Loren Frank, PhD

Professor
Physiology
415-502-7357

Learning and Spatial Coding in the Hippocampal-Cortical Circuit

Research Overview
The ability to use experience to guide behavior (to learn) 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.

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.

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 hypotheses 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. 

Lab Members

Emily Anderson, PhD
Postdoctoral Fellow
emily@phy.ucsf.edu

Gideon Rothschild, PhD
Postdoctoral Fellow
gideon@phy.ucsf.edu

Jai Yu, PhD
Postdoctoral Fellow
jai@phy.ucsf.edu

Anna Gillespie, PhD
Postdoctoral Fellow
anna.gillespie@ucsf.edu

David Kastner, PhD
Postdoctoral Fellow
david.kastner2@ucsf.edu

Mari Sosa
Neuroscience Graduate Student
marielena.sosa@ucsf.edu

Demetris Roumis
Neuroscience Graduate Student
demetris.roumis@ucsf.edu

Jason Chung
Neuroscience Graduate Student
jason.chung@ucsf.edu

Hannah Joo
Neuroscience Graduate Student
hannah.joo@ucsf.edu

Daniel Liu
Bioengineering Graduate Student
daniel.liu@ucsf.edu

Gomathi Ramakrishnan
HHMI Lab Manager
gomathi.ramakrishnan@ucsf.edu

Charlotte Geaghan-Breiner
Jr. Specialist
charlotte.geaghan-breiner@ucsf.edu

Kevin Fan
Jr. Specialist
kevin.fan2@ucsf.edu

Jessica Zhou
Research Technician
jessica.zhou@ucsf.edu

Andrew Tritt
Systems Analyst
ajtritt@lbl.gov

Sachi Desse
Summer 2016 Intern
sachidesse@msn.com

Lab Website

Publications: