Metabolic Mapping of Mouse Brain Activity after Extinction of a Conditioned Emotional Response

Abstract

Metabolic mapping with fluorodeoxyglucose (FDG), a radiolabeled glucose analog, was used to assess regional activity changes in the mouse brain that result from extinction of a conditioned emotional response (CER). In the extinction group, Pavlovian tone-foot shock conditioning, followed by repeated tone-alone presentations, resulted in the reduction of the CER (freezing behavior). A second group underwent CER acquisition alone (nonextinction group), and a third group showed no CER after pseudorandom training. Then mice were injected with FDG, and tone-evoked brain activity was mapped. In the auditory system, increased activity resulted from the associative effects of acquisition training. Effects common to extinction and nonextinction groups, presumably reflecting the tone-foot shock association independently of CER expression, were found in the medial geniculate, hippocampus, and subiculum. In the extinction group, a major finding was the elevated activity in prefrontal cortex regions. In addition, brain-behavior correlations between FDG uptake and freezing behavior confirmed that subjects with higher prefrontal activity were more successful at inhibiting the CER. Interregional activity correlations showed extensive functional coupling across large-scale networks in the extinction group. The increased activity of the prefrontal cortex and its negative interactions with other regions within the extinction group suggest a functional network inhibiting the CER composed of prefrontal cortex, medial thalamus, auditory, and hippocampal regions. This is the first time that such a functional network resulting from Pavlovian extinction has been demonstrated, and it supports Pavlov's original hypothesis of extinction as the formation of cortical inhibitory circuits, rather than unlearning or reversal of the acquisition process.

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

“…The use of male and female rats in our study enabled us to investigate whether the effects of peri-pubertal stress were sex-specific. Our study replicates the lower activation of the infralimbic cortex in non-stressed males with impaired AFC extinction (Barrett, Shumake, Jones, & Gonzalez-Lima, 2003;Hefner et al, 2008;Herry & Garcia, 2002;Muigg et al, 2008). Yet we expand that knowledge by showing that the correlation between infralimbic cortex activation & extinction is not found in control females or in animals of both sexes previously exposed to stress.…”

Mechanisms of fear extinction

“…122,127 Visualization of PFC activity via metabolic mapping in rodents killed following extinction training reveals increased uptake of a labeled glucose analog by prefrontal tissue. 128 In humans, expression of extinction of conditioned fear is associated with increased BOLD response in the subgenual anterior cingulate (vmPFC) as assessed by fMRI, 105 and increased thickness of prefrontal cortex as revealed by structural MRI. 129 Immunocytochemistry shows increased expression of immediate early genes within mPFC following extinction training 125,130 (but see Morrow et al 131 ).…”

Glutamate NMDA Receptors within the Amygdala Participate in the Modulatory Effect of Glucocorticoids on Extinction of Conditioned Fear in Rats

“…These results suggest that BLA is a critical locus for the glucocorticoid enhancement effect on fear extinction. Numerous studies suggest that several brain structures are also involved in the extinction of conditioned fear that includes the BLA (Maren, 2001;Davis and Whalen, 2001;LeDoux, 2002), medial prefrontal cortex (mPFC) (Quirk et al, 2000;Grace and Rosenkranz, 2002;Barrett et al, 2003;Quirk and Milad, 2002) and dorsal hippocampus (Corcoran and Maren, 2001;Barrett et al, 2003). Recent evidence showed that extensive damage to the BLA did not interfere with the extinction of tone-elicited fear response indicating that structures other than BLA are essential for the extinction (Sotres-Bayon et al, 2004).…”