Metabolic mapping of rat brain activity associated with conditioned fear extinction and renewal, and improvement of extinction memory by the metabolic enhancer methylene blue
textChanges in brain metabolism associated with the consolidation, extinction
and recall of fear memories were investigated in rats using two complementary
brain metabolic mapping approaches. First, fluorodeoxyglucose (FDG) metabolic
mapping technique was used to track the stimulus-evoked changes in brain
glucose uptake that mostly occur during the first ten minutes following the FDG
administration. Second, cytochrome oxidase (CO) histochemistry, which is wellsuited
for tracking long-term changes in brain metabolic capacity, was utilized. By
combining these two techniques, brain structures involved in fear extinction
memory consolidation and retention were compared to brain regions that
displayed altered metabolic activity during conditioned fear memory recall.
Additionally, since memory consolidation requires expenditure of energy,
enhancement of brain oxidative phosphorylation through CO activity increase
was tested as a possible way for improving extinction memory retention in rats.
Low doses of the metabolic enhancer methylene blue (MB) were used to
enhance CO activity in the post-extinction training period, to test the hypothesis
that neurons with high metabolic demand which are engaged in consolidation
and retention of the extinction memory would benefit most from the presence of a
metabolic-enhancing drug. The results suggest that during conditioned fear
renewal, the auditory conditioned stimulus activates the neural representation of
the footshock unconditioned stimulus, thus supporting Pavlov’s stimulussubstitution
model of classical conditioning. Quantitative CO histochemistry
revealed that Pavlovian fear acquisition training increased metabolic capacity in
several brain regions, including medial prefrontal cortex (mPFC) and septum,
while extinction training reduced CO activity to levels comparable to the
pseudorandom group. A functional neural network model of extinction explored
how the direct influences on regions such as mPFC and amygdala might change
between fear extinction recall and fear renewal. Finally, the third experiment
illustrated that MB might be a useful adjunct to exposure therapy, since it
improved consolidation and retention of fear extinction in our animal model of
specific phobias.Institute for Neuroscienc