Lee (Albert) Lab

The primary focus of the lab is the neural basis of learning and memory.  In particular, we study hippocampal and reward-related spatial learning in rodents.  Both are immensely rich topics that should provide fundamental insights into the foundations of mammalian behavior.  Our approach mainly involves two electrophysiological methods that complement each other: whole-cell intracellular and multiple-single-unit extracellular recording in freely behaving rats and mice.  With multielectrode extracellular recording we can follow the simultaneous activity of many neurons from several brain areas for weeks as an animal learns and then retrieves specific memories.  In vivo whole-cell recording in freely moving rats, a new technique that I developed with Professor Michael Brecht (Humboldt University, Berlin) and Dr. Jérôme Epsztein (INMED-INSERM, Marseille), provides an unprecedented ability to measure and manipulate an individual neuron as an animal learns (Lee et al. 2006, Lee et al. 2009, Epsztein et al. 2010, Epsztein et al. 2011).  It also allows one to connect neural activity during behavior to the recorded cell’s specific anatomy.  More generally, this technique can bring two large areas of neuroscience closer together: in vitro cellular/molecular studies of neuronal integration and plasticity on the one hand, and behavioral and extracellular studies of animals engaged in learning and memory tasks on the other (Epsztein et al. 2011).

The hippocampus is a brain region that has been shown to be crucial for both the formation of episodic memories (i.e., memories of events from daily life) in humans, and spatial learning (i.e., learning the layout of a given environment) in rodents.  Recent electrophysiological recordings in the human hippocampus have revealed neurons that fire in a highly specific manner for famous people and objects (Quiroga et al. 2005).  This sparse coding bears a striking resemblance to that of the well-known rodent hippocampal place cells (which fire selectively when the animal is in a particular location of an environment), thus adding new significance to the study of place cells as an animal model of human hippocampal-dependent memory.  Previously, in the laboratory of Professor Matthew Wilson, I studied sequence learning across populations of place cells recorded extracellularly in freely moving rats (Lee and Wilson 2002), employing multiple spike train analysis methods that I developed for this purpose (Lee and Wilson 2004).  Similar phenomena could underlie human episodic memory encoding.  To make this connection more explicit, a rodent learning a temporal sequence of places by linking a set of place cells could be homologous to a human encoding an experience consisting of a sequence of items each represented by a small group of hippocampal cells (e.g., enter restaurant, notice famous person, meet friends, sit at corner table).
 
However, to really get at the cellular/synaptic mechanisms of hippocampal learning requires more detailed measurement and control of place cells than is possible with extracellular recording.  Whole-cell recording in freely moving rodents allow us to measure the subthreshold membrane potential activity associated with place cells.  Since subthreshold activity reflects the synaptic inputs to a cell better than spiking (which represents the cell’s output) does, we can more directly measure the synaptic plasticity correlates of hippocampal learning as the animal actually forms spatial memories (Epsztein et al. 2011).  Furthermore, by stimulating or suppressing spiking in the recorded cell (through whole-cell current injection), we can directly test various proposed mechanisms of synaptic plasticity, such as those that do or do not depend on postsynaptic spiking.
 
Ultimately, hippocampal spatial learning serves the survival needs of the animal.  Learning in order to successfully obtain rewards is clearly a key part of this.  Thus we use extracellular recording of populations of neurons from hippocampal and reward-related brain areas to study changes in neural activity over timescales of up to several weeks as a rodent learns natural, biologically-relevant tasks.  Through collaborations with other Janelia researchers, we can complement our recordings with techniques such as activation and inactivation of specific parts of the circuits underlying these behaviors.  The hope is that the basic interactions between these regions will be common to both rodents and humans.

A major focus of the lab is the further technical development of whole-cell recording in freely moving rodents.  We have previously demonstrated that our current method can yield high-quality whole-cell recordings of remarkable stability that last for up to an hour in freely moving animals (Lee et al. 2006).  However, as it is a new technique, it is still difficult to perform, so the first task is to improve the success rate and make it easier to use.  The long-term technical goal is to make it a standard tool for cellular/synaptic studies of behavior, thus more directly linking in vitro and in vivo research.  In addition to our studies of hippocampal learning mechanisms, we and our colleagues will be able to answer fundamental questions about basic cell physiology properties and synaptic integration in different types of anatomically identified neurons from various brain areas during natural behaviors (Epsztein et al. 2011).  Janelia Farm provides an ideal environment for pursuing the development of new techniques for neuroscience through its excellent infrastructure and support, stated research goals, and array of highly talented scientists.