Consolidation of associative memories may depend on communication between the lateral entorhinal cortex (LEC) and hippocampus (HPC) for recently learned memories and the LEC and medial prefrontal cortex (mPFC) for remote memories. To determine whether direct connections between these regions are necessary for the retrieval of a recently or remotely learned memory, rats acquired an associative memory through trace eyeblink conditioning and were tested for memory retention after inactivating the regions of interest with the GABAA agonist, muscimol. Inactivating the LEC-HPC connection did not impair memory retrieval. However, inactivating the LEC-mPFC connection impaired remote, but not recent, memory retrieval. Thus, the LEC and mPFC connection is necessary for the retrieval of a remotely, but not recently learned associative memory. Increased reliance on the entorhinal-prefrontal connection indicates the strengthening of functional connectivity between the two regions, which may be a biological correlate for the proposed reorganization during systems consolidation.

Decades of research have demonstrated that people sometimes provide self-evaluations that emphasize their most flattering qualities. Different theoretical accounts have been offered to explain the mechanisms underlying positively-biased self-evaluation. Some researchers theorize that positively-biased self-evaluations arise from a self-protection motivation because positivity biases increase in situations of heightened self-esteem threat. Alternative views question whether self-protection motivation is a necessary or even dominant source of positivity bias by demonstrating that positively-biased self-evaluations occur even when threat is not heightened, and that a general judgment approach leads to positivity biases in some domains but also to negativity biases in other domains. One reason for this gap in knowledge is that behavioral measures are limited in their ability to resolve whether the processes underlying positively-biased self-evaluation are the same or different depending on contextual motivators. Neuroimaging methods are well suited to examine whether different mechanisms underlie similar behaviors, specifically similar positively-biased responses in different contexts. The four studies presented here explore the neural mechanisms of positively-biased self-evaluation by first identifying a core set of neural regions associated with positivity bias (Study 1A and 1sB), examining whether a heightened self-protection motivation changes the engagement of those neural systems (Study 2), and specifying the precise mechanisms supported by those regions (Study 3). Studies 1A and 1B revealed evidence for a neural system comprised of medial and lateral orbitofrontal cortex (OFC) and, to a lesser extent dorsal anterior cingulate (dACC) that was modulated by positivity bias. Study 2 found that a heightened self-protection motivation changes the engagement of medial OFC in positively-biased self-evaluation. Finally, Study 3 found evidence that medial OFC may support a common mechanism in positively-biased judgment that is implemented differently as a function of the motivational context. Taken together, these studies represent a first step toward developing a neural model of positively-biased self-evaluation. The findings provide some preliminary evidence that positivity biases may represent distinct processes in different motivational contexts. This dissertation sets the stage for future work to examine how specific positively-biased cognitive mechanisms may be supported by specific neural systems and computations as a function of motivational contexts. / text

Impulse control, an executive process that restrains inappropriate actions, is impaired in numerous psychiatric conditions. This thesis reports three experiments that utilized a novel animal model of impulse control, the response inhibition (RI) task, to examine the substrates that underlie learning this task. In the first experiment, rats were trained to withhold responding on the RI task, and then euthanized for electrophysiological testing. Training in the RI task increased the AMPA/NMDA ratio at the synapses of pyramidal neurons in the prelimbic, but not infralimbic, region of the medial prefrontal cortex. This enhancement paralleled performance as subjects underwent acquisition and extinction of the inhibitory response. AMPA/NMDA was elevated only in neurons that project to the ventral striatum. Thus, this experiment identified a synaptic correlate of impulse control. In the second experiment, a separate group of rats were trained in the RI task prior to electrophysiological testing. Training in the RI task produced a decrease in membrane excitability in prelimbic, but not infralimbic, neurons as measured by maximal spiking evoked in response to increasing current injection. Importantly, this decrease was strongly correlated with successful inhibition in the task. Fortuitously, subjects trained in an operant control condition showed elevated infralimbic, but not prelimbic, excitability, which was produced by learning an anticipatory signal that predicted imminent reward availability. These experiments revealed two cellular correlates of performance, corresponding to learning two different associations under distinct task conditions. In the final experiment, rats were trained on the RI task under three conditions: Short (4-s), long (60-s), or unpredictable (1-s to 60-s) premature phases. These conditions produced distinct errors on the RI task. Interestingly, amphetamine increased premature responding in the short and long conditions, but decreased premature responding in the unpredictable condition. This dissociation may arise from interactions between amphetamine and underlying cognitive processes, such as attention, timing, and conditioned avoidance. In summary, this thesis showed that learning to inhibit a response produces distinct synaptic, cellular, and pharmacological changes. It is hoped that these advances will provide a starting point for future therapeutic interventions of disorders of impulse control. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2011-07-11 09:44:54.815

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.

La dopamine du cortex préfrontal (PFC) est impliquée dans l’apprentissage et dans la prise de décision liée à l’effort. Comme l’apprentissage ne peut se faire sans effort, il n’est pas clair aujourd’hui si la dopamine est nécessaire pour l’apprentissage, ou pour l’engagement de l’effort pour apprendre. Dans ce travail, les rats apprenaient à pousser un levier pour obtenir de la nourriture, soit avec (apprentissage par observation, LeO) ou sans (essai-et-erreur, TE) observation préalable d’un congénère exécutant la tâche. TE et la phase d’exécution de LeO nécessitent l’effort physique (overt learning), l’observation dans LeO ne requiert pas d’effort physique (covert learning). Avant chaque session, les rats recevaient des injections de SCH23390 ou de la saline dans le cingulaire antérieur (ACC) ou l’orbitofrontal (OFC). Si la dopamine est nécessaire à l’apprentissage, le blocage des récepteurs D1 affecterait aussi bien l’apprentissage overt que covert. Si la dopamine n’est pas requise pour l’apprentissage mais pour l’engagement de l’effort, le blocage affecterait l’apprentissage overt, et non covert. Les résultats montrent que le blocage de la dopamine dans ACC ou OFC supprime l’apprentissage overt, laissant intact l’apprentissage covert. Une fois les injections arrêtées, les rats récupèrent la capacité d’apprendre, mais dans le cas de ACC, pas la tolérance à l’effort. Ces résultats suggèrent que la dopamine dans ACC et OFC n’est pas nécessaire pour l’apprentissage, et que les déficits d’apprentissage pourraient reflèter une réduction de la tolérance effort à l’effort liée au blocage de la dopamine. / Because prefrontal cortex (PFC) dopamine plays a pivotal role in associative learning and in effort-related decision making, it is not clear as of today whether PFC dopamine activity is required for learning per se, or rather for engaging the effort necessary to learn. In this work, we used observational learning (LeO) and trial-and-error (TE) learning to dissociate learning from physical effort. Both TE and the execution phase of LeO require physical effort (overt learning). Observation does not require physical effort (covert learning). Rats learned to push a lever for food rewards either with or without prior observation of an expert conspecific performing the same task. Before daily testing sessions, the rats received bilateral ACC or OFC microinfusions of SCH23390, or saline-control infusions. If dopamine activity is required for task acquisition, its blockade should impair both overt and covert learning. If dopamine is not required for task acquisition, but solely for regulating effort tolerance, blockade should impair overt learning but spare covert learning. We found that dopamine blockade in ACC or OFC suppressed overt learning selectively, leaving covert learning intact. In subsequent testing sessions without dopamine blockade, rats recovered their overt-learning capacity but, in ACC experiments, the animals did not recover their normal level of effort tolerance. These results suggest that ACC and OFC dopamine is not required for the acquisition of conditioned behaviours and that apparent learning impairments could instead reflect a reduced level of effort tolerance due to cortical dopamine blockade.

Following a cortical injury, neurons in areas near and connected to the site of injury begin to degenerate. The observed neuronal death may contribute to the severity of the observed behavioral impairments. The purpose of the present study was to examine if progesterone, a hormone known for its effectiveness at reducing cerebral edema, could protect against secondary neuronal death and facilitate the acquisition of an avoidance learning task in an ablation model of cortical injury. Rats served as sham controls or received bilateral ablation of the medial prefrontal cortex followed by a 10-day regimen of progesterone (4 mg/kg) or oil vehicle (1 ml/kg) beginning 1 h after cortical lesions. Progesterone-treated lesion rats showed a significant facilitation of avoidance learning compared to oil- treated lesion controls. In addition, progesterone-treated lesion animals did not differ from either progesterone- or oil-treated sham controls in avoidance learning. Anatomical analysis revealed that progesterone treatment decreased the amount of neuronal death seen in the striatum and the mediodorsal nucleus of the thalamus. The findings are consistent with the notion that progesterone is an effective neuroprotective agent and suggest that the hormone can reduce the behavioral impairments associated with frontal cortical ablation injury.

It is well established that low level Pb-exposure is associated with a wide range of cognitive and neurobehavioral dysfunctions in children. In fact, Pb-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum - the anatomical sites which are crucial in modulating emotional response, memory and learning. Previously it was also shown that nitric oxide (NO) signaling pathway as well as glutamatergic neurotransmission are both involved in brain development, neurotoxicity and neurodegeneration processes whereas Pb2+ interfere with both. For this reason we investigated the effect of ontogenetic Pb2+ exposure on dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) of rats after amphetamine (AMPH) and/or 7-nitroindazole (7-NI) administration. Furthermore, the possible role of oxidative stress in Pb2+-induced neurotoxicity in prenatally Pb2+-treated rats was explored in the content of hydroxyl radical (HO•) species in mPFC after AMPH and/or 7-NI injection, assessed by HPLC analysis of 2.3-dihydroxybenzoic acid (2.3-DHBA) - spin trap product of salicylate. As shown, the results of this study suggest that Pb2+ exposure during intrauterine life did not substantially affect cortical dopaminergic neurotransmission in adult offspring rats evaluated by means of microdialysis of mPFC and the content of the cortical HO•. It is likely that striatum, nucleus accumbens or other dopamine rich brain areas are more intricately associated with Pb2+ precipitated behavioral, dopamine - dependent impairments observed in mammalians.

In the present study, we examined the possible effect of chronic treatment with glucocorticoids on the morphology of the rat brain and levels of endogenous agmatine and arginine decarboxylase (ADC) protein, the enzyme essential for agmatine synthesis. Seven-day treatment with dexamethasone, at a dose (10 and 50 μg/kg/day) associated to stress effects contributed by glucocorticoids, did not result in obvious morphologic changes in the medial prefrontal cortex and hippocampus, as measured by immunocytochemical staining with β-tubulin III. However, 21-day treatment (50 μg/kg/day) produced noticeable structural changes such as the diminution and disarrangement of dendrites and neurons in these areas. Simultaneous treatment with agmatine (50 mg/kg/day) prevented these morphological changes. Further measurement with HPLC showed that endogenous agmatine levels in the prefrontal cortex and hippocampus were significantly increased after 7-day treatments with dexamethasone in a dose-dependent manner. On the contrary, 21-day treatment with glucocorticoids robustly reduced agmatine levels in these regions. The treatment-caused biphasic alterations of endogenous agmatine levels were also seen in the striatum and hypothalamus. Interestingly, treatment with glucocorticoids resulted in a similar change of ADC protein levels in most brain areas to endogenous agmatine levels: an increase after 7-day treatment versus a reduction after 21-day treatment. These results demonstrated that agmatine has neuroprotective effects against structural alterations caused by glucocorticoids in vivo. The parallel alterations in the endogenous agmatine levels and ADC expression in the brain after treatment with glucocorticoids indicate the possible regulatory effect of these stress hormones on the synthesis and metabolism of agmatine in vivo.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第20813号 / 人健博第50号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 三谷 章, 教授 二木 淑子, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(人間健康科学) / 乙第13171号 / 論人健博第5号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 十一 元三, 教授 木下 彩栄, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM