Loren Frank, PhD

Professor
Physiology

Research Overview

The ability to store experiences and then use them to guide behavior is one of the most remarkable abilities of the brain. Our goal is to understand how activity and plasticity in neural circuits underlie both learning and the ability to use learned information to make decisions. In particular, our laboratory focuses on the circuitry of the hippocampus and anatomically related regions. We use a combination of techniques, including large scale multielectrode recording, targeted optogenetic interventions and behavioral manipulations of awake, behaving animals to understand how the brain learns and remembers.

Learning in the Hippocampus and Cortex

Previous studies have shown that neurons throughout the hippocampal formation show place specific firing patterns, where a given neuron is active only in a subregion of the animal's environment. Most of these studies focused on describing patterns of activity during well learned tasks, and we therefore know little about neural processing during learning. We have developed a spatial alternation task that animals can learn over the course of a few days of exposure. We have shown that rapid learning in this task requires an intact hippocampus, and thus this task provides a powerful paradigm for examining the relationship between dynamic patterns of neural activity and changes in behavior.

Although the hippocampus is essential for spatial learning, storing and retrieving new information requires complex networks spread throughout the brain. One prominent hypothesis states that learning takes place first in the hippocampus and over time information is transferred to neocortical regions in a process known as consolidation. We are therefore recording both in the hippocampus and in downstream areas to understand how hippocampal and cortical circuits could support learning, consolidation and memory guided behavior.

These studies continue to provide important new insights into how the brain changes as animals learn and how memory retrieval might occur, but these insights are fundamentally correlational in nature. We have therefore been developing and apply new techniques, including optogenetic manipulations, to take these correlational hypothesis and turn them into causal understanding. We can now express optically activated channels in specific subpopulations of neurons in the rat hippocampus and activate these channels with an implanted fiber optic. We have also combined this optical activation with large scale multielectrode recording, allowing us to manipulate the circuit and record the results both locally and in more distant brain regions.
Anatomical Organization of the Hippocampus

The hippocampal formation has a unique anatomical organization in that the connectivity between adjacent hippocampal regions is almost exclusively unidirectional. The majority of neocortical input to the hippocampus comes in through the superficial layers of the entorhinal cortex and connections proceed through the dentate gyrus, to CA3 and on to CA1 (the hippocampus proper), and then to the subiculum. Nearly all neocortically bound outputs from the hippocampus originate in CA1 and the subiculum and target cells in the deep layers of the entorhinal cortex, which projects both to numerous neocortical regions as well as to back to the superficial layers of the entorhinal cortex. Our research uses that organization to compare patterns of activity across regions and to use the similarities and differences among the patterns to identify the transformations that occur in the hippocampal circuit.

An Animal Model for Hippocampal Function

Numerous researchers have shown that a human without a hippocampus is unable to form new memories of facts or events. In rodents these same structures play an essential role in animal's abilities to learn about and remember complex associations, including tasks where the animal must learn and remember information about a set of spatial cues in order to navigate through an environment. Event/fact memory in humans and spatial memory in rodents both require learning complex relationships, and that parallel strongly suggests that qualitatively similar processing occurs in the human and the rat hippocampus.

Publications: 

Spatial preferences account for inter-animal variability during the continual learning of a dynamic cognitive task.

Cell reports

Kastner DB, Miller EA, Yang Z, Roumis DK, Liu DF, Frank LM, Dayan P

A Variable Clock Underlies Internally Generated Hippocampal Sequences.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Deng X, Chen S, Sosa M, Karlsson MP, Wei XX, Frank LM

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Cell reports

Aery Jones EA, Rao A, Zilberter M, Djukic B, Bant JS, Gillespie AK, Koutsodendris N, Nelson M, Yoon SY, Huang K, Yuan H, Gill TM, Huang Y, Frank LM

Hippocampal replay of experience at real-world speeds.

eLife

Denovellis EL, Gillespie AK, Coulter ME, Sosa M, Chung JE, Eden UT, Frank LM

Rats use memory confidence to guide decisions.

Current biology : CB

Joo HR, Liang H, Chung JE, Geaghan-Breiner C, Fan JL, Nachman BP, Kepecs A, Frank LM

Hippocampal replay reflects specific past experiences rather than a plan for subsequent choice.

Neuron

Gillespie AK, Astudillo Maya DA, Denovellis EL, Liu DF, Kastner DB, Coulter ME, Roumis DK, Eden UT, Frank LM

Scalable method for micro-CT analysis enables large scale quantitative characterization of brain lesions and implants.

Scientific reports

Kastner DB, Kharazia V, Nevers R, Smyth C, Astudillo-Maya DA, Williams GM, Yang Z, Holobetz CM, Santina LD, Parkinson DY, Frank LM

Real-Time Point Process Filter for Multidimensional Decoding Problems Using Mixture Models.

Journal of neuroscience methods

Rezaei MR, Arai K, Frank LM, Eden UT, Yousefi A

Memory alone does not account for the speed of learning of a simple spatial alternation task in rats.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Kastner DB, Gillespie AK, Dayan P, Frank LM

Robust and replicable measurement for prepulse inhibition of the acoustic startle response.

Molecular psychiatry

Miller EA, Kastner DB, Grzybowski MN, Dwinell MR, Geurts AM, Frank LM

Constant Sub-second Cycling between Representations of Possible Futures in the Hippocampus.

Cell

Kay K, Chung JE, Sosa M, Schor JS, Karlsson MP, Larkin MC, Liu DF, Frank LM

A microfabricated, 3D-sharpened silicon shuttle for insertion of flexible electrode arrays through dura mater into brain.

Journal of neural engineering

Joo HR, Fan JL, Chen S, Pebbles JA, Liang H, Chung JE, Yorita AM, Tooker A, Tolosa V, Geaghan-Breiner C, Roumis D, Liu D, Haque R, Frank L

BRAIN Initiative: Cutting-Edge Tools and Resources for the Community.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Litvina E, Adams A, Barth A, Bruchez M, Carson J, Chung JE, Dupre KB, Frank LM, Gates KM, Harris KM, Joo H, William Lichtman J, Ramos KM, Sejnowski T, Trimmer JS, White S, Koroshetz W

Chronic Implantation of Multiple Flexible Polymer Electrode Arrays.

Journal of visualized experiments : JoVE

Chung JE, Joo HR, Smyth CN, Fan JL, Geaghan-Breiner C, Liang H, Liu DF, Roumis D, Chen S, Lee KY, Pebbles JA, Tooker AC, Tolosa VM, Frank LM

Efficient Decoding of Multi-Dimensional Signals From Population Spiking Activity Using a Gaussian Mixture Particle Filter.

IEEE transactions on bio-medical engineering

Yousefi A, Gillespie AK, Guidera JA, Karlsson M, Frank LM, Eden UT

High-Density, Long-Lasting, and Multi-region Electrophysiological Recordings Using Polymer Electrode Arrays.

Neuron

Chung JE, Joo HR, Fan JL, Liu DF, Barnett AH, Chen S, Geaghan-Breiner C, Karlsson MP, Karlsson M, Lee KY, Liang H, Magland JF, Pebbles JA, Tooker AC, Greengard LF, Tolosa VM, Frank LM

The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.

Cell

Willsey AJ, Morris MT, Wang S, Willsey HR, Sun N, Teerikorpi N, Baum TB, Cagney G, Bender KJ, Desai TA, Srivastava D, Davis GW, Doudna J, Chang E, Sohal V, Lowenstein DH, Li H, Agard D, Keiser MJ, Shoichet B, von Zastrow M, Mucke L, Finkbeiner S, Gan L, Sestan N, Ward ME, Huttenhain R, Nowakowski TJ, Bellen HJ, Frank LM, Khokha MK, Lifton RP, Kampmann M, Ideker T, State MW, Krogan NJ

A Comparison Study of Point-Process Filter and Deep Learning Performance in Estimating Rat Position Using an Ensemble of Place Cells.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

Rezaei MR, Gillespie AK, Guidera JA, Nazari B, Sadri S, Frank LM, Eden UT, Yousefi A

Specific hippocampal representations are linked to generalized cortical representations in memory.

Nature communications

Yu JY, Liu DF, Loback A, Grossrubatscher I, Frank LM

International Neuroscience Initiatives through the Lens of High-Performance Computing.

Computer

Kristofer E. Bouchard, James B. Aimone, Miyoung Chun, Thomas Dean, Michael Denker, Markus Diesmann, David D. Donofrio, Loren M. Frank, Narayanan Kasthuri, Christof Koch, Oliver Rubel, Horst D. Simon, F.T. Sommer, Prabhat

Characterizing Complex, Multi-Scale Neural Phenomena Using State-Space Models.

Dynamic Neuroscience

Uri T. Eden, Loren M. Frank, Long Tao

Neural Activity Patterns Underlying Spatial Coding in the Hippocampus.

Current topics in behavioral neurosciences

Sosa M, Gillespie AK, Frank LM

Hippocampal-Prefrontal Reactivation during Learning Is Stronger in Awake Compared with Sleep States.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Tang W, Shin JD, Frank LM, Jadhav SP

A Fully Automated Approach to Spike Sorting.

Neuron

Chung JE, Magland JF, Barnett AH, Tolosa VM, Tooker AC, Lee KY, Shah KG, Felix SH, Frank LM, Greengard LF

Distinct hippocampal-cortical memory representations for experiences associated with movement versus immobility.

eLife

Yu JY, Kay K, Liu DF, Grossrubatscher I, Loback A, Sosa M, Chung JE, Karlsson MP, Larkin MC, Frank LM

High-Performance Computing in Neuroscience for Data-Driven Discovery, Integration, and Dissemination.

Neuron

Bouchard KE, Aimone JB, Chun M, Dean T, Denker M, Diesmann M, Donofrio DD, Frank LM, Kasthuri N, Koch C, Ruebel O, Simon HD, Sommer FT

Cover Image, Volume 26, Issue 10.

Hippocampus

Howard Eichenbaum, David G. Amaral, Elizabeth A. Buffalo, György Buzsáki, Neal Cohen, Lila Davachi, Loren Frank, Stephan Heckers, Richard G. M. Morris, Edvard I. Moser, Lynn Nadel, John O'Keefe, Alison Preston, Charan Ranganath, Alcino Silva, Menno Witter

Rapid classification of hippocampal replay content for real-time applications.

Journal of neurophysiology

Deng X, Liu DF, Karlsson MP, Frank LM, Eden UT

Hippocampus at 25.

Hippocampus

Eichenbaum H, Amaral DG, Buffalo EA, Buzsáki G, Cohen N, Davachi L, Frank L, Heckers S, Morris RG, Moser EI, Nadel L, O'Keefe J, Preston A, Ranganath C, Silva A, Witter M

Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.

Neuron

Gillespie AK, Jones EA, Lin YH, Karlsson MP, Kay K, Yoon SY, Tong LM, Nova P, Carr JS, Frank LM, Huang Y

A hippocampal network for spatial coding during immobility and sleep.

Nature

Kay K, Sosa M, Chung JE, Karlsson MP, Larkin MC, Frank LM

Decoding position from multiunit activity using a marked point process filter.

BMC Neuroscience

Xinyi Deng, Daniel F Liu, Kenneth Kay, Loren M Frank, Uri T Eden

Hippocampal sharp-wave ripples in waking and sleeping states.

Current opinion in neurobiology

Roumis DK, Frank LM

Dynamic Hippocampal Circuits Support Learning- and Memory-Guided Behaviors.

Cold Spring Harbor symposia on quantitative biology

Anderson EB, Grossrubatscher I, Frank L

Reconceiving the hippocampal map as a topological template.

eLife

Dabaghian Y, Brandt VL, Frank LM

Hippocampal-cortical interaction in decision making.

Neurobiology of learning and memory

Yu JY, Frank LM

Memory Replay in the Hippocampus.

Space,Time and Memory in the Hippocampal Formation

Shantanu P. Jadhav, Loren M. Frank

Towards a large-scale recording system: demonstration of polymer-based penetrating array for chronic neural recording.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

Tooker A, Liu D, Anderson EB, Felix S, Shah KG, Lee KY, Chung JE, Pannu S, Frank L, Tolosa V

Insertion of flexible neural probes using rigid stiffeners attached with biodissolvable adhesive.

Journal of visualized experiments : JoVE

Felix SH, Shah KG, Tolosa VM, Sheth HJ, Tooker AC, Delima TL, Jadhav SP, Frank LM, Pannu SS

A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge.

Nature

Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K

Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Kim SM, Ganguli S, Frank LM

Awake hippocampal sharp-wave ripples support spatial memory.

Science (New York, N.Y.)

Jadhav SP, Kemere C, German PW, Frank LM

Optetrode: a multichannel readout for optogenetic control in freely moving mice.

Nature neuroscience

Anikeeva P, Andalman AS, Witten I, Warden M, Goshen I, Grosenick L, Gunaydin LA, Frank LM, Deisseroth K

Acquisition of neural learning in cerebellum and cerebral cortex for smooth pursuit eye movements.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Li JX, Medina JF, Frank LM, Lisberger SG

Probability of repeating patterns in simultaneous neural data.

Neural computation

Smith AC, Nguyen VK, Karlsson MP, Frank LM, Smith P

Experience-dependent development of coordinated hippocampal spatial activity representing the similarity of related locations.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Singer AC, Karlsson MP, Nathe AR, Carr MF, Frank LM

Reactivating memories for consolidation.

Neuron

Jadhav SP, Frank LM

Awake replay of remote experiences in the hippocampus.

Nature neuroscience

Karlsson MP, Frank LM

Network dynamics underlying the formation of sparse, informative representations in the hippocampus.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Karlsson MP, Frank LM

69: The role of primary human herpesvirus 6, 7 (HHV-6, HHV-7) infection in febrile status epilepticus.

Journal of Clinical Virology

L. Epstein, D.R. Nordli, A. Hamidullah, J.M. Pellock, L.M. Frank, D.V. Lewis, D.C. Hesdorffer, A. Marmarou, C. O'Dell, S. Shinnar

Functional magnetic resonance imaging activity during the gradual acquisition and expression of paired-associate memory.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Law JR, Flanery MA, Wirth S, Yanike M, Smith AC, Frank LM, Suzuki WA, Brown EN, Stark CE

An analysis of hippocampal spatio-temporal representations using a Bayesian algorithm for neural spike train decoding.

IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society

Barbieri R, Wilson MA, Frank LM, Brown EN

Hippocampal plasticity across multiple days of exposure to novel environments.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Frank LM, Stanley GB, Brown EN

Dynamic analysis of neural encoding by point process adaptive filtering.

Neural computation

Eden UT, Frank LM, Barbieri R, Solo V, Brown EN

Dynamic analyses of information encoding in neural ensembles.

Neural computation

Barbieri R, Frank LM, Nguyen DP, Quirk MC, Solo V, Wilson MA, Brown EN

Dynamic analysis of learning in behavioral experiments.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Smith AC, Frank LM, Wirth S, Yanike M, Hu D, Kubota Y, Graybiel AM, Suzuki WA, Brown EN

A Bayesian decoding algorithm for analysis of information encoding in neural ensembles.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

Barbieri R, Frank LM, Nguyen DP, Quirk MC, Solo V, Wilson MA, Brown EN

Persistent activity and memory in the entorhinal cortex.

Trends in neurosciences

Frank LM, Brown EN

Single neurons in the monkey hippocampus and learning of new associations.

Science (New York, N.Y.)

Wirth S, Yanike M, Frank LM, Smith AC, Brown EN, Suzuki WA

Construction and analysis of non-Gaussian spatial models of neural spiking activity.

Neurocomputing

Riccardo Barbieri, Loren M. Frank, Michael C. Quirk, Victor Solo, Matthew A. Wilson, Emery N. Brown

Contrasting patterns of receptive field plasticity in the hippocampus and the entorhinal cortex: an adaptive filtering approach.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Frank LM, Eden UT, Solo V, Wilson MA, Brown EN

The time-rescaling theorem and its application to neural spike train data analysis.

Neural computation

Brown EN, Barbieri R, Ventura V, Kass RE, Frank LM

Entorhinal Place Cells: Trajectory Encoding.

The Neural Basis of Navigation

Loren M. Frank, Emery N. Brown, Matthew A. Wilson

An analysis of neural receptive field plasticity by point process adaptive filtering.

Proceedings of the National Academy of Sciences of the United States of America

Brown EN, Nguyen DP, Frank LM, Wilson MA, Solo V

Diagnostic methods for statistical models of place cell spiking activity.

Neurocomputing

Riccardo Barbieri, Loren M. Frank, Michael C. Quirk, Matthew A. Wilson, Emery N. Brown

Construction and analysis of non-Poisson stimulus-response models of neural spiking activity.

Journal of neuroscience methods

Barbieri R, Quirk MC, Frank LM, Wilson MA, Brown EN

A time-dependent analysis of spatial information encoding in the rat hippocampus.

Neurocomputing

Riccardo Barbieri, Loren M Frank, Michael C Quirk, Matthew A Wilson, Emery N Brown

REPLY.

Epilepsia

L. Matthew Frank

A Statistical Paradigm for Neural Spike Train Decoding Applied to Position Prediction from Ensemble Firing Patterns of Rat Hippocampal Place Cells.

Journal of Neuroscience

Emery N. Brown, Loren M. Frank, Dengda Tang, Michael C. Quirk, Matthew A. Wilson

A statistical paradigm for neural spike train decoding applied to position prediction from ensemble firing patterns of rat hippocampal place cells.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Brown EN, Frank LM, Tang D, Quirk MC, Wilson MA

Prediction of chronic vegetative state with somatosensory evoked potentials.

Neurology

L. M. Frank, T. L. Furgiuele, J. E. Etheridge

PREDICTION OF CEREBRAL DEATH BY CRANIAL SECTOR SCAN.

Critical Care Medicine

Terry L. Furquiele, L. Matthew Frank, Carolyn Riegle, Frederick Wirth, Linda C. Early