Our study investigated the potential for a combination of diabetes and nicotine treatment to affect blood pressure in the rat. We used streptozotocin injection and oral nicotine feeding as models of type-1 diabetes and smoking respectively. Blood pressure was assessed using the indirect tail-cuff technique. In an attempt to further characterize our experimental model, we also observed body weight, plasma glucose and the contractility of aortic segments in various treatment groups. Our data was expressed as mean ± SEM, and significance was regarded as P < 0.05. We found that a combination of streptozotocin and nicotine treatment resulted in a significant elevation of systolic blood pressure compared with either treatment alone, or control. Furthermore, assessment of aortic contractility showed alteration of reactivity to both phenylephrine and sodium nitroprusside as a result of the combination treatment. We also observed a trend for our combination treatment to exacerbate the elevation of plasma glucose level seen in streptozotocin induced diabetic rat models. This study serves as an experimental basis to underline the importance of cessation of tobacco use for individuals with diabetes mellitus.

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

<p>Perception arises from sensory inputs detected by peripheral organs and processed in the brain by complex neuronal circuits required for the integration of external information with internal states such as expectation and attention. Stimulus discrimination requires activation of primary sensory areas in the brain, but expectation is traditionally associated with the activation of higher-order brain areas. Sensory information obtained by tactile organs is represented along the primary areas that comprise the trigeminal thalamocortical pathway. In anesthetized animals, neuronal activity in the somatosensory system has been extensively described over the past century. However, it is still unclear how the different thalamocortical structures contribute to active tactile discrimination and represent relevant features of the stimulus. It is also unknown whether expectation modulates tactile representations in these regions. In this dissertation, I investigated neuronal ensemble activity recorded from freely behaving rats performing a whisker-based tactile discrimination t-+ask. Multielectrode arrays were chronically implanted to record simultaneously from the main stages of the trigeminal thalamocortical pathways involved in whisking: the primary somatosensory cortex (S1), the ventral posterior medial nucleus of the thalamus (VPM), the posterior medial complex (POm) and the zona incerta (ZI). In Chapter 1 I describe the behavior of rats performing the tactile discrimination task, which requires animals to associate two different tactile stimuli with two corresponding choices of spatial trajectory in order for reward to be delivered. I found that both cortical and thalamic neurons are dynamically engaged during execution of the task. The data reveal a very complex mosaic of responses comprising single or multiple periods of inhibition and excitation. Thalamocortical activity was modulated during whisker stimulation as well as after stimulus removal, up until reward delivery. To investigate whether reward expectation plays a role in tactile processing at early processing stages, I also recorded neuronal activity from rats performing a freely-rewarded version of the tactile discrimination task. Comparing data from regularly-rewarded and freely-rewarded sessions, I show in chapter 2 that the activity of single neurons in the primary somatosensory thalamocortical loop is strongly modulated by reward expectation. Stimulus-related information coded by primary thalamocortical neurons is high when a correct association between stimulus and response is crucial for reward, but decreases significantly when the association is irrelevant. These results indicate that tactile processing in primary somatosensory areas of the thalamus and cerebral cortex is directly affected by reward expectation.</p> / Dissertation

According to traditional Chinese medicine , Cordyceps sinensis (CS) can prevent subjects from renal failure. The aim of this study was to investigate the protective effect of CS preconditioning on ischemic renal acute failure in rats and to assess its mechanism. The animal model of ischemic acute renal failure was performed by left nephrectomy and clamping right renal vessel for 45 mins in S-D rats. Cordyceps group had been pretreated with two-day 600 mg/kg CS before I/R injury. Rats were sacrificed at 1, 3, 6, 16, 48 and 120 h after reperfusion for evaluation of renal function and histopathological PASD staining. The immunohistochemistry and Western blotting of SDF-1£\, CXCR4 and Ki67 were also performed. £E-galactosidase activity was detected with the senescence staining. The results showed that the level of creatinine in Cordyceps group were significant lower after 48 hours I/R injury (p =0.04). PSAD staining in Cordyceps group revealed less tubular necrosis, tubular dilatation, and cast formation at 6 and 16 hour than in control group. Immunohistochemistry of SDF-1£\ in Cordyceps group demonstrated staining in the distal tubules and collecting ducts at 1, 3, 6, and 16 h. The CXCR4 signal of control group had gradually intensified from 1 to 6 hr after I/R . In Cordyceps group, the CXCR4 expression had been stabilized until 16 h after I/R. The £]-galactosidase activity was higher in control group at 1, 3 and 6 hours. However, the senescence was presented at 1 and 3 hours in Cordyceps group. The nuclear staining of repair enzyme Ki67 in Cordyceps group showed higher density than in control group. Pathologic morphology indicated CS may protect subjects from ischemic acute renal failure. CS also induced SDF-1£\ expression in early stage of I/R injury, and maintained the stable CXCR4 expression. CS can not only reduce the activity of senescence-related £]-galactosidase, but also regulate the expression of repair enzyme Ki67, indicating that CS may alleviate the ischemic-induced senescence and enhance renal repair.

Disuse of weight bearing bones has been shown to cause bone loss. This poses a health concern for people exposed to microgravity, such as astronauts. Animal studies are used to study factors related to bone loss and countermeasures to prevent bone loss. This study used a hindlimb unloaded (HU) rat model to simulate microgravity and a muscle stimulation countermeasure to simulate resistive exercise. Uniaxial strain gages were implanted on the antero-medial aspect of the proximal tibia to measure the mechanical strain during a typical exercise session. In a separate but parallel study, the exercise was shown to be an effective countermeasure to disuse related bone loss. The current study sought to understand the loading of the bone during the exercise. To determine if the strain response changes during a protocol using this countermeasure, strains were measured on a group of weight bearing animals and a group that were hind limb unloaded and received the countermeasure for 21 days. Strain magnitudes and rates were considered and related to torques at the ankle joint. No significant differences in strain magnitudes were noted between the baseline control group and the hindlimb unloaded group that received the countermeasure. The two kinds of contractions used in an exercise session are isometric and eccentric. The isometric contractions are used to adjust the stimulation equipment for the eccentric contractions, which constitute the exercise. Peak strain levels during the isometric contractions ranged from 900 to 2200 microstrain while the eccentric were 38% lower and ranged from 600 to 1400. Eccentric strain rates were 62% lower than the isometric contractions strain rates. These results indicate that the strain environment during the isometric contractions may be causing more of the osteogenic response than the eccentric contractions, which have previously been thought to be the primary part of the countermeasure.

Excessive risk-taking is a characteristic of several psychopathological disorders. In order to alleviate maladaptive risky behavior, a thorough understanding of the neurobiological and pharmacological substrates of risky choice must be developed. In this dissertation, the “risky decision-making task” was utilized to explore the mechanisms by which dopamine mediates risky choice. In experiment 1, we characterized rats in risky decision-making as well as a variety of other behavioral traits. This was performed to determine if the behavioral patterns obtained in the risky decision-making task represent an independent cognitive construct rather than a function of a separate behavioral trait. Risky decision-making performance was not correlated with measures of motivation, anxiety, pain tolerance, or other types of decision-making. In contrast, risky choice was correlated with impulsive action as assessed by the Differential Rates of Low Responding Task, suggesting that risky choice may be mechanistically similar to impulsive action. In experiment 2, the effects of various dopaminergic drugs on risky decision-making was investigated. Amphetamine administration attenuated risky choice, while the dopamine antagonist α-flupenthixol had no effect on risky choice. Agonists and antagonists specific to D1 dopamine receptors had no effects on risky choice; however, the D2 dopamine receptor agonist bromocriptine reduced risky choice in a manner similar to amphetamine. Furthermore, coadministration of amphetamine with a D2 antagonist abolished amphetamine’s effects on risky choice, and amphetamine’s effects were unaffected by coadministration of a D1 antagonist. These data suggest that D2 signaling at the receptor is particularly critical to risky decision-making behavior. In experiment 3, D2 dopamine receptor mRNA abundance was assessed in rats that had been previously characterized in risky decision-making using in situ hybridization. Levels of D2 cRNA hybridization in both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) predicted risky decision-making behavior as assessed by nonlinear curve estimation analyses. Interestingly, opposite relationships between D2 mRNA abundance and risky choice were observed in these two cortical areas, with OFC D2 mRNA abundance showing a U-shaped relationship with risky choice, and mPFC D2 mRNA resembling an inverted U-curve. Additionally, increased levels of D2 mRNA in dorsal striatum were observed in risk-averse rats in comparison to risk-taking rats. In conclusion, these data suggest that signaling via D2 dopamine receptors is an important mediator of risky decision-making behavior, and that D2 signaling in frontostriatal circuitry may be particularly relevant toward these behaviors.

Hepatic steatosis is common in the general population and is present in 13.25% of donor organs. It can affect graft survival and recovery of the donor after partial hepatectomy. Liver biopsy is the standard method to measure the degree of hepatic steatosis, but it¡¦s also an invasive procedure and may have sampling error. Non-invasive tools, such as computed tomography and magnetic resonance image, are generally utilized and developed. This study was designed to build a standard model for the quantification of the fat content in a fat-water mixed phantom model. Pork fat and pure water were mixed in different ratios by volume (from 0% fraction of fat to 100% fat in steps of 5%), and then measured for fat content in different concentrations of fat-water mixed phantom by using (1) CT number (Hounsfield unit; HU), (2) Dixon method (in-phase & opposed-phase), and (3) 1H spectroscopy (SVS30 & SVS136, without water suppression). The CT number decreased with increasing fat concentration. The Hounsfield units of pure fat were about -122 HU. At Dixon method, the fat image intensity increased to its maximum when the fat concentration reached 25% and then decreased. Fat concentration higher than 25% and lower than 25% both had the same value of the fat image intensity. Combined with SVS30 water/fat peak height ratio, the fat concentration could be estimated. Furthermore, the fat image could be utilized to observe the topographic distribution of hepatic steatosis. Then a rat fatty liver model fed with a choline deficient and iron supplemented L-amino acid defined (CDAA) diet was established. Fatty liver grade was evaluated by radiological and biochemical assessments. CT and MRS technique displayed the highest fat contents the same with histological examination in CDAA diet rats at 6 weeks. The results showed that MRS was a suitable method for quantifying fat to water concentration. As a result of this study, model of measurement scale can be established to measure fat concentration both in phanatoms and animal. Further study in human fatty liver was expected.

名古屋大学博士学位論文 学位の種類 : 医学博士(論文) 学位授与年月日:平成4年9月22日 大野元嗣氏の博士論文として提出された

Vascular reactivity to vasopressin and phenylephrine is potentiated by constrictor prostanoids (CP) in normotensive female (F) but not male (M) rat aorta and CP function is estrogen-dependent. This study investigated the effects of estrogen on CP function and arterial blood pressure (MAP) during development of aortic coarctation-induced hypertension (HT). M and F rats, (15-18 wks.) in four groups: normotensive (NT), hypertensive (HT), ovariectomized (OVX), and OVX estrogen-replaced (OE), underwent abdominal aortic coarctation or sham surgery (NT). At 14 days, SQ 29,548 (SQ, Thromboxane A2 (TXA2) receptor antagonist) was given i.v. to the groups. In another experiment, rats received Ridogrel (TXA2 receptor antagonist+TXA2 synthase (TXS) inhibitor) or vehicle (methyl cellulose) daily, for 14 days. Thoracic aortae were analyzed for morphology, incubated in Kreb’s Henseleit Buffer (KHB) ± angiotensin II (ANG II), or underwent continuous pulsatile flow and pressure experiments (PFP) with KHB ± ANG II. Perfusate was analyzed for thromboxane B2 (TXB2) and prostaglandin F1&#945; (PGF1&#945;). RT-PCR and immunohistochemistry were performed for TXS. MAP was higher in F-HT than in M-HT after 14 days. SQ infusion reduced MAP substantially more in F-HT and OE-HT than in others. Ridogrel prevented increases in MAP in F/OE-HT rats, but not M/OVX-HT. Basal release of TXB2 and PGF1&#945; increased to a greater extent in F-HT than in M-HT relative to their controls. ANG II-stimulated TXB2 and PGF1&#945; release increased to a greater extent in F-HT than in M-HT. With or without ANG II, TXB2 production in HT during PFP increased with estrogen. PGF1&#945; increased during PFP with estrogen, however not with ANG II. Pressurization resulted in less diameter change in F and OE-HT than in OVX-HT. Elastin increased with HT (inhibited by Ridogrel) in all but M. Collagen increased in HT with estrogen (inhibited by Ridogrel). Neither OVX-HT nor Ridogrel had any effect on morphology. Estrogen increased TXS with HT. Estrogen enhanced vascular CP and MAP in F-HT by increased expression of TXS and collagen density in the vasculature indicating that in aortic coarctation-induced HT, CP are upregulated by estrogen. Specific forms of HT in human beings may involve estrogen-induced vascular CP upregulation.

Disuse of weight bearing bones has been shown to cause bone loss. This poses a health concern for people exposed to microgravity, such as astronauts. Animal studies are used to study factors related to bone loss and countermeasures to prevent bone loss. This study used a hindlimb unloaded (HU) rat model to simulate microgravity and a muscle stimulation countermeasure to simulate resistive exercise. Uniaxial strain gages were implanted on the antero-medial aspect of the proximal tibia to measure the mechanical strain during a typical exercise session. In a separate but parallel study, the exercise was shown to be an effective countermeasure to disuse related bone loss. The current study sought to understand the loading of the bone during the exercise. To determine if the strain response changes during a protocol using this countermeasure, strains were measured on a group of weight bearing animals and a group that were hind limb unloaded and received the countermeasure for 21 days. Strain magnitudes and rates were considered and related to torques at the ankle joint. No significant differences in strain magnitudes were noted between the baseline control group and the hindlimb unloaded group that received the countermeasure. The two kinds of contractions used in an exercise session are isometric and eccentric. The isometric contractions are used to adjust the stimulation equipment for the eccentric contractions, which constitute the exercise. Peak strain levels during the isometric contractions ranged from 900 to 2200 microstrain while the eccentric were 38% lower and ranged from 600 to 1400. Eccentric strain rates were 62% lower than the isometric contractions strain rates. These results indicate that the strain environment during the isometric contractions may be causing more of the osteogenic response than the eccentric contractions, which have previously been thought to be the primary part of the countermeasure.