The direction in which another is looking at triggers a spontaneous orienting of attention towards gaze direction in the viewer. However, whether the facial expression displayed by the gazing individual modulates this attention orienting is unclear. In this thesis, the modulation of gaze-oriented attention with facial expressions was explored in non-anxious individuals at the behavioral level and at the neural level using Event-Related Potentials (ERP). In the gaze-cueing paradigm used, a dynamic face cue averting gaze and expressing an emotion was presented, followed by a lateral, to-be-localized target. At the behavioral level, a faster response to targets appearing at the gazed-at location (congruent targets) than to targets appearing opposite to the gazed-at location (incongruent targets) was observed (Chapters 3-5). This so-called Gaze Orienting Effect (GOE) was enhanced with fearful, angry and surprised expressions relative to neutral and happy expressions and was driven by emotional differences in response speed to congruent targets (Chapters 3-5). These effects could not be attributed to better discrimination of those emotions when presented with an averted gaze (Chapter 2). These results confirm the impact of fear and surprise on gaze-oriented attention in non-anxious individuals and demonstrate, for the first time, a similar impact for angry expressions. All the emotions enhancing the GOE signal an evolutionary relevant stimulus in the periphery, are threat-related and carry a negative valence, which suggests that one of these attributes (or all combined) is driving the emotional modulation of gaze-oriented attention (surprise is treated like fear in the context of fearful expressions). In Chapter 4, the effect of the dynamic cue sequence on these GOE modulations was investigated. An emotional modulation of the GOE was found only when the gaze shift preceded the emotional expression, but not when the emotion was expressed before gaze shift or when expression and gaze shift were simultaneous. These results highlight the importance of using a sequence closer to real life situations (we usually orient attention before reacting to an object in the environment) in studying the modulation of the GOE with emotions. At the neural level, we investigated the ERPs associated with gaze-oriented attention at target presentation and at cue presentation (Chapters 3 and 5). Confirming previous reports, the amplitude of a target-triggered P1 ERP component was larger in the congruent than in the incongruent condition, reflecting enhanced processing of gaze-congruent targets. In addition, cue-triggered ERPs previously observed in response to arrow cues, were investigated. An Early Directing Attention Negativity (EDAN) and an Anterior Directing Attention Negativity (ADAN) were found, indexing respectively attention-orienting to the cued location and maintenance of attention at the cued location. This is the first study to report both EDAN and ADAN components in response to gaze cues. These results show clear markers of attention orienting by gaze at the neural level, during both cue and target processing. Neither EDAN nor ADAN was modulated by emotion. The congruency effect on P1 was enhanced for fearful, surprised and happy faces compared to neutral faces in Chapter 3 but no differences between the emotions were found in Chapter 5. Thus, the emotional modulation of the brain processes involved in gaze-oriented attention is very weak and protracted or occurs mainly between target onset and response to target. The relationships between participants’ autistic traits and their emotional modulation of gaze-oriented attention were also investigated. Results showed a negative correlation with the GOE to happy upright faces and with the P1 congruency effect, which suggests that individuals with more severe autistic traits are less sensitive to the impact of social emotions like joy. The implication of these results for attention orienting in general and for individuals with Autism Spectrum Disorder is discussed. Together, the findings reported in this thesis clarify the behavioral and neural processes involved in gaze oriented attention and its modulation by facial expression in addition to demonstrating a relationship between gaze oriented attention, its modulation with social emotions and autistic traits.

Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.

Dopamine D3 receptors (D3Rs) have been implicated in mediating behavioural sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. Neil Richtand proposed a role for D3Rs in the modulation of sensitization by acting as an inhibitor of D1/D2 receptor-mediated behaviours, and several reports suggest D3Rs up-regulate in response to chronic drugs of abuse. In separate experiments, we examined EtOH sensitization in D3R knockout (KO) as well as in D1R and D2R KO mice. We also examined amphetamine sensitization in D3R KOs compared to wild type mice. We challenged C57Bl/6 and DBA/2 mice with a D3R agonist (PD128907) and antagonist (U99194A) to examine how acute and chronic D3R activation and inactivation may affect the induction and expression of EtOH sensitization. We investigated D1/D3R interactions in sensitized and control mice and examined whether EtOH sensitization leads to changes in D3R binding using [125I]-7-OH-PIPAT autoradiography. Results showed that D3R KOs, were resistant to EtOH but not to amphetamine sensitization. Chronic but not acute D3R blockade with U99194A inhibited the induction, whereas acute D3R activation with PD128907 attenuated the expression of EtOH sensitization. In our D1/D3R interaction study we observed that although PD128907 attenuated D1 agonist-induced hyperactivity with SKF81297, this effect was the same in sensitized and control animals, even though sensitized mice were more responsive to PD128907 than controls. This enhanced response, which suggests a functional up-regulation of D3Rs, was not accompanied by changes in D3R binding as indicated by autoradiography, and could mean that functional changes in the D3R associated with EtOH sensitization occur elsewhere than at the level of the membrane-bound receptor. Taken together, these results suggest a modulatory role for the D3R in EtOH but not amphetamine sensitization, where D3R activation attenuates the expression and D3R blockade prevents the induction of EtOH sensitization. These results are important because a better understanding of the role of the D3R in EtOH sensitization may help not only to identify some of the underlying neural mechanisms of sensitization, but also help in the identification of treatment strategies for patients that may be susceptible to alcohol abuse.

There have been increased efforts to develop methods for improving attention across a range of tasks including those assessing sustained attention. Using a variety of techniques, researchers have reported modest reductions in errors on sustained attention tasks. However, published reports often have not documented changes in response times (RTs) that might accompany error reductions, which is problematic given that the error reductions could be mediated by a slowing strategy (i.e., speed-accuracy trade-off). In three studies, I explored the effects of speed-accuracy trade-offs in a sustained attention task (The Sustained Attention to Response Task; SART). In Study 1, I examined the effects of changing SART instructions from the double-edged "be fast and accurate" to the more conceptually accurate goal of maintaining high accuracy by responding slowly and carefully, and found that instructions to respond slowly and accurately resulted in both significantly longer RTs and fewer SART errors. In Studies 2 and 3, I developed a modified version of the SART that allowed me to experimentally manipulate RTs and found that errors were a systematic function of manipulated differences in RT independent of individual differences in response strategies. The results of these experiments indicate that it is possible that any technique that alters RT might indirectly alter error rates independently of improvements in sustained attention. I therefore conclude that investigators need to carefully attend to, control for, and report any changes in RT that accompany improvements in accuracy of performance, or alternatively employ tasks controlling for RT.

Experience of the built-environment is said to be dependent on visual perception and the physical properties of space. Scene and environmental preference research suggests that particular visual features greatly influence one’s response to their environment. Typically, environments which are informative and allow an individual to gain further knowledge about their surroundings are preferred. Although, such findings could be applied to the design process it is first necessary to develop a way in which to accurately and objectively describe the visual properties within an environment. Recently it has been proposed that isovist analysis could be employed to describe built-environments. In two experiments we examined whether or not isovist analysis can capture experience of real-world environments. In Experiment one we demonstrated that isovist analysis can be employed to describe experience of environment within a controlled, laboratory environment. In Experiment two we employed some of the methods of post-occupancy analysis to examine the robustness of the isovist approach and whether it would capture experience of a complex, real-world environment. The results of Experiment two suggest that isovist analysis could capture certain experiences, such as spaciousness, but failed to capture other responses. Regression analysis suggests that a large number of variables predicted experience, including previous experience with the building and the presence of other individuals. These findings suggest that experience of real-world, complex environments cannot be captured by the visual properties alone, but also highlight some of the other factors, such as presence of others and previous experiences may influence experience of built settings. Implications for the design processes are described.

The consequence of many psychiatric and neurodegenerative disorders, such as Parkinson's disease and schizophrenia, is an impairment in ‘executive functioning'; an umbrella term for several cognitive processes, including the focussing and shifting of attention and the inhibition of responding. The ability to form an ‘attentional set' involves learning to discriminate qualities of a multidimensional cue, and to subsequently learn which quality is relevant, and therefore predictive of reward. According to recent research, the subthalamic nucleus (STN) and possibly the adjacent zona incerta (ZI) may mediate the formation of attentional set. Dysregulation of the STN as a result of Parkinson's disease contributes to characteristic motor symptoms, and whilst deep-brain stimulation of this region may treat gross motor impairments, it may also impair cognition. The work in this thesis aimed to expand our understanding of the mechanisms of attentional set-formation, and the role of the STN in this process. This thesis evaluates new methods for examining set-formation in the attentional set-shifting task; rather than inferring this behaviour solely from the cost of shifting set, modifications to the task design in Chapters 3 & 4 explored several hypotheses designed to exploit a deficit in this behaviour. Chapter 6 revealed that inhibition of this region with designer receptors leads to a disruption in attentional selectivity, which compromises the ability to form an attentional set. This manifested as an inability to parse relevant information from irrelevant, and instead, animals learned the stimuli holistically. The findings in this thesis also suggested that reversal and attentional shifting processes do not operate independently, but rather in a hierarchy, and that consequently, the STN is a region that may be crucial in selecting appropriate responses during associative learning that leads to the formation of an attentional set.

<p>  </p> <p>Posttraumatic stress disorder involves a constellation of neural and behavioral alterations in response to trauma exposure. Aside from symptoms involved in posttraumatic stress disorder diagnosis, patients frequently present with working memory impairments. Working memory training has been established as an effective intervention to reduce posttraumatic stress symptoms. Working memory is associated with posttraumatic stress disorder in that it is commonly impaired in patients and that training can reduce the severity of posttraumatic stress symptoms. Taken together, these points suggest the possibility of a shared mechanism between working memory and posttraumatic stress disorder but working memory has not been studied thoroughly in rodent models of posttraumatic stress disorder. The present study utilizes footshock trauma to induce a posttraumatic stress state in rats and evaluates the effect of trauma and trauma-paired cues on working memory performance. Results demonstrate the emergence of chronic deficits in working memory among traumatized animals three weeks post-trauma. Presentation of trauma-paired cues caused further decrement in working memory performance. Regression analysis indicates that the degree of working memory impairment in response to a trauma-paired cue can be significantly predicted by behavioral phenotypes typic of diagnostic symptoms for posttraumatic stress disorder. This study enhances existing animal models by replicating the clinical observations of working memory deficits associated with posttraumatic stress disorder. This will pave the way for future work to probe underlying mechanistic dysregulation of working memory following trauma exposure and for future development of novel treatment strategies. </p>

<p dir="ltr">Metacontrol describes outsourcing cognitive control to environmental cues, allowing for efficient instantiation of appropriate cognitive control. While recent years have seen many studies characterizing metacontrol in behavioral terms, relatively little effort has been made to characterize the neural mechanisms underlying metacontrol. Thus, the current dissertation project aimed to investigate the neural systems and interactive features of metacontrol, more specifically, proactive and reactive metacontrol that exert context-appropriate control states in preparatory and just-in-time manners, respectively. Specifically, Study 1 employed a functional magnetic resonance imaging technique and identified brain regions activated under proactive and reactive metacontrol operations. Importantly, the study revealed that the two metacontrol modes were supported by distinct neural systems. Building on the premise that distinct neural systems supporting the two metacontrol modes would enable the concurrent operation of both modes, Study 2 tested whether a preparatory metacontrol mode, proactive metacontrol, can coexist with a just-in-time metacontrol mode, reactive metacontrol. Using electroencephalography, Study 2 revealed that the two metacontrol modes can operate in parallel. Lastly, extending Study 2, Study 3 investigated how proactive metacontrol interacts with reactive metacontrol. Study 3 observed that high preparatory control states during proactive metacontrol benefit reactive metacontrol. Specifically, reactive metacontrol was observed only when penalties were at stake, which promoted heightened preparatory control states. In summary, Study 1 demonstrated that the two metacontrol modes are not only operationally distinctive but also characterized by separate neural systems underlying them. This aligns with the observation from Study 2 showing that the parallel operation of two metacontrol modes is feasible. Lastly, Study 3 suggests that despite the two metacontrol modes being supported by distinct neural systems (as shown in Study 1), they are not entirely independent and can interact with each other. Collectively, these findings reveal the relationship between the two metacontrol modes and elucidate their intricate interactions, thereby deepening our understanding of the neurocognitive mechanisms underlying metacontrol.</p>

<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>

<p dir="ltr">Activity-based anorexia (ABA) is a rodent model of anorexia nervosa (AN) that induces several key components of AN, including voluntary reduction in food intake, reduced body weight, hyperactivity, and alterations to the hypothalamic-pituitary-adrenal (HPA) axis. Experiencing ABA during adolescence also effects behavior in social contexts, including contributing to the development of social avoidance even after cessation of exposure to the paradigm and restoration of weight lost during ABA. We used the social partition (SPT), novelty suppressed feeding (NSF), marble burying, and elevated plus maze (EPM) tests to determine the effects of two bouts of adolescent ABA on anxiety-like behavior in weight restored young adult female rats. One-way ANOVA analyses showed that two bouts of adolescent ABA contribute to prolonged increases in general and social avoidance in young adult female rats compared with control rats. To explain our behavioral findings, we next explored the effects of two bouts of adolescent ABA on glial fibrillary acidic protein (GFAP) and corticotropin-releasing hormone receptor 1 (CRFR1) expression in the oval bed nucleus of the stria terminalis (_ovBNST), a brain region involved in anxiety and social behavior. While previous research shows that two bouts of adolescent ABA contribute to HPA axis hyperactivation and _ovBNST inflammation following weight restoration from adolescent ABA, our one-way ANOVA analyses showed no significant differences in GFAP or CRFR1 expression in the _ovBNST across groups. Finally, to explore whether adolescent AN symptoms can predict anxiety in young adult women, we had female university students complete retrospective surveys of adolescent food restriction, eating disorder symptoms (EDEQ), and physical activity, as well as retrospective surveys of worry, behavioral inhibition, childhood adversity, and parental style. Using these variables, we created four adolescent predictor models: 1 (EDEQ; physical activity), 2 (restrictive eating; physical activity), 3 (EDEQ; physical activity; worry; behavioral inhibition; childhood adversity; and parental style), and 4 (restrictive eating; physical activity; worry; behavioral inhibition; childhood adversity; and parental style), which we regressed onto participants’ current generalized anxiety, fear of food, social avoidance, obsessions, compulsions, social physique anxiety, compulsive physical activity, and perceived stress scores. Regressing each predictor model onto these variables revealed that predictor model 1 better predicted and accounted for more variance in all anxiety types compared with predictor model 2. Moreover, predictor model 1 accounted for the most variance in fear of food and social physique anxiety compared with all anxiety types. Finally, predictor models 3 and 4 explained the most additional variance in generalized anxiety and social avoidance compared with all anxiety types. Cumulatively, our data suggest that, while adolescent eating disorder signs and symptoms predict several anxiety types in female university students, the effects of two bouts of ABA during adolescence on anxiety-like behavior in weight restored female rats is limited to specific anxiety-provoking stimuli.</p>