Brain activity associated with fear renewal.

This is the first mapping study of the brain activity associated with the renewal of an extinguished conditioned response. Rats were given radiolabeled fluorodeoxyglucose, a glucose analog, to map brain effects of an extinguished tone during context-dependent renewal of conditioned fear. A tone conditioned stimulus was paired with a footshock unconditioned stimulus in a first context, followed by conditioned response extinction in a second context and conditioned response renewal in a third context. Control rats were treated identically, except that tone and shock were presented pseudorandomly. Compared with control subjects, rats with conditioned response renewal had increased tone-evoked fluorodeoxyglucose uptake in the auditory system (auditory cortex, medial geniculate, inferior colliculus and lateral lemniscal nuclei), as well as somatic and visceral sensory nuclei (external cuneate, spinal trigeminal, solitary tract and vestibular nuclei). In addition, perirhinal cortex, anterior lateral hypothalamus and ventrolateral periaqueductal gray showed conditioned response renewal effects. Brain-behavior correlations indicated that the activity of the external cuneate nucleus strongly predicted the conditioned response in the renewal group. It is suggested that context-dependent fear renewal is associated with (1) tone-evoked activation of the excitatory conditioned stimulus representation in the auditory system, (2) associative activation of the unconditioned stimulus representation in somatic and visceral sensory nuclei in the absence of the unconditioned stimulus, and (3) neural activation of the perirhinal cortex, hypothalamus and periaqueductal gray. These findings support Pavlov's stimulus-substitution theory as a neural mechanism contributing to the renewal effect.