The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound ?? shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over-training of overexpectation. Expression of the overexpectation effect produced by two compound ?? shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error.

Thesis advisor: Gorica D. Petrovich / Environmental cues that are neutral in respect to hunger and feeding can come to predict food through Pavlovian appetitive conditioning. These learned cues can drive food seeking and eating independent of physiological hunger leading to overeating and obesity. However, the food outcome, and thus the value of the cues, can change due to environmental alterations. A change in the values of learned cues requires altering behavioral responses to accurately reflect the cue’s new outcome. This behavioral flexibility is necessary to respond appropriately to changes in the environment and, as such, is an adaptive trait. The aim of this dissertation was to determine critical neural mechanisms specifically within the basolateral amygdala (BLA) and also with its interactions with the medial prefrontal cortex (mPFC) during behavioral flexibility when outcomes of learned appetitive cues change using the appetitive reversal learning paradigm. The main focus was on the BLA (Chapter 2) and its connection with the mPFC (Chapters 3 and 4) since both of these areas are critical in appetitive cue learning and valuation and subsequent behavioral modifications. The first study in this dissertation examined if separate neuronal ensembles within the BLA respond to different learned cues, a cue that signals food availability and a cue that does not. Additionally, we investigated if these potentially distinct neuronal ensembles are necessary during periods of behavioral flexibility when the value of the specific learned cues are changed during reversal learning. We determined that there are distinct neuronal ensembles within the BLA that respond to different learned cues, and that the cue-specific ensembles are necessary for updating the value of each specific cue (Chapter 2). Next, we examined a projection target of the BLA, the mPFC, to determine if BLA-projecting neurons are activated during learning (Chapter 3). Using retrograde tract tracing combined with Fos detection, we found recruitment of the anterior BLA to prelimbic area of the mPFC across cue-food learning, signifying that the BLA can inform the mPFC of the value of learned cues. Then to establish that communication between the BLA and mPFC is necessary for cue value learning and updating (Chapter 4), we functionally disconnected communication between these regions and examined appetitive learning using discriminative conditioning, reversal learning, and devaluation paradigms. We found impairments in cue value recall and subsequent updating of the cues’ values during reversal learning. Together, these studies indicate the BLA may be important in informing the mPFC of the value of learned cues, and their interaction is critical to optimally guide behavioral responding. The findings from these experiments are valuable for our understanding of the neural mechanisms that motivate eating behavior under the control of learned food cues and to understand the mechanisms necessary for behavioral flexibility when the outcomes of learned cues are changed. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

The Generalized Unsafety Theory of Stress proposes that physiological markers of generalized stress impair learning of safe cues in stressful environments. Based on this model, chronic problems inhibiting physiological arousal lead to a heightened perception of threat, which involves experiencing anxiety symptoms without any obvious precipitating stressful or traumatic event. This investigation aims to determine the impact of stressor- versus context-related emotional learning on generalized unsafety, using a Pavlovian threat-conditioning paradigm. The difference in learning threatening cues ([CS+] paired with an aversive stimulus) compared to safety cues ([CS-] not paired with an aversive stimulus) was used as a proxy measure of generalized unsafety, as conceptualized by the GUTS model. This difference is expected to be moderated by individual differences in tonic cardiac regulation (i.e. heart rate variability). Lastly, a temporal-differences learning model was used to predict skin-conductance learning during stressor, stressor context and general contexts to determine which best predicts Pavlovian learning. TD learning is expected to better predict skin-conductance in individuals with higher fear inhibition in comparison to those with low fear inhibition. / Doctor of Philosophy / This study examined the claims of a theory about how human bodies respond to stress and what this tells us about how anxiety develops in and affects the mind and body. The theory is named the Generalized Unsafety Theory of Stress (GUTS) and two main hypotheses were tested in this study: 1) the theory suggests that a person's feeling of safety is affected by the variation in their heart rate at rest, and 2) that a person's feeling of safety could be observed most accurately by their body's defense responses when they are experiencing a threatening situation that is objectively safe. Individuals experiencing anxiety often report being aware that they are safe, yet their heart rate remains elevated and palms remain sweaty. Most studies that have examined the body's defense response have focused almost solely on reactions to a threat by looking at the reactions of one or more organs that make up the body's defense-response systems (e.g., heart). Results of this study confirmed the unique GUTS perspective. Specifically, the heart rate's variation at rest affects the defense response (sweaty hands) during threatening and objectively safe contexts, which in turn, predicts a person's feeling of safety. These results confirm that there are measurable biological constraints that change the way people learn about and react to their environments, which is very important for understanding the development and maintenance of anxiety physiology and behavior. The way a person learns to associate emotional responses to certain cues in their environment, particularly threat and safety cues, can be measured as defense responses in the body in response to a series of trials. Exploratory analyses examined human threat learning in comparison with mathematically-generated learning in order to better model the processes whereby anxiety develops based on learning of threat and safety cues.

Thesis advisor: Gorica D. Petrovich / Thesis advisor: Michael McDannald / Cues existing in the surrounding environment repeatedly paired with biologically relevant events can exert a powerful drive over behavior. When learned cues recurrently signal consumption, this can lead to eating in the absence of hunger or physiological need. The difficulties associated with resisting palatable foods and maintaining healthy habits may be related to the neurobiological underpinnings of pervasive responding to food cues. Behavioral flexibility through updating information about formed reward associations is vital to appropriately adapt to the surrounding environment and physiological need. Studying the renewal of responding of extinguished food-seeking behaviors can help us better understand the mechanisms mediating behavioral control over responding to learned reward cues. This dissertation aimed to explore behavioral sex differences and the neural substrates of renewal of responding to food cues after extinction by utilizing a context-mediated renewal of responding paradigm. The first chapter in this dissertation explored the effects of context habituation on context-induced renewal of responding to food cues in males and females. We investigated if increased familiarity with the behavioral contexts, and if presentation of food reward or not during these habituation sessions, would impact the strength of cue-food learning and renewal of responding after extinction differently in males and females. We discovered that when males received context habituation paired with food prior to training they exhibited elevated food-seeking behaviors throughout conditioning, as well as strengthened renewal. This suggests that for males the context habituation with food had a lasting, amplifying effect on cue-food learning. For females, however, increased context familiarity did not improve renewal of responding and, moreover, these experiments revealed evidence for resistance to extinguishing food-seeking behaviors in females. Then, in Chapter 2, we found neural evidence for potential plasticity mechanisms in the prelimbic (PL) and infralimbic (ILA) subregions, which were both recruited during context-mediated renewal of responding to food cues. Our findings are in line with evidence demonstrating that the PL and ILA are both recruited during appetitive learning and possibly provide overlapping contributions to encoding and responding in context-based reward learning. Taken together, the experiments outlined in this dissertation add to existing evidence of sex differences in appetitive motivated behaviors and the intricacies of the roles of the PL and ILA in cue-food learning and contextual processing. The findings from these studies advance our understanding of persistent food-seeking behaviors and highlight the importance of elucidating the neural substrates mediating behavioral responding to learned reward cues. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

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Dysfunktionale Lernvorgänge (wie z.B. Pawlowsche Konditionierung) können bei Patienten mit Alkoholabhängigkeit das Rückfallrisiko erhöhen, was innerhalb der vorliegenden Arbeit mittels drei Studien untersucht wurde.

Background: Contemporary learning theories of drug addiction ascribe a key role to Pavlovian learning mechanisms in the development, maintenance, and relapse of addiction. In fact, cue-reactivity research has demonstrated the power of alcohol-associated cues to activate the brain’s reward system, which has been linked to craving and subsequent relapse. However, whether de novo Pavlovian conditioning is altered in alcohol use disorder (AUD) has rarely been investigated. Methods: To characterize de novo Pavlovian conditioning in AUD, 62 detoxified patients with AUD and 63 matched healthy control participants completed a Pavlovian learning task as part of a Pavlovian-to-instrumental transfer paradigm during a functional magnetic resonance imaging session. Patients were followed up for 12 months to assess drinking behavior and relapse status. Results: While patients and healthy controls did not differ in their ability to explicitly acquire the contingencies between conditioned and unconditioned stimuli, patients with AUD displayed significantly stronger amygdala responses toward Pavlovian cues, an effect primarily driven by stronger blood oxygen level–dependent differentiation during learning from reward compared with punishment. Moreover, in patients compared with controls, differential amygdala responses during conditioning were positively related to the ability of Pavlovian stimuli to influence ongoing instrumental choice behavior measured during a subsequent Pavlovian-to-instrumental transfer test. Finally, patients who relapsed within the 12-month follow-up period showed an inverse association between amygdala activity during conditioning and relapse latency. Conclusions: We provide evidence of altered neural correlates of de novo Pavlovian conditioning in patients with AUD, especially for appetitive stimuli. Thus, heightened processing of Pavlovian cues might constitute a behaviorally relevant mechanism in alcohol addiction.

N-methyl-D-asparate (NMDA) receptors located within the basolateral complex of the amygdala are required for the consolidation and expression of Pavlovian conditioned fear. The events downstream of receptor activation that mediate these processes are not well defined. An intermediate step that may be of significance is the synthesis of the gas nitric oxide (NO). Nitric oxide is synthesised as a result of NMDA receptor activation and acts as an unconventional neurotransmitter freely diffusing across cell membranes interacting with its targets in a non-synaptic manner. The targets of NO include cellular components that play significant roles during the consolidation of conditioned fear and the neurotransmission associated with its expression. This implies that NO may be an important intermediary of NMDA receptor activation and both these processes. The current study sought to examine this possibility using fear potentiated startle to examine the expression of learned fear. Three experiments were conducted, fifty rats received intra-BSC microinfusions of the global nitric oxide synthase inhibitor L-NAME either prior to fear conditioning, fear testing, or examination of the shock sensitization of the acoustic startle affect. The results indicated that NO was indeed required for both the consolidation and expression of learned fear, whereas it was not required for shock enhanced startle responding. This study provides new information about the sub-cellular basis of conditioned fear, and highlights the pivotal role played by NO in processes associated with conditioned fear.

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder that affects over 7.7 million adults and carries an estimated societal cost of $3.1 billion every year. People develop PTSD after exposure to a traumatic event. Alone or combined, approved pharmacotherapies or psychotherapy are somewhat effective, but symptoms for many remain refractory. Emerging evidence suggests that opiate systems may modulate the development and expression of PTSD, and their role can be investigated preclinically. Pavlovian fear conditioning is a preclinical model which elicits behaviors mirroring those that occur in humans during and after exposure to trauma. This presents an experimental tool that can help elucidate the opiate mechanisms involved in traumatic memory as well as the resulting fear behavior. Mu opioid receptor (MOR) analgesics, such as morphine, are often given as a response to trauma, and there is emerging evidence that they are, at least partially, protective against PTSD. The kappa opioid receptor (KOR) system has also been implicated in stress-related processes, with KOR agonists reported to enhance stress in both laboratory animals and in humans, and KOR antagonists reported to attenuate stress-like behaviors preclinically. This project attempted to clarify part of the role of the mu and kappa opiate receptor systems in mediating effects of Pavlovian fear conditioning in mice as a predictor of their involvement in some of the signs and symptoms of PTSD. Kappa agonists increased acute fear responses but surprisingly also facilitated fear extinction learning. This would suggest that the use of kappa agonists might increase the efficiency and effectiveness of this therapy and could improve existing PTSD patient outcomes. MOR agonists, as well as KOR antagonists reduced acute and long-term fear behavior. These results support that the use KOR analgesics like morphine and fentanyl in the treatment of trauma could have an added benefit of reducing the emergence and persistence of PTSD. Self-medication may help explain the comorbidity of opioid abuse in PTSD patient populations. Understanding the relative effects of these opiate ligands could lead to more informed usage of MOR analgesics which vary in mu and kappa receptor activity under battlefield and other traumatic conditions.

Thesis advisor: Gorica Petrovich / Thesis advisor: Christina Reppucci / Previously our lab has shown that food-deprived male and female rats will inhibit food consumption when presented with a conditioned stimulus that signals danger, and that this effect persists much longer in females than in males. The current experiment is part of a larger study that has two aims: 1) delineate the brain areas associated with fear-cue induced anorexia and 2) determine whether there are sex-differences in brain activation patterns. Female rats previously conditioned in an aversive paradigm inhibited food intake compared to female rats in the control group during three extinction tests, while experimental males only inhibited intake compared to male controls during test one. Following the third test, rats were sacrificed and brain tissue processed to assess activation patterns via Fos-expression within the central nucleus of the amygdala (CEA). We found that males had higher activation than females during test 3 in the CEA. / Thesis (BS) — Boston College, 2013. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology Honors Program. / Discipline: Psychology.