A rabbit lateral meniscectomy model was used to induce osteoarthritis. Separate studies were conducted to evaluate the progression of osteoarthritis and to identify possible biological markers. First, 21 male, New Zealand White rabbits were divided into 3 groups (n = 7 / group). A randomly selected left or right stifle underwent a lateral meniscectomy. The 3 groups were: corticosteroid administration, forced exercise and surgical control. An open field maze was used to assess mobility weekly. The rabbits were euthanitized 47 days after surgery. Histopathologic examination found that the lateral meniscectomy induced more severe lesions than in the non-surgical contralateral stifle. It also showed a significant sparing effect on erosion of cartilage in the corticosteroid group. The corticosteroid group, but not the exercise group, caused a significant increase in mobility (p = 0.008) compared to the surgical control. Secondly, synovial fluid was harvested from the 12 rabbits on days 0, 6, 26, 40, and 57 with surgery occurring on day 12. Trypan blue was used in the lavage fluid to estimate the volume of harvested synovial fluid. There was a significant increase in the volume harvested on day 26 (p < 0.001). Superoxide dismutase concentration in synovial fluid increased after surgery, although not significantly. These studies verify that the lateral meniscectomy model produce histopathologic lesions consistent with osteoarthritis. Furthermore, use of trypan blue appears to be a reliable concentration marker in a lavage sample to measure harvested synovial fluid. / Master of Science

<p>Atrial fibrillation is a common disease. With pharmacological therapy most patients with atrial fibrillation have moderate or little symptoms, but a number of patients have severely symptomatic disease. This study evaluates two new non-pharmacological therapies for atrial fibrillation, the Maze procedure and atrial overdrive pacing.</p><p>In the patients planned for Maze surgery the quality of life, assessed with the SF-36 questionnaire, was very low before the operation. The quality of life was markedly improved 6 and 12 months after the Maze operation, and was comparable to values of the general Swedish population.</p><p>In the patients with sinus rhythm before surgery, the atrial size and transport function was assessed with echocardiography, and the autonomic balance was assessed with heart rate variability (HRV). The sizes of both atria were reduced and the transmitral early filling / atrial filling (E/A) ratio was increased at 6 months after the operation compared to before. A progressive increase of the E/A ratio was seen during the 24 months follow-up period, indicating a progressive decline of the left atrial transport function.</p><p>All components of HRV, including the parameters expressing sympathetic and parasympathetic modulation, were markedly decreased early after the Maze procedure compared to before. Late after the operation all components of HRV were still markedly depressed. This is interpreted as a partial autonomic denervation of the heart</p><p>Single-site right atrial overdrive pacing with two different levels of overdriving was compared with no pacing in patients with paroxysmal atrial fibrillation in a cross-over study. Overdrive pacing reduced the median number of episodes of atrial fibrillation with 50% compared to no pacing. There was no difference between medium rate overdrive pacing and high rate overdrive pacing.</p>

Atrial fibrillation is a common disease. With pharmacological therapy most patients with atrial fibrillation have moderate or little symptoms, but a number of patients have severely symptomatic disease. This study evaluates two new non-pharmacological therapies for atrial fibrillation, the Maze procedure and atrial overdrive pacing. In the patients planned for Maze surgery the quality of life, assessed with the SF-36 questionnaire, was very low before the operation. The quality of life was markedly improved 6 and 12 months after the Maze operation, and was comparable to values of the general Swedish population. In the patients with sinus rhythm before surgery, the atrial size and transport function was assessed with echocardiography, and the autonomic balance was assessed with heart rate variability (HRV). The sizes of both atria were reduced and the transmitral early filling / atrial filling (E/A) ratio was increased at 6 months after the operation compared to before. A progressive increase of the E/A ratio was seen during the 24 months follow-up period, indicating a progressive decline of the left atrial transport function. All components of HRV, including the parameters expressing sympathetic and parasympathetic modulation, were markedly decreased early after the Maze procedure compared to before. Late after the operation all components of HRV were still markedly depressed. This is interpreted as a partial autonomic denervation of the heart Single-site right atrial overdrive pacing with two different levels of overdriving was compared with no pacing in patients with paroxysmal atrial fibrillation in a cross-over study. Overdrive pacing reduced the median number of episodes of atrial fibrillation with 50% compared to no pacing. There was no difference between medium rate overdrive pacing and high rate overdrive pacing.

This study investigated spatial learning in Caenorabditis elegans; the ability to associate reinforcing cues with a location. Naive, wildtype C. elegans were trained in a microfluidic t-maze in the presence of diacetyl (a volatile attractant associated with food) and subsequently tested to see if they could associate diacetyl with one arm of the t-maze. 70-80% of the subjects chemotaxed towards diacetyl during training phase, but they randomly chose left or right when diacetyl was absent (number of subjects that chose diacetyl being under 65%). From our experiments, it is unlikely that the worms are associating diacetyl with one arm of the t-maze, but appears to be using some component of the atmosphere as a cue.

No description available.

No description available.

Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.

Die hohe Dichte und breite Verteilung von P2Y-Rezeptoren im Hirn von Säugetieren lässt für diese Rezeptoren eine wichtige Rolle in den Prozessen des zentralen Nervensystems vermuten. Um die Beteiligung von P2Y-Rezeptoren bei der Verarbeitung von Angst zu untersuchen, wurde in dieser Arbeit das P2Y1,11,12,13 -rezeptorspezifische ADP-Analogon Adenosin-5\'-O-2-thiodiphosphat (ADPßS), der P2X1,3-Rezeptoragonist a,b-methylen-ATP (a,bmeATP), der unspezifische P2-Rezeptorantagonist Pyridoxalphosphat-6-azophenyl-2’,4’-disulfonat (PPADS) und der spezifische P2Y1-Rezeptorantagonist N6-methyl-2’-deoxyadenosin-3’:5’bisphosphat (MRS 2179) Ratten intracerebroventrikulär injiziert und die Wirkung in einem Verhaltensversuch im standardisierten Angstmodell des elevated plus-maze untersucht. Die Substanzen wurden zu 0,5 μl verabreicht. ADPßS (50 fmol und 500 fmol) zeigte dabei anxiolytische Wirkung mit vermehrten Eintritten und gesteigerter Aufenthaltszeit der Tiere auf den offenen Armen. Eine Prämedikation mit PPADS (5 pmol) oder MRS 2179 (5 pmol) konnte diesen Effekt vollständig antagonisieren. Auch eine Vorbehandlung durch den unspezifischen NO-Synthase-Inhibitor Nw-nitro-L-arginin-methyl-ester (L-NAME) konnte die ADPβS-Wirkung verhindern. Bei alleiniger Gabe zeigten diese drei Substanzen anxiogene Wirkung mit einer verminderten Aufenthaltszeit und einer geringeren Zahl von Eintritten in die offenen Armen. Der anxiogene Effekt konnte wiederum durch eine Gabe von L-Arginin (500 pmol), einem Substrat der NO-Synthase (NOS), verhindert werden, nicht aber durch das Enantiomer D-Arginin (500 pmol), das kein Substrat der NOS darstellt. Die doppelte Immunfluoreszenz konnte die Präsenz der P2Y1-Rezeptoren an Neuronen in dorsomedialen Hypothalamus, Amygdala, Hippokampus und zentralen Höhlengrau wie auch die Kolokalisation von P2Y1-Rezeptoren und nNOS nachweisen. Die höchste Dichte an Immunoreaktivität fand sich im dorsomedialen Hypothalamus. Durch die lokale bilaterale Mikroinjektion von ADPßS und MRS 2179 konnten die in den vorausgegangen Versuchen erreichten Ergebnisse reproduziert und bestätigt werden. Zusammenfassend lässt sich postulieren, dass P2Y1-Rezeptoren maßgeblich an der Verarbeitung von Angst bei männlichen Wistar-Ratten beteiligt sind, die Wirkung eng mit der Veränderung der NO-Konzentration verbunden ist und dass diese im dorsomedialen Hypothalamus vermittelt wird. Inwieweit diese Mechanismen auch in Amygdala und Hippokampus eine Rolle spielen kann mit den vorliegenden Daten nicht abschließend beantwortet werden.

Studies have shown that there is a strong correlation between aging and neurodegenerative diseases. Aging is considered the number one risk factor to develop neuropathologies such as memory loss, senile dementia, Alzheimer's disease (AD), and Parkinson's disease. Neurodegenerative diseases tend to start during adulthood, and aggravate over time, making them difficult to prevent and to treat. In the Unites States, demographic studies by U.S. Bureau of the Census have determined that our aging population of >65 years is expected to increase from the present 35 million to 78 million in 2030. This would result, not only to an increase of age-related chronic illness, and mental disability, but to a decrease of quality of life, and an elevation of medical cost. Thus, this dissertation has focused on investigating the molecular mechanisms during the process of aging and its correlation to chronic inflammation and cognitive impairments. The etiology of neurodegenerative diseases is not very well understood, but research has shown that the process of aging is a key factor, which involved oxidative stress, an over reactive microglia, and increased production of pro-inflammatory cytokines. All these factors are known to decrease cell proliferation, which limit neuroplasticity and they might lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. Previously, we have shown that natural compounds such as polyphenols from blueberry, and green tea, and amino acids like carnosine are high in antioxidant and anti-inflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body. Therefore, we examined the hypothesis that the pro-inflammatory cytokine TNF-[U+F061] may be a critical factor that modulates classical conditioning behavior, the effects of NT-020 on adult neurogenesis, inflammatory markers of the CNS, and the effect of NT-020 on cognitive function as shown using spatial navigation task. The results show that in aged rats, endogenous production of pro-inflammatory cytokine TNF-α impairs the acquisition of learning and memory consolidation in the delay eyeblink classical conditioning task (EBC). It was shown that this effect can be replicated by infusing young rats with exogenous TNF-α prior to EBC. Using NT-020 as a dietary supplement for one month, it was found that NT-020 ameliorates the age-related impairments typically found in aged rats in the spatial navigation tasks Morris water maze and radial arm water maze. By looking at immunohistochemistry analysis, it was found a decreased number of OX6 MHC II positive cells, increased neurogenesis, and increased number of proliferating cells in the dentate gyrus (DG) of the hippocampus in the aged rats fed with NT-020 relative with their counterpart aged control. In the CNS, Inflammatory markers were analyzed, and it was found that aged rat fed with NT-020 supplemented diet has decrease levels of pro-inflammatory cytokines in compared with aged rats fed with NIH-31 control diet. In conclusion, TNF-α, a pro-inflammatory cytokine has shown to have a modulatory effect during classical conditioning. Moreover, NT-020 may promote a healthy CNS milieu, proliferation of neuronal progenitors, and maintenance of nature neurons in the aged rats and it might exert anti-inflammatory actions which promote a functional stem cell pool in the CNS of aged rats.

The hippocampus plays a critical role in the detection of changes in familiar contexts. It accomplishes these functions through a continual process of comparing predicted features of a context or situation to those experienced. A mismatch between expected and experienced decision-making skills has been proven in previous studies that can be shown using the water maze, a test that is widely used to study spatial and working memory. Expectations are processed by specific neuronal networks, including the hippocampus and prefrontal cortex, to aid subsequent decision-making and response selection. Mice undergoing reversal learning in the water maze test must process the information relative to the new position of the escape platform and decide whether to navigate towards the latest or to the previous target. From previous studies conducted in the lab, it has been observed that an enhanced inter-individual variability in decision-making during reversal learning. Noteworthy, the decision-making of individual mice can be predicted based on their intrinsic state of anxiety and activity of stress response. Here, we aim at investigating: 1) How individuality affects decision making and 2) The neuronal activity controlling decision making and the selection of specific behavioral responses. We observed that based on their individual behaviour and intrinsic anxiety, the time taken to reach a goal platform as well as the distance covered by each mouse differs from one another.