Activation in the hippocampus (HC) and prefrontal cortex (PFC) is critical to accurately retrieve overlapping sequences. Experiments 1 and 2 tested the hypotheses that activation in and interaction between HC and PFC increases as overlap between sequences increases in a non-spatial task. Experiment 3 tested the hypothesis that theta oscillations are involved in orchestrating interactions between HC and PFC in a spatial task with overlapping elements. In the first two studies, 17 participants (aged 18-34; 11 female) learned sequences consisting of a picture frame, face, and scene. Conditions varied by degree of overlap. Using fMRI, Experiment 1 tested how degree of overlap affected HC and PFC activation. In overlapping sequences, middle and posterior HC were active when predictability of the correct response increased, dorsolateral PFC was active when participants were able to ascertain the correct set of sequences, and ventrolateral PFC was active when inhibition of interfering associations was required. Experiment 2 examined functional connectivity of HC and PFC during disambiguation. Low- and high-overlap conditions were associated with increased connectivity in separate regions at different times indicating that retrieval under the two conditions used different neural networks and strategies. Low-overlap trials were associated with increased connectivity between HC and prefrontal and parietal regions. High-overlap trials showed increased connectivity between lateral PFC and visual areas, indicating that imagery may be necessary for accurate performance. Using EEG recording, Experiment 3 examined theta activity during retrieval of well-learned, overlapping and non-overlapping mazes in 17 participants (aged 18-34, 11 female). Theta activity increased in overlapping mazes during the first of four hallways, suggesting participants were looking ahead to upcoming turns in the maze. Theta activity increased at the beginning and choice point of the third overlapping hallway, possibly in response to interference from the paired, overlapping maze. These studies provide evidence that (1) overlapping associations in non-spatial sequences elicit interactions between hippocampus and lateral prefrontal cortex, (2) increasing the degree of overlap changes the neural processes required to perform the task, and (3) theta power increases in response to increased cognitive demand and maintenance of sequence information needed to differentiate between overlapping spatial routes.

Switching between a state of fear and safety is a critical aspect of adaptive behavior. Aversive and non-aversive associations must be formed quickly and reliably but remain malleable as these associations change dynamically. When these associations become biased towards aversive associations by traumatic and stressful circumstances, as in PTSD, fear generalization and impaired fear extinction arise. These changes are associated with reduced activity in the medial prefrontal cortex (mPFC) and enhanced activity in the basolateral amygdala (BLA). It has been hypothesized that the mPFC mediates top-down control of the BLA to signal safety. It has previously been demonstrated that synchronous activity within the mPFC-BLA circuit is strongly engaged during fear conditioning, but it is unknown how activity in this circuit changes to mediate aversive discrimination. We investigated how the mPFC and BLA cooperate to mediate successful discrimination between aversive and non-aversive stimuli both for learned and innately-valent associations. Extracellular elecrophysiological recordings were obtained simultaneously form the mPFC and BLA in mice during innate anxiety, fear discrimination, and fear extinction. Local field potentials were recorded in both structures along with single unit recordings from the BLA. We discovered that fear was associated with enhanced theta-frequency synchrony and theta-gamma coupling within the mPFC-BLA circuit. On the other hand, safety was associated with predominant mPFC-to-BLA directionality of synchronous information flow and enhanced fast gamma frequency activity in both structures. Interestingly, gamma oscillations in the BLA were strongly coupled to theta frequency activity arising in the mPFC. This data is consistent with entrainment of inhibitory circuits in the BLA by mPFC input to mediate safety.

The ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) are each required for the expression of anxiety-like behavior. Yet the role of each individual element of the circuit is unclear. The projection from the vHPC to the mPFC has been implicated in anxiety-related neural synchrony and spatial representations of aversion. The role of this projection was examined using multi-site neural recordings combined with optogenetic terminal inhibition. Inhibition of vHPC input to the mPFC disrupted anxiety and mPFC representations of aversion, and reduced theta synchrony in a pathway-, frequency- and task-specific manner. Moreover, bilateral, but not unilateral, inhibition altered physiological correlates of anxiety in the BLA, mimicking a safety-like state. These results reveal a specific role for the vHPC-mPFC projection in anxiety-related behavior and the spatial representation of aversive information within the mPFC. Moreover, these data suggested that theta-frequency input from the vHPC plays a causal role in anxiety-like behavior. Next, it was investigated whether optogenetic stimulation of the vHPC-mPFC at a theta frequency was sufficient to increase anxiety. Stimulating the vHPC input to the mPFC with a sinusoidal light pattern at 8 Hz significantly increased anxiety behavior. The anxiogenic effect of vHPC terminal stimulation was frequency- (8 Hz but not 20 Hz) and pattern- (sinusoids but not pulses) specific. To understand how pulses and sinusoidal light modulate mPFC neurons differentially, mPFC pyramidal neurons were recorded both in vitro and in vivo while stimulating vHPC terminals with the same sinusoidal or pulsatile patterns. In vitro, sinusoidal stimulation increased the rate of spontaneous EPSCs, while pulses evoked strong, stimulus-locked EPSCs. In vivo, sinusoidal stimulation of vHPC terminals increased the phase-locking of mPFC single unit spiking to the optical stimulation pattern without changing overall firing rates. Together, these results suggest that sinusoidal stimulation at 8 Hz enhances theta-frequency activity in mPFC neurons as well as anxiety-related behavior. Moreover, they suggest that theta-frequency components of neural activity play a privileged role in vHPC-mPFC communication and hippocampal-dependent forms of anxiety.

The overall goal of this dissertation is to elucidate the cellular and circuit mechanisms underlying flexible behavior in the prefrontal cortex. We are often faced with situations in which the appropriate behavior in one context is inappropriate in others. If these situations are familiar, we can perform the appropriate behavior without relearning how the context relates to the behavior — an important hallmark of intelligence. Neuroimaging and lesion studies have shown that this dynamic, flexible process of remapping context to behavior (task switching) is dependent on prefrontal cortex, but the precise contributions and interactions of prefrontal subdivisions are still unknown. This dissertation investigates two prefrontal areas that are thought to be involved in distinct, but complementary executive roles in task switching — the dorsolateral prefrontal cortex (dlPFC) and the anterior cingulate cortex (ACC). Using electrophysiological recordings from macaque monkeys, I show that synchronous network oscillations in the dlPFC provide a mechanism to flexibly coordinate context representations (rules) between groups of neurons during task switching. Then, I show that, wheras the ACC neurons can represent rules at the cellular level, they do not play a significant role in switching between contexts — rather they seem to be more related to errors and motivational drive. Finally, I develop a set of web-enabled interactive visualization tools designed to provide a multi-dimensional integrated view of electrophysiological datasets. Taken together, these results contribute to our understanding of task switching by investigating new mechanisms for coordination of neurons in prefrontal cortex, clarifying the roles of prefrontal subdivisions during task switching, and providing visualization tools that enhance exploration and understanding of large, complex and multi-scale electrophysiological data.

O córtex pré-frontal medial ventral (CPFMv) é uma estrutura límbica que está envolvida em respostas autonômicas associadas a reações aversivas. O CPFMv é dividido em córtex pré- límbico (PL), córtex infralímbico (IL) e córtex dorsopeduncular (DP). A estimulação elétrica ou química destas regiões causa respostas defensivas e alterações autonômicas tais como respostas cardiovasculares, dependendo da sub-região estimulada. O estresse de restrição (ER) causa alterações hormonais e respostas autonômicas, tais como aumento de pressão arterial (PA) e frequência cardíaca (FC). A ativação de neurônios presentes no CPFMv durante essa situação aversiva, assim como os resultados da inibição farmacológica das sinapses presentes no PL e IL sugerem o envolvimento destas estruturas na modulação das respostas cardiovasculares causadas pelo ER. Entretanto, os possíveis neurotransmissores presentes no vCPFM, envolvidos nesta modulação, ainda não foram elucidados. O sistema opioidérgico central modula o sistema cardiovascular inclusive durante situações aversivas, sendo que tanto receptores quanto peptídeos opióides estão presentes no CPFMv. Considerando o exposto acima, a hipótese a ser testada no presente trabalho foi que a neurotransmissão opioidérgica do PL e IL está envolvida na modulação das respostas cardiovasculares de aumento da PA e FC desencadeadas pelo ER. Assim, a administração de naloxona (antagonista não-seletivo de receptores opióides) no PL ou IL reduziu a resposta pressora e taquicardíaca induzida pelo ER, sendo o perfil da curva dose-inibição em forma de U-invertido. A administração de CTAP (antagonista dos receptores opióides µ) ou nor-BNI (antagonista dos receptores opióides ?) no PL também reduziu a resposta pressora e taquicardíaca induzida pelo ER, de forma semelhante à naloxona, sugerindo o envolvimento desses receptores na modulação das respostas cardiovasculares desencadeadas pelo ER, enquanto que no IL, apenas a administração de nor-BNI reduziu a resposta cardiovascular induzida pelo ER. O tratamento com naltrindole (antagonista ?-seletivo) em ambas as estruturas não alterou a resposta pressora e taquicardíaca gerada pelo ER. A administração de UPF-101 (antagonista ORL-1) no PL potencializou a resposta taquicardíaca, sem alterar a resposta pressora enquanto a administração no IL não gerou efeito. Em resumo, os resultados indicam que o sistema opioidérgico, presente no PL e IL, desempenha papel facilitatório sobre as respostas cardiovasculares induzidas pelo ER, enquanto o sistema nociceptina/orfanina FQ apresentaria papel inibitório. / The ventral medial prefrontal cortex (vMPFC) is a limbic structure involved in the mediation of autonomic responses associated to aversive situations. The vMPFC is divided into prelimbic cortex (PL), infralimbic cortex (IL) and dorsal peduncular cortex (DP). The electrical or chemical stimulation of these regions cause defensive responses and autonomic changes, such as cardiovascular responses, depending on the subregion stimulated. The restraint stress (RS) evokes hormonal and autonomic responses, as well as arterial pressure and heart rate increases. Neuronal activation in the vMPFM was reported during this aversive situation, and the pharmacological inhibition of synapses in the PL and IL has suggested the involvement of these structures in the modulation of cardiovascular responses caused by RS. However, the possible neurotransmitters present in vCPFM that are involved in this modulation have not yet been identified. Opioid peptides and their receptors are present in the CPFMv. Furthermore, the central opioid system is known to modulate the cardiovascular system, even during aversive situations. Therefore, the hypothesis of this study was that PL and IL opioid neurotransmission is involved in the modulation of cardiovascular responses caused by RS. Naloxone (opioid nonselective antagonist) administration in PL or IL reduced the pressure and tachycardiac response evoked by RS, with the dose-inhibition curve having an U-inverset shape. Similar to naloxone, the selective µ-opioid antagonist CTAP and the selective ?-opioid antagonist nor-BNI when administered into the PL also reduced the pressor and tachycardiac response induced by RS, thus suggesting an involvement of these receptors in the modulation of cardiovascular responses evoked by RS, while in the IL, only administration of nor- BNI reduced the cardiovascular response induced by RS. In both structures, the treatment with the selective ?-opioid antagonist naltrindole did not affect the pressor and tachycardic response caused by RS. The pretreatment of the PL with the selective ORL-1 antagonist UPF-101 increased the tachycardic response, without affecting the RSevoked pressor, while the administration of UPF-101 into the IL did not affect the RS-evoked cardiovascular response. In summary, the opioid system in PL and IL appear to play a facilitatory role on the cardiovascular responses induced by RS, while the system nociceptin / orphanin FQ would have an inhibitory role on these responses.

Damage to the ventromedial prefrontal cortex (vmPFC) can lead to disturbances in personality, emotional dysregulation, impairments in social conduct, and difficulties in decision-making. Many researchers have likened the conduct of individuals with vmPFC lesions to that of criminal psychopaths, labeling the effects of vmPFC damage “pseudopsychopathy” or “acquired sociopathy.” However, although psychopathy—a condition marked by a distinct mosaic of antisocial personality traits and behaviors—has been studied and characterized as a psychological and behavioral disorder by many researchers, the overlap between acquired sociopathy and psychopathy remains ambiguous. This study assessed the severity of psychopathic personality traits in neurological patients with acquired damage to the vmPFC using both informant-report and self-report measures. On both informant-report and self-report measures, individuals with vmPFC damage showed no significant elevations across a wide range of psychopathic traits relative to demographically-matched neurologically healthy comparison participants and patients with damage outside of the vmPFC. The results showed only one trait, Fearlessness, that was significantly higher in patients with vmPFC lesions relative to the neurologically-healthy comparison group.

Decision makers flexibly deploy decision-making strategies based on the specific features of the problems they face (Ford, Schmitt, Schechtman, Hults, & Doherty, 1989; Payne, Bettman, & Johnson, 1993). However, research on the neuroscience of decision making has focused on a "policy capture" approach that utilizes static decision problems to study the relationships between input (the problem presented), output (the choices made), and the brain. Since the decision problems are prepackaged, this approach does not provide information about the neural bases of predecisional processes critical for flexible decision making, such as selecting an appropriate decision-making strategy and dynamically acquiring and integrating the information needed to progress toward choice. The aim of the current project is to use the lesion method to explore the neural bases of predecisional processes. The fronto-limbic information acquisition network (FLIAN) is proposed as a neural framework critical for predecisional processes in flexible decision making. According to the FLIAN model, the ventromedial prefrontal cortex (vmPFC) represents the decision problem as currently perceived (i.e., the decision space), which is the basis for selecting a decision strategy via interactions with limbic structures. The vmPFC implements the strategy through the coordination of attribute-based information acquisition induced by the amygdala and relational, option-based acquisition induced by the hippocampus. In Chapter 1, the literature pertinent to FLIAN structures is reviewed, including the neuroanatomical and functional backgrounds of those structures, their roles in decision making, and their potential roles in predecisional processes. Chapter 2 provides a review of the behavioral literature on predecisional processes and outlines the FLIAN model in detail. Chapters 3 and 4 present studies that test, and provide partial support for, the FLIAN model using the lesion method and information board tasks. As predicted, the hippocampus is shown to be critical for relational, option-based information acquisition. The vmPFC is shown to be critical for determining how attributes are weighted in the decision space representation and for organizing predecisional behavior. The amygdala was not found to play its role in attribute-based acquisition, but previous studies do support this function and further research is warranted on the role of the amygdala, as well as the hippocampus and vmPFC, in predecisional processes. Future research should also explore the consequences of abnormal predecisional functioning for social behavior, memory, and emotion processing.

Philosophical and scientific investigations into the nature of belief and knowledge are ancient, extending back to the beginnings of rational thought. It is not until the last few decades that we have been able to peer into and examine the organ of belief, the brain. Neuroanatomical perspectives have begun to address the long-standing questions of epistemology by identifying specific neural regions that are critical for the storage and evaluations of beliefs. Here, a novel neuroanatomical model of belief and doubt is presented, where post-rolandic association cortices are critical for the storage of beliefs and the prefrontal cortex is necessary for the doubt and evaluation process. It is proposed that the singular function of the prefrontal cortex is "false tagging" (the neuroanatomical essence of doubt) to mental representations in post-rolandic cortices. Individuals that have dysfunction to the prefrontal cortex, such as patients with explicit damage to the prefrontal cortex, from tumor resections or cerebral vascular events, should show a "doubt deficit", accompanied by a general increased belief to information. Evidence is presented indicating that deficiencies in the "false tagging" function may explain a wide assortment of abnormalities in neurological and psychiatric patients. Several experiments in various populations (neurological, developmental, and psychiatric) were conducted to examine the role of specific brain regions in the believing and doubting process. First, two studies gave participants explicitly-labeled false beliefs and measured the ability of the participants to falsify these beliefs. It was predicted that participants with dysfunction to the prefrontal cortex would be poor at falsifying novel beliefs. Results confirmed the predictions. Second, participants were given pairs of statements that represented opposite opinions on some issue and responded by agreeing or disagreeing with each statement. Participants with dysfunction to the prefrontal cortex, who, theoretically, have a "doubt deficit," should show compartmentalized minds, where cognitions are easily believed but rarely doubted against other extant mental information. Results suggested that participants with prefrontal cortex dysfunction were more likely to agree to opposing statements. Third, individuals with dysfunction to the prefrontal cortex should lack a dissonant state that can change attitudes, when two cognitions are in conflict. Using a free-choice paradigm, it was found that participants with prefrontal dysfunction showed either extreme attitude change after choice or no attitude change after choice, which is consistent with a "no dissonance" state. Finally, individuals with compartmentalized minds tend evince an authoritarian personality. A psychometric scale and a behavioral measure of authoritarianism were examined in the participants. Results indicated that participants with prefrontal cortex dysfunction showed increased authoritarianism on the psychometric scale, but decreased authoritarian behavior, reflecting a dissociation between knowledge and behavior. In conclusion, the results support the theoretical assertions that the prefrontal cortex is critical for "false tagging" or doubting cognitive representations. Data from neurological, developmental, and psychiatric populations are broadly consistent with the theory and offer strong external validity.

This thesis provides an overview of the literature both in the field of academic anxiety and emotion regulation. The two research fields have proceeded independently in the literature at least until recently and the thesis highlights their integration. The thesis aims to answer: what happens in the brain during cognitive reappraisal and how can we use cognitive reappraisal as a strategy for dealing with academic anxiety. Brain-imaging studies show that cognitive reappraisal (an emotion regulation strategy) involves many different higher-order cognitive processes, such as emotion processing, manipulation of appraisals in working memory, inhibiting the old and selecting new appraisals. Different regions of the prefrontal cortex are believed to support these functions, moreover, the prefrontal cortex modulates amygdala activity and decreases negative emotions. Previous research in the lab and in the classroom suggests that cognitive reappraisal might be a strategy for dealing with academic anxiety. The arousal reappraisal intervention encourages students to reinterpret their increased arousal as beneficial to their performance. Only a small number of studies have tested the intervention in academic contexts, however the results are promising, e.g. students improved exam performance. The goal is to teach students that it is possible to perform well regardless of one’s anxiety. The findings presented in this thesis provide an initial glimpse into the fruitful integration of these two research fields.

The current set of experiments was designed to test the hypothesis that there is a sex difference in impulsivity and in brain areas associated with impulse control in prepubertal and adult rats, such that females have greater inhibitory control than do males. Preliminary studies established that neonatal testosterone exposure is able to masculinize and increase impulsive behavior in prepubertal female rats. In the current study, male and female prepubertal rats exposed to treatments that resulted in either neonatal androgen or estrogen receptor activation made more impulsive choices than did control females and their performance mirrored that of control males. Assessment of impulsivity in adult rats indicated that impulsive choice behavior was similar in males and females whereas impulsive action behavior was greater in males than in females. Analysis of protein levels of markers of dopaminergic and noradrenergic reuptake in the orbital frontal cortex (OFC) and dorsal striatum (dSTR), two brain areas important for impulse control, revealed no differences between male and female prepubertal or adult rats, whereas analysis of protein levels of markers of myelination in the OFC and dSTR revealed similar levels between the sexes in prepubertal rats but increased myelin levels in the OFC but not dSTR of adult female rats as compared to males. Furthermore, analysis of the projections from the OFC to dSTR discovered that the strength of these projections was significantly greater in adult females as compared to males. However, inactivation of the OFC during an impulsive action task in adult rats failed to have an effect on impulsive action responding. Collectively, these results demonstrate for the first time that there is a sex difference in impulsive choice control in prepubertal rats that is organized neonatally by actions of both androgens and estrogens, this sex difference subsides in adulthood, but a sex difference in impulsive action control is present in adulthood. Furthermore, the novel discovery that adult female rats have increased levels of myelination within the OFC and increased strength of projections from the OFC to dSTR as compared to males establishes a molecular sex difference that could underlie the enhanced impulse control in females. / acase@tulane.edu