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BACKGROUND: Mild Traumatic Brain Injury (mTBI) is increasingly recognized as an adverse health consequence for athletes who participate in contact sports, such as football or boxing, as well as military personnel who are exposed to concussive blasts during training and combat operations. A consequence of this repetitive brain injury can be the development of a number of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE), a disease involving the buildup of toxic phosphorylated tau (p-tau) in the pre-frontal cortical tissue. Additionally, it has been found that military personnel suffering repeated mTBI from primary blast concussions are prone to development of post traumatic stress disorder (PTSD), a disease that is becoming increasingly common among returning service members. Because mTBI is a common cause for both PTSD and CTE, it is possible for the two diseases to manifest comorbidly in an individual. Though much is known about PTSD psychologically and CTE neuropathologically, little is known about the overlapping effect of the two diseases together as well as PTSD neuropathologically. What is known, however, is that aquaporin-4; a channel involved in the movement of water through the blood brain barrier, is often affected by CTE and may play a role in PTSD as well. OBJECTIVE: The objective of this study was to primarily to analyze the disruption of aquaporin-4 around cerebral blood vessels due to chronic traumatic encephalopathy. A secondary objective of this project was to determine if any unique physiopathological biomarkers exist in PTSD and if the effects of CTE are exacerbated when present comorbidly with PTSD. METHODS: This study involved the analysis of multiple cohorts that had suffered from CTE, PTSD and CTE comorbidly, or neither disease as a control. In order to assess the primary objective, two cohorts, a CTE-only and a control, were analyzed to determine the effect of p-tau on aquaporin-4 directly around cerebral vessels in the pre-frontal cortex. The samples were cut from blocks and stained for the desired markers. Following staining, images were taken using a confocal microscope and the images were analyzed using Amaris and FIJI. For the secondary objective, samples were prepared in a similar way with three cohorts: CTE-only, CTE+PTSD comorbid, and a control. Images were obtained and processed in the same way. RESULTS: It was found that aquaporin-4 density is significantly reduced around both arterial and venous lesional vessels. Additionally, it was found that p-tau was more readily deposited in the depths of the sulci of the pre-frontal cortex due to the unique forces caused by repeated mTBI. However, PTSD was not found to significantly compound the disease when comorbidly present with CTE nor to have a unique biomarkers present. CONCLUSION: P-tau present in CTE causes a significant reduction in aquaporin-4 around cerebral vessels in the pre-frontal cortex, thereby potentially inhibiting the movement of fluids and clearance of metabolites into and out of the brain. Additionally, p-tau is more readily deposited in the depths of the sulci of the pre-frontal cortex. However, PTSD does not compound the CTE disease process when comorbidly present. / 2018-07-13T00:00:00Z

[pt] Este estudo investiga o envolvimento do córtex pré-frontal medial ventral nos comportamentos de defesa inatos e aprendidos em paradigmas de condicionamento de medo e estimulação elétrica intracraniana em ratos. A lesão cortical aumentou significativamente o comportamento defensivo condicionado. No comportamento defensivo incondicionado, a lesão cortical diminuiu significativamente o congelamento pós-fuga dos animais. Os resultados replicam os dados da literatura científica a respeito do papel do córtex infralímbico como uma estrutura inibitória do estímulo condicionado em um circuito amidaloide de medo condicionado, e indicam uma participação do córtex pré-frontal na modulação dos comportamentos de defesa originários da estimulação da MCPd, em especial a sustentação do congelamento motor pós fuga. / [en] This study investigates the role of the prefrontal cortex in the innate and conditioned defensive behaviors in rats during classical conditioning and intracranial electrical stimulation procedurals. It was found that the cortical lesion augmented the conditioned freezing behavior to contextual fear cues. On the other hand, the lesions impaired the motor freezing presented after the escaping provoked by dPAG stimulation. These results replicate the findings from the literature about a prefrontal cortex role as an inhibitory structure in the aversive classic conditioning circuitry, as well as presenting a role for it in modulating freezing behavior in a panic circuitry involving the dPAG, especially regarding its function as a possible short term memory device for innate fear expression.

O córtex pré-frontal medial (PFCm) é caracterizado por entradas glutamatérgicas e dopaminérgicas que convergem sobre os mesmos neurônios alvos. Devido à escassa informação sobre as bases anatômicas das interações entre a dopamina (DA) e o glutamato (Glu), mapeamos a distribuição de subunidades (Su) de receptores (Rs) de Glu do tipo AMPA, NMDA e kainato no PFCm e investigamos a sua expressão em neurônios contendo a fosfoproteína DARPP-32 e em interneurônios. Os resultados mostram que as Su GluR2/3 dos Rs do tipo AMPA são as mais amplamente distribuídas no PFCm e expressas em todos os neurônios DARPP-32+. GluR2/3 é também amplamente co-localizado com as Su NMDAR1 dos Rs de Glu do tipo NMDA e GluR5/6/7 dos Rs do tipo kainato. Em contraste, as Su GluR1 e GluR4 são somente fracamente expressos no PFCm e não são co-localizados com DARPP-32, porém com GABA ou parvalbumina. Os resultados indicam que as Su GluR2/3, NMDAR1 e GluR5/6/7 são amplamente expressos em neurônios piramidais DARPP-32+ enquanto GluR1 e GluR4 são predominantemente expressos em interneurônios do PFCm. / The medial prefrontal cortex (PFCm) is characterized by glutamatergic and dopaminergic afferents that converge on the same target neurons. Since there is only limited information about the anatomical bases for interactions between dopamine (DA) and glutamate (Glu), we mapped the distribution of AMPA, NMDA and kainate Glu receptor (Rs) subunits (Su) in the PFcm and investigated their expression in neurons containing the phosphprotein DARPP-32 and in interneurons. Results show that the Su GluR2/3 of AMPA type Rs are the most prominently distributed in the PFCm and expressed in all neurons DARPP-32+. GluR2/3 is also widely co-localized with the NMDA type Su NMDAR1 and the Kainate Su GluR5/6/7. In contrast, the Su GluR1 and GluR4 are only weakly expressed in the PFCm and are not colocalized with DARPP-32 but with GABA or parvalbumin. Results indicate that the Su GluR2/3, NMDAR1, and GluR5/6/7 are prominently expressed in DARPP-32+ pyramidal neurons, whereas GluR1 and GluR4 are predominantly expressed by interneurons in the PFC.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may result from an exposure to a severely traumatic life-event. It is characterised by a delayed onset of psychological and physical symptoms including re-experiencing the event, avoidance of reminders associated with the trauma, increased autonomic arousal and distinct memory deficits. This disorder is also characterised by a maladaptive hypothalamic-pituitary-adrenal (HPA)-axis response and altered monoamine concentrations in the hippocampus and pre-frontal cortex. The Time Dependent Sensitization (TDS) model is a putative animal model of PTSD that is based on the concept of repeated trauma, using three acute stressors (TS) of intense severity followed by a mild situational reminder (RS) on day 7 subsequent to the acute stressors. The aims of this study were to determine if the Triple Stressor (TS) induces stress and if the situational reminder (RS) is necessary for the maintenance of the stress response over time and whether these two stress responses are qualitatively and quantitively different. This was done to further validate the TDS model and to characterize the development and progression of the stress-related pathology of PTSD. Methods used were High Performance Liquid Chromatography (HPLC) with electrochemical detection (biochemical correlates) for quantifying the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) concentrations in the hippocampus and pre-frontal cortex (PFC); radio immuno assay (RIA) for the determination of plasma corticosterone concentrations (neuroendocrine parameter) and the use of the Elevated Plus Maze (EPM) to detect anxiety-like behaviour (behavioural analyses). The study was subdivided into an Acute and Re-Stress study (n = 10). In the Acute Study rats were exposed to TS as the only stressor. Group 1 was sacrificed immediately after TS, Group 2 was sacrificed 3 days post TS and Group 3 on day 7 post TS. In the Re-Stress Study both TS and RS were used as stressors. Group 4 was sacrificed immediately after the situational reminder, Group 5 was sacrificed 3 days post RS and Group 6 on day 7 post RS. A group of unstressed rats were used as Control. The results of this study found corticosterone concentrations elevated immediately after the TS (p<0.05). Exposure to the RS resulted in a profound hypocortisolism (p<0.05). These results indicate a possible disturbance in the regulation of the HPA-axis, which manifests as an enhanced negative feed-back upon re-introduction of the stressful situation. Changes in MA concentrations were evident. Although no definite fixed trend is apparent in this study, it is evident that the TDS model does induce monoamine dysregulation. Hippocampal NA. DA and 5-HT concentrations were noted to be elevated on day 7 post TS (p<0.05). On day 7 post RS only hippocampal 5HT was decreased significantly (p<0.05). Behavioural analyses indicate that stress related anxiety was not sustained after the TS but 7 days after the exposure to the RS rats were most anxious (p<0.05). The results confirm that the TDS model does induce PTSD-like symptoms in rats and that the situational reminder (RS) is necessary for the maintenance of the stress response. This model may be useful in the investigation of future experimental pharmacological interventions in the management of PTSD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may result from an exposure to a severely traumatic life-event. It is characterised by a delayed onset of psychological and physical symptoms including re-experiencing the event, avoidance of reminders associated with the trauma, increased autonomic arousal and distinct memory deficits. This disorder is also characterised by a maladaptive hypothalamic-pituitary-adrenal (HPA)-axis response and altered monoamine concentrations in the hippocampus and pre-frontal cortex. The Time Dependent Sensitization (TDS) model is a putative animal model of PTSD that is based on the concept of repeated trauma, using three acute stressors (TS) of intense severity followed by a mild situational reminder (RS) on day 7 subsequent to the acute stressors. The aims of this study were to determine if the Triple Stressor (TS) induces stress and if the situational reminder (RS) is necessary for the maintenance of the stress response over time and whether these two stress responses are qualitatively and quantitively different. This was done to further validate the TDS model and to characterize the development and progression of the stress-related pathology of PTSD. Methods used were High Performance Liquid Chromatography (HPLC) with electrochemical detection (biochemical correlates) for quantifying the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) concentrations in the hippocampus and pre-frontal cortex (PFC); radio immuno assay (RIA) for the determination of plasma corticosterone concentrations (neuroendocrine parameter) and the use of the Elevated Plus Maze (EPM) to detect anxiety-like behaviour (behavioural analyses). The study was subdivided into an Acute and Re-Stress study (n = 10). In the Acute Study rats were exposed to TS as the only stressor. Group 1 was sacrificed immediately after TS, Group 2 was sacrificed 3 days post TS and Group 3 on day 7 post TS. In the Re-Stress Study both TS and RS were used as stressors. Group 4 was sacrificed immediately after the situational reminder, Group 5 was sacrificed 3 days post RS and Group 6 on day 7 post RS. A group of unstressed rats were used as Control. The results of this study found corticosterone concentrations elevated immediately after the TS (p<0.05). Exposure to the RS resulted in a profound hypocortisolism (p<0.05). These results indicate a possible disturbance in the regulation of the HPA-axis, which manifests as an enhanced negative feed-back upon re-introduction of the stressful situation. Changes in MA concentrations were evident. Although no definite fixed trend is apparent in this study, it is evident that the TDS model does induce monoamine dysregulation. Hippocampal NA. DA and 5-HT concentrations were noted to be elevated on day 7 post TS (p<0.05). On day 7 post RS only hippocampal 5HT was decreased significantly (p<0.05). Behavioural analyses indicate that stress related anxiety was not sustained after the TS but 7 days after the exposure to the RS rats were most anxious (p<0.05). The results confirm that the TDS model does induce PTSD-like symptoms in rats and that the situational reminder (RS) is necessary for the maintenance of the stress response. This model may be useful in the investigation of future experimental pharmacological interventions in the management of PTSD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

O córtex pré-frontal medial (PFCm) é caracterizado por entradas glutamatérgicas e dopaminérgicas que convergem sobre os mesmos neurônios alvos. Devido à escassa informação sobre as bases anatômicas das interações entre a dopamina (DA) e o glutamato (Glu), mapeamos a distribuição de subunidades (Su) de receptores (Rs) de Glu do tipo AMPA, NMDA e kainato no PFCm e investigamos a sua expressão em neurônios contendo a fosfoproteína DARPP-32 e em interneurônios. Os resultados mostram que as Su GluR2/3 dos Rs do tipo AMPA são as mais amplamente distribuídas no PFCm e expressas em todos os neurônios DARPP-32+. GluR2/3 é também amplamente co-localizado com as Su NMDAR1 dos Rs de Glu do tipo NMDA e GluR5/6/7 dos Rs do tipo kainato. Em contraste, as Su GluR1 e GluR4 são somente fracamente expressos no PFCm e não são co-localizados com DARPP-32, porém com GABA ou parvalbumina. Os resultados indicam que as Su GluR2/3, NMDAR1 e GluR5/6/7 são amplamente expressos em neurônios piramidais DARPP-32+ enquanto GluR1 e GluR4 são predominantemente expressos em interneurônios do PFCm. / The medial prefrontal cortex (PFCm) is characterized by glutamatergic and dopaminergic afferents that converge on the same target neurons. Since there is only limited information about the anatomical bases for interactions between dopamine (DA) and glutamate (Glu), we mapped the distribution of AMPA, NMDA and kainate Glu receptor (Rs) subunits (Su) in the PFcm and investigated their expression in neurons containing the phosphprotein DARPP-32 and in interneurons. Results show that the Su GluR2/3 of AMPA type Rs are the most prominently distributed in the PFCm and expressed in all neurons DARPP-32+. GluR2/3 is also widely co-localized with the NMDA type Su NMDAR1 and the Kainate Su GluR5/6/7. In contrast, the Su GluR1 and GluR4 are only weakly expressed in the PFCm and are not colocalized with DARPP-32 but with GABA or parvalbumin. Results indicate that the Su GluR2/3, NMDAR1, and GluR5/6/7 are prominently expressed in DARPP-32+ pyramidal neurons, whereas GluR1 and GluR4 are predominantly expressed by interneurons in the PFC.

Made available in DSpace on 2016-03-15T19:40:41Z (GMT). No. of bitstreams: 1 Rita dos Santos de Carvalho Picinini.pdf: 1897105 bytes, checksum: 40db215aab8bca0781df1d15de88b3d3 (MD5) Previous issue date: 2009-01-27 / Fundo Mackenzie de Pesquisa / Different mathematical skills have been investigated over time and, with the advance of neuroimaging techniques, such as PET (Positron Emission Tomography) and fMRI (functional Magnetic Resonance), central components of arithmetical processing have been identified in the parietal and the pre-frontal cortices. Besides the advances of the neuroimaging techniques, other techniques such as non-invasive brain modulation have also been studied such as the transcranial magnetic stimulation (TMS) and the transcranial direct current stimulation (TDCS) in the involvement of cognitive functions in the area of calculation. This study aimed at investigating the impact of anodal TDCS applied over the left dorsolateral pre-frontal cortex (LDLPFC), right parietal cortex (RPC), left parietal cortex (LPC) while the subject was performing multiplication operations. Fifteen healthy volunteers, students of psychology, aged between 18 and 30 years old, have held subtests of the WAIS III and the multiplication task. The results showed that the anodal TDCS over the RPC improved the performance of men regarding the number of rightness. The influence of TDCS on volunteers who had worse performance took place not on complex tasks, but simple arithmetical ones. Besides, the influence of TDCS on volunteers who had better performance was in complex tasks, not simple ones. These results show that the effects of the TDCS on a certain function depend on the baseline values of each volunteer. The other stimulation conditions over the LDLPFC and LPC did not show any significant results. The TDCS can bring a beneficial effect in calculation tasks, depending on the intensity, polarity, time and location of stimulation, resulting in the increased or diminished cortex excitability. / Diferentes habilidades matemáticas vêm sendo investigadas ao longo dos tempos e, com o avanço das técnicas de neuroimagem, como PET (Tomografia por emissão de Pósitrons) e fMRI (ressonância magnética funcional) componentes centrais no processamento aritmético vêm sendo identificados em córtex parietal e pré-frontal. Além do avanço das técnicas de neuroimagem, outras técnicas como de modulação cerebral não-invasiva também vêm sendo estudadas, como Estimulação Magnética Transcraniana (EMT) e a Estimulação Transcraniana por Corrente Contínua (ETCC) no envolvimento das funções cognitivas com a área de cálculo. Este estudo teve como objetivo investigar o impacto da ETCC anódica quando aplicada no Córtex Pré-Frontal Dorsolateral (CPFDLE), Córtex Parietal Direito (CPD), Córtex Parietal Esquerdo (CPE) no desempenho em operações de multiplicação. Quinze voluntários saudáveis, estudantes de psicologia, com faixa etária entre 18 e 30 anos, realizaram subtestes do WAIS III e a tarefa de multiplicação. Os resultados desse estudo mostraram que a ETCC anódica aplicada no CPD melhorou o desempenho dos homens em relação ao número de acertos. A influência da ETCC em participantes com pior desempenho em Aritmética se deu em tarefa simples de multiplicação, mas não complexa, ao passo que a influência da ETCC em participantes com melhor desempenho em Aritmética se deu em tarefa complexa de multiplicação, mas não em simples. Tais resultados sinalizam que os efeitos da estimulação em uma determinada função dependem dos valores de linha de base de cada participante As outras condições de estimulações, CPFDLE e CPE não resultaram em efeitos significativos. A ETCC pode produzir um efeito benéfico em tarefas de cálculo, dependendo da intensidade, polaridade, tempo e localização da estimulação, podendo resultar em aumento ou diminuição na excitabilidade do córtex.