What are the molecular events underlying ventral striatal plasticity?

Leaders: Jacqueline McGinty and Christine Konradi.


ABSTRACT:

Our focus is on the medium spiny projection neurons (MSNs) of the nucleus accumbens because (1) most stimulus-induced changes in gene expression which are relevant to ventral striatal plasticity take place in these neurons, (2) MSNs integrate dopamine and glutamate inputs via intracellular cascades that link neuronal activity to signal transduction, and (3) their projections are the main arteries that link the cognitive/motivational aspects to the locomotor aspects of behavior. Stimulation of dopamine and glutamate receptors on MSNs activates a complex network of phosphorylation/dephosphorylation events that modulate ion channel activity, cytoskeletal changes, and nuclear transcription. Short and long-term changes in these intracellular cascades are thought to underlie the altered physiological responses reflected in LTP/LTD, cortical gating, and experience-dependent adaptations in neuronal activity.

Changes in gene expression have been detected for the last 20 years with what are now termed "conventional" hybridization techniques. These techniques are limited by the number of genes that can be manipulated at a time. Strategies to identify alterations in the expression of many, even novel, genes include PCR-based differential display and its newer variants, which select for low abundance genes of interest. The newest strategy that has augmented this toolbox is array-based technology. cDNA and oligonucleotide arrays allow investigation of gene expression levels and provide static and dynamic information on changes in the expression of hundreds to thousands of genes, many of unknown significance. Such gene screen strategies can identify gene products that can be manipulated in animals, knocked down with antisense oligonucleotides, knocked out or over-expressed in transgenic mice, or introduced into specific brain areas with viral vector constructs. These animals can then be treated with drugs in order to test their physiological significance in vivo.

Specific issues addressed by this focus group include: (a) how the prototypical MSN integrates metabotropic and ionotropic signaling information via its complex intracellular cascades, (b) the relevance of this information to physiology and behavior, (c) whether the molecular models are too focused on the striatum and have not yet expanded adequately to address drug-induced molecular changes in other areas such as the prefrontal cortex, amygdala, and VTA, and (d) what combination of techniques are the most promising for the future of the investigation of gene regulation in this circuitry.

Members: William Carlezon, Pastor Couceyro, Kalpana Merchant, Kristen Keefe, and David Self.