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La maladie de Parkinson (MP) est la deuxième affection neurodégénérative la plus fréquente après la maladie d’Alzheimer. Elle se caractérise par un dysfonctionnement du système des ganglions de la base, en rapport avec une dégénérescence des neurones dopaminergiques de la substance noire compacte. A côté des symptômes moteurs, la MP s’accompagne de troubles cognitifs, en particulier une altération des capacités de sélectivité attentionnelle. Ce déficit attentionnel se traduit par des difficultés à sélectionner les informations pertinentes pour la conduite en cours et peut entraîner des troubles cognitifs légers. L’origine des troubles attentionnels reste imprécise : on ignore s'ils résultent d’une défaillance des mécanismes volontaires d’orientation de l’attention ou d'une perturbation des processus automatiques de capture attentionnelle. Le filtrage sensoriel permet de focaliser notre attention grâce à une sélection des informations pertinentes pour l’action en cours et une inhibition des informations non pertinentes. Il peut être exploré en neurophysiologie par le paradigme d’inhibition par le prepulse (PPI). Ce dernier correspond à l’atténuation de la réponse motrice et corticale suite à la présentation d’un stimulus sursautant (pulse) lorsque celui-ci est précédé de quelques millisecondes d’un stimulus non sursautant (prepulse). Le PPI est influencé par l’attention, son amplitude étant majorée lorsque l’attention est portée volontairement sur le prepulse. L’objectif général était donc de mieux identifier la nature des troubles de la sélectivité attentionnelle dans la MP par un paradigme actif de PPI au cours duquel la réponse corticale au pulse est enregistrée. Nous faisions l’hypothèse que les parkinsoniens présenteraient une inhibition plus faible que les témoins sains. En cas de défaillance de mobilisation volontaire des ressources attentionnelles, l'inhibition de la réponse corticale au pulse devrait être moins importante lorsque les ressources attentionnelles allouées au traitement du prepulse mettent en jeu la mobilisation volontaire de l’attention. A l’inverse, en cas de défaut de capture attentionnelle, l’inhibition de la réponse serait moins importante lorsque le traitement du prepulse implique les processus automatiques de capture.Pour répondre à cet objectif, nous avons dans un premier temps développé et validé un paradigme actif de PPI au cours duquel l’effet de la mobilisation volontaire de l’attention et de la capture attentionnelle sur le processus de filtrage sensoriel a été évalué. Pour ce faire, 26 témoins sains jeunes ont bénéficié d’un électroencéphalogramme à haute résolution tout en réalisant une tâche attentionnelle sur laquelle a été greffé un paradigme actif de PPI. Nous avons recueilli la réponse corticale évoquée et induite par la présentation du pulse. 16 témoins sains âgés, 16 patients parkinsoniens sans trouble cognitif et 16 patients avec troubles cognitifs légers ont bénéficié du même enregistrement au cours de la même tâche attentionnelle. Chez les témoins sains jeunes, nous avons montré que les processus de mobilisation volontaire de l’attention et de capture attentionnelle modulaient de façon différentielle la réponse évoquée et induite par la présentation du pulse. Au cours du vieillissement, nous avons observé une meilleure sensibilité de la réponse corticale induite, ce qui nous a conduit à choisir ce marqueur cortical pour évaluer le filtrage sensoriel dans la MP. Nos résultats montrent une réduction de l’inhibition de la réponse induite chez les parkinsoniens avec troubles cognitifs légers, confirmant la distractibilité. La MP s’accompagne aussi d’une altération dans la génération des oscillations corticales dans la bande de fréquence thêta quand la focalisation de l’attention est engagée. / Parkinson’s disease (PD) is the most frequent neurodegenerative disorder after Alzheimer’s disease. It is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, causing a progressive loss of dopamine neurotransmission within the basal ganglia. Apart from motor symptoms, PD patients have cognitive disorders. Namely, focused attention is impaired and PD patients fail to select task-relevant information, leading sometimes to mild cognitive impairment (MCI). The origin of this impairment is still debated: PD-related selective attention deficit may be due either to a failure of goal-directed or stimulus-driven attention. Sensory gating helps the individuals to selectively allocate their attentional resources to salient stimuli and to inhibit irrelevant information. One of the physiological marker of this process is referred to as prepulse inhibition (PPI). It corresponds to the attenuation of the motor and cortical responses to a startling stimulus (pulse) when a non-startling stimulus (the prepulse) precedes the pulse by few milliseconds. PPI can be modulated by attention, its magnitude being greater after a to-be attended prepulse. Moreover, PPI is mediated by basal ganglia.The main aim of this work was to better identify the mechanisms involved in selective attention deficits in PD. We used an active PPI paradigm and recorded the cortical response to the pulse. We assumed that PD patients would exhibit a lower inhibition of the cortical response than healthy controls. If attention deficits in PD are related to an impairment of goal-directed attention, PD patients would exhibit lower inhibition after a to-be attended prepulse than in the other conditions. At the opposite, if it is due to a failure of stimulus-driven attention, inhibition would be lower after a prepulse which involuntarily captures attention than in the other conditions.In order to reach this objective, we have first developed and validated a new active PPI paradigm in order to investigate the role of goal-directed and stimulus-driven attention on sensory-cognitive gating. To this end, high resolution electroencephalogram was recorded in 26 young healthy subjects. They performed a selective attention task combined with an active PPI paradigm and the auditory-evoked and induced cortical response to the pulse was recorded. Then, the same procedure was administered in 16 elderly healthy subjects, 16 PD patients without MCI and 16 PD patients with MCI. In young healthy subjects, we found that stimulus-driven and goal-directed attention each had specific effects on the inhibition of the evoked and induced response to the pulse. The investigation of age-related changes on sensory gating revealed that the induced cortical response was more sensitive for assessing age-related changes than the evoked response. Then, we chose this cortical marker to investigate sensory gating in PD. Our results showed that PD patients with MCI exhibit lower inhibition of induced cortical response to the pulse than healthy controls. This finding confirms previous results showing a high distractibility in these patients. Moreover, PD patients exhibit impaired theta synchronization when focused attention was engaged.

We have shown that repeated neonatal quinpirole (QUIN; a dopamine D2-like receptor agonist) treatment in rats produces long-lasting supersensitization of dopamine D2 receptors that persists into adulthood but without producing a change in receptor number. The current study was designed to analyze the effects of neonatal QUIN on auditory sensorimotor gating as measured through prepulse inhibition (PPI). Male and female Sprague–Dawley rats were neonatally treated with QUIN (1mg/kg) or saline from postnatal days (P)1–21. At P60, the number of yawns was recorded for a 1h period in response to an acute QUIN (1mg/kg) injection as yawning is a D2-like receptor mediated behavioral event. Five days later, rats began (PPI) behavioral testing in two phases. In phase I, three different prepulse intensities (73, 76, and 82dB) were administered 100-ms before a 115dB pulse on 10 consecutive days. In phase II, three different interstimulus intervals (ISI; 50, 100, and 150ms) were inserted between the 73 or 76dB prepulse and 115dB pulse over 10 consecutive days of testing. A PPI probe trial was administered at the end of each phase after an acute 100μg/kgi.p. injection of QUIN to all animals. Replicating previous work, neonatal QUIN enhanced yawning compared to controls, verifying D2 receptor supersensitization. Regarding PPI, neonatal QUIN resulted in deficits across both phases of testing persistent across all testing days. Probe trial results revealed that acute QUIN treatment resulted in more robust PPI deficits in neonatal QUIN animals, although this deficit was related to prepulse intensity and ISI. These findings provide evidence that neonatal QUIN treatment results in deficits of auditory sensorimotor gating in adulthood as measured through PPI.

Women are twice as likely as men to suffer from depression and anxiety disorders and have an increased risk of onset during periods associated with hormonal changes, such as the postpartum period and the menopausal transition. Furthermore, some women seem more sensitive to normal hormone fluctuations across the menstrual cycle, since approximately 3-5% suffers from premenstrual dysphoric disorder (PMDD). Why these disorders are so common in women has not been established but there is a probable involvement of the ovarian hormones. The aim of this thesis was to investigate the effect of the ovarian hormones on the female brain during different reproductive states using psychological tests known to affect brain activity in different ways. Paper one examined the effect of the ovarian hormones on prepulse inhibition (PPI) on the acoustic startle response (ASR) and comprised cycling women and postmenopausal women. The cycling women had lower levels of PPI compared to postmenopausal women and postmenopausal women with moderate estradiol levels had lower PPI compared to postmenopausal women with low estradiol levels. Paper two examined the effect of anticipation and affective modulation on the ASR in women with PMDD and healthy controls. Women with PMDD have an increased modulation during anticipation of affective pictures compared to healthy controls during the luteal phase of the menstrual cycle. Paper three examined brain activity during response inhibition among women with PMDD and healthy controls by the use of a Go/NoGo task and fMRI. Women with PMDD displayed a decreased activity in the left insula during follicular phase and an increased activity during the luteal phase compared to controls. Paper four comprised women in the postpartum period and non-pregnant controls to examine brain activity during response inhibition. While this study revealed decreased activity at 4 weeks postpartum compared to 48 hours postpartum we cannot ascertain the role of the ovarian steroids, since none of the significant brain areas correlated with ovarian steroid or neurosteroid serum concentrations. The results of this thesis demonstrate that the ovarian hormones, or at least various hormonal states, have a probable impact on how the female brain works.

The correct development and function of CNS is critical for brain health of the organism. Early or chronic stress causes prominent alterations in brain function, and affects the expression of neurotrophic factors in limbic brain regions involved in the regulation of mood and cognition. Recent evidences have opened the idea that in complex organisms, an altered expression of certain neurotrophins by stress could be involved in the onset and pathophysiology of most psychiatric disorders, such as depression, squizophrenia or anxiety disorders. It is hypothesized that altered levels of neurotrophic factors could contribute to the atrophy and cell death of these regions, including the hippocampus and prefrontal cortex, which would produce a malfunction in limbic-related areas, and as a consequence, a precipitation or worsening of psychiatric illnesses. We were interested in panic disorder pathophysiology, which is a stress-related disorder and is characterized by an altered cognitive processing of emotional information. Although little evidence has been found supporting a neurotrophic role in PD, recent data has revealed that NT-3/TrkC signaling might play a key role in limbic system morphology and function. Therefore, we suggest that NT-3/TrkC system is involved in PD pathogenesis. The main objective in the work of this doctoral thesis lie to determine the role of NTRK3 gene, that codifies for TrKC, in emotional cognition and stress response processes that underlies PD. To this end, we used a genetically modified mouse model of NTRK3 overexpression, which was validated as a model of PD. Here, it is characterized the effects produced by the increase of NTRK3 expression in the CNS, focusing in neural alterations that might influence changes in cognitive processes involved in coping strategies. Moreover, it is studied the mechanisms that underlie in these processes by different approaches, 1/physiologically, measuring the HPA axis response, 2/brain activation, analyzing the activation pattern to a stress stimulus, 3/cellular and gene expression profiling, characterizing key brain regions in cognitive processes, and 4/pharmacologically, studying neurotransmitters function.

Title from PDF of title page. / Document formatted into pages; contains 18 pages. / Thesis (Au.D.)--University of South Florida, 2003. / Includes bibliographical references. / Text (Electronic thesis) in PDF format. / ABSTRACT: This study examined the effects of genetic background on the acoustic startle response (ASR) and its modulation by prepulse inhibition (PPI) by comparing nine inbred strains of mice. The ASR, a jerk-like motor reflex, is elicited by bursts of noise or tones with sound pressure levels of 80-90 dB and greater. PPI is a type of modulation of the ASR, requires no training, and results in observable response in both mice and humans. Data were obtained from nine inbred mouse strains, sixteen per strain, which were shipped at approximately 3-5 weeks old from The Jackson Laboratory. In general, ASRs were generally smaller when the startle stimulus was less intense. PPI was relatively weak for the 4 kHz prepulse, and stronger with prepulses of 12 kHz and 20 kHz. However, means varied widely across strains for both ASR and PPI, suggesting a strong influence of genetic background on these behaviors. / ABSTRACT: In addition to genetic influences, peripheral hearing loss and central auditory processing factors must be taken into consideration. / System requirements: World Wide Web browser and PDF reader. / Mode of access: World Wide Web.

Background. Various studies show that cannabis use alters attention and cognitive functioning in healthy humans and may contribute to development of schizophrenia or worsening of pre-existing psychosis. However, the impact of cannabis use on brain function in humans is not well understood. Schizophrenia is associated with a deficit in prepulse inhibition (PPI), the normal inhibition of the startle reflex by a non-startling stimulus (prepulse), presented before the startle stimulus at short time intervals (lead-time intervals). Such PPI deficit is thought to reflect a sensorimotor gating dysfunction in schizophrenia. PPI is also modulated by attention and PPI reduction in schizophrenia is observed when patients are asked to attend to, not ignore, the stimuli producing PPI. The aim of the current study was to investigate the association between self-reported chronic cannabis use and attentional modulation of PPI in healthy controls and in patients with schizophrenia. Furthermore, the association between cannabis use and other startle reflex modulators, including prepulse facilitation (PPF) of the startle reflex magnitude at long lead-time intervals, prepulse facilitation of the startle reflex onset latency and habituation of the startle reflex magnitude, were examined. Method. Auditory-evoked electromyographic signals were recorded from orbicularis oculi muscles in chronic cannabis users (29 healthy controls and 5 schizophrenia patients) and non-users (22 controls and 14 patients). The data for 36 participants (12 non-user controls, 16 healthy cannabis users, and eight non-user patients) were used in the final analyses and the patient data were used as a pilot study, because relatively few participants met the rigorous exclusionary criteria. Participants were instructed to attend to or to ignore either the startle stimuli alone (70 100 dB) or prepulse (70 dB) and startle stimuli (100 dB) separated by short lead-time intervals (20 200 ms) and long lead-time intervals (1600 ms). In order to ignore the auditory stimuli the participants played a visually guided hand-held computer game. A pilot study showed that the response component of playing the game had no effects on attentional modulation of the startle reflex magnitude and onset latency. Results. Relative to controls, cannabis use in healthy humans was associated with a reduction in PPI similar to that observed in schizophrenia while attending to stimuli, and with an attention-dependent dysfunction in the startle reflex magnitude habituation. While ignoring the stimuli there were no statistical differences in PPI between cannabis users and controls, although PPI in cannabis users tended to differ from that of the patients. The reduction in PPI in cannabis users was correlated with the increased duration of cannabis use, in years, but not with the concentration of cannabinoid metabolites in urine or with the recency of cannabis use in the preceding 24 hours. Furthermore, cannabis use was not associated with any differences in PPF, onset latency facilitation, and startle reflex magnitude in the absence of prepulses. The accuracy of self-reports of substance use was also investigated in this study and was found to be excellent. In addition, the study examined the validity of the substance use module of the diagnostic interview, CIDI-Auto 2.1, which was found to be acceptable for cannabis misuse diagnoses (abuse and/or dependence). Finally, cannabis dependence was found to be associated with more diagnoses of mental illness other than schizophrenia (mainly depression). Conclusions. The results of the current study suggest that chronic cannabis use is associated with schizophrenia-like deficit in PPI in otherwise healthy humans. This PPI reduction is associated with attentional impairment rather than a global sensorimotor gating deficit in healthy cannabis users.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A esquizofrenia à um transtorno mental grave que afeta cerca de 1 % da populaÃÃo acima da idade de 18 anos e à capaz de comprometer o pensamento, vontade prÃpria, percepÃÃo, afeto e interaÃÃo social. O efeito insuficiente da farmacoterapia atual sobre os sintomas negativos e dÃficits cognitivos reflete nossa mà compreensÃo da etiologia da esquizofrenia. Tem sido hipotetizado que as alteraÃÃes na sinalizaÃÃo nitrÃrgica e o desequilÃbrio oxidativo desempenham um papel na neurobiologia da esquizofrenia. EvidÃncias preliminares sugerem que o tratamento adjuvante com minociclina à eficaz para sintomas negativos e cognitivos desse transtorno. Assim, esse estudo investigou os efeitos da minociclina na prevenÃÃo e reversÃo de comportamentos tipo esquizofrenia induzidos por cetamina em camundongos. No protocolo de reversÃo, diferentes grupos de animais receberam cetamina (20 mg/kg) ou DMSO (veÃculo usado nos grupos controles) por 14 dias e, do 8 ao 14 dia, receberam adicionalmente minociclina (25 ou 50mg/kg), risperidona (0,5mg/kg) ou DMSO 30 minutos depois. No protocolo de prevenÃÃo, os camundongos foram prÃ-tratados com ambas as doses de minociclina, risperidona ou DMSO por 14 dias e, do 8 ao 14 dia, receberam adicionalmente cetamina 30 minutos depois. Todas as drogas foram administradas intraperitonealmente e uma vez ao dia. Comportamentos relacionados aos sintomas positivos (inibiÃÃo prÃ-pulso e atividade locomotora), negativos (interaÃÃo social) e cognitivos (labirinto Y) da esquizofrenia tambÃm foram avaliados. Glutationa (GSH), substÃncias reativas ao Ãcido tiobarbitÃrico (TBARS) e os nÃveis de nitrito foram medidos no cÃrtex prÃ-frontal (CPF), hipocampo (HC) e no corpo estriado (CE). Os resultados dos testes comportamentais mostraram que a cetamina promoveu um dÃficit no filtro sensÃrio-motor, aumento da atividade locomotora, diminuiÃÃo da interaÃÃo social e prejuÃzo na memÃria de trabalho. Praticamente todos esses parÃmetros foram prevenidos e revertidos pela administraÃÃo de minociclina (25 e 50mg/kg) e risperidona. A cetamina tambÃm promoveu alteraÃÃes nos marcadores oxidativos, atravÃs do aumento da peroxidaÃÃo lipÃdica e diminuiÃÃo dos nÃveis do antioxidante GSH, alÃm do aumento dos nÃveis de nitrito no CE. Seguindo a mesma linha dos resultados comportamentais, a minociclina e risperidona foram capazes de prevenir e reverter tais alteraÃÃes. Estes dados fornecem evidÃncias prÃ-clÃnicas para uma melhor avaliaÃÃo da minociclina como um novo agente antipsicÃtico e sugerem que seu mecanismo de aÃÃo inclui efeitos nos sistemas antioxidantes e nitrÃrgicos. / Schizophrenia is a serious mental disorder that affects approximately 1 % of the population over the age of 18 and is able to compromise the thought, will, perception, social interaction and affection. The insufficient effect of current pharmacotherapy on negative symptoms and cognitive deficits reflects our poor understanding of the etiology of schizophrenia. It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. Thus, this study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, different groups of animals received ketamine (20 mg/kg) or DMSO (vehicle used in controls) for 14 days, and, from the 8th to 14th day, additionally received minocycline (25 or 50mg/kg), risperidone (0.5 mg / kg) or DMSO 30 minutes after. In the prevention protocol, mice were pre-treated with both doses of minocycline, risperidone or DMSO for 14 days, from the 8th to 14th day, additionally received ketamine 30 minutes later. All drugs were administered intraperitoneally and once a day. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The result of behavioral tests showed that ketamine promoted a deficit in sensorimotor filter, increased locomotor activity, decreased social interaction and prejudice in working memory. Virtually all of these parameters were prevented and reversed by the administration of minocycline (25 and 50 mg/kg) and risperidone. Ketamine also promoted changes in oxidative markers by increasing lipid peroxidation and antioxidant GSH levels decrease, in addition to increased levels of nitrite in the ST. Following the same line of the behavioral results, minocycline and risperidone were able to prevent and reverse such changes.These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitergic systems.

This study analyzed whether the positive allosteric modulator of metabotropic glutamate receptor type 5 (mGlu5) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) would alleviate deficits in prepulse inhibition (PPI) and affect dopamine (DA) D2 signaling in the dorsal striatum and prefrontal cortex (PFC) in the neonatal quinpirole (NQ) model of schizophrenia (SZ). Male and female Sprague-Dawley rats were neonatally treated with either saline (NS) or quinpirole HCL (1 mg/kg; NQ), a DAD2 receptor agonist, from postnatal days (P) 1–21. Rats were raised to P44 and behaviorally tested on PPI from P44-P48. Before each trial, rats were subcutaneous (sc) administered saline or CDPPB (10 mg/kg or 30 mg/kg). On P50, rats were given a spontaneous locomotor activity test after CDPPB or saline administration. On P51, the dorsal striatum and PFC were evaluated for both arrestin-2 (βA-2) and phospho-AKT protein levels. NQ-treated rats demonstrated a significant deficit in PPI, which was alleviated to control levels by the 30 mg/kg dose of CDPPB. There were no significant effects of CDPPB on locomotor activity. NQ treatment increased βA-2 and decreased phospho-AKT in both the dorsal striatum and PFC, consistent with an increase DAD2 signaling. The 30 mg/kg dose of CDPPB significantly reversed changes in βA-2 in the dorsal striatum and PFC and phospho-AKT in the PFC equivalent to controls. Both doses of CDPPB produced a decrease of phospho-AKT in the PFC compared to controls. This study revealed that a mGlu5 positive allosteric modulator was effective to alleviate PPI deficits and striatal DAD2 signaling in the NQ model of SZ.

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal's lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.