Our ultimate goal is to provide a mechanistic understanding of a behaviorally relevant brain function. To this end we are attempting to produce a biophysically based explanation of how the information-processing and storage capabilities of single and small networks of neurons participate in the formation of certain types of memories. Because it gives unique access to this problem, we work in the hippocampal region of the central nervous system.
The hippocampus is a region that is intimately involved in the production of higher cognitive functions such as episodic memory formation. Importantly, this region exhibits well-described behavioral phenomena that open a window into these higher functions. There are separate encoding and consolidation stages to sequence memory formation that occur during different behavioral states (i.e., theta and sharp-wave states), and each of these stages is associated with distinct network activity patterns within the hippocampus. We do not, however, understand how these activity patterns are created by the network or how they are involved in the formation of episodic memories. To reach a fuller understanding, we would like to know what single-cell computations are performed and also what information is stored within the network during the different stages of memory encoding and consolidation.
Our hypothesis is that the computational capabilities of most neurons are a product of their integrative properties and the various forms of plasticity available to them. The integrative properties of neurons, or how they blend and shape input from many thousands of synapses into some specific action potential output pattern, are determined by a complicated interplay between the active, passive, and synaptic properties of the neurons. The informational storage capabilities of neurons are in turn an extension of the various synaptic and dendritic plasticity mechanisms available to them. Two questions drive our research: How are the integrative properties of neurons involved in the transformation of a particular input pattern into a specific output pattern? How is this pattern stored through the various forms of synaptic and nonsynaptic plasticity? Answering these questions requires (1) some knowledge of the functional properties of the neuron (morphological, active and passive membrane, and synaptic properties), (2) an understanding of how these properties interact differentially during a range of behaviorally relevant conditions, and (3) an understanding of how these various properties are maintained or altered according to specific rules that allow both information storage and proper long-term functioning.
We use a variety of in vitro techniques to address each of these issues. Direct electrical recordings are made from various regions of neurons, using multiple patch-clamp techniques (cell attached, outside out, and whole cell) to determine the fundamental biophysical properties of the voltage-gated and agonist-gated channels located within the more accessible dendritic regions. Studies of this kind have demonstrated that neuronal dendrites do indeed contain a wide variety of voltage-gated ion channels, and we have characterized their properties. We also use a variety of optical techniques (high-speed confocal and two-photon imaging and photostimulation) in combination with whole-cell patch recordings to investigate the electrical and Ca2+ signals that are produced during dendritic integration. Finally, we use all of these techniques to examine the different forms of synaptic and dendritic plasticity induced in neurons. In the process of these studies we have discovered new signals and novel forms of plasticity that are critical components of neuronal information processing and storage.
The Janelia Farm approach provides a unique opportunity for us to extend our in vitro examinations to regions of neurons that are difficult to study. We are eager to team with systems and molecular level groups to examine dendritic integration and plasticity during specific behaviors. This combined approach will allow us to determine more accurately the type of processing and storage that occurs during specific behaviors and to recreate these conditions more accurately in our in vitro experiments. Such collaborations are an opportunity for real advancement in our understanding of a behaviorally relevant brain function.