Patients with schizophrenia show a number of cognitive deficits that may be related to abnormal hippocampal physiology and function. One such cognitive deficit is in transitive inference. Simply stated, transitive inference is the ability to infer A > C after directly learning A > B and B > C. The hippocampus has been implicated in transitive inference as lesions of the hippocampus in C57BL/6 mice after initial training and testing impairs transitive inference. Likewise, lesions of the hippocampus in rats prior to training also impair transitive inference. However, lesions of the whole hippocampus are not able to specifically examine the role of the dorsal versus ventral hippocampus in this task. This is important because studies suggest that the dorsal and ventral poles of the hippocampus may be functionally different. The present experiment used reversible inactivation of the dorsal and ventral hippocampus to examine the role of these structures in transitive inference. Mice were trained to learn that A>B, B>C, C>D, and D>E during training phases and then were tested to show if they learned that A>E (the novel control pairing) and that B>D (the novel pairing which requires transitive inference) during test sessions. Following these test sessions, cannulae were inserted into the hippocampus and the mice were allowed 5 days to recover. After the recovery period, mice underwent 4 more test sessions. The GABAA agonist muscimol or saline was infused into the dorsal or ventral hippocampus thirty minutes before each test session. The mice which received muscimol infusion into the dorsal hippocampus performed similarly to controls on the novel control pairing (A>E) but were significantly impaired on the novel pairing (B>D) which required transitive inference. The DBA/2 strain of mice have altered hippocampal function and has been used to model schizophrenia. The study also compared performance of DBA/2J and C57BL/6J inbred mice in TI, and foreground and background fear conditioning, which both involve the hippocampus. Separate mice were then trained with two different fear conditioning paradigms. For background fear conditioning, mice are trained with two paired presentations of a conditioned stimulus (CS, 30 second, 85 dB white noise) and an unconditioned stimulus (US, 2 second, 0.57 mA foot shock). Mice are then tested the next day for both freezing to the training context. Foreground fear conditioning differed in that the mice were presented with only the shocks during training. DBA/2J mice performed significantly worse than the C57BL/6J in both foreground and background fear conditioning and transitive inference. These results provide further support for the role of the dorsal hippocampus in transitive inference. Moreover, these results may help provide a better understanding of the cognitive deficits associated with schizophrenia. / Psychology

Caffeine is the most widely used psychoactive substance in the world. While findings suggest that chronic caffeine exerts negligible effects on cognition in adults, the effects of chronic caffeine on cognition in children and adolescents are not well understood. The hippocampus, a brain region important for learning and memory, undergoes extensive structural and functional modifications during pre-adolescence and adolescence. As a result, chronic caffeine may have differential effects on hippocampus-dependent learning and memory in pre-adolescents and adolescents compared to adults. The present study characterized the effects of chronic caffeine and withdrawal from chronic caffeine on hippocampus-dependent (contextual) and hippocampus-independent (cued) fear conditioning in pre-adolescent, adolescent, and adult mice. In addition, we investigated whether exposure to chronic caffeine during pre-adolescence, adolescence, or adulthood had long-lasting effects on conditioning in adulthood. Results indicate that exposure to chronic caffeine during pre-adolescence and adolescence either enhances or impairs contextual conditioning in a concentration-dependent manner. However, withdrawal from chronic caffeine impairs contextual conditioning in pre-adolescent mice only. In addition, exposure to chronic caffeine during pre-adolescence either enhances or impairs retention of contextual memories in adulthood in a concentration-dependent manner. In contrast, exposure to chronic caffeine during adolescence impairs cued conditioning in adulthood. These findings support the hypothesis that exposure to chronic caffeine during pre-adolescence and adolescence compromises hippocampus-dependent learning and memory. Furthermore, exposure to chronic caffeine during adolescence may produce long-lasting deficits in learning and memory in adulthood. / Psychology

Social Anxiety (SAD) increases in prevalence as children enter adolescence. Adolescents with Autism Spectrum Disorder (ASD) are diagnosed with comorbid SAD at higher rates than these individuals are diagnosed with other clinical disorders, including depression and other anxiety disorders. However, there is little research on whether the presentation and neural underpinning of comorbid SAD within the context of ASD is the same as SAD alone. Individual and diagnostic differences exist in neural and biological mechanisms of fear conditioning. Characterization of whether neural mechanisms of fear are different within ASD with comorbid SAD and SAD alone may better inform clinical treatments. Accordingly, the present study characterizes neural responses during a fear-inducing experiment, as measured by fMRI. Fifty-seven adolescents participated in this study, with adolescents with ASD and SAD (n=17), SAD alone (n=20), and typically developing adolescents (n=20). All participants completed two fear conditioning and reversal paradigms while completing an fMRI scan. The paradigm consisted of a Social condition and Nonsocial condition. An ANOVA for fear conditioning was conducted. Results revealed significant activation in the Inferior Temporal Gyrus (ITG) during fear conditioning. No between group differences were observed, but within-group differences indicated differential modulation of the ITG in the ASD with SAD group in the Social condition compared to the Nonsocial condition. The SAD group demonstrated differential activation between conditioning stimuli in the Nonsocial condition, but not in the Social condition. Results indicate that adolescents with ASD and SAD may display different neural mechanisms for acquiring fear compared to typically developing peers. Results have potential to inform treatment approaches. / Doctor of Philosophy / Based on the 2012 international energy agency (IEA) report, global waste heat energy is estimated to be in the range of 246 Exajoule (1 EJ = 10¹⁸ J). Tapping even small fraction of this wasted energy through thermal energy harvesting techniques will allow us to generate significant magnitude of green energy. Thermoelectrics (TEs) are one of the most promising thermal energy conversion materials as they offer cost-effective and environmentally friendly option with solid-state silent operation and scalability. Among many different options for high temperature TE materials, half-Heusler system is one of the leading candidates as it has the potential to provide high performance and thermal stability at temperatures as high as 873 K. The progress in developing practical half-Heusler materials has been limited for last two decades. Despite many publications, the maximum figure of merit (zT) of n-type half-Heusler materials has been stagnant (zT ~ 1.0). Further, there has been a lack of focus towards module development that can operate under realistic conditions. This dissertation provides comprehensive studies on novel thermoelectric compositions and nanocomposites that are suitable for manufacturing of high temperature modules. Microstructural architectures proposed here provide the ability to tailor electronic transport and phonon scattering beyond the commonly demonstrated regimes. Optimized materials were successfully implemented in efficient and stable thermoelectric generator exhibiting power density on the order of 13.81 W⸱cm⁻² , which is 1400 % higher than that of the fuel cell (~1 W⸱cm⁻² ).

Nicotine has been shown to enhance multiple forms of learning and memory. However the substrates through which these effects occur are not well understood. To examine the specific substrates of nicotine's acute effects on trace fear conditioning, I infused nicotine into areas thought to support trace fear conditioning, the dorsal hippocampus, ventral hippocampus and medial prefrontal cortex. Additionally, we investigated the contributions of nicotinic acetylcholinergic signaling to trace fear conditioning by infusing the nicotinic antagonists dihydro-beta-erythroidine (DHbE) and methyllycaconitine (MLA) into these areas. Nicotine had different effects on both trace and contextual fear conditioning depending on dose and brain region, as did the nicotinic antagonists. In the dorsal hippocampus nicotine infusion enhanced both trace and contextual conditioning, although these effects were dissociable by dose and training protocol. Additionally, the high-affinity nicotinic antagonist DHbE produced selective deficits in trace conditioning, suggesting that while enhancement of nicotinic signaling can affect both contextual and trace learning, nicotinic activity in the dorsal hippocampus is critically involved in trace but not contextual conditioning. In the ventral hippocampus nicotine infusion produced deficits in both trace and contextual fear conditioning, without affecting delay conditioning, while the antagonists had no effect. This finding suggests that altered nicotinic signaling in the ventral hippocampus can suppress hippocampus dependent learning. In the mPFC nicotine selectively enhanced trace conditioning though both antagonists also enhanced trace fear conditioning. Unlike in the mPFC or dorsal hippocampus, where nicotine and antagonist induced effects occurred during training, effects in the ventral hippocampus occurred at both training and testing, suggesting that the ventral hippocampus may be able to modulate acquisition as well as expression of hippocampus dependent learning. Additionally, antagonist infusion into the mPFC during testing produced deficits in expression, suggesting that this area can modulate fear expression. Thus, the substrates of nicotinic acetylcholinergic contributions to trace and contextual fear conditioning are diverse. I put forth a multi-component model of these contributions, where trace fear conditioning is supported by dorsal hippocampus dependent maintenance of the CS during the trace interval, long-term storage in the mPFC and ventral hippocampal mediated acquisition and expression. / Psychology

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.

The mechanisms underlying cannabinoid impairment of fear memory is not clear. This study investigated the effects of the synthetic cannabinoid HU210 and the endocannabinoid hydrolysis inhibitor JZL 195 on fear memory following contextual fear conditioning (CFC; an animal model of fear). The long-term depression (LTD)-blocking peptide Tat-GluR2 was utilized to investigate whether the expression of cannabinoid-induced LTD (CB-LTD) is required for the cannabinoid impairment of acquisition and consolidation of contextual fear memory. HU210 reduced freezing throughout the test phase of the acquisition protocol, which was not affected by pre-administration of Tat-GluR2. High and moderate doses of HU210 reduced freezing during the first and last half, respectively, of the test phase of the consolidation protocol, which was prevented by pre-treatment with Tat-GluR2. HU210 did not affect freezing during the test phase of the retrieval protocol. Thus, these results suggest that HU210 impairs acquisition and consolidation, but not retrieval of contextual fear memory, and that in vivo CB-LTD expression is required for HU210 impairment of the consolidation, but not acquisition, of contextual fear memory. We also observed that HU210 and JZL 195 do not facilitate the acquisition of contextual fear memory extinction.

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.

The amygdala is crucially involved in the acquisition and retention of fear memories. Experimental research on fear conditioning has shown that memory retrieval shortly followed by pharmacological manipulations or extinction, thereby interfering with memory reconsolidation, decreases later fear expression. Fear memory reconsolidation depends on synaptic plasticity in the amygdala, which has been demonstrated in rodents using both pharmacological manipulations and retrieval-extinction procedures. The retrieval-extinction procedure decreases fear expression also in humans, but the underlying neural mechanism have not been studied. Interfering with reconsolidation is held to alter the original fear memory representation, resulting in long-term reductions in fear responses, and might therefore be used in the treatment of anxiety disorders, but few studies have directly investigated this question. The aim of this thesis was to examine the effects of the retrieval-extinction procedure on amygdala activity and behavioral fear expression in humans. The work presented here also investigated whether findings from studies on recent fear memories, established through fear conditioning, extends to naturally occurring long-term phobic fears. Study I, combining fear conditioning and a retrieval-extinction procedure with functional magnetic resonance imaging (fMRI), demonstrated that memory retrieval shortly followed by extinction reduces later amygdala activity and fear expression in healthy subjects. In Study II, these subjects were re-tested 18 months later. The results showed that the effects on fear expression were still present and that initial amygdala activity predicted long-term fear expression. Using an adapted version of the retrieval-extinction procedure, Study III showed that memory retrieval shortly followed by exposure to spider pictures, attenuates subsequent amygdala activity and increases approach behavior in subjects with life-long fear of spiders. In Study IV, these subjects were re-tested 6 months later, and the results showed that effects on amygdala activity as well as approach behavior were maintained. In summation, retrieval-extinction leads to long-lasting reductions in amygdala activity and fear expression. These findings are consistent with the hypothesis that retrieval-extinction alters an amygdala dependent fear memory. Retrieval-extinction can also attenuate long-term phobic fears, indicating that this manipulation could be used to enhance exposure-based treatments for anxiety disorders.

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.

Chez les mammifères, le néocortex constitue une structure remarquablement plastique assurant leurs multiples capacités d’adaptation et d’apprentissage. Par exemple, l’apprentissage associatif permet à chaque individu d’apprendre les relations entre un événement particulier (un danger par exemple) et les signaux environnementaux qui y sont associés, afin d’en anticiper les conséquences s’il se reproduit dans le futur. Dans le cas de la peur conditionnée, l'apprentissage associatif améliore les capacités de discrimination des signaux de menace et de sécurité, garantissant ainsi une représentation précise de l'environnement. Ce processus comportemental est en partie dépendant de l'interaction entre deux structures cérébrales: le cortex préfrontal (PFC) et le complexe basolatéral de l'amygdale (BLA). Bien que le PFC puisse encoder à la fois les mémoires de menace et de sécurité qui seraient recrutées préférentiellement après l'apprentissage, on ignore toujours si une telle représentation discriminative existe réellement, et si oui, les mécanismes neuronaux et synaptiques qui en sont à l'origine. Au cours de mon travail de thèse, j'ai démontré que l'activité des neurones excitateurs du PFC est nécessaire à la discrimination entre les signaux de menace et de sécurité grâce à la formation d'ensembles spécifiques de neurones. Au cours de l'apprentissage, les neurones pyramidaux sont potentialisés et recrutés au sein de ses ensembles grâce à l'association au niveau dendritique d'événements synaptiques non-linéaires issus des entrées sensorielles avec des entrées synaptiques provenant de la BLA. En conclusion, nos données fournissent la preuve d'un nouveau mécanisme synaptique qui associe, pendant l'apprentissage, l'expérience perçue avec l’état émotionnel transmis par la BLA permettant ainsi la formation d'ensembles neuronaux dans le cortex préfrontal. / The ability of an organism to predict forthcoming events is crucial for survival, and depends on the repeated contingency and contiguity between sensory cues and the events (i.e. danger) they must predict. The resulting learned association provides an accurate representation of the environment by increasing discriminative skills between threat and safety signals, most likely as a result of the interaction between the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Although it suggests that local neuronal networks in the PFC might encode opposing memories that are preferentially selected during recall by recruiting specific cortical or subcortical structures, whether such a discriminative representation is wired within discrete prefrontal circuits during learning and by which synaptic mechanisms remain unclear. Here, the work at issue demonstrates that discrimination learning of both safe and fear-conditioned stimuli depends on full activity of the frontal association cortex, and is associated with the formation of cue-specific neuronal assemblies therein. During learning, prefrontal pyramidal neurons were potentiated through sensory-driven dendritic non-linearities supported by the activation of long-range inputs from the basolateral amygdala (BLA). Taken together, these data provide evidence for a new synaptic level mechanism that coincidently link (or meta-associate) during learning features of perceived experience with BLA mediated emotional state into prefrontal memory assemblies.