The basolateral complex of the amygdala (BLA) is a key component of the neuronal circuitry underlying the acquisition and the extinction of Pavlovian conditioned fear. The present series of experiments examined the role of neuronal activity and NMDA receptors (NMDAr) activation in the BLA on learning and relearning context conditioned fear and its extinction. Disruption of neuronal activity in the BLA prevented the acquisition of fear responses to a novel, a moderately familiar or a highly familiar context. It also prevented the reacquisition of fear responses to a conditioned or an extinguished context. Local blockade of NMDAr containing the NR2B subunit prior to training extinction or re-extinction impaired the short- and long-term loss of fear responses. In contrast, a similar blockade subsequent to training extinction or re-extinction left the long-term loss of fear responses unaffected. Disruption of neuronal activity in the BLA prior to training extinction and re-extinction depressed fear responses. It impaired the long-term loss of fear produced by extinction training but spared and even facilitated the long-loss of fear produced by re-extinction training when extinction had already been learned. The exact same outcome was observed when neuronal activity in the BLA was disrupted subsequent to training extinction and re-extinction. These findings suggest that the BLA is critical for both learning and relearning context conditioned fear. In contrast, the BLA is necessary for learning but not relearning extinction of conditioned fear. This implies that once extinction has been learned, others structures support the retrieval and the expression of extinction memory. This is consistent with current neural model of extinction that involves interactions between several neural substrates including the BLA and the medial prefrontal cortex.

<p>An inescapable component to survival in a dynamic environment is detecting and reacting to signals of danger. One of the most elegant processes animals possess to handle this complex task is classical conditioning, wherein stimuli associated with an aversive event acquire the capacity to elicit defensive behaviors. This process helps ensure quick reactions prior to the occurrence of an imminent threat. A problem of living in a dynamic environment, however, is that reliable signals of danger are rarely re-encountered in the exact same form from one situation to the next. Thus, to be truly adaptive it is imperative for defensive responses to extend beyond a specific instance towards other exemplars that might portend the same negative outcome. While the phenomenon of stimulus generalization was recognized in the earliest studies of conditioning from Pavlov's laboratory, a century of conditioning research has not resolved how humans and other animals actually meet this challenge. The research presented herein employs a combination of psychophysiological and functional imaging methods to examine how humans recruit neurocognitive systems to determine what stimuli do (and do not) pose a threat. Results show that human fear generalization is a complex phenomenon affected by the perceptual and conceptual nature of the stimulus. Brain regions and functional networks involved in fear generalization comprise cortical areas involved in coding the representation of conditioned stimuli and subcortical regions involved conditioned learning and the production of behavioral responses, most notably the amygdala. These results reveal the importance of stimulus-specific factors in fear learning and generalization, provide support for anatomically constrained models of fear generalization, and contribute to the development of model systems of fear generalization processes in human anxiety disorders.</p> / Dissertation

Tidigare studier har visat på sambandet mellan oräddhet, psykopati, aggressivitet och antisocialt beteende. Denna studie undersökte fenotypiska och genetiska relationer mellan komponenter i the skin conductance fear conditioning task och i psykopatiska personlighetsdrag. Data hämtades från den longitudinella studien; Tvillingstudie om riskfaktorer för antisocialt beteende (RFAB) vid University of Southern California och data från pågående tillfälle 5 inkluderades i studien. Resultatet visade på betydelsen av både genetiska och icke-gemensamma miljö influenser förklarade variansen i obetingad respons. I överensstämmelse med tidigare forskning visade resultaten att individer som visade på högre nivåer av manipulativt och svekfullt beteende också uppvisade större brister i rädslobetingelser. / Previous studies have shown a relationship among fearlessness, psychopathy, aggression and antisocial behavior. This study examined the phenotypic and genetic relationships among components of the skin conductance fear conditioning task and psychopathic personality traits. Data were retrieved from a longitudinal study; the Twin Study of Risk Factor for Antisocial Behavior at the University of Southern California. The present study included data from the ongoing Wave 5. Results indicated the importance of both genetic and non-shared environmental influences in explaining the variance in the unconditioned response. Consistent with previous research, the results showed that individuals who displayed higher levels of manipulative and deceitful traits also showed deficits in fear conditioning.

The basolateral complex of the amygdala (BLA) is a key component of the neuronal circuitry underlying the acquisition and the extinction of Pavlovian conditioned fear. The present series of experiments examined the role of neuronal activity and NMDA receptors (NMDAr) activation in the BLA on learning and relearning context conditioned fear and its extinction. Disruption of neuronal activity in the BLA prevented the acquisition of fear responses to a novel, a moderately familiar or a highly familiar context. It also prevented the reacquisition of fear responses to a conditioned or an extinguished context. Local blockade of NMDAr containing the NR2B subunit prior to training extinction or re-extinction impaired the short- and long-term loss of fear responses. In contrast, a similar blockade subsequent to training extinction or re-extinction left the long-term loss of fear responses unaffected. Disruption of neuronal activity in the BLA prior to training extinction and re-extinction depressed fear responses. It impaired the long-term loss of fear produced by extinction training but spared and even facilitated the long-loss of fear produced by re-extinction training when extinction had already been learned. The exact same outcome was observed when neuronal activity in the BLA was disrupted subsequent to training extinction and re-extinction. These findings suggest that the BLA is critical for both learning and relearning context conditioned fear. In contrast, the BLA is necessary for learning but not relearning extinction of conditioned fear. This implies that once extinction has been learned, others structures support the retrieval and the expression of extinction memory. This is consistent with current neural model of extinction that involves interactions between several neural substrates including the BLA and the medial prefrontal cortex.

In the present study, footshock, which produces a powerful aversive emotional response was used in a Pavlovian conditioning experiment as an unconditioned stimulis (UCS), and was paired with the presentation of a light used as a conditioned stimulis (CS). There is an accumulation of evidence that supports the assertion that dopaminergic (DA) neurons within the ventral tegmental area (VTA) are active in processes that contribute to the amygdala-based circuitry involved in regulating emotionally salient responses. To build upon findings implicating VTA DA, excitatory glutamate (Glu), NMDA and AMPA receptors, were examined with respect to their role in Pavlovian conditioned fear responding. Fear potentiated startle (FPS) was used to assess the effects of intra-VTA infused AP5, and intra-VTA infused CNQX on conditioned fear responding in laboratory rats. The administration of the NMDA receptor antagonist AP5 (at 1.0, 2.5, and 5.0ug doses), blocked the ability of a conditioned stimulus (CS) previously paired with footshock to become conditioned to the UCS. Similarly, administration of the AMPA receptor antagonist CNQX (at 1.0, 2.5, 5.0ug doses), inhibited the ability of the CS to become conditioned to the UCS. The results of this study indicate the VTA is an important site for synaptic modifications associated with fear learning, and that activation of excitatory Glutamatergic receptors in the VTA play a necessary part of the processing underlying fear conditioning. Measures of shock reactivity demonstrated that the infusion of AP5 and CNQX into the VTA did not inhibit baseline startle amplitudes. The administration of AP5 and CNQX did not suppress the perception of footshock as an aversive stimulus. This study provides further definition to established knowledge surrounding the neural processes whereby neutral environmental cues gain negative emotional salience as occurs in fear conditioning. It was hypothesised that the action of excitatory glutamatergic transmission within the VTA acts on NMDA and AMPA receptors is to assist in the acquisition of Pavlovian conditioned fear, possibly through the same synaptic mechanisms that govern LTP.

When a human or animal is threatened or confronted with a stimuli signalling danger, internal defence mechanisms are activated that evoke feelings of fear and anxiety. These emotional responses promote the behaviour patterns necessary for an organism's survival. Animal research seeks to understand how these emotions affect behaviour both physiologically and neurologically in order to develop effective treatment for those suffering from severe anxiety disorders. The aim of this thesis was to examine the role of the amygdala, and dorsal and ventral hippocampus in relation to immediate fear arousal brought on by footshock. This was assessed by examining whether muscimol would interfere with the acoustic startle response before or after footshock presentation, and then comparing these reactions to a control group that received saline infusions. The results of this research are extremely important because they identify various brain structures involved in the fear-arousing effects of footshock as measured by the shock sensitization of acoustic startle. Laboratory rats received muscimol (0.1ug and 0.01ug) infusions into the basolateral amygdala, dorsal and ventral hippocampus. These three brain regions have been identified as playing a prominent role in fear neurocircuitry. The results demonstrated that the GABA A receptor agonist muscimol in doses of 0.1ug and 0.01ug reliably blocked shock sensitization of the acoustic startle response. The muscimol doses did not alter the shock reactivity amplitudes therefore indicating a normal perception of the fear arousing properties of footshock. Therefore, the present study's results suggest that a decrease of GABA activity in the amygdala, dorsal and ventral hippocampus may be essential for the neuronal basis of fear acquisition and expression of unconditioned and conditioned stimuli.

High density electroencephalographic (EEG) measures were used to assess the effects of acute delta 9-tetrahyrdrocannabidol (THC) administration on extinction of conditioned fear responses. Fear conditioning was initiated using a differential classical conditioning paradigm that paired an aversive unconditioned stimulus (shock) with a signaling stimulus (CS+), whereas another stimulus served as a safety signal (CS-). Evoked potentials, induced event-related spectral perturbations (ERSP), and associated intertrial coherence (ITC) measures were used to quantify the acquisition and extinction of conditioned fear responses. Participants (N = 10 males) exhibited conditioning to the CS+ across fear acquisition training, as reflected by greater late positive (posterior sites) and late negative (anterior sites) potential amplitude to the CS+ relative to the CS-. Acute administration of THC facilitated extinction of the conditioned response to the CS+ relative to placebo, as reflected by greater LPP and LNP amplitude to the CS+ relative to the CS- in the placebo, but not THC condition. ERSP analyses suggest the lack of difference between CS+ and CS- ERP amplitude may be partially explained by a shifting of attention from external stimuli to internal processing in the THC condition. However, relative to placebo, THC administration also increased the amplitude of some measures of the conditioned response (LNP) to the CS-, suggesting a generalization of fear or lack of discrimination in this condition.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22318号 / 医博第4559号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 林 康紀, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In traditional Pavlovian fear conditioning paradigms, animals associate a neutral sensory cue, such as a sound or light, with an aversive stimulus like a mild electric shock. Over time, they develop a conditioned fear response to the cue alone. However, in the real world, cues that predict danger usually lack temporal predictability. Environmental unpredictability is known to enhance aversive memory. The basolateral amygdala (BLA) plays a critical role in forming aversive memories, mediating the convergence of multimodal sensory information. Previous research on the BLA has shown that different neuronal populations within this area encode valence-associative memories during fear conditioning. Our study aims to explore neuronal network activity within the BLA between predictable versus unpredictable fear conditioning. We employed time-lapse microendoscopic recording techniques to observe BLA neurons' somal calcium activity during fear conditioning and an auditory fear recall test (Chapter 3). We identified neurons with different patterns during these paradigms. 'Memory Winners' showed successful convergence of sensory information consistent with retention of the fear memory, while 'Memory Losers' failed to display conditioned stimulus (CS)-evoked calcium responses during fear recall, indicating a loss of fear memory. A further group, the 'Fear Expression' neurons lacked learning-related plasticity for the tone and shock but showed early CS-evoked activity during fear recall. When we introduced unpredictability during fear conditioning, we observed that the distinct functional classes of neurons remained consistent across paradigms. However, the tone and footshock evoked activity did differ within these neuronal classifications. 'Memory Winners' showed early tone- and shock-evoked increased responsivity, while 'Memory Losers' displayed varying shock responsivity depending on whether the conditioning was predictable or unpredictable. Additionally, we identified an extinction-related functional sub-classification of neurons within the BLA. These included neurons that became less responsive during late extinction trials ('extinction-sensitive'), neurons that showed increased CS-evoked activity during late extinction ('extinction learning'), and neurons that maintained consistent activity levels during fear recall and late extinction trials ('fear sustained'). In a departure from most studies that focus on unexpected stimuli or outcomes, we also investigated whether attention signals, defined by transient changes in BLA neuronal calcium activity, are generated when expected stimuli are omitted (Chapter 4). Using neuronal calcium imaging in the BLA, we found that many amygdala neurons displayed attention signals in a stochastic manner during omitted punishment. These neurons showed enhanced sensory processing and plasticity compared to neurons without error signals. Finally, in Chapter 5, we found that unpredictable fear conditioning affected fear-related freezing behaviors and increased the cFos expression in both the BLA and the lateral septum (LS). This supports the notion that the amygdala is strategically positioned to perceive unpredictable aversive cues during conditioning. Collectively, our findings suggest that unpredictability of aversive cues results in specific alterations in the BLA and other brain areas. / 2025-01-24T00:00:00Z

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