Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insen-sitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. NEW & NOTEWORTHY Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.

Transcutaneous auricular vagal nerve stimulation (taVNS) is a non-invasive method of activating axons in the auricular branch of the vagus nerve through the concha of the outer ear. taVNS is under investigation as an alternative treatment option for a wide range of disorders. Vagal afferent fibers terminate in the nucleus of the solitary tract (NTS) where information is processed and relayed to higher brain regions influencing sympathetic and parasympathetic systems. Due to extensive neuronal connections, it is likely that taVNS could serve as a treatment option for many disorders, specifically cardiac, migraine, and gastric motility disorders. Human fMRI studies have indicated that taVNS elicits neuronal responses within NTS and spinal trigeminal nucleus (Sp5c). Studies have indicated that caudal NTS (cNTS) has substantial connections with the cardiac system, rostral NTS (rNTS) is relevant for gastric motility, and Sp5c is likely involved in migraine disorders due to meningeal connections. Aberrant neuronal signaling is likely responsible for the development of these disorders, and taVNS has the potential to modulate neuronal activity to reestablish homeostatic signaling. In this study, electrophysiological methods were used to interrogate neuronal activity of 50-70 neurons within cNTS, rNTS, and Sp5c following taVNS. A high-impedance tungsten electrode was placed stereotaxically in 15 male Sprague-Dawley rats anesthetized with chloralose. Changes in neuronal firing rates were investigated during and immediately following taVNS by comparing changes in neuronal activity to baseline levels using the software Spike 2 v9.14. Neurons were classified as negative responders if activity decreased more than 20%, positive responders if activity increased more than 20%, or non-responders if activity changes were less than 20%. Six different taVNS parameters were investigated using three frequencies (20, 100, 250Hz) at two intensity levels (0.5, 1.0mA). Data from this study suggest that taVNS can modulate neuronal activity in a frequency and intensity-dependent manner. The greatest positive activation for all 3 brain regions occurred at 20Hz, 1.0mA stimulation where an average of 46% ± 9% neurons showed increased firing compared to 29% ± 2% positive responders for other paradigms. The greatest negative activation for all 3 regions occurred at 100Hz, regardless of intensity, where an average of 33% ± 1% neurons showed reduced firing compared to 15% ± 2% negative responders for remaining paradigms. Based on what is known about cardiac, migraine, and gastric motility disorders, it is likely that taVNS can be used to modulate activity in NTS and Sp5c to provide beneficial treatment options to patients. Specifically, using paradigms yielding decreased activity in Sp5c could improve migraine symptoms, and paradigms increasing activity in cNTS and rNTS could improve cardiac and gastric motility disorders, respectively.

The main area of inquiry for this thesis is super-maximum security prisons or as commonly referred to “supermax prisons”. First, the thesis traces the shift from the use of physical punishment to the use of disciplinary measures in punitive institutions and the development of the modern prison until it reaches its latest form as embodied in the supermax model. Secondly, the design, characteristics, and conditions of these prisons are also explored to demonstrate how they systematically contribute to the dehumanization and depersonalization of prisoners. These institutions are subsequently found to represent physical spaces of the lawless “state of exception” that reduces inmates to a “bare” animal-like form of living through depriving them of all the rights and prerogatives granted to them by law. Third, the thesis analyzes the penological rationale commonly invoked to justify supermax prisons and concludes that it suffers from a clear deficiency in demonstrating any evidence-based credibility. Finally, the thesis sheds light on the devastating and long-lasting impacts of supermax confinement on mental health and argues that it may be in violation of fundamental human rights such as the right against torture and other cruel, inhumane, and degrading treatment or punishment as provided by international law.

The health of pollinators, especially bees, is of the utmost importance to success of many agricultural ecosystems. Microorganisms can cause diseases in bees; such microbes are pathogenic. The ability of a pathogen to cause harm to its host (such as a bee) is termed its virulence. Studying the evolution of different levels of virulence can lead researchers to a better understanding of pathogens, and potentially predict how much harm a pathogen can cause in the future. We studied the evolution of virulence levels for a fungal disease of bees. This group of fungi is composed of 28 species, and some cause a disease in bees called chalkbrood while others do not. Using what we know about virulence evolution we wanted to see if the pathogens could infect all bees, if the pathogens varied in virulence when infecting at the same time as another pathogen, and if solitary bees had any behavioral adaptations that might increase or decrease chalkbrood infection. By using DNA sequences, the relationship between the genetic structures of each of the fungal species was studied, and we found that pathogens of solitary bees grouped together while pathogens of social bees (honey bees) were not part of this group. We then found that a solitary bee pathogen did not infect honey bees very well, and vice versa. The nuances of the relationship between two solitary bee pathogens were examined more closely to determine how the two pathogens interact in this bee. In this case, under varying conditions of infection, one pathogen always maintained a similar level of virulence and spore production, while the other pathogen varied in these measures. In addition, when doses of these fungi were fed to bee larvae at different times, more bees survived than when the doses were given at the same time, suggesting that bee immune responses are very important. Finally, we found no evidence of any specific behaviors of solitary bees exposed to infective spores that would suggest these bees have behaviors that are evolved to alter chalkbrood levels in populations.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20557号 / 理博第4315号 / 新制||理||1620(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 友永 雅己, 准教授 後藤 幸織, 教授 平井 啓久 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Distribution of prolactin-releasing peptide-like immunoreactivity (PrRP- LI) was investigated in the rat medulla with the use of a rabbit polyclonal antiserum against the human PrRP-31 peptide. PrRP-positive neurons were noted mainly in two areas of the caudal medulla: ventrolateral reticular formation and commissural nucleus of the nucleus of the solitary tract (NTS), corresponding to the A1 and A2 areas. PrRP-LI neurons were absent in the medulla rostral to the area postrema. Double-labeling the sections with PrRP antisera and tyrosine hydroxylase (TH) monoclonal antibodies revealed extensive colocalization of PrRP- and TH-like immunoreactivity (TH-LI) in neurons of the A1 and A2 areas. Our results show that PrRP-LI is expressed in a population of A1 and A2 noradrenergic neurons of the rat caudal medulla.

Cocaine- and amphetamine-regulated transcript (CART) was first identified in the rat striatum where levels were upregulated following cocaine or amphetamine administration. A dense plexus of CART-immunoreactive fibers is noted in the nucleus of the solitary tract (NTS). Results from tract-tracing and immunohistochemical studies suggest that the dense network of CARTp-fibers in the NTS may arise from nodose ganglia. The present study was undertaken to evaluate the hypothesis that CARTp may alter baroreceptor function in rats. Rats were intravenously administered phenylephrine every 10 min to elicit a baroreflex. CARTp (0.1- 3 nmol) by intracisternal or bilateral intra-NTS microinjection consistently attenuated the phenylephrineinduced bradycardia. In contrast, CARTp antibody potentiated the bradycardia produced from phenylephrine. Microinjection of saline, normal rabbit serum, or concomitant injection of CARTp and CART antibody into the NTS caused no significant change of phenylephrineinduced baroreflex. The result suggests that CARTp released from primary afferents may modulate baroreflex.

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Single-person households have become a popular trend that has grown dramatically since the 1960s. And loneliness is an unpleasant experience that can bring a negative impact on the physical and mental health of human beings. This study focused on designing an interactive solution in order to reduce loneliness for lonely solitary living people. The study used the qualitative research method and identified a design opportunity to reduce loneliness for lonely people living alone - promoting offline social meetings. The study designed a solution— Matching Pal to engage people in offline social meetings by adding gamification factors, providing two ways of playing, and other useful factors. As a result, the solution showed a positive result in attracting and encouraging people to meet new friends. This shows that gamification can have a positive influence on encouraging users´ behavior in the context of promoting offline social meetings. Also, it provides a design idea that designing multiple ways of interaction based on the traits of different types of users in the solution could help more users achieve the goal.