In a warming world, glaciers and ice sheets have an increasingly large influence on the environment, particularly through their contribution to sea level rise. Their response to anthropogenic climate change, in addition to natural variability, has a critical impact on dependent populations and will be key to predict future climates. Understanding the past natural transitions is also important as if the natural variability of the climate system is not well understood, we stand little change of accurately predicting future climate changes, especially in the context of rapid global warming. Ice cores represent the best time capsules for the recovery of paleo-climate informations. For that, the recovery of a suitable 1.5 million-year-old ice core in Antarctica is fundamental to better understand the natural climate reorganisation which occurred between 0.9 and 1.2 Ma. Constraining the englacial and basal temperature evolution of glaciers and ice sheets through time is the first step in understanding their temporal stability and therefore potential impacts on climate. Furthermore, obtaining the best constraints on basal conditions is essential as such million-year-old ice will be located very near to the bedrock, where the thermal regime has the strongest impact. However, measurements of current englacial and basal temperature have only been obtained at a few drill sites for glaciers and ice sheets. We must therefore turn to thermodynamical models to provide theoretical and statistical constraints on governing thermal processes. Thermodynamical models rely on a suite of governing equations, which we describe in this thesis. Our first study area is the McCall glacier, in Alaska (USA), where we show that the glacier cooled down in the warming climate of the last 50 years using a 1D thermodynamical model. We calculate the present-day englacial temperature distribution using recently acquired data in the form of englacial temperature measurements and radio-echo sounding surveys of the glacier. We show the important of absence of latent heat release due to the refreezing of meltwater inside an active surface layer and reconstruct the last 50 years of equilibrium line altitude (ELA) elevation changes. In the context of Beyond Epica Oldest Ice, a European project aimed at recovering a 1.5 million year-old ice core, we propose for the first time a map of the location of adequate drilling sites for the entire Antarctic Ice Sheet. We use a 3D thermomechanical model to calculate a new basal temperature map of the Antarctic Ice Sheet, as well as a 1D thermodynamical model to constrain the poorly known geothermal heat flux (GHF). These combined model runs use the latest acquired data sets for the GHF, ice flow velocity, ice thickness and subglacial lakes. In order to take into account 2 Ma of Antarctic climate history, we use a transient 1D thermodynamical model to provide constraints on GHF by calculating the maximum value of GHF allowed to keep frozen basal conditions everywhere underneath the ice sheet. These values are then statistically compared to published GHF data sets to propose a probabilistic map of frozen and thawed bedrock locations. This transient model uses high spatial resolution radar data acquired over the Dome Fuji and Dome C regions to examine their likelihood of having preserved 1.5-million-year ice. We define a number of important criteria such as GHF, bedrock variability, ice thickness and other parameter values for Oldest Ice survival. We anticipate that our methods will be highly relevant for Oldest Ice prospection in other areas of the ice sheet that so far remain little or un-surveyed, as well as for the thermal modelling of other glaciers and ice sheets, and in particular, of the Greenland Ice Sheet. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

L-Dihydroxyphenylalanine (L-DOPA), the anti-parkinsonian drug affording the greatest symptomatic relief of parkinsonian symptoms, is still misunderstood in terms of its neurotoxic potential and the mechanism by which generated dopamine (DA) is able to exert an effect despite the absence of DA innervation of target sites in basal ganglia. This review summaries important aspects and new developments on these themes. On the basis of L-DOPA therapy in animal models of Parkinson's disease, it appears that L-DOPA is actually neuroprotective, not neurotoxic, as indicated by L-DOPAs reducing striatal tissue content of the reactive oxygen species, hydroxyl radical (HO•), and by leaving unaltered the extraneuronal in vivo microdialysate level of HO•. In addition, the potential beneficial anti-parkinsonian effect of L-DOPA is actually increased because of the fact that the basal ganglia are largely DA-denervated. That is, from in vivo microdialysis studies it can be clearly demonstrated that extraneuronal in vivo microdialysate DA levels are actually higher in the DA-denervated vs. the intact striatum of rats - owing to the absence of DA transporter (i.e., uptake sites) on the absent DA nerve terminal fibers in parkinsonian brain. In essence, there are fewer pumps removing DA from the extraneuronal pool. Finally, the undesired motor dyskinesias that commonly accompany long-term L-DOPA therapy, can be viewed as an outcome of L-DOPAs sensitizing DA receptors (D1-D5), an effect easily replicated by repeated DA agonist treatments (especially agonist of the D 2 class) in animals, even if the brain is not DA-denervated. The newest findings demonstrate that L-DOPA induces BDNF release from corticostriatal fibers, which in-turn enhances the expression of D3 receptors; and that this effect is associated with motor dyskinesias (and it is blocked by D3 antagonists). The recent evidence on mechanisms and effects of L-DOPA increases our understanding of this benefical anti-parkinsonian drug, and can lead to improvements in L-DOPA effects while providing avenues for reducing or eliminating L-DOPAs deleterious effects.

Animals respond to changes in the environment and internal states to modify their behavior. The basal ganglia, including the striatum contribute to action selection by integrating sensory, motor and reward information. Therefore, dysregulation of striatal function is common in many neuropsychiatric disorders, including Parkinson’s disease, Huntington disease, schizophrenia, and addiction. Here, using fiber photometry, pharmacology, and behavioral approaches in transgenic mice, I explored the cellular and circuit mechanisms underlying key striatal functions. In Chapter 1, I begin by presenting the existing literature on the anatomy and physiology of the striatum. Next, I review the important functions of the striatum. Within this general review, I highlight the specific roles that striatal (DA) and acetylcholine (ACh) play in striatal circuitry and function. In Chapter 2, I demonstrate the naturally evoked ACh dip has a DA component and a non-DA component. Specifically, I show that DA via cholinergic DA D2 receptors (D2Rs) modulate the length of the ACh dip and rebound ACh levels following the dip. In addition, I show that DA coordinates the activity between DA and ACh during behavior. Finally, I present data that supports a role for ACh in motivated behavior. In Chapter 3, I show that cholinergic D2Rs are not necessary for reward learning but do facilitate reversal learning in a probabilistic choice task. In addition, I show that changes in DA and ACh levels contribute to reversal learning in a probabilistic choice task. Finally, in Chapter 4, I discuss the general conclusions and study implications, as well as future directions.

The early postnatal period is marked by the rapid acquisition of sensorimotor processing capabilities. Initially responding to a limited set of environmental stimuli with a restricted repertoire of behaviors, mammals exhibit a remarkable proliferation of sensorimotor abilities in the early postnatal period. Central to action selection, reinforcement, and contingency learning are a subcortical set of evolutionarily conserved nuclei called the basal ganglia. The striatum, which is the primary input nucleus of the basal ganglia, receives afferent innervation from throughout the CNS. Its projection neurons (SPNs) integrate these diverse inputs, regulating movement and encoding salient cue-outcome contingencies. Here, using electrophysiological, electrochemical, imaging, and behavioral approaches in mice, I will explore the postnatal maturation of the striatal cholinergic interneuron (ChI), a critical modulator of dopamine signaling, afferent excitation, and SPN excitability. In Chapter 1, I will set the stage for this exploration by reviewing the current literature on striatal postnatal development, including cellular physiology, axonal elaboration and synapse formation, and plasticity expression. I will survey striatal deficits observed in clinical neurodevelopmental conditions such as autism, ADHD, tic disorders, and substance use disorders. I will additionally summarize evidence that the striatum is uniquely vulnerable to physiological and immunological insult, as well as early life adversity. In Chapter 2, I turn my focus specifically to the striatal ChI, uncovering fundamental cell-intrinsic changes that occur postnatally in this population. I will also elaborate on the postnatal maturation of dopamine release properties and regulation thereof by cholinergic signaling from the ChI. In Chapter 3, I investigate the circuit connectivity and circuit-driven firing dynamics of ChIs as they mature postnatally. I utilize a brain slice preparation retaining thalmostriatal afferents in order to assay the ChI pause, a synchronized transient quiescence in ChIs thought to facilitate cue learning and behavioral flexibility. I find that the ChI pause is refined postnatally, dependent on developmental changes in thalamic input strength and the cell- intrinsic expression of specific ionic conductances. Finally, in Chapter 4, I present preliminary evidence that ChI circuit maturation as defined in preceding chapters is delayed by chronic stress exposure postnatally. Following the maternal separation model of early life stress, ChI intrinsic characteristics mature normally, but they retain heightened thalamic innervation and thalamus-driven pause expression.

Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and non-truncating de novo mutations contribute to autism. Moreover, we find that truncating mutations affecting the same exon lead to strikingly similar intellectual phenotypes in unrelated ASD probands and propose that exons, rather than genes, represent a unit of effective phenotypic impact for truncating mutations in autism. The phenotypic effects are likely mediated by nonsense-mediated decay of splicing isoforms and similar patterns may be observed in other genetic disorders. While multiple cell types and brain areas are affected, the impact of ASD mutations converge on a strongly interconnected system of neural structures that involve basal ganglia loops and the limbic system. We observe that distant projections constitute a disproportionately large fraction of the network composition, suggesting that the integration of diverse brain regions is a key property of the neural circuit. We demonstrate that individual de novo mutations impact several disparate components of the network and may further explain the phenotypic variability. Overall, our study presents a method that, to our knowledge, is the first unbiased approach using genetic variants to comprehensively discover and identify the neural circuitry affected in a psychiatric disorder.

Parkinson’s Disease is a disorder of the midbrain dopaminergic system with characteristic neurodegenerative patterns, recognized for its motor symptoms. The neurodegeneration is most prevalent in the substantia nigra pars compacta, while dopaminergic neurons in neighboring structures are comparatively spared. There are many possible explanations for this disparity, including differences in tolerance to oxidative stress, and vulnerability to α-synuclein aggregates. The substantia nigra is part of the basal ganglia, a network of nuclei in the midbrain and base of the forebrain which are responsible for coordinating voluntary movement. Dopamine has an inhibitory effect in the basal ganglia. It dampens signals to remove noise, so the basal ganglia circuitry is not hyperactive. In the absence of dopamine, the flow of information through the basal ganglia is disrupted. This results in tremor, bradykinesia, and rigidity, known as the classic triad. No cure currently exists and therapies are unable to slow disease progression, so treatments are aimed at symptom management. Degenerative processes in Parkinson’s Disease occur rapidly, early in the disease progression, with about 60% neuronal death in the substantia nigra prior to diagnosis. There is a need for biomarkers or other signs which can be used to clinically to diagnose the disease at an earlier stage. In conclusion this paper provides suggestions for future lines of research.

The composition of the gut microbiome can be affected by environmental factors, such as diet. The Western dietary pattern is associated with microbiome dysbiosis and adverse health outcomes, including obesity and metabolic disorders. The objective of this study was to examine the effect of gut microbiota from lean or obese human donors on metabolism and weight gain in recipient mice fed one of three basal diets: 1) the standard AIN93G diet, which promotes rodent health; 2) the total Western diet (TWD), which mimics the American dietary pattern and promotes inflammation-associated colorectal carcinogenesis; and 3) a 45% high fat diet-induced obesity (DIO) diet, which promotes excessive weight gain and symptoms of metabolic syndrome. We hypothesized that fecal microbiome transfer (FMT)from obese human donors would lead to an obese phenotype with symptoms of metabolic syndrome in recipient mice, and that consumption of TWD or DIO diets would further exacerbate the metabolic syndrome phenotype. The experiment design consisted of two main factors: body type of the human donor (obese or lean) and experimental diet (AIN, DIO or TWD), which was fed to mice for 22 weeks. Prior to FMT, the resident gut microbiome in mice was depleted using an established broad spectrum antibiotic/antifugal oral dosing regimen. Interestingly, human donor body type did not significantly affect final body weight or body composition in recipient

京都大学 / 0048 / 新制・論文博士 / 博士(人間・環境学) / 乙第12883号 / 論人博第40号 / 新制||人||169(附属図書館) / 26||論人博||40(吉田南総合図書館) / 31601 / (主査)教授 石原 昭彦, 教授 船橋 新太郎, 教授 林 達也, 准教授 神﨑 素樹, 准教授 久代 恵介 / 学位規則第4条第2項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19272号 / 医博第4036号 / 新制||医||1011(附属図書館) / 32274 / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 村井 俊哉, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19930号 / 医博第4150号 / 新制||医||1017(附属図書館) / 33016 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 小川 誠司, 教授 高田 穣 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM