Neural and Molecular Mechanisms of Sensitization

The overall objective of this project to provide insights into one of the most fundamental problems in the neurosciences – the physiological basis of learning and memory. One animal that is well suited for the cellular analyses of learning and memory is the marine mollusc Aplysia . This animal has a relatively simple nervous system with large, identifiable neurons that are accessible for detailed anatomical, biophysical and biochemical studies. In addition, several behaviors of this animal have been shown to be modified by learning and many of the neurons and neural circuits that mediate these behaviors have been identified. For example, the neuronal mechanisms of habituation, sensitization and classical conditioning of the siphon/tail withdrawal reflex have been studied extensively in our laboratory. Currently, we are focusing on the analysis of sensitization. Sensitization is a simple form of nonassociative learning in which the response to a test stimulus is enhanced as result of delivering a strong, generally noxious, stimulus to an animal.

Three broad aspects of this topic are being investigated.

The first goal is to continue to elucidate the mechanisms of synaptic plasticity that underlie short-term sensitization. Of particular interest is the interaction of multiple second messenger/kinase pathways.

A second major goal is to investigate the unique mechanisms underlying long-term sensitization (LTS) from three perspectives: the induction, consolidation, and expression of LTS.

The third goal of this project is to examine distributed representations of learning and memory and to determine whether mechanisms for induction, maintenance and expression are shared among different sites. Although a great deal is known about plasticity at the sensorimotor synapse, modification of other sites in the circuit will be investigated in order to understand the full expression of the behavioral modification.

Neural and Molecular Mechanisms of Classical and Operant Conditioning

Reward-related learning guides a vast array of adaptive and maladaptive behaviors. The overall goals of this project are to analyze the mechanisms underlying two forms of reward-related learning; appetitive classical and reward operant conditioning. Results from our previous studies indicate that similarities exist between classical and operant conditioning at the systems level, but at the cellular level the mechanisms mediating these two forms of learning are fundamentally different. The goals of the present project are to extend this analysis to the molecular level and to other circuit elements. Three broad aspects of this topic are being investigated.

Investigate the subcellular mechanisms of operant reward learning.
Characterize the signaling cascades in neurons that underlie short- and long-term appetitive classical conditioning.
Identify and analyze additional sites of plasticity using voltage sensitive dyes following the in-vitro analogues of operant and classical conditioning. Although several sites of plasticity have been identified following operant and classical conditioning, other sites, yet to be identified, are necessary to explain all of the changes in behavior following conditioning.

Modeling the Dynamics of Genes and Proteins involved in Long-Term Memory

As the basic principles of gene regulation in neurons and the interactions between genes become characterized, it has become evident that these processes are highly nonlinear and dynamic. Application of analytical and numerical methods is essential to gain an overall conceptual understanding of the operations of these systems.

This Project will investigate how neural function and plasticity emerge from the interactions among processes by modeling two distinct levels of organization. At the molecular level, a detailed model will be developed for a key genetic regulatory system important for long-term synaptic facilitation and the formation of long-term memory. This system utilizes CREB and related transcription factors. At the level of a single neuron, models of the electrical activity of identified neurons will be developed to describe the modification of electrical properties as a consequence of gene expression and feedback from electrical activity to gene expression. In addition, we will develop an analogous model to simulate biochemical events underlying the induction of long-term synaptic potentiation (LTP) in vertebrates. Ordinary differential equations (ODEs) will be used to represent the rates of change of concentrations of transcription factors related to CREB and other transcription factors in various states of phosphorylation or oligomerization, and of second messengers (e.g., cAMP, calcium) and protein kinases (e.g., PKA, PKC, CamKII, MAPK). Bifurcation analysis will identify key control parameters to which the system is particularly sensitive. The ODE approach will be complemented with stochastic simulations in cases where molecule number appears to be low.

Modeling the CREB genetic regulatory system promises to advance the understanding of the formation of long-term memory and of mechanisms that could account for observed effects of stimulus frequencies on transcription.  A particular focus is to use computational approaches to design optimal training protocols for inducing long-term memory.