The long term objective of this proposal is to examine changes in presynaptic structure that may occur with fear conditioning and the molecular mechanisms that underlie such changes. The specific goals of this study are:
Aim 1) To describe the structural changes that take place in the axonal projections from the medial geniculate nucleus (MGN) of the thalamus that project to the lateral amygdala after auditory fear conditioning. We will do this by injecting anterograde tracers and quantifying changes in the structure, axonal length and synaptic bouton number within the lateral amygdala.
Aim 2) To determine whether these axonal changes correlate with molecular changes that have already been shown to be involved in auditory fear conditioning are due to presynaptic BDNF expression. In particular, does excising the gene for BDNF n the MGN affect acquisition of fear and the structural plasticity that occurs with fear learning. Finally, in Aim 3) we will examine whether presynaptic TrkB is mechanistically implicated in the structural changes by constructing a virus that expresses both dominant negative TrkB which inhibits the BDNF receptor, and cre- recombinase, into a mouse who has a gene for floxed-membrane bound GFP reporter molecule that clearly outlines axonal membranes. With this technique, we can observe and quantify structural changes in the axonal projections of neurons in which the TrkB receptor is inhibited. We will inject this virus into the MGN, and then observe fear expression, structural changes and molecular expression of BDNF, trkB, and phospho-TrkB. In summary, we will first describe the structural changes that occur in these medial geniculate-amygdala synaptic connections after fear conditioning. Second, we will examine whether or not presynaptic BDNF expression is important for fear conditioning and structural plasticity. Thirdly, we will examine whether or not presynaptic TrkB is essential for fear conditioning and structural plasticity. These proposed experiments will significantly further our understanding of structural plasticity and fear conditioning in general. Many psychiatric disorders including posttraumatic stress disorder, anxiety disorders and phobias occur when an individual becomes excessively or inappropriately fearful. Better understanding of how fear learning occurs will provide further insight into treatment for these devastating disorders.
|Mahan, Amy L; Ressler, Kerry J (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35:24-35|