Department of Physiology
University of California, San Francisco
Email: [email protected]
UCSF Sandler Neurosciences Center
675 Nelson Rising Lane, Room 514F
San Francisco, CA 94158-0444
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, real-time signal processing and targeted optogeneticinterventions and behavioral manipulations of awake, behaving animals to understand how the brain learns, remembers and decides.
Anatomical organization of the hippocampus and neocortex
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 thesubiculum. Nearly all neocortically bound outputs from the hippocampus originate in CA1 and thesubiculum and target cells in the deep layers of the entorhinal cortex and in many other regions, which projects both to numerous neocortical regions as well as to back to the superficial layers of theentorhinal cortex. Our research uses that organization to compare patterns of activity across regions within the hippocampus and across hippocampal and cortical networks. We use the similarities and differences among the patterns to identify the transformations that occur in each stage of processing.
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, remembering and deciding.
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. Similarly, the hippocampus is critical for memory retrieval for a period after learning: cortical inputs are thought to trigger a retrieval event wherein the hippocampus coordinates the reactivation of patterns across the brain. Our work has linked a specific pattern of activity, the rapid replay of sequences of place cells during so called “Sharp-Wave Ripple” events, to learning and memory-guided decision making. We are now carrying out complementary studies where we examine activity in the hippocampus and in downstream areas to understand how these events are triggered and how they contribute to the computations underlying decision-making We are also continuing to develop and apply new tools, including real-time signal processing, new biocompatible electrodes and optogenetic manipulations in awake, behaving animals. Learning, remembering and deciding all involve complex and dynamic patterns of information flow through the brain, and our goal is to be able to identify and understand those patterns. We also know that not all memories are created equal: some experiences last a lifetime while others fade quickly. That inspires complementary efforts to understand the processes that modulate memory, with the long term goal of improving memory by amplifying activity in the brain regions that modulate the strength of initial memory encoding, the intensity of memory consolidation and the accuracy of memory retrieval.