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The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

abstract: Animals must learn to ignore stimuli that are irrelevant to survival, which is a process referred to as ‘latent inhibition’. This process has been shown to be genetically heritable (Latshaw JS, Mazade R, Sinakevitch I, Mustard JA, Gadau J, Smith BH (submitted)). The locus containing the AmTYR1 gene has been shown through quantitative trait loci mapping to be linked to strong latent inhibition in honey bees. The Smith lab has been able to show a correlation between learning and the AmTYR1 receptor gene through pharmacological inhibition of the receptor. In order to further confirm this finding, experiments were designed to test how honey bees learn with this receptor knocked out. Here this G-protein coupled receptor for the biogenic amine tyramine is implemented as an important factor underlying latent inhibition in honey bees. It is shown that double-stranded RNA (dsRNA) and Dicer-substrate small interfering RNA (dsiRNA) that are targeted to disrupt the tyramine receptors specifically affects latent inhibition but not excitatory associative conditioning. The results therefore identify a distinct reinforcement pathway for latent inhibition in insects. / Dissertation/Thesis / Masters Thesis Biology 2017

Eleven experiments examined two late-developing learning and memory systems in rats: fear-potentiated startle (FPS) and the contextual regulation of latent inhibition and extinction. The first study was based on three previous developmental findings on FPS: (1) FPS to an odour CS emerges at postnatal day (PN) 23; Rats conditioned at PN16 to an odour CS express freezing but not FPS when tested at PN23, and (3) FPS to an odour CS trained at PN16 is activated if rats are also trained to a difference odour at PN23 (Yap, Stapinski, & Richardson, 2005). Yap et al. (2005) hypothesised that the activation effect only occurs if rats are given training to the second odour at an age when FPS has emerged. Study 1 assessed this hypothesis and trained the second odour CS at either PN23 or PN20. Contrary to expectations, the results of this study showed the activation effect for both groups of rats. Surprisingly, the results also revealed a significant FPS effect to the odour CS trained at PN20. Subsequent experiments examined this unexpected result, and found that learning to odour 1 at PN16 facilitated the age of onset for FPS at PN20. The results of Study 1 are discussed in relation to past findings on enrichment, cumulative learning, and neurobiological models of conditioned fear. The second section of this thesis (Studies 2 and 3) examined the context-specificity of two memory interference paradigms, latent inhibition and extinction, in developing rats. The studies found that both phenomena were context-specific at PN23-25 but not at PN16-18. Moreover, the results suggest that the context-specificity of both latent inhibition depended on the age of the rat during the second phase of training, but not their age during the first phase of training or their age at test. The implications of these findings for theoretical and neural models of learning, as well as the occurrence of latent inhibition and extinction during development are discussed.

The present research reports the first comprehensive map of brain networks underlying latent inhibition learning, the first application of structural equation modeling to cytochrome oxidase data, and the first effects of methylene blue, a known metabolic enhancer, on latent inhibition. In latent inhibition, repeated exposure to a stimulus results in a latent form of learning that inhibits subsequent associations with that stimulus. As neuronal energy demand to form learned associations changes, so does the induction of the respiratory enzyme cytochrome oxidase. Therefore, cytochrome oxidase can be used as an endpoint metabolic marker of the effects of experience on regional brain metabolic capacity. Quantitative cytochrome oxidase histochemistry was used to map brain regions in mice trained on a tone-footshock fear conditioning paradigm with either tone preexposure (latent inhibition), conditioning only (acquisition), conditioning followed by tone alone (extinction), or no handling or conditioning (naïve). In normal latent inhibition, the ventral cochlear nucleus, medial geniculate, CA1 hippocampus, and perirhinal cortex showed modified metabolic capacity due to latent inhibition. Structural equation modeling was used to determine the causal influences in an anatomical network of these regions and others thought to mediate latent inhibition, including the accumbens and entorhinal cortex. An uncoupling of ascending influences between auditory regions was observed in latent inhibition. There was also a reduced influence on the accumbens from the perirhinal cortex in both latent inhibition and extinction. These results suggest a specific network with a neural mechanism of latent inhibition that involves sensory gating, as evidenced by modifications in metabolic capacity, effective connectivity between auditory regions, and reduced hippocampal influence on the accumbens. The effects of methylene blue on disrupted latent inhibition were also investigated. Reduced tone-alone presentations disrupted the latent inhibition effect and led to an increase in freezing behavior. Repeated low-dose administration of methylene blue decreased freezing levels and facilitated the disrupted latent inhibition effect. Methylene blue administration also resulted in changes in metabolic capacity in limbic and cortical regions. A unique functional neural network was found in methylene blue-restored latent inhibition that emphasized sensory gating of auditory information, attention processing, and cortical inhibition of behavior. / text

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科学研究費補助金 研究種目:基盤研究(C) 課題番号:08610079 研究代表者:石井 澄 研究期間:1996-1998年度