|Examining the Amygdala in Mouse Models of Fragile X
by Joesph LeDoux, 3/1/2006
Fragile X syndrome in humans is accompanied by alterations of in regions of the brain that are thought to
control anxiety related behaviors. In particular, the amygdala, a small structure located near the back of the brain, has structural abnormalities which are accompanied by behavioral changes associated with amygdala activation, including increased fear and anxiety and elevated secretion of the stress hormone cortisol. Progress in understanding the neurobiological basis for such changes is likely to come from studies of a genetically modified mouse which mimics Fragile X syndrome. This animal is referred to as the Fmr1 knockout (Fmr1 KO), indicating a mutation in the Fmr1 gene. Existing data regarding fear and anxiety in the Fmr1 KO mouse are inconclusive, especially in studies using fear conditioning, the behavioral model of fear which is thought to reflect anxiety and is best understood at the neural level. Findings in some studies are inconsistent with the human manifestation of Fmr1 gene mutation, and results from different studies are contradictory. Because detailed information about the neural system and cellular and molecular mechanisms is available, fear conditioning would be an important tool for attempting to relate behavioral symptoms of Fragile X to brain mechanisms.
Our research plan has four aims.
The first is to attempt to clarify the behavioral effects of fear conditioning in the Fmr1 KO mouse.
Second, we will examine the expression and localization of certain key gene products in the amygdala, a
key component of the neural circuitry underlying fear learning. These gene products have been implicated
in the disease process in other brain regions and may have a similar impact on amygdala function.
Third, we explore the role of receptors known to control learning and anxiety in amygdala in the Fmr1 KO mouse.
We will focus on receptors whose function has been show to be modified by mutations of Fmr1.
Finally, we will assess the therapeutic value of certain compounds which alter receptor signaling
compounds by examining Fragile X symptoms in the mouse models which have been given dietary supplements
of these compounds.