Yes / It has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia.

Yes / Rationale The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. Results PCP significantly (p < 0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p < 0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.

La schizophrénie est une maladie mentale grave qui se caractérise par un spectre hétérogène de manifestations cliniques. L’utilisation des antipsychotiques depuis la fin des années 1940 pour traiter la maladie ne permet au mieux que d’aider à contrôler certains symptômes et n’arrive pas à enrayer son décours. Ceci est particulièrement vrai pour le traitement des symptômes cognitifs (troubles attentionnels, de mémoire, et surtout troubles de la fonction exécutive) qui sont au cœur de la maladie. L’amélioration des performances cognitives des malades par les différents traitements ne peut être considérée comme un succès et il semble que ce soit un rendez-vous manqué tant les besoins thérapeutiques pour traiter ces symptômes sont essentiels dans la schizophrénie. Dans cette thèse nous avons étudié les déficits de la fonction exécutive dans un modèle hyperdopaminergique, les DAT-KO, qui sont des souris invalidées pour le gène du transporteur de la dopamine (DA). [...]. Nous avons dans un premier temps caractérisé notre modèle animal dans l’Attentional Set-Shifting Test (ASST) qui est un équivalent chez le rongeur du Wisconsin Card Sorting Test (WCST), un test permettant de mesurer chez l’Homme les performances de la fonction exécutive. Nous avons démontré que les DAT-KO présentent des performances déficitaires dans l’ASST, conformément à notre hypothèse. En utilisant des antagonistes spécifiques des récepteurs, D1 (le SCH23390) et D2 (le sulpiride) nous avons démontré que le SCH23390 améliorait les performances des souris DAT-KO dans l’ASST contrairement au sulpiride. Ce résultat nous a permis de suggérer que l’hyperdopaminergie, responsable de l’altération de la fonction exécutive des DAT-KO, aurait pour conséquence la sur-activation des récepteurs D1. Nous avons par la suite cherché à voir si l’on peut établir un lien direct entre hyperdopaminergie dans le mPFC qui est reconnu pour être la région traitant le set-shifting et le déficit comportemental. Nous avons modifié la transmission DAergique de deux façons complémentaires, soit par une induction pharmacologique avec un inhibiteur du DAT, le GBR12935, soir par une induction par optogénétique chez les souris DATcre/ChR2 exprimant la Channel Rhodopsin dans les neurones DAergiques. Avec ces deux modèles, nous avons pu montrer que l’action de la DA sur l’altération de la fonction exécutive passait par une sur-activation de la neurotransmission D1 et non D2. Néanmoins, la modulation de l’activité des neurones du PFC par la DA n’est pas uniforme. Elle module les fonctions du PFC en faisant appel à des neurones ayant un rôle spécialisé. Nous avons donc voulu essayer d’établir les mécanismes pouvant être mis en jeu pendant le set-shifting et ainsi essayer d’identifier le substrat neuronal pouvant être impliqué dans la fonction exécutive. A l’aide de deux marqueurs de l’activité neuronale, c-fos et P-ERK, nous avons pu établir que l’activité des neurones du cortex prélimbique (PrL) augmentait pendant une tâche de set-shifting. Nous avons aussi corrélé la modulation par les antipsychotiques du niveau de performance des DAT-KO dans le set-shifting avec le niveau d’activité du PrL et nous avons pu identifier le profil d’activation des deux principales populations neuronales du PFC, les neurones pyramidaux glutamatergiques et les interneurones GABAergiques. Nous avons pu relier ce profil d’activation avec la modulation comportementale des DAT-KO par les antipsychotiques mais aussi par d’autres ligands pharmacologiques actuellement à l’étude comme complément ou traitement alternatif aux antipsychotiques, le LY3979268, un agoniste mGluR2/3 et le CDPPB, un potentiateur mGluR5. L’ensemble de ces résultats nous a permis de mieux comprendre les effets de l’hyperdopaminergie sur le set-shifting mais aussi de pouvoir commencer à identifier le support neuronal de la modulation dopaminergique de la fonction exécutive. / Schizophrenia is a severe mental illness with a large spectrum of clinical manifestations. Since the introduction of antipsychotic medications in the 40’s, only modest progress has been made in the treatment of the disease. Currently used antipsychotics have only partial efficacy, controlling positive symptoms but usually failing to stop the mental decline of the patient. This lack of full-blown efficacy is particularly evident in the treatment of executive function deficits, which are now considered as core symptoms of schizophrenia. Increased dopamine (DA) neurotransmission is considered as a core neurochemical alteration in schizophrenia and all prescribed antipsychotics are dopamine-D2 receptor antagonists. In addition, major cognitive functions that are disarrayed in schizophrenia depend on proper DA regulation. However, there are no studies investigating the link between increased DA-ergic tone and executive function. The present thesis focuses on executive function deficits in a hyperdopaminergic mouse model, the genetically engineered mouse that lacks the dopamine transporter (DAT; DATKO mouse). First, we characterized our animal model in the Attentional Set-Shifting Test (ASST), which is a rodent adaptation of the Wisconsin Card Sorting Test, a test used to evaluate executive function in humans. DATKO mice had impaired performances in the ASST, confirming our working hypothesis. Systemic administration of the selective D1 antagonist SCH23390 ameliorated the performance of the DATKO in the ASST. In contrast, the D2 antagonist sulpiride had no effect, suggesting that the overactivation of D1 (but not D2) receptors might be involved in hyperdopaminergia-induced ASST deficits. To further investigate a possible causal link between elevated DA and ASST deficits we have induced a hyperdopaminergic state selectively in the prefrontal cortex (PFC), the region involved in executive function. This was done (i) pharmacologically, with local microinfusions of the DAT inhibitor GBR12935; (ii) optogenetically, by generating and utilising a novel transgenic tool the DATcre/ChR2 mice which express Channel-Rhodopsin selectively in DA-ergic neurons. In both constructs, PFC hyperdopaminergia resulted in ASST deficits. These, were reversed with SCH23390 but not with sulpiride, clearly establishing a role for D1 receptors in the deleterious effects of PFC hyperdopaminergia on executive function. It has been postulated that dopamine modulates PFC synaptic plasticity and associated cognitive functions through two distinct but interconnected neuronal populations: glutamatergic (Glu-) pyramidal neurons and GABA- interneurons. Immunocytochemistry experiments combining neuronal activation markers (p-ERK; c-fos) and selective labelling of Glu- versus GABA- neurons allowed to parse the role of these two populations in the ASST. A balaced Glu- versus GABA- activation was necessary for a succesful ASST performance. A dysregulated pattern of Glu- versus GABA- activation correlated with ASST deficits, leading us to speculate a putative link between cortical hyperdopaminergia and cortical Gluhypoactivation. Interestingly, glutamatergic ligands such as the mGluR2/3 agonist LY3979268 and the mGluR5 potentiator CDPPB (which are under current investigation in schizophrenia) corrected both the behavioral deficits and the altered neuronal activation pattern of hyperdopaminergic mice in the ASST. Overall, this work: (i) demonstrates for the first time a causal link between PFC hyperdopaminergia and executive deficits; (ii) proposes and validates a new model to study the cellular, molecular and synaptic mechanisms underlying executive dysfunction; (iii) suggests D1 receptor antagonism, in adjunct with current antipsychotic medications, as a novel therapeutic strategy to treat cognitive dysfunction in schizophrenia.

Background: Patients with anorexia nervosa have been consistently reported to show impairments in set shifting ability. Such deficits may be associated with characteristics commonly observed in this patient group, such as obsessive thoughts and behaviours around eating, maladaptive problem solving and a rigid thinking style. Objective: Much of the preceding literature on set shifting ability has involved inpatient samples meeting strict diagnostic criteria for anorexia nervosa. However most eating disorder patients are outpatients and commonly do not meet full criteria for anorexia nervosa. This study thus aimed to investigate the relationship between set shifting ability and psychological characteristics in a community sample of outpatients with symptoms of anorexia nervosa. Methods: Performance on selected measures of set-shifting ability (Wisconsin Card Sort Test, WCST; Delis-Kaplan Executive Function System, Hayling & Brixton) were compared between an eating disorders group comprising 17 female outpatients with symptoms of anorexia nervosa and a control group comprising 27 students. Set shifting performance was then correlated with eating disorder severity (Eating Disorders Examination), obsessive-compulsive symptoms (Yale-Brown Obsessive Compulsive Scale), and the Social Problem Solving Inventory. Results: The eating disorder group demonstrated significantly worse set shifting ability than the healthy control group on the primary outcome measure (WCST), with 47% of eating disorder participants showing impairment on this measure. Severity of obsessive-compulsive symptoms and an impulsive and careless approach to problem solving were associated with poorer scores on the WCST in the eating disorder group. Although the eating disorder group were significantly more impaired in set shifting than controls, set shifting ability was not associated with eating disorder severity. Conclusions: The results indicate that set shifting impairments are present in outpatients with eating disorders with anorexic symptoms, and may be trait characteristics. Impaired set shifting was associated with obsessive-compulsive symptoms and maladaptive problem solving. These findings highlight a need for neuropsychological assessment of eating disorder outpatients in order to identify individuals who may benefit from psychological interventions to reduce the impact of these impairments.

The ability to selectively attend to aspects of the environment which signal opportunity or danger, while marginalising irrelevant stimuli is critical to an animal's survival. With finite cognitive resources, the brain must dedicate resources to only those stimuli that are biologically significant. Incoming thalamic information must therefore be filtered. The thalamic reticular nucleus has long been considered critically involved in modulating thalamic sensory processing. Sharing connections with both the thalamus and cortex, it is ideally located to modulate the transfer of pertinent incoming sensory information. This thesis sought to determine the functional role of the thalamic reticular nucleus in attentional processes by combining lesion techniques and well established behavioural paradigms. Chapter 3 examined the role of visual thalamic reticular nucleus lesions on performance in a two-alternative forced choice reaction time task when auditory distractors were presented. No effect of the lesion was found. Chapter 4 examined excitotoxic lesions of thalamic retlcular nucleus on performance in the 7-stage attentional set shifting task. No effect of lesion on performance was found. Chapter 5 examined mediodorsal thalamus and rostral thalamic reticular nucleus lesions on performance in the attentional set shifting task. Despite strong connectivity with prefrontal regions known to be involved in this task, there was no effect of either lesion. Finally, chapter 6 examined the effects of reducing dopamine input into the thalamic reticular nucleus on a two alternative forced choice reaction time task. Following bilateral lesions the animals were impaired in the re-orientation of attention – suggesting a critical role for both the thalamic reticular nucleus and dopamine in attentional processes. Taken together, these results suggest that while the thalamic reticular nucleus is involved in attention, it is not involved in every aspect.

<p>Anorexia nervosa (AN) is a dangerous disorder characterized by unrelenting rigidity that continues even in the presence of deadly outcomes. Despite this, our understanding of factors that promote and maintain rigidity is lacking. The current paper proposes a model suggesting that rigid behaviors in AN can be formulated as maladaptive rule-governed behavior that emerges in contexts of uncertainty and loss of control, such as in the presence of affective arousal. An empirical study examining the differences between individuals weight recovered from AN (AN-WR) and healthy controls (CN) on parameters of rule-governed behavior in neutral and stressful contexts is described. Seventy-four adults (AN-WR: 36; CN: 38) were randomized to undergo either a stressful or neutral mood manipulation and then completed a laboratory assessment of rule-governed behavior, along with questionnaires measuring difficulties with uncertainty. While the AN-WR group demonstrated greater flexibility in rule implementation compared to the CN group, they evidenced greater impairment in behavioral extinction. Furthermore, although affective arousal did not significantly impact rule-governed behavior as expected, difficulties tolerating uncertainty were significantly related to rule-governed outcomes exclusively in the AN-WR group. Taken together, findings provide preliminary support for maladaptive rule-governed behavior in AN and suggest that this is related to an intolerance of uncertainty. Findings and treatment implications are discussed in light of study limitations.</p> / Dissertation

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.

Schizophrenia is a neuropsychological disorder in which the neural systems which regulate attention allocation, primarily the dorsolateral prefrontal cortex, are dysfunctional, resulting in deficient gating of attention to irrelevant inputs from the environment. This sensory processing dysfunction hinders goal-directed behaviour to the extent that the subsequent cognitive deficits of schizophrenia prevent many chronic patients from leading normal lives. It is the onus of neuroscience to understand the nature of deficits induced by the disorder, thus providing target mechanisms for remediation of those deficits in patients. To accomplish this, manipulations in rats with relevance to schizophrenia are examined in assays with translation to human neurobiology and behaviour. In this thesis, three manipulations with relevance to schizophrenia, were examined for attentional regulation in the attentional set-shifting task, and similar assays, to determine how different forms of schizophrenia-related pathology influence attentional regulation and behavioural flexibility. The foremost findings of the experiments herein were that manipulations inducing schizophrenia-related neurobiology, resulted in impaired performance in extradimensional set-shifting and reversal learning. These deficits were found following: acute inhibition of the mPFC in adult rats, in adult rats who had been exposed to a glutamate receptor antagonist during the neonatal period of development, and/or in adult rats who had gestational disruption of neuron proliferation. Across all three manipulations, a clear behavioural pattern of deficient sensory gating, evidenced by responding to irrelevant stimuli during the set-shifting task was found. These findings suggest that at the core of the cognitive deficits in schizophrenia is the ‘loosening of associations' such that patients suffer the inability to regulate attention, and limit sensory processing to relevant information. The subsequent aberrant learning about irrelevant information then impairs performance during goal-directed behaviours.

Indiana University-Purdue University Indianapolis (IUPUI) / Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug-exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.

y / The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days’ washout. PCP-treated rats then received PNU-120596 (10mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors. / This work was partially funded by Johnson & Johnson Pharmaceutical Research and Development.