The neural pathways underlying the symptoms of Post Traumatic Stress Disorder (PTSD) have not been fully elucidated. Intrusive memories, persistent anxiety and other cognitive deficits have been attributed to maladaptive or otherwise aberrant processing in specific brain regions, including the hippocampus, amygdala and prefrontal cortex. Our laboratory has developed an animal model of PTSD which results in the enhancement of memory for a place associated with exposure to a predator, anxiety-like behavior, increased startle and impaired memory in a non-aversive memory task. To better understand how the interaction of the hippocampus and prefrontal cortex contribute to the different symptoms of the disorder, we investigated the transient inactivation of each structure during an intense stressor. Our results show that long-term contextual fear associations involve activity in both the hippocampus and the prefrontal cortex, but only the prefrontal cortex is involved in cued fear memories as well.

Many autistic adults experience debilitating anxiety that interferes with their daily functioning. Atypical sensory processing and intolerance of uncertainty are cognitive processes linked to atypical limbic system functioning and impaired fear conditioning as potential mediators of anxiety in autism. A previous fear conditioning study using fMRI found atypical amygdala functioning in autism when the threat stimulus was only partially reinforced. The first aim of this dissertation is a multimethod examination of brain and psychophysiological response in autistic and in neurotypical adults during a fear conditioning/extinction task with the threat stimulus reinforced 100% percent of the time. We were also interested in the responses of autistic and neurotypical adults during an auditory looming task that requires no learning contingencies. We used fMRI, pupillometry, and skin conductance response as the dependent measures. Results demonstrated a significant main effect for insula activation, but not amygdala activation, during the 100%-reinforcement fear conditioning task with no between-group differences or group x condition interactions. There were likewise no condition differences (Safe vs Threat) for amygdala in the auditory looming task. However, the autism group demonstrated increased insula response to both Threat and Safe auditory conditions of the looming task, suggesting the autism group utilized alternative cognitive resources than the neurotypical group. Results indicate intact fear conditioning and extinction in autism for more certain conditions and suggests that behavioral (exposure) anxiety treatments for phobias could be useful under certain conditions. Results of this study are inconsistent with the atypical/hyperactive amygdala hypotheses of anxiety with autism and inconsistent with the portion of the South & Rodgers (2017) anxiety model regarding the importance of intolerance of uncertainty in autism samples.

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20531号 / 生博第373号 / 新制||生||49(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 松田 道行, 教授 上村 匡, 教授 見学 美根子 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation.

<p dir="ltr">Juvenile stress (JS) is a known risk factor for the development of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), both of which frequently occur together, suggesting common genetic influences on vulnerability toward these disorders. The present study investigated the impact of JS on contextual fear learning and extinction, as well as corticosterone (CORT) responses before and after JS, before and after contextual fear conditioning (CFC), and after fear extinction in male and female high-alcohol-preferring (HAP2) and low-alcohol-preferring (LAP2) mice. We also measured unconditioned anxiety-related behavior in the light-dark-transition test. No line differences were seen in fear acquisition, however, HAP2 mice showed faster fear extinction compared to LAP2 mice. No effects of JS were seen in HAP2 mice, whereas in LAP2 mice, JS reduced fear acquisition in males and facilitated fear extinction in females. Females showed greater fear relative to males, regardless of subgroup. Anxiety-related behavior, assessed by the light-dark transition test, did not correspond with fear-related behavior, as LAP2 females demonstrated more anxiolytic-like responses than LAP2 males, while HAP2 males demonstrated more anxiolytic-like responses than LAP2 males. There were no line differences in CORT during the juvenile stage; however, adult LAP2 mice showed greater CORT levels than HAP2 mice at baseline and after CFC and extinction testing. These findings provide new information regarding fear learning and extinction in these unique mouse lines that model mechanisms theorized to contribute to co-morbid AUD and PTSD.</p>

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Research in both humans and animals demonstrates that nicotine addiction is a complex disorder that can be influenced by several factors. For instance, individual differences in genetics can impact sensitivity to nicotine and can modulate the severity of nicotine withdrawal. Although nicotine alters cognitive processes such as learning and memory, it remains unknown whether genetic variability modulates the effects of nicotine on these cognitive functions. Thus, the present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning in 8 strains of inbred mice. Furthermore, nicotine withdrawal-related changes in somatic signs and the elevated plus maze were examined because nicotine withdrawal consists of multiple symptoms that can include increased somatic signs and increased anxiety. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed in several inbred strains. However, the effects of acute nicotine on contextual fear conditioning were not associated with the effects of nicotine withdrawal, suggesting that different genetic substrates may mediate these two effects. Nicotine withdrawal produced few changes in somatic signs and exploration in the elevated plus maze. Overall, these data demonstrate that genetics contribute to variability in the effects of acute nicotine and withdrawal from chronic nicotine treatment on contextual fear conditioning. The identification of genes that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction. The age during which nicotine use begins is a second factor that may influence the severity of nicotine addiction. Pre-adolescence and adolescence are periods of development that have an increased risk for developing addiction to nicotine. Nicotine alters contextual learning, but it remains unknown whether these effects are age-dependent. Therefore, the present study examined the effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning in pre-adolescent, adolescent, and adult mice. In addition, we investigated whether exposure to chronic nicotine during pre-adolescence or adolescence has long-lasting effects on contextual learning that occurs during adulthood. Pre-adolescent mice were more sensitive to the effects of acute nicotine than adolescents and adults, showed enhanced contextual learning when treated with high doses of chronic nicotine, and were less sensitive than adolescents and adults to nicotine withdrawal-related deficits in contextual learning. In contrast, adolescent mice were less sensitive to the effects of acute nicotine on contextual learning than pre-adolescents and adults and were more sensitive to nicotine withdrawal-related deficits in contextual learning relative to pre-adolescents and adults. Chronic nicotine exposure during pre-adolescence or adolescence also produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure had no effect on fear conditioning. Together, these data suggest that pre-adolescent and adolescent nicotine exposure has both short-term and long-term effects on contextual learning that may play an important role in the development and maintenance of nicotine addiction. / Psychology

Fear memories are necessary to initiate anticipatory fear responses when we are confronted with cues that predict an impending threat. However, when a cue no longer predicts threat, an extinction memory is formed that actively inhibits the expression of the fear memory. Failure to acquire, consolidate, or recall extinction memories causes fear memory expression (i.e., fear responding) in the absence of threat, which is a hallmark characteristic of most anxiety-related disorders and post-traumatic stress disorder (PTSD). Of further importance, these disorders occur approximately twice as often in women than men, which is thought to partially rely on sex hormone mediated differences in fear extinction. Moreover, deficits in extinction memory processing can also hinder the success of extinction-based exposure therapy, which is commonly used to treat these disorders. Thus, a better understanding of the factors determining the quality of extinction memories is of utmost importance. The present thesis focuses on three of these factors including the female sex hormone 17β-estradiol (E2), fear extinction timing, and the noradrenergic arousal system. To examine the role of E2 (Manuscript 1; low E2 levels or high E2 levels) and fear extinction timing (Manuscript 2; either immediately or delayed after the initial fear memory formation), we used a special differential fear conditioning procedure that allowed us to separately assess fear memories and extinction memories via peripheral arousal responses (measured via skin conductance responses [SCR]) and, most importantly, via central neurophysiological indicators (measured via electroencephalography [EEG]). Concerning EEG parameters, we were especially interested in neural oscillations (especially in the theta and gamma range). To further advance the understanding of the neurophysiological foundations of both memory systems, we also aimed at disentangling oscillatory and non-oscillatory brain activity (Manuscript 2). Moreover, the crucial role of the noradrenergic arousal system for the quality of extinction memories is highlighted in a review of relevant rodent and human studies (Manuscript 3). By using the described multi-methodological approach, we were able to demonstrate for the first time that peripheral arousal as well as fear-related theta oscillations are sensitive to E2. This was indicated by less fear responding (attenuated peripheral arousal and attenuated theta oscillations) during the recall of fear and extinction memories under high peripheral E2 levels (Manuscript 1). Concerning the role of fear extinction timing, we demonstrate that delayed extinction is advantageous over immediate extinction in reducing peripheral arousal during the recall of the extinction memory (Manuscript 2). Additionally, by disentangling oscillatory and non-oscillatory brain activity, we demonstrate for the first time that oscillatory and non-oscillatory brain activity is sensitive to fear expression. Moreover, by reviewing different rodent and human studies, we highlight the important role of noradrenergic arousal for the recall of extinction memories and, importantly, provide a detailed mechanistic framework of how extinction deficits might be caused after immediate extinction (Manuscript 3). In sum, the present thesis underscores the important role of E2, fear extinction timing, and the noradrenergic system for the recall quality of fear memories and extinction memories in humans.