京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22340号 / 医博第4581号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 影山 龍一郎, 教授 井上 治久, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The mammalian neocortex is an exquisite, highly organized brain structure composed of hundreds of subpopulations of neurons and glia, precisely connected to enable motor control, sensory perception, information integration, and planning. Unique molecular, structural, and anatomical neuronal properties underlie diverse functionality, endowing much of the neocortex’s complex processing power. Neocortical size correlates with information processing capacity, suggesting that increased neuronal number and diversity begets increased sophistication. One excitatory projection neuron type, callosal projection neurons (CPN), has disproportionately expanded with cortical size increase. CPN directly connect homotypic regions of the two neocortical hemispheres by sending axons via the largest white matter fiber tract in the brain, the corpus callosum (CC), allowing quick relay, integration, and comparison of information. In humans, the CC contains over 300,000 axons, CPN have been centrally implicated in autism spectrum disorders, and absence or surgical disruption of CPN connectivity in humans is associated with defects in abstract reasoning, problem solving, and generalization. Therefore, CPN are critical to complex brain functions, and their diversity likely contributes to these roles. Work presented in this dissertation addresses molecular controls over CPN development, specifically genes that are expressed by, and function in, particular subpopulations of CPN. While much progress has been made in identifying molecular controls over neocortical arealization, lamination, and broad subtype specification, CPN diversity has remained largely unaddressed. Therefore, this work begins by identifying genes more highly expressed in CPN than other closely related projection neuron populations, and uncovers molecular diversity within CPN. From this molecular diversity, functional analysis of three candidate molecular controls over CPN subtype diversity follows. Cited2 acts broadly in neocortical progenitor development and postnatally in refining somatosensory CPN identity. Caveolin1 identifies a population of CPN with dual axonal projections. Tmtc4 is mutated in human CC disease and can function in CPN axonal development. These analyses of CPN molecular diversity in mouse then expand to an investigation of which molecular subpopulations are conserved, expanded, or uncommon between rodent and primate, allowing both for comparative evolutionary theories of CPN function, and indicating which CPN populations critical for human brain function can be best studied in rodent models.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20806号 / 医博第4306号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上 治久, 教授 髙橋 良輔, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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A key function of the nervous system is to sample data from the external world, generate internal signals, and transform them into meaningful information that can be used to trigger behaviour. In order to gain insight into the underlying mechanism for signal transformation, the visual system has been extensively studied: partly owing to the stimulus being reliably presentable, and the anatomy being well described. The Drosophila visual system is one such system, with the added advantage of genetic tractability. In this thesis, I studied the filtering property of visual neurons at two levels, biophysical and circuit levels. The first study looks at signal transformation at the biophysical level, at the input of the visual system, in photoreceptors. Voltage-gated potassium channels counteract the depolarization caused by opening of light sensitive channels, and the heterogeneous properties of their kinetics can fine-tune the photoreceptor’s frequency response to fulfill the animal’s ecological requirements. Shaker (Kv1) and Shab (Kv2) have been identified as fast and slow inactivating components of the photoreceptor’s outward currents, however a current with intermediate kinetics (IKf) has not been molecularly identified, but had been postulated to be Shal (Kv4). I focused on characterizing this current using whole-cell patch clamp in wild type and mutants, and using antibodies for Shal. My results from whole-cell patch clamp indicated that IKf in adult R1-6 cells are not Shal, from their voltage dependence and insensitivity to a Kv4 blocker. This calls for alternative molecular basis for IKf, which is likely to be a slow inactivating component of Shaker, or a combination of its many splice variants. The second study looks at signal transformation at the circuit level, at the output end, in the third optic neuropil, lobula. Visual projection neurons project from the lobula to the central brain, and have been proposed to carry behaviourally relevant visual features to higher brain regions. It was recently shown that optogenetic activation of individual visual projection neuron types could induce distinct behaviours such as takeoff and backward walking, linking these visual neurons to specific behavioural programs downstream. Using in vivo two-photon calcium imaging, I recorded visually evoked calcium responses from three of these cell types. Cell types that showed induced takeoff and backward walking preferentially responded to dark looming stimuli or fragmented expanding local features, suggesting their role in behaviours triggered by object approach. To explore how this visual information is transformed in the downstream circuit, we identified several candidate neurons that receive input from this cell type by anatomical overlap, and then validated their connections using optogenetic activation and calcium imaging. One downstream cell-type that projects bilaterally had very similar response properties to its upstream partner, whereas another cell-type that projects ipsilaterally seemed to filter out some information from its upstream partner. This is one of the first studies that functionally characterizes lobula visual projection neurons and their downstream partners in Drosophila, and their response properties agree with the general idea that visual information becomes increasingly selective as it is sent to higher brain regions.