Behavioral flexibility, the ability to change behavior in accordance with the changing environment, was studied in pigeons using a series of reversal learning paradigms. All experiments involved a series of 5-trial sequences and I was interested in whether pigeons are sensitive to the reversal by switching to the other alternative after a single error. In Experiments 1 and 2, the overall probability of the two stimuli was equated over sequences, but the probability correct of the two stimuli changed across trials. In both experiments, subjects showed no sensitivity to the differences in sequence type. Instead they used the overall average of the probability of reinforcement on each trial as the basis of choice. In the final two experiments, the likelihood that a reversal would occur on a given trial was equated such that there was an equal overall probability that the two stimuli would be correct on a given trial, but the overall probability of each stimulus being correct across sequences favored the second correct stimulus (S2). In Experiment 3, the overall probability of S2 correct was 80%, and results showed that subjects consistently chose S2 regardless of sequence type or trial number. In Experiment 4, the overall likelihood of S2 correct was 65%, and results showed that subjects began all sequences at chance, and as the sequence progressed, began choosing S2 more often. In all experiments, subjects showed remarkably similar behavior regardless of where (or whether) the reversal occurred in a given sequence. Therefore, subjects appeared to be insensitive to the consequences of responses within a sequence (local information) and instead, seemed to be averaging over the sequences based on the overall probability of reinforcement for S1 or S2 being correct on each trial (aggregate information), thus not maximizing overall reinforcement. Together, the results of this series of experiments suggest that pigeons have a basic disposition for using the overall probability instead of using local feedback cues provided by the outcome of individual trials. The fact that pigeons do not use the more optimal information afforded by recent reinforcement contingencies to maximize reinforcement has implications for their use of flexible response strategies under reversal learning conditions.

Executive functions are important cognitive processes critical for survival. Damage to the prefrontal cortex impairs executive functions, such as working memory, decision making and set-shifting. Interestingly, patients diagnosed with different psychiatric disorders are also impaired in executive functions, especially in the set-shift domain, often measured by the Wisconsin Card Sorting Task (WCST). Set-shifting is an essential cognitive process, in that it allows the individual to suppress non-reinforcing strategies and engage in new rewarding strategies. To date, little is known about the etiology of executive dysfunction in psychiatric disorders. However, some epidemiological and serological experiments have shown strong correlations between prenatal infection and the increased risk to develop psychiatric disorders in the adult offspring. One study found that schizophrenic patients pre-exposed to a prenatal infection perseverated more during the WCST, than non-pre-exposed patients. Despite these findings, there are still numerous limitations (e.g., ethical concerns) when conducting these studies. Thus, animal models are important and can further elucidate the etiology of executive dysfunctions in psychiatric disorders. Prenatal infection animal models have consistently shown that inflammation during gestation in rodents induces behavioural, anatomical and cognitive changes in the adult offspring similar to psychiatric patients. However, no studies have investigated the effects of prenatal infection on set-shifting in the adult offspring. Therefore, the present thesis examined whether prenatal treatment with PolyI:C (a viral mimetic) during middle/late gestation of the rat would induce cognitive inflexibilities (i.e., set-shifting and reversal learning in an operant based task analogous to the WCST) in the adult male and female offspring. The results showed PolyI:C male offspring perseverated during the set-shift but had fewer regressive errors during the reversal learning day. PolyI:C treated female offspring were not impaired during any of the test days; however, females were slower to respond to the lever and required more training when compared the male rats. Taken together, these results give support for prenatal infection in inducing cognitive inflexibility, by potentially altering the PFC in the adult offspring. MS-based thesis: Zhang, Y., Cazakoff, B. N., Thai, C. A., & Howland, J. G. (2011). Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology, [epub ahead of print]. doi:10.1016/j.neuropharm.2011.02.022

Executive functions are important cognitive processes critical for survival. Damage to the prefrontal cortex impairs executive functions, such as working memory, decision making and set-shifting. Interestingly, patients diagnosed with different psychiatric disorders are also impaired in executive functions, especially in the set-shift domain, often measured by the Wisconsin Card Sorting Task (WCST). Set-shifting is an essential cognitive process, in that it allows the individual to suppress non-reinforcing strategies and engage in new rewarding strategies. To date, little is known about the etiology of executive dysfunction in psychiatric disorders. However, some epidemiological and serological experiments have shown strong correlations between prenatal infection and the increased risk to develop psychiatric disorders in the adult offspring. One study found that schizophrenic patients pre-exposed to a prenatal infection perseverated more during the WCST, than non-pre-exposed patients. Despite these findings, there are still numerous limitations (e.g., ethical concerns) when conducting these studies. Thus, animal models are important and can further elucidate the etiology of executive dysfunctions in psychiatric disorders. Prenatal infection animal models have consistently shown that inflammation during gestation in rodents induces behavioural, anatomical and cognitive changes in the adult offspring similar to psychiatric patients. However, no studies have investigated the effects of prenatal infection on set-shifting in the adult offspring. Therefore, the present thesis examined whether prenatal treatment with PolyI:C (a viral mimetic) during middle/late gestation of the rat would induce cognitive inflexibilities (i.e., set-shifting and reversal learning in an operant based task analogous to the WCST) in the adult male and female offspring. The results showed PolyI:C male offspring perseverated during the set-shift but had fewer regressive errors during the reversal learning day. PolyI:C treated female offspring were not impaired during any of the test days; however, females were slower to respond to the lever and required more training when compared the male rats. Taken together, these results give support for prenatal infection in inducing cognitive inflexibility, by potentially altering the PFC in the adult offspring. MS-based thesis: Zhang, Y., Cazakoff, B. N., Thai, C. A., & Howland, J. G. (2011). Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology, [epub ahead of print]. doi:10.1016/j.neuropharm.2011.02.022

Substance-abusing individuals have been shown to perform poorer on decision-making tasks than non-substance abusing individuals (e.g. Bechara et al., 2001; Grant, Contoreggi, & London, 2000; Sanfey, Loewenstein, McClure, & Cohen, 2006). Research suggests that this difference in performance is likely due to cognitive deficits resulting from impaired functioning of the frontal lobes. Previous research suggests that two important cognitive processes regarding decision making are reversal learning (e.g. Fellows and Farah, 2005) and working memory (e.g. Hinson, Jameson, and Whitney, 2002; Jameson, Hinson, and Whitney, 2004). The purpose of the current research project was to better understand how these processes affect performance on a decision making task and to determine if a previously administered executive stressor can impact current decision making performance. One hundred thirty six individuals categorized as having either high or low working memory functioning were randomly assigned to complete one of three modified Stroop tasks (Stressor, Priming, and Control). Following completion of the modified Stroop task participants completed the Iowa Gambling Task, which is a task requiring appropriate decision making skills to complete successfully. Statistical analyses examining the quantity and frequency of cards drawn from each deck during the IGT suggested that there was no difference in performance between individuals receiving different modified Stroop tasks or high or low working memory functioning. Analyses examining the monetary outcome of performance on the IGT suggest that there may have been no differential effect between the Stressor and Priming groups, but that these active groups may have performed differently than the Control group. Within the Low working memory block, participants in these active groups may have performed worse than Control group participants, but within the High working memory block participants in these active groups may have performed better than Control group participants. These findings are discussed with regards to previous similar investigations as well as within the broader literature of decision making. Limitations of the current study as well as implications for future investigations are also discussed. / Ph. D.

Yes / Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α2-adrenergic than dopaminergic D2 receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. Methods: After operant training, rats were treated acutely with D-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or sub-chronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute D-amphetamine– and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. Results: Deficits in reversal learning induced by acute D-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 d) treatment to improve subchronic PCP-induced impairments. Conclusion: These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation. / This research was supported by Schering-Plough Corporation, now Merck & Co., Inc. and Pfizer Inc.

Yes / Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D1-like receptor agonist, SKF-38393, to improve PCPinduced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (Pb0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D1-like receptor antagonist (Pb0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (Pb0.001); SKF-38393 (6.0 mg/kg) improved this PCPinduced deficit, an effect antagonised by SCH-23390 (Pb0.05). These results suggest a role for D1-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

No / Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.

In the Monty Hall Dilemma (MHD), three doors are presented with a prize behind one and participants are instructed to choose a door. One of the unchosen doors is then shown to not have the prize and the participant can choose to stay with their door or switch to the other one. The optimal strategy is to switch. Herbranson and Schroeder (2010) found that humans performed poorly on this task, whereas pigeons learned to switch readily. However, we found that pigeons learned to switch at level only slightly above humans. We also found that pigeons stay nearly exclusively when staying is the optimal strategy and when staying and switching are reinforced equally (Stagner, Rayburn-Reeves, & Zentall, 2013). In Experiment 1, rats were trained under these same conditions to observe if possible differences in foraging strategy would influence performance on this task. In Experiment 2, pigeons were trained in an analogous procedure to better compare the two species. We found that both species were sensitive to the overall probability of reinforcement, as both switched significantly more often than subjects in a group that were reinforced equally for staying and switching and a group that was reinforced more often for staying. Overall, the two species performed very similarly within the parameters of the current procedure.

This study examined the relationships between motivation and cognitive performance in male and female common marmosets (Callithrix jacchus). This question was driven by prior data from the Lacreuse lab showing a robust female impairment in reversal learning, as assessed by the number of trials needed to acquire a reversal following a simple discrimination between two stimuli. This thesis tested the hypothesis that the female impairment in reversal learning was mediated by deficits in motivation. Two sets of measures were used to test this hypothesis. I evaluated physical effort via testing on the progressive ratio (PR), a test that requires animals to produce an increasing number of responses to get a reward. Cognitive effort was evaluated through the number of refusals (aborted trials) produced during performance of a reversal. Because estrogen replacement was previously shown to impair reversal learning in ovariectomized females, I also examined whether PR performance was affected by estrogen levels in a subset of female subjects. Contrary to my hypothesis, reversal learning was not significantly associated with cognitive or physical effort in either males or females. Estrogen levels did not significantly affect physical effort, but there was too much variability in a small sample of females for these results to be compelling. We conclude that the sex difference in reversal learning performance is unlikely to be mediated by sex differences in motivation. Instead females may be more likely than males to engage in habitual processes implicating the dorsal striatum, likely through the action of estrogens on this brain region.

Die Zwangserkrankung gehört zu den häufigeren psychiatrischen Krankheitsbildern und kann zu erheblichen Einschränkungen im Alltag der Patienten führen. Typisch für diese Erkrankung sind immer wiederkehrende und als belastend empfundene Gedanken einerseits sowie repetitive, ritualisierte Verhaltensweisen andererseits. Bei der Pathogenese der Zwangserkrankung werden genetische, immunologische, psychologische und neurobiologische Faktoren diskutiert. Mit Hilfe unterschiedlicher Bildgebungsverfahren konnten bei Zwangspatienten Veränderungen im orbitofrontalen Cortex, den Basalganglien und dem Thalamus festgestellt werden. Zudem konnten Hinweise auf Veränderungen von Neurotransmittersystemen wie dem Serotonin- und Dopamin-Stoffwechsel festgestellt werden. Aus diesen Erkenntnissen wurde die Hypothese der fronto-striatalen Dysbalance postuliert: Bei Zwangsstörungen kommt es zu einem Ungleichgewicht zwischen erregenden und hemmenden Bahnen im Regelkreis zwischen orbitofrontalem Cortex, Striatum und Thalamus. Dieser Regelkreis ist bedeutsam für die Verhaltensanpassung an sich ändernde Umgebungsbedingungen. Daher wurde postuliert, dass ein Ungleichgewicht in diesem Regelkreis zu Beeinträchtigungen der flexiblen Verhaltensanpassung führt. Unflexibles, repetitives Verhalten, wie es bei Zwangsstörungen beobachtet wird, könnte also auf Störungen im fronto-striatalen Regelkreis zurückgeführt werden. Um flexible Verhaltensanpassung an eine sich ändernde Umgebung in einem experimentellen Setting zu testen, wurde in der vorliegenden Arbeit eine Reversal-Learning-Aufgabe verwendet, um Beeinträchtigungen der flexiblen Verhaltensanpassung bei Zwangspatienten im Vergleich zu gesunden Kontrollen zu testen. Hierfür wurden 30 Patienten mit einer diagnostizierten Zwangsstörung und 30 gesunde Probanden, welche hinsichtlich Alter, Geschlecht und Schulbildung angepasst wurden, in Bezug auf die Leistung während einer Reversal-Learning-Aufgabe verglichen. Zusätzlich wurde der Einfluss von neuropsychologisch erfasster, kognitiver Leistungsfähigkeit, ängstlicher und depressiver Komorbidität und Medikation auf die Leistung während der Aufgabe untersucht. Die Patienten- und die gesunde Kontrollgruppe unterschieden sich jedoch nicht in Bezug auf die Anzahl der Fehler oder der Reaktionszeit. Zwei kognitive Tests hatten einen Einfluss auf die Reaktionszeit aber keiner der Tests hatte einen Einfluss auf die Anzahl der Fehler. Der Einfluss auf die Reaktionszeit unterschied sich jedoch nicht zwischen den Gruppen. Zudem hatte nur die Angstsymptomatik einen Einfluss auf die Reaktionszeit. Auch hier unterschied sich der Einfluss der Angstsymptomatik nicht zwischen den Gruppen. Zuletzt unterschied sich die Anzahl der Fehler nicht zwischen medizierten und unmedizierten Patienten. Interessanterweise brauchten aber gerade die medizierten Patienten länger zur Bearbeitung der Aufgabe, obwohl die Symptomausprägung sich nicht zwischen den beiden Gruppen unterschied. Die vorliegende Studie konnte auf behavioraler Ebene das postulierte Ungleichgewicht im fronto-striatalen Regelkreis und die daraus resultierende Inflexibilität bei Menschen mit Zwangsstörungen nicht belegen. Es wurden jedoch Hinweise auf potentielle Einflussfaktoren gefunden. Durch Berücksichtigung solcher Einflussfaktoren, aber auch der teils starken Heterogenität der Gruppe, der geringen Fallzahl und durch Verbesserung der verwendeten Reversal-Learning-Aufgabe, wäre es in weiteren Studien eventuell möglich, die postulierten Defizite bei Zwangspatienten zu finden.