Bio

Academic Appointments


Honors & Awards


  • James S McDonnell Foundation Scholar, James S McDonnell Foundation Scholar (2016 - 2022)
  • Robertson Neuroscience Investigator – New York Stem Cell Foundation, New York Stem Cell Foundation (2015-2019)
  • Klingenstein-Simons Fellowship Award in the Neurosciences, Klingenstein-Simons Foundation (2014-2017)
  • Sloan Fellow, Alfred P. Sloan Foundation (2013-2015)
  • Peter and Patricia Gruber International Research Award, The Gruber Foundation (2012)

Professional Education


  • BA, Baylor University, Psychology (2002)
  • PhD, Boston University, Neuroscience (2008)

Research & Scholarship

Current Research and Scholarly Interests


My laboratory studies the cellular and molecular mechanisms underlying the organization of cortical circuits important for spatial navigation and memory. We are particularly focused on medial entorhinal cortex, where many neurons fire in spatially specific patterns and thus offer a measurable output for molecular manipulations. We combine electrophysiology, genetic approaches and behavioral paradigms to unravel the mechanisms and behavioral relevance of non-sensory cortical organization. Our first line of research is focused on determining the cellular and molecular components crucial to the neural representation of external space by functionally defined cell types in entorhinal cortex (grid, border and head direction cells). We plan to use specific targeting of ion channels, combined with in vivo tetrode recordings, to determine how channel dynamics influence the neural representation of space in the behaving animal. A second, parallel line of research, utilizes a combination of in vivo and in vitro methods to further parse out ionic expression patterns in entorhinal cortices and determine how gradients in ion channels develop. Ultimately, our work aims to understand the ontogenesis and relevance of medial entorhinal cortical topography in spatial memory and navigation.

Teaching

2018-19 Courses


Stanford Advisees


Graduate and Fellowship Programs


Publications

All Publications


  • Principles governing the integration of landmark and self-motion cues in entorhinal cortical codes for navigation. Nature neuroscience Campbell, M. G., Ocko, S. A., Mallory, C. S., Low, I. I., Ganguli, S., Giocomo, L. M. 2018

    Abstract

    To guide navigation, the nervous system integrates multisensory self-motion and landmark information. We dissected how these inputs generate spatial representations by recording entorhinal grid, border and speed cells in mice navigating virtual environments. Manipulating the gain between the animal's locomotion and the visual scene revealed that border cells responded to landmark cues while grid and speed cells responded to combinations of locomotion, optic flow and landmark cues in a context-dependent manner, with optic flow becoming more influential when it was faster than expected. A network model explained these results by revealing a phase transition between two regimes in which grid cells remain coherent with or break away from the landmark reference frame. Moreover, during path-integration-based navigation, mice estimated their position following principles predicted by our recordings. Together, these results provide a theoretical framework for understanding how landmark and self-motion cues combine during navigation to generate spatial representations and guide behavior.

    View details for DOI 10.1038/s41593-018-0189-y

    View details for PubMedID 30038279

  • Grid scale drives the scale and long-term stability of place maps NATURE NEUROSCIENCE Mallory, C. S., Hardcastle, K., Bant, J. S., Giocomo, L. M. 2018; 21 (2): 270-+

    Abstract

    Medial entorhinal cortex (MEC) grid cells fire at regular spatial intervals and project to the hippocampus, where place cells are active in spatially restricted locations. One feature of the grid population is the increase in grid spatial scale along the dorsal-ventral MEC axis. However, the difficulty in perturbing grid scale without impacting the properties of other functionally defined MEC cell types has obscured how grid scale influences hippocampal coding and spatial memory. Here we use a targeted viral approach to knock out HCN1 channels selectively in MEC, causing the grid scale to expand while leaving other MEC spatial and velocity signals intact. Grid scale expansion resulted in place scale expansion in fields located far from environmental boundaries, reduced long-term place field stability and impaired spatial learning. These observations, combined with simulations of a grid-to-place cell model and position decoding of place cells, illuminate how grid scale impacts place coding and spatial memory.

    View details for DOI 10.1038/s41593-017-0055-3

    View details for Web of Science ID 000424269900018

    View details for PubMedID 29335607

    View details for PubMedCentralID PMC5823610

  • Cell types for our sense of location: where we are and where we are going NATURE NEUROSCIENCE Hardcastle, K., Ganguli, S., Giocomo, L. M. 2017; 20 (11): 1474–82

    Abstract

    Technological advances in profiling cells along genetic, anatomical and physiological axes have fomented interest in identifying all neuronal cell types. This goal nears completion in specialized circuits such as the retina, while remaining more elusive in higher order cortical regions. We propose that this differential success of cell type identification may not simply reflect technological gaps in co-registering genetic, anatomical and physiological features in the cortex. Rather, we hypothesize it reflects evolutionarily driven differences in the computational principles governing specialized circuits versus more general-purpose learning machines. In this framework, we consider the question of cell types in medial entorhinal cortex (MEC), a region likely to be involved in memory and navigation. While MEC contains subsets of identifiable functionally defined cell types, recent work employing unbiased statistical methods and more diverse tasks reveals unsuspected heterogeneity and adaptivity in MEC firing patterns. This suggests MEC may operate more as a generalist circuit, obeying computational design principles resembling those governing other higher cortical regions.

    View details for DOI 10.1038/nn.4654

    View details for Web of Science ID 000413916800006

    View details for PubMedID 29073649

  • A Multiplexed, Heterogeneous, and Adaptive Code for Navigation in Medial Entorhinal Cortex NEURON Hardcastle, K., Maheswaranathan, N., Ganguli, S., Giocomo, L. M. 2017; 94 (2): 375-?

    Abstract

    Medial entorhinal grid cells display strikingly symmetric spatial firing patterns. The clarity of these patterns motivated the use of specific activity pattern shapes to classify entorhinal cell types. While this approach successfully revealed cells that encode boundaries, head direction, and running speed, it left a majority of cells unclassified, and its pre-defined nature may have missed unconventional, yet important coding properties. Here, we apply an unbiased statistical approach to search for cells that encode navigationally relevant variables. This approach successfully classifies the majority of entorhinal cells and reveals unsuspected entorhinal coding principles. First, we find a high degree of mixed selectivity and heterogeneity in superficial entorhinal neurons. Second, we discover a dynamic and remarkably adaptive code for space that enables entorhinal cells to rapidly encode navigational information accurately at high running speeds. Combined, these observations advance our current understanding of the mechanistic origins and functional implications of the entorhinal code for navigation. VIDEO ABSTRACT.

    View details for DOI 10.1016/j.neuron.2017.03.025

    View details for Web of Science ID 000399451400020

    View details for PubMedID 28392071

  • Environmental Boundaries as an Error Correction Mechanism for Grid Cells NEURON Hardcastle, K., Ganguli, S., Giocomo, L. M. 2015; 86 (3): 827-839

    Abstract

    Medial entorhinal grid cells fire in periodic, hexagonally patterned locations and are proposed to support path-integration-based navigation. The recursive nature of path integration results in accumulating error and, without a corrective mechanism, a breakdown in the calculation of location. The observed long-term stability of grid patterns necessitates that the system either performs highly precise internal path integration or implements an external landmark-based error correction mechanism. To distinguish these possibilities, we examined grid cells in behaving rodents as they made long trajectories across an open arena. We found that error accumulates relative to time and distance traveled since the animal last encountered a boundary. This error reflects coherent drift in the grid pattern. Further, interactions with boundaries yield direction-dependent error correction, suggesting that border cells serve as a neural substrate for error correction. These observations, combined with simulations of an attractor network grid cell model, demonstrate that landmarks are crucial to grid stability.

    View details for DOI 10.1016/j.neuron.2015.03.039

    View details for Web of Science ID 000354069800021

    View details for PubMedID 25892299

  • Hyperpolarization-Activated Cyclic Nucleotide-Gated 1 Independent Grid Cell-Phase Precession in Mice HIPPOCAMPUS Eggink, H., Mertens, P., Storm, E., Giocomo, L. M. 2014; 24 (3): 249-256
  • Emergent elasticity in the neural code for space. Proceedings of the National Academy of Sciences of the United States of America Ocko, S. A., Hardcastle, K., Giocomo, L. M., Ganguli, S. 2018

    Abstract

    Upon encountering a novel environment, an animal must construct a consistent environmental map, as well as an internal estimate of its position within that map, by combining information from two distinct sources: self-motion cues and sensory landmark cues. How do known aspects of neural circuit dynamics and synaptic plasticity conspire to accomplish this feat? Here we show analytically how a neural attractor model that combines path integration of self-motion cues with Hebbian plasticity in synaptic weights from landmark cells can self-organize a consistent map of space as the animal explores an environment. Intriguingly, the emergence of this map can be understood as an elastic relaxation process between landmark cells mediated by the attractor network. Moreover, our model makes several experimentally testable predictions, including (i) systematic path-dependent shifts in the firing fields of grid cells toward the most recently encountered landmark, even in a fully learned environment; (ii) systematic deformations in the firing fields of grid cells in irregular environments, akin to elastic deformations of solids forced into irregular containers; and (iii) the creation of topological defects in grid cell firing patterns through specific environmental manipulations. Taken together, our results conceptually link known aspects of neurons and synapses to an emergent solution of a fundamental computational problem in navigation, while providing a unified account of disparate experimental observations.

    View details for DOI 10.1073/pnas.1805959115

    View details for PubMedID 30482856

  • Self-motion processing in visual and entorhinal cortices: Inputs, integration, and implications for position coding. Journal of neurophysiology Campbell, M. G., Giocomo, L. M. 2018

    Abstract

    The sensory signals generated by self-motion are complex and multimodal, but the ability to integrate these signals into a unified self-motion percept to guide navigation is essential for animal survival. Here, we summarize classic and recent work on self-motion coding in the visual and entorhinal cortices of the rodent brain. We compare motion processing in rodent and primate visual cortices, highlighting the strengths of classic primate work in establishing causal links between neural activity and perception, and discuss the integration of motor and visual signals in rodent visual cortex. We then turn to the medial entorhinal cortex (MEC), where calculations using self-motion to update position estimates are thought to occur. We focus on several key sources of self-motion information to MEC: the medial septum, which provides locomotor speed information; visual cortex, whose input has been increasingly recognized as essential to both position and speed tuned MEC cells; and the head direction system, which is a major source of directional information for self-motion estimates. These inputs create a large and diverse group of self-motion codes in MEC, and great interest remains in how these self-motion codes might be integrated by MEC grid cells to estimate position. However, which signals are used in these calculations and the mechanisms by which they are integrated remain controversial. We end by proposing future experiments that could further our understanding of the interactions between MEC cells that code for self-motion and position, and clarify the relationship between the activity of these cells and spatial perception.

    View details for DOI 10.1152/jn.00686.2017

    View details for PubMedID 30089025

  • Heterogeneity in hippocampal place coding. Current opinion in neurobiology Mallory, C. S., Giocomo, L. M. 2018; 49: 158–67

    Abstract

    The discovery of place cells provided fundamental insight into the neural basis by which the hippocampus encodes spatial memories and supports navigation and prompted the development of computational models to explain the emergence of their spatial selectively. Many such works posit that input from entorhinal grid cells is critical to the formation of place fields, a prediction that has received mixed experimental support. Potentially reconciling seemingly conflicting findings is recent work indicating that subpopulations of pyramidal neurons are functionally distinct and may be driven to varying degrees by different inputs. Additionally, new studies have demonstrated that hippocampal principal neurons encode a myriad of features extending beyond current position. Here, we highlight recent evidence for how extensive heterogeneity in connectivity and genetic expression could interact with membrane biophysics to enable place cells to encode a diverse range of stimuli. These recent findings highlight the need for more computational models that integrate these heterogeneous features of hippocampal principal neurons.

    View details for DOI 10.1016/j.conb.2018.02.014

    View details for PubMedID 29522977

  • From entorhinal neural codes to navigation NATURE NEUROSCIENCE Mallory, C. S., Giocomo, L. M. 2018; 21 (1): 7–8

    View details for DOI 10.1038/s41593-017-0048-2

    View details for Web of Science ID 000423155800005

    View details for PubMedID 29269761

  • Environmental boundaries as a mechanism for correcting and anchoring spatial maps JOURNAL OF PHYSIOLOGY-LONDON Giocomo, L. M. 2016; 594 (22): 6501-6511

    Abstract

    Ubiquitous throughout the animal kingdom, path integration-based navigation allows an animal to take a circuitous route out from a home base and using only self-motion cues, calculate a direct vector back. Despite variation in an animal's running speed and direction, medial entorhinal grid cells fire in repeating place-specific locations, pointing to the medial entorhinal circuit as a potential neural substrate for path integration-based spatial navigation. Supporting this idea, grid cells appear to provide an environment-independent metric representation of the animal's location in space and preserve their periodic firing structure even in complete darkness. However, a series of recent experiments indicate that spatially responsive medial entorhinal neurons depend on environmental cues in a more complex manner than previously proposed. While multiple types of landmarks may influence entorhinal spatial codes, environmental boundaries have emerged as salient landmarks that both correct error in entorhinal grid cells and bind internal spatial representations to the geometry of the external spatial world. The influence of boundaries on error correction and grid symmetry points to medial entorhinal border cells, which fire at a high rate only near environmental boundaries, as a potential neural substrate for landmark-driven control of spatial codes. The influence of border cells on other entorhinal cell populations, such as grid cells, could depend on plasticity, raising the possibility that experience plays a critical role in determining how external cues influence internal spatial representations.

    View details for DOI 10.1113/JP270624

    View details for Web of Science ID 000389029900007

    View details for PubMedID 26563618

  • Large scale in vivo recordings to study neuronal biophysics. Current opinion in neurobiology Giocomo, L. M. 2015; 32: 1-7

    Abstract

    Over the last several years, technological advances have enabled researchers to more readily observe single-cell membrane biophysics in awake, behaving animals. Studies utilizing these technologies have provided important insights into the mechanisms generating functional neural codes in both sensory and non-sensory cortical circuits. Crucial for a deeper understanding of how membrane biophysics control circuit dynamics however, is a continued effort to move toward large scale studies of membrane biophysics, in terms of the numbers of neurons and ion channels examined. Future work faces a number of theoretical and technical challenges on this front but recent technological developments hold great promise for a larger scale understanding of how membrane biophysics contribute to circuit coding and computation.

    View details for DOI 10.1016/j.conb.2014.09.009

    View details for PubMedID 25291296

  • Large scale in vivo recordings to study neuronal biophysics CURRENT OPINION IN NEUROBIOLOGY Giocomo, L. M. 2015; 32: 1-7
  • Neuroscience: Internal compass puts flies in their place. Nature Clandinin, T. R., Giocomo, L. M. 2015; 521 (7551): 165-166

    View details for DOI 10.1038/521165a

    View details for PubMedID 25971505

  • Spatial representation: maps of fragmented space. Current biology Giocomo, L. M. 2015; 25 (9): R362-3

    Abstract

    Grid cells in medial entorhinal cortex are thought to act as a neural metric for spatial navigation. A new study has examined the ability of grid cells to use self-motion cues to form a global map across fragmented spaces.

    View details for DOI 10.1016/j.cub.2015.02.065

    View details for PubMedID 25942547

  • Computational diversity in the hippocampus: a matter of components. journal of physiology Giocomo, L. 2015; 593 (7): 1525-1526

    View details for DOI 10.1113/jphysiol.2014.288456

    View details for PubMedID 25828642

  • Imagine a journey through time and space. Nature neuroscience Giocomo, L. M. 2015; 18 (2): 163-164

    View details for DOI 10.1038/nn.3926

    View details for PubMedID 25622569

  • Topography of head direction cells in medial entorhinal cortex. Current biology Giocomo, L. M., Stensola, T., Bonnevie, T., Van Cauter, T., Moser, M., Moser, E. I. 2014; 24 (3): 252-262

    Abstract

    Neural circuits in the medial entorhinal cortex (MEC) support translation of the external environment to an internal map of space, with grid and head direction neurons providing metrics for distance and orientation.We show here that head direction cells in MEC are organized topographically. Head direction tuning varies widely across the entire dorsoventral MEC axis, but in layer III there is a gradual dorsal-to-ventral increase in the average width of the directional firing field. Sharply tuned cells were encountered only at the dorsal end of MEC. Similar topography was not observed among head direction cells in layers V-VI. At all MEC locations, in all layers, the preferred firing direction (directional phase) showed a uniform distribution. The continuity of the dorsoventral tuning gradient coexisted with discrete topography in the spatial scale of simultaneously recorded grid cells.The findings point to dorsoventral gradients as a fundamental property of entorhinal circuits, upon which modular organization may be expressed in select subpopulations.

    View details for DOI 10.1016/j.cub.2013.12.002

    View details for PubMedID 24440398

  • The neural encoding of space in parahippocampal cortices FRONTIERS IN NEURAL CIRCUITS Giocomo, L. M., Roudi, Y. 2012; 6

    View details for DOI 10.3389/fncir.2012.00053

    View details for Web of Science ID 000307633000002

    View details for PubMedID 22912603

  • Phase precession and variable spatial scaling in a periodic attractor map model of medial entorhinal grid cells with realistic after-spike dynamics HIPPOCAMPUS Navratilova, Z., Giocomo, L. M., Fellous, J., Hasselmo, M. E., McNaughton, B. L. 2012; 22 (4): 772-789

    Abstract

    We present a model that describes the generation of the spatial (grid fields) and temporal (phase precession) properties of medial entorhinal cortical (MEC) neurons by combining network and intrinsic cellular properties. The model incorporates network architecture derived from earlier attractor map models, and is implemented in 1D for simplicity. Periodic driving of conjunctive (position × head-direction) layer-III MEC cells at theta frequency with intensity proportional to the rat's speed, moves an 'activity bump' forward in network space at a corresponding speed. The addition of prolonged excitatory currents and simple after-spike dynamics resembling those observed in MEC stellate cells (for which new data are presented) accounts for both phase precession and the change in scale of grid fields along the dorso-ventral axis of MEC. Phase precession in the model depends on both synaptic connectivity and intrinsic currents, each of which drive neural spiking either during entry into, or during exit out of a grid field. Thus, the model predicts that the slope of phase precession changes between entry into and exit out of the field. The model also exhibits independent variation in grid spatial period and grid field size, which suggests possible experimental tests of the model.

    View details for DOI 10.1002/hipo.20939

    View details for Web of Science ID 000301776200011

    View details for PubMedID 21484936

  • Spatial Representation: Maps in a Temporal Void CURRENT BIOLOGY Giocomo, L. M., Moser, E. I. 2011; 21 (23): R962-R964

    Abstract

    It has been suggested that the matrix-like firing structure of entorhinal grid cells is caused by interference between membrane oscillations at slightly different theta frequencies. A recent report suggests that grid signals can be generated in the absence of theta oscillations.

    View details for Web of Science ID 000298028100018

    View details for PubMedID 22153167

  • Grid Cells Use HCN1 Channels for Spatial Scaling CELL Giocomo, L. M., Hussaini, S. A., Zheng, F., Kandel, E. R., Moser, M., Moser, E. I. 2011; 147 (5): 1159-1170

    Abstract

    Entorhinal grid cells have periodic, hexagonally patterned firing locations that scale up progressively along the dorsal-ventral axis of medial entorhinal cortex. This topographic expansion corresponds with parallel changes in cellular properties dependent on the hyperpolarization-activated cation current (Ih), which is conducted by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. To test the hypothesis that grid scale is determined by Ih, we recorded grid cells in mice with forebrain-specific knockout of HCN1. We find that, although the dorsal-ventral gradient of the grid pattern was preserved in HCN1 knockout mice, the size and spacing of the grid fields, as well as the period of the accompanying theta modulation, was expanded at all dorsal-ventral levels. There was no change in theta modulation of simultaneously recorded entorhinal interneurons. These observations raise the possibility that, during self-motion-based navigation, Ih contributes to the gain of the transformation from movement signals to spatial firing fields.

    View details for DOI 10.1016/j.cell.2011.08.051

    View details for Web of Science ID 000297376600025

    View details for PubMedID 22100643

  • Frequency of Subthreshold Oscillations at Different Membrane Potential Voltages in Neurons at Different Anatomical Positions on the Dorsoventral Axis in the Rat Medial Entorhinal Cortex JOURNAL OF NEUROSCIENCE Yoshida, M., Giocomo, L. M., Boardman, I., Hasselmo, M. E. 2011; 31 (35): 12683-12694

    Abstract

    Neurons from layer II of the medial entorhinal cortex show subthreshold membrane potential oscillations (SMPOs) which could contribute to theta-rhythm generation in the entorhinal cortex and to generation of grid cell firing patterns. However, it is unclear whether single neurons have a fixed unique oscillation frequency or whether their frequency varies depending on the mean membrane potential in a cell. We therefore examined the frequency of SMPOs at different membrane potentials in layer II stellate-like cells of the rat medial entorhinal cortex in vitro. Using whole-cell patch recordings, we found that the fluctuations in membrane potential show a broad band of low power frequencies near resting potential that transition to more narrowband oscillation frequencies with depolarization. The transition from broadband to narrowband frequencies depends on the location of the neuron along the dorsoventral axis in the entorhinal cortex, with dorsal neurons transitioning to higher-frequency oscillations relative to ventral neurons transitioning to lower-frequency oscillations. Once SMPOs showed a narrowband frequency, systematic frequency changes were not observed with further depolarization. Using a Hodgkin-Huxley-style model of membrane currents, we show that differences in the influence of depolarization on the frequency of SMPOs at different dorsal to ventral positions could arise from differences in the properties of the h current. The properties of frequency changes in this data are important for evaluating models of the generation of grid cell firing fields with different spacings along the dorsal-to-ventral axis of medial entorhinal cortex.

    View details for DOI 10.1523/JNEUROSCI.1654-11.2011

    View details for Web of Science ID 000294451900031

    View details for PubMedID 21880929

  • Computational Models of Grid Cells NEURON Giocomo, L. M., Moser, M., Moser, E. I. 2011; 71 (4): 589-603

    Abstract

    Grid cells are space-modulated neurons with periodic firing fields. In moving animals, the multiple firing fields of an individual grid cell form a triangular pattern tiling the entire space available to the animal. Collectively, grid cells are thought to provide a context-independent metric representation of the local environment. Since the discovery of grid cells in 2005, a number of models have been proposed to explain the formation of spatially repetitive firing patterns as well as the conversion of these signals to place signals one synapse downstream in the hippocampus. The present article reviews the most recent developments in our understanding of how grid patterns are generated, maintained, and transformed, with particular emphasis on second-generation computational models that have emerged during the past 2-3 years in response to criticism and new data.

    View details for DOI 10.1016/j.neuron.2011.07.023

    View details for Web of Science ID 000294521600006

    View details for PubMedID 21867877

  • Cellular dynamical mechanisms for encoding the time and place of events along spatiotemporal trajectories in episodic memory BEHAVIOURAL BRAIN RESEARCH Hasselmo, M. E., Giocomo, L. M., Brandon, M. P., Yoshida, M. 2010; 215 (2): 261-274

    Abstract

    Understanding the mechanisms of episodic memory requires linking behavioral data and lesion effects to data on the dynamics of cellular membrane potentials and population interactions within brain regions. Linking behavior to specific membrane channels and neurochemicals has implications for therapeutic applications. Lesions of the hippocampus, entorhinal cortex and subcortical nuclei impair episodic memory function in humans and animals, and unit recording data from these regions in behaving animals indicate episodic memory processes. Intracellular recording in these regions demonstrates specific cellular properties including resonance, membrane potential oscillations and bistable persistent spiking that could underlie the encoding and retrieval of episodic trajectories. A model presented here shows how intrinsic dynamical properties of neurons could mediate the encoding of episodic memories as complex spatiotemporal trajectories. The dynamics of neurons allow encoding and retrieval of unique episodic trajectories in multiple continuous dimensions including temporal intervals, personal location, the spatial coordinates and sensory features of perceived objects and generated actions, and associations between these elements. The model also addresses how cellular dynamics could underlie unit firing data suggesting mechanisms for coding continuous dimensions of space, time, sensation and action.

    View details for DOI 10.1016/j.bbr.2009.12.010

    View details for Web of Science ID 000282505600011

    View details for PubMedID 20018213

  • Cholinergic Modulation of the Resonance Properties of Stellate Cells in Layer II of Medial Entorhinal Cortex JOURNAL OF NEUROPHYSIOLOGY Heys, J. G., Giocomo, L. M., Hasselmo, M. E. 2010; 104 (1): 258-270

    Abstract

    In vitro whole cell patch-clamp recordings of stellate cells in layer II of medial entorhinal cortex show a subthreshold membrane potential resonance in response to a sinusoidal current injection of varying frequency. Physiological recordings from awake behaving animals show that neurons in layer II medial entorhinal cortex, termed "grid cells," fire in a spatially selective manner such that each cell's multiple firing fields form a hexagonal grid. Both the spatial periodicity of the grid fields and the resonance frequency change systematically in neurons along the dorsal to ventral axis of medial entorhinal cortex. Previous work has also shown that grid field spacing and acetylcholine levels change as a function of the novelty to a particular environment. Using in vitro whole cell patch-clamp recordings, our study shows that both resonance frequency and resonance strength vary as a function of cholinergic modulation. Furthermore, our data suggest that these changes in resonance properties are mediated through modulation of h-current and m-current.

    View details for DOI 10.1152/jn.00492.2009

    View details for Web of Science ID 000279586400024

    View details for PubMedID 20445030

  • Evaluation of the Oscillatory Interference Model of Grid Cell Firing through Analysis and Measured Period Variance of Some Biological Oscillators PLOS COMPUTATIONAL BIOLOGY Zilli, E. A., Yoshida, M., Tahvildari, B., Giocomo, L. M., Hasselmo, M. E. 2009; 5 (11)

    Abstract

    Models of the hexagonally arrayed spatial activity pattern of grid cell firing in the literature generally fall into two main categories: continuous attractor models or oscillatory interference models. Burak and Fiete (2009, PLoS Comput Biol) recently examined noise in two continuous attractor models, but did not consider oscillatory interference models in detail. Here we analyze an oscillatory interference model to examine the effects of noise on its stability and spatial firing properties. We show analytically that the square of the drift in encoded position due to noise is proportional to time and inversely proportional to the number of oscillators. We also show there is a relatively fixed breakdown point, independent of many parameters of the model, past which noise overwhelms the spatial signal. Based on this result, we show that a pair of oscillators are expected to maintain a stable grid for approximately t = 5mu(3)/(4pisigma)(2) seconds where mu is the mean period of an oscillator in seconds and sigma(2) its variance in seconds(2). We apply this criterion to recordings of individual persistent spiking neurons in postsubiculum (dorsal presubiculum) and layers III and V of entorhinal cortex, to subthreshold membrane potential oscillation recordings in layer II stellate cells of medial entorhinal cortex and to values from the literature regarding medial septum theta bursting cells. All oscillators examined have expected stability times far below those seen in experimental recordings of grid cells, suggesting the examined biological oscillators are unfit as a substrate for current implementations of oscillatory interference models. However, oscillatory interference models can tolerate small amounts of noise, suggesting the utility of circuit level effects which might reduce oscillator variability. Further implications for grid cell models are discussed.

    View details for DOI 10.1371/journal.pcbi.1000573

    View details for Web of Science ID 000274228500021

    View details for PubMedID 19936051

  • A phase code for memory could arise from circuit mechanisms in entorhinal cortex NEURAL NETWORKS Hasselmo, M. E., Brandon, M. P., Yoshida, M., Giocomo, L. M., Heys, J. G., Fransen, E., Newman, E. L., Zilli, E. A. 2009; 22 (8): 1129-1138

    Abstract

    Neurophysiological data reveals intrinsic cellular properties that suggest how entorhinal cortical neurons could code memory by the phase of their firing. Potential cellular mechanisms for this phase coding in models of entorhinal function are reviewed. This mechanism for phase coding provides a substrate for modeling the responses of entorhinal grid cells, as well as the replay of neural spiking activity during waking and sleep. Efforts to implement these abstract models in more detailed biophysical compartmental simulations raise specific issues that could be addressed in larger scale population models incorporating mechanisms of inhibition.

    View details for DOI 10.1016/j.neunet.2009.07.012

    View details for Web of Science ID 000271175800010

    View details for PubMedID 19656654

  • Knock-Out of HCN1 Subunit Flattens Dorsal-Ventral Frequency Gradient of Medial Entorhinal Neurons in Adult Mice JOURNAL OF NEUROSCIENCE Giocomo, L. M., Hasselmo, M. E. 2009; 29 (23): 7625-7630

    Abstract

    Layer II stellate cells at different locations along the dorsal to ventral axis of medial entorhinal cortex show differences in the frequency of intrinsic membrane potential oscillations and resonance (Giocomo et al., 2007). The frequency differences scale with differences in the size and spacing of grid-cell firing fields recorded in layer II of the medial entorhinal cortex in behaving animals. To determine the mechanism for this difference in intrinsic frequency, we analyzed oscillatory properties in adult control mice and adult mice with a global deletion of the HCN1 channel. Data from whole-cell patch recordings show that the oscillation frequency gradient along the dorsal-ventral axis previously shown in juvenile rats also appears in control adult mice, indicating that the dorsal-ventral gradient generalizes across age and species. Knock-out of the HCN1 channel flattens the dorsal-ventral gradient of the membrane potential oscillation frequency, the resonant frequency, the time constant of the "sag" potential and the amplitude of the sag potential. This supports a role of the HCN1 subunit in the mechanism of the frequency gradient in these neurons. These findings have important implications for models of grid cells and generate predictions for future in vivo work on entorhinal grid cells.

    View details for DOI 10.1523/JNEUROSCI.0609-09.2009

    View details for Web of Science ID 000267130800027

    View details for PubMedID 19515931

  • Time constants of h current in layer II stellate cells differ along the dorsal to ventral axis of medial Entorhinal cortex JOURNAL OF NEUROSCIENCE Giocomo, L. M., Hasselmo, M. E. 2008; 28 (38): 9414-9425

    Abstract

    Chronic recordings in the medial entorhinal cortex of behaving rats have found grid cells, neurons that fire when the rat is in a hexagonal array of locations. Grid cells recorded at different dorsal-ventral anatomical positions show systematic changes in size and spacing of firing fields. To test possible mechanisms underlying these differences, we analyzed properties of the hyperpolarization-activated cation current I(h) in voltage-clamp recordings from stellate cells in entorhinal slices from different dorsal-ventral locations. The time constant of h current was significantly different between dorsal and ventral neurons. The time constant of h current correlated with membrane potential oscillation frequency and the time constant of the sag potential in the same neurons. Differences in h current could underlie differences in membrane potential oscillation properties and contribute to grid cell periodicity along the dorsal-ventral axis of medial entorhinal cortex.

    View details for DOI 10.1523/JNEUROSCI.3196-08.2008

    View details for Web of Science ID 000259288900010

    View details for PubMedID 18799674

  • Computation by Oscillations: Implications of Experimental Data for Theoretical Models of Grid Cells HIPPOCAMPUS Giocomo, L. M., Hasselmo, M. E. 2008; 18 (12): 1186-1199

    Abstract

    Recordings in awake, behaving animals demonstrate that cells in medial entorhinal cortex (mEC) show "grid cell" firing activity when a rat explores an open environment. Intracellular recording in slices from different positions along the dorsal to ventral axis show differences in intrinsic properties such as subthreshold membrane potential oscillations (MPO), resonant frequency, and the presence of the hyperpolarization-activated cation current (h-current). The differences in intrinsic properties correlate with differences in grid cell spatial scale along the dorsal-ventral axis of mEC. Two sets of computational models have been proposed to explain the grid cell firing phenomena: oscillatory interference models and attractor-dynamic models. Both types of computational models are briefly reviewed, and cellular experimental evidence is interpreted and presented in the context of both models. The oscillatory interference model has variations that include an additive model and a multiplicative model. Experimental data on the voltage-dependence of oscillations presented here support the additive model. The additive model also simulates data from ventral neurons showing large spacing between grid firing fields within the limits of observed MPO frequencies. The interactions of h-current with synaptic modification suggest that the difference in intrinsic properties could also contribute to differences in grid cell properties due to attractor dynamics along the dorsal to ventral axis of mEC. Mechanisms of oscillatory interference and attractor dynamics may make complementary contributions to the properties of grid cell firing in entorhinal cortex.

    View details for DOI 10.1002/hipo.20501

    View details for Web of Science ID 000261871800005

    View details for PubMedID 19021252

  • Mechanisms for Memory-Guided Behavior Involving Persistent Firing and Theta Rhythm Oscillations in the Entorhinal Cortex 12th International Summer School on Neural Networks Hasselmo, M. E., Giocomo, L. M., Brandon, M. P., Yoshida, M. SPRINGER-VERLAG BERLIN. 2008: 28–37
  • Neuromodulation by glutamate and acetylcholine can change circuit dynamics by regulating the relative influence of afferent input and excitatory feedback MOLECULAR NEUROBIOLOGY Giocomo, L. M., Hasselmo, M. E. 2007; 36 (2): 184-200

    Abstract

    Substances such as acetylcholine and glutamate act as both neurotransmitters and neuromodulators. As neuromodulators, they change neural information processing by regulating synaptic transmitter release, altering baseline membrane potential and spiking activity, and modifying long-term synaptic plasticity. Slice physiology research has demonstrated that many neuromodulators differentially modulate afferent, incoming information compared to intrinsic and recurrent processing in cortical structures such as piriform cortex, neocortex, and the hippocampus. The enhancement of afferent (external) pathways versus the suppression at recurrent (internal) pathways could cause cortical dynamics to switch between a predominant influence of external stimulation to a predominant influence of internal recall. Modulation of afferent versus intrinsic processing could contribute to the role of neuromodulators in regulating attention, learning, and memory effects in behavior.

    View details for DOI 10.1007/s12035-007-0032-z

    View details for Web of Science ID 000250305300004

    View details for PubMedID 17952661

  • Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing SCIENCE Giocomo, L. M., Zilli, E. A., Fransen, E., Hasselmo, M. E. 2007; 315 (5819): 1719-1722

    Abstract

    Grid cells in layer II of rat entorhinal cortex fire to spatial locations in a repeating hexagonal grid, with smaller spacing between grid fields for neurons in more dorsal anatomical locations. Data from in vitro whole-cell patch recordings showed differences in frequency of subthreshold membrane potential oscillations in entorhinal neurons that correspond to different positions along the dorsal-to-ventral axis, supporting a model of physiological mechanisms for grid cell responses.

    View details for DOI 10.1126/science.1139207

    View details for Web of Science ID 000245106900042

    View details for PubMedID 17379810

    View details for PubMedCentralID PMC2950607

  • Grid cell firing may arise from interference of theta frequency membrane potential oscillations in single neurons HIPPOCAMPUS Hasselmo, M. E., Giocomo, L. M., Zilli, E. A. 2007; 17 (12): 1252-1271

    Abstract

    Intracellular recording and computational modelling suggest that interactions of subthreshold membrane potential oscillation frequency in different dendritic branches of entorhinal cortex stellate cells could underlie the functional coding of continuous dimensions of space and time. Among other things, these interactions could underlie properties of grid cell field spacing. The relationship between experimental data on membrane potential oscillation frequency (f) and grid cell field spacing (G) indicates a constant scaling factor H = fG. This constant scaling factor between temporal oscillation frequency and spatial periodicity provides a starting constraint that is used to derive the model of Burgess et al. (Hippocampus, 2007). This model provides a consistent quantitative link between single cell physiological properties and properties of spiking units in awake behaving animals. Further properties and predictions of this model about single cell and network physiological properties are analyzed. In particular, the model makes quantitative predictions about the change in membrane potential, single cell oscillation frequency, and network oscillation frequency associated with speed of movement, about the independence of single cell properties from network theta rhythm oscillations, and about the effect of variations in initial oscillatory phase on the pattern of grid cell firing fields. These same mechanisms of subthreshold oscillations may play a more general role in memory function, by providing a method for learning arbitrary time intervals in memory sequences.

    View details for DOI 10.1002/hipo.20374

    View details for Web of Science ID 000251553400012

    View details for PubMedID 17924530

  • Muscarinic suppression in stratum radiatum of CA1 shows dependence on presynaptic M1 receptors and is not dependent on effects at GABA(B) receptors NEUROBIOLOGY OF LEARNING AND MEMORY Kremin, T., Gerber, D., Giocomo, L. M., Huang, S. Y., Tonegawa, S., Hasselmo, M. E. 2006; 85 (2): 153-163

    Abstract

    Cholinergic modulation of synaptic transmission is vital to memory processes and may be responsible for setting network dynamics in the hippocampus appropriate for encoding of information. found evidence suggesting M1 receptors cause presynaptic inhibition of glutamatergic transmission, while research supports a role of the M2 receptor. We examined muscarinic inhibition of fEPSPs in stratum radiatum of mice lacking m1 subtype receptors (KO) compared to wild type (WT) controls. WT mice exhibit greater suppression of transmission by muscarine as compared to KO in a dose dependent fashion. Oxotremorine shows no significant difference in suppression between WT and KO, while MCN-A-343, an M1 agonist, exhibits a significant difference between KO and WT, with KO showing no suppression. One hundred micromolar SGS-742, a selective GABA(B) antagonist, fails to affect either normal transmission or muscarinic suppression in either WT or KO suggesting that differences in suppression between the groups is not attributable to differences in GABA(B) receptor activation due to muscarinic activation of GABAergic interneurons. These findings support a role for presynaptic m1 mAChRs in modulation of synaptic transmission in CA1, but indicate that other muscarinic receptor subtypes, such as M2, are also involved in suppression of synaptic potentials.

    View details for DOI 10.1016/j.nlm.2005.09.005

    View details for Web of Science ID 000235896900006

    View details for PubMedID 16290192

  • Difference in time course of modulation of synaptic transmission by group II versus group III metabotropic glutamate receptors in region CA1 of the hippocampus HIPPOCAMPUS Giocomo, L. M., Hasselmo, M. E. 2006; 16 (11): 1004-1016

    Abstract

    We investigated the time course of modulation of synaptic transmission by group II and group III metabotropic glutamate receptors in region CA1 of the hippocampus. In the presence of 50 microM picrotoxin, pressure pulse application of 1 mM glutamate resulted in a fast onset of suppression of synaptic transmission in stratum lacunosum moleculare and a slower onset of suppression in stratum radiatum, with both effects returning to baseline over the course of several minutes. Application of 50 microM of the group II agonist (2R,4R)-APDC in stratum lacunosum moleculare resulted in the same fast onset of suppression while having no effect in stratum radiatum. Pressure pulse application of 100 microM DL-AP4 in stratum lacunosum moleculare and stratum radiatum resulted in a much slower onset of suppression of synaptic transmission than (2R,4R)-APDC. Suppression by (2R,4R)-APDC was accompanied by a rapid enhancement of paired pulse facilitation, indicative of a presynaptic mechanism. This demonstrates that activation of group II mGluRs in the hippocampus causes a fast onset of suppression in stratum lacunosum moleculare, while activation of group III mGluRs causes a slower onset of suppression. The difference in time course for group II vs. group III mGluRs suggests a different functional role, with group II playing a potential role in making synapses act as low pass filters.

    View details for DOI 10.1002/hipo.20231

    View details for Web of Science ID 000241833500010

    View details for PubMedID 17039485

  • Cholinergic modulation of cortical function 12th International Symposium on Cholinergic Mechanisms Hasselmo, M. E., Giocomo, L. M. HUMANA PRESS INC. 2006: 133–35

    Abstract

    Extensive physiological research has demonstrated a number of common effects of acetylcholine within cortical structures, including the hippocampus, piriform cortex, and neocortex (Hasselmo, 1995, 1999). This article will provide a description of how the different physiological effects of acetylcholine could interact to alter specific functional properties of the cortex. The physiological effects of acetylcholine serve to enhance the influence of feed- forward afferent input to the cortex while decreasing background activity by suppressing excitatory feedback connections within cortical circuits. By enhancing the response to sensory input, high levels of acetylcholine enhance attention to sensory stimuli in the environment and enhance encoding of memory for specific stimuli. Interference from prior memory is reduced by suppressing synapses modified by prior learning (Sevilla et al., 2002; Linster et al., 2003).

    View details for DOI 10.1385/JMN/30:1-2:133

    View details for Web of Science ID 000242432200059

    View details for PubMedID 17192659

  • Nicotinic modulation of glutamatergic synaptic transmission in region CA3 of the hippocampus EUROPEAN JOURNAL OF NEUROSCIENCE Giocomo, L. M., Hasselmo, M. E. 2005; 22 (6): 1349-1356

    Abstract

    Cholinergic modulation of synaptic transmission in the hippocampus appears to be involved in learning, memory and attentional processes. In brain slice preparations of hippocampal region CA3, we have explored the effect of nicotine on the afferent connections of stratum lacunosum moleculare (SLM) vs. the intrinsic connections of stratum radiatum (SR). Nicotine application had a lamina-selective effect, causing changes in synaptic transmission only in SLM. The nicotinic effect in SLM was characterized by a transient decrease in synaptic potential size followed by a longer period of enhancement of synaptic transmission. The effect was blocked by gamma-aminobutyric acid (GABA)ergic antagonists, indicating the role of GABAergic interneurons in the observed nicotinic effect. The biphasic nature of the nicotinic effect could be due to a difference in receptor subtypes, as supported by the effects of the nicotinic antagonists mecamylamine and methyllycaconitine. Nicotinic modulation of glutamatergic synaptic transmission could complement muscarinic suppression of intrinsic connections, amplifying incoming information and providing a physiological mechanism for the memory-enhancing effect of nicotine.

    View details for DOI 10.1111/j.1460-9568.2005.04316.x

    View details for Web of Science ID 000232142000009

    View details for PubMedID 16190890