/fncir.2021.653116},

issn = {1662-5110},

year  = {2021},

date = {2021-01-01},

journal = {Front Neural Circuits},

volume = {15},

pages = {653116},

abstract = {Circuit interactions within the medial entorhinal cortex (MEC) translate movement into a coherent code for spatial location. Entorhinal principal cells are subject to strong lateral inhibition, suggesting that a disinhibitory mechanism may drive their activation. Cortical Vasoactive Intestinal Peptide (VIP) expressing inhibitory neurons are known to contact other interneurons and excitatory cells and are thus capable of providing a local disinhibitory mechanism, yet little is known about this cell type in the MEC. To investigate the electrophysiological and morphological properties of VIP cells in the MEC, we use  whole-cell patch-clamp recordings in VIPcre/tdTom mice. We report several gradients in electrophysiological properties of VIP cells that differ across laminae and along the dorsal-ventral MEC axis. We additionally show that VIP cells have distinct morphological features across laminae. Together, these results characterize the cellular and morphological properties of VIP cells in the MEC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32691490,

title = {The McGill-Mouse-Miniscope platform: A standardized approach for high-throughput imaging of neuronal dynamics during behavior},

author = {Coralie-Anne Mosser and Zeeshan Haqqee and Andrés Nieto-Posadas and Keith K Murai and Stefano Stifani and Sylvain Williams and Mark P Brandon},

doi = {10.1111/gbb.12686},

issn = {1601-183X},

year  = {2021},

date = {2021-01-01},

journal = {Genes Brain Behav},

volume = {20},

number = {1},

pages = {e12686},

abstract = {Understanding the rules that govern neuronal dynamics throughout the brain to subserve behavior and cognition remains one of the biggest challenges in neuroscience research. Recent technical advances enable the recording of increasingly larger neuronal populations to produce increasingly more sophisticated datasets. Despite bold and important open-science and data-sharing policies, these datasets tend to include unique data acquisition methods, behaviors, and file structures. Discrepancies between experimental protocols present key challenges in comparing data between laboratories and across different brain regions and species. Here, we discuss our recent efforts to create a standardized and high-throughput research platform to address these issues. The McGill-Mouse-Miniscope (M3) platform is an initiative to combine miniscope calcium imaging with standardized touchscreen-based animal behavioral testing. The goal is to curate an open-source and standardized framework for acquiring, analyzing, and accessing high-quality data of the neuronal dynamics that underly cognition throughout the brain in mice, marmosets, and models of disease. We end with a discussion of future developments and a call for users to adopt this standardized approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33164988,

title = {Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating},

author = {Mathieu Favier and Helena Janickova and Damian Justo and Ornela Kljakic and Léonie Runtz and Joman Y Natsheh and Tharick A Pascoal and Jurgen Germann and Daniel Gallino and Jun-Ii Kang and Xiang Qi Meng and Christina Antinora and Sanda Raulic and Jacob Pr Jacobsen and Luc Moquin and Erika Vigneault and Alain Gratton and Marc G Caron and Philibert Duriez and Mark P Brandon and Pedro Rosa Neto and M Mallar Chakravarty and Mohammad M Herzallah and Philip Gorwood and Marco Am Prado and Vania F Prado and Salah El Mestikawy},

doi = {10.1172/JCI138532},

issn = {1558-8238},

year  = {2020},

date = {2020-12-01},

journal = {J Clin Invest},

volume = {130},

number = {12},

pages = {6616--6630},

abstract = {Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32541860,

title = {DG-CA3 circuitry mediates hippocampal representations of latent information},

author = {Alexandra T Keinath and Andrés Nieto-Posadas and Jennifer C Robinson and Mark P Brandon},

doi = {10.1038/s41467-020-16825-1},

issn = {2041-1723},

year  = {2020},

date = {2020-06-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {3026},

abstract = {Survival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we image the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrate that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesize that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings reveal an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG-CA3 circuitry completely and reversibly abolishes the CA1 representation of latent information. These results reveal a causal and specific role of DG-CA3 circuitry in the maintenance of latent information within the hippocampus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}