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本研究採用結紮眼血管的方法誘發短暫性視網膜缺血，針對同缺血時間同存活時間化成年金黄地鼠中視網膜節細胞的存活和小型膠質細胞的激活。首先，我們的據顯示，和假缺血手術組相對應的存活時間比較，暫時性視網膜缺血10分鐘或30分鐘沒有導致視網膜節細胞的存活明顯下。暫時性視網膜缺血60分鐘再灌注後7天，視網膜節細胞的存活下至58%，14後為51%，28後為44%。暫時性視網膜缺血120分鐘之後再灌注7天，視網膜節細胞的存活急劇下，僅保22%，至14天，僅剩17%, 之後節細胞的死亡速減緩，至28天時，仍由18%存活。視網膜缺血10分鐘、30分鐘、60分鐘和120分鐘均引起大小型膠質細胞激活，激活在第七天達到頂峰，之後在14天和28天顯著並逐步下。相關性分析發現損傷後7天，視網膜節細胞的死亡和視網膜節細胞層中的小型膠質細胞存在緊密的相關性。 / 其次，我們首次證實缺血性預處僅有於提高視網膜節細胞對抗視網膜缺血/再灌注損傷，還對視神經斷後的視網膜節細胞同樣具有保護作用。結果顯示無是5分鐘還是10分鐘的缺血性預處，無是軸突橫斷術前1天還是前3天實施預處，都對視網膜節細胞有明顯的保護作用。在缺血性預處對抗神經橫斷損傷的實驗組, 的表達只表現在陽性細胞上的明顯優勢，但占全部存活細胞的百分比存在差；而缺血性預處對抗視網膜缺血再灌注損傷的實驗組，的陽性節細胞的無論還是存活百分比都存在差。在預處組和假處組的比較中， 的表達也只是陽性細胞上較多，占全部存活細胞的百分比存在差。在缺血性預處加視網膜缺血分鐘的實驗組中，我們測視網膜矢片中各層的厚。結果顯示，缺血性預處組中，視網膜的整體厚和節細胞層的厚都與正常組相當，而假處組中，這層的厚明顯減少。 / 進一步地，我們研究遠端缺血性後處對視網膜節細胞對抗視神經軸突橫斷術的保護作用。我們選用鉗夾右股動脈作為遠端缺血性後處的方法，鉗夾股動脈分鐘，之後放開，再鉗夾再放開，共個循環。結果顯示，軸突橫斷術后分鐘實施缺血性后處組，視網膜節細胞的存活較假處組明顯增加，包括術後天和天；軸突橫斷術后小時實施缺血性後處組，視網膜節細胞的存活只在術後天較假處組明顯較多，但在天的實驗組，者的差消失；軸突橫斷術小時實施缺血性後處組，視網膜節細胞的存活比假處組多。在缺血性後處的實驗中，視神經橫斷術后分鐘實施遠端缺血性後處的實驗組與假處組比較，的表達僅表現在陽性細胞上的明顯增加，而且占全部存活細胞的百分比也明顯增加。的表達與預處實驗組的結果相似，只存在上的優勢。 / 我们的實驗證明，缺血性預處在對抗視神經橫斷和視網膜缺血的損傷中，可以為節細胞提供有效的保護作用，遠端缺血性後處可以對抗視神經橫斷損傷提高節細胞的存活。陽性節細胞在三個同條件的實驗中，表現出同的結果，这可能暗示遠端缺血性後處對抗視神經橫斷術的損傷，節細胞的再生能較優，與遠端缺血性後處對抗視神經橫斷術的神經保護作用有一定關。的表達在三個實驗組中，處組與假處組比較，均只表現出陽性細胞上的優勢，占存活細胞的百分比就存在差，可能意味著與缺血性預處和後處的保護作用關係不大。 / Ligature of the ophthalmic vessels (LOV) was used as an animal model to study transient retinal ischemia/reperfusion in adult hamsters. Firstly, we quantified the loss of retinal ganglion cells (RGCs) and activation of microglia after10 min, 30 min, 60 min or 120 min retinal ischemia at 7, 14 and 28 days post-ischemia. The results showed that after 10-min or 30-min retinal ischemia, the number of RGCs had no significant decrease compared to sham LOV group at 7 days. In the retinal ischemia 60 min group, there were 58% of the RGCs population remained alive at 7 days, 51% at 14 days and 44% at 28 days post-ischemia, respectively. In the retinal ischemia 120 min group, the number of RGCs was reduced to 22% at 7 days and 17% at 14 days, but cell death slowed down from 14 to 28 days. Meanwhile, the number of microglia was increased sharply at 7 days and decreased gradually from 7 to 28 days. At the same time, it was found that the loss of RGCs and activation of microglia in the ganglion cell layer at 7 days post-insult existed strong positive correlation. / Secondly, the effects of ischemic preconditioning (IPC) were proved to promote RGCs survival after axotomy or retinal ischemia 120 min. It was presented firstly that a 5 or 10 min brief IPC which performed 1 or 3 days prior to axotomy enhanced the RGCs survival at 7 days and 14 days post-axotomy. The number of HSP27-positive RGCs was significantly higher in the IPC plus axotomy subgroup compared with the sham-operated subgroup, while the percentage of HSP27-positive RGCs did not show significant difference between subgroups. For the IPC plus retinal ischemia 60 min group, both the number and the percentage of HSP27-positive RGCs had no significant difference between IPC and sham-operated subgroups. The number of HSP70-positive RGCs exhibited significant difference but not the percentage in IPC plus axotomy or retinal ischemia 60 min experimental groups. The thicknesses of the whole retina and GCL were similar to the normal value in the IPC plus ischemia 60 min subgroup, while in the sham-operated subgroup, these two values decreased significantly. / Consequently, the effect of remote ischemic postconditioning (RIPostC) was also explored to promote RGCs survival after axotomy. Four cycles of 10 min occlusion and 10 min release of the right femoral artery were initiated on animals at 10 min, 6 h or 24 h after axotomy. In the10 min group, the effect of RIPostC on promoting RGCs survival was significant at both 7 and 14 days post-injury. In the 6 h group, the survival of RGCs was more in the RIPostC treatment subgroup at 7 days, while there was no significant difference at 14 days post-axotomy. In the 24 h group, RGC survival was not significantly different at 7 days post-axotomy. Both the number and the percentage of HSP27-positive RGCs were significantly higher in the RIPostC treatment subgroup. The results of the induction of HSP70 only showed a priority in absolute number of the HSP70-positive RGCs in the RIPostC treatment subgroup. / In summary, the effect of IPC has been proved that it could protect RGCs against axotomy and retinal ischemia/reperfusion injury, in addition, the application of RIPostC also protected RGCs from axotomy. The proportion of HSP27-positive RGCs increased significantly in the process of RIPostC against axotomy, which may clue that the ability of axonal regeneration is stronger which induced by the RIPostC intervention. The upregulation of HSP27 might play a role in the neuroprotection of the RIPostC against axotomy. The expression of HSP70 maybe plays a little role in the neuroprotection of the IPC and RIPostC. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liu, Xia. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 182-196). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / Abstract in Chinese --- p.iv / Acknowledgements --- p.vii / Table of Abbreviations --- p.viii / Table of Contents --- p.ix / Chapter Chapter 1 --- General Introduction --- p.1 / Chapter Chapter 2 --- Changes of retinal ganglion cells and microglia after different types of injuries / Introduction --- p.38 / Materials and Methods --- p.43 / Results --- p.49 / Discussion --- p.57 / Figures and tables --- p.71 / Chapter Chapter 3 --- Ischemic preconditioning protect retinal ganglion cells against axotomy and retinal ischemia/reperfusion injury and expression of heat shock protein 27 and 70 / Introduction --- p.93 / Materials and Methods --- p.98 / Results --- p.103 / Discussion --- p.109 / Figures and tables --- p.116 / Chapter Chapter 4 --- Remote ischemic postconditioning protect retinal ganglion cells against axotomy and expression of heat shock protein 27 and 70 / Introduction --- p.143 / Materials and Methods --- p.147 / Results --- p.150 / Discussion --- p.154 / Figures and tables --- p.161 / Chapter Chapter 5 --- General Discussion --- p.175 / References --- p.182

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A cardinal role of selective visual attention is to serve our action by selecting all the relevant information. One task that has been applied extensively to explore attention is visual search for a target among distractors. Given the extensive practice of human observers with visual search, and its ecological relevance, one could expect a high level of efficiency when performing visual search tasks. Indeed, a prominent in the literature Ideal Observer model (Najemnik & Geisler, 2005, 2008) suggests, that human visual system is extremely efficient, in that every eye movement during visual search is executed to the locations that could be expected to yield maximum information; similarly to the Ideal Observer, humans require the minimum number of eye moments possible to find the target (Najemnik & Geisler, 2005, 2008). The present programme of research tests the prediction of the Ideal Observer model (Najemnik & Geisler, 2005, 2008) against a simpler, but similarly effective stochastic selection model (Clarke, Green, Chantler, & Hunt, 2016), by examining human visual search strategies under normal viewing conditions, and conditions that simulate visual field deficit. Across nine experiments, I observed strikingly inefficient search behaviour that speaks against the assumptions of the Ideal Observer model. Although on the surface these cumulative results appear to be in line with the random process of fixation selection (Clarke et al., 2016), such conclusion appears to be valid only for the observed group results. The individual observer's data that was carefully documented in each of the experiments did not allow such a conclusion. The individual observers' data showed full spectrum of search strategies, with some observers being extremely efficient, some being average searchers, and others applying a very inefficient strategy. The large individual differences between participants suggest that the fixation selection process is neither optimal nor random, but rather idiosyncratic.

Appropriately organized synaptic connections are essential for proper neural circuit function. Prior to forming and refining synaptic connections, axons of projection neurons must first navigate long distances to their targets. Research in the axon guidance field has generated a great deal of knowledge about how axons successfully navigate through intermediate choice points and form initial connections with their synaptic targets. One aspect of neural circuit development that has been less well studied is whether axons are organized within their tracts. Axons could be highly ordered, or arranged haphazardly, to be sorted out within their destination target zone. Findings from several systems indicate that axon tracts are organized and, furthermore, that pre-target organization is important for accurate targeting. Chapter 1 will survey these findings as an introduction to my thesis. The remaining chapters present my research in the mouse retinogeniculate pathway, in which I examine three aspects of pre-target axon organization: the organization of cohorts of retinal ganglion cell (RGC) axons in the optic nerve and tract; the role of axon self association in tract organization; and the relationship between tract order and targeting. RGC axons project either ipsi- or contralaterally at the optic chiasm. In the first thalamic target, the dorsal lateral geniculate nucleus (dLGN), RGC axon terminals are organized based on retinotopy and laterality (i.e., into ipsi- and contralateral zones). Chapter 2 presents my findings on the organization of ipsilateral (ipsi) and contralateral (contra) RGC axons in the optic nerve and tract. Ipsilateral RGC axons cluster together in the optic nerve, are less tightly bundled in the optic chiasm, and once in the optic tract, again bundle together and are segregated from contralateral axons. Topographic and ipsi/contra axon order in the optic tract are largely in register, although ipsi- and contralateral axons from the same topographic region maintain distinct ipsi/contra segregation in the tract. Chapter 3 explores one potential mechanism involved in creating the organization between ipsi and contra RGC axons in the tract: differential fasciculation behavior between RGC axon cohorts. I used in vitro retinal explant culture systems to test the hypothesis that ipsilateral RGC axons have a greater preference to self-fasciculate than contralateral axons. Ipsilateral neurites display greater self-association/fasciculation than contralateral neurites, indicating an axon-intrinsic mechanism of ipsilateral-specific self-association. Chapter 4 examines tract organization and fasciculation in the EphB1 mutant retinogeniculate pathway. EphB1 is expressed exclusively by ipsilateral RGCs, and loss of EphB1 leads to a reduced ipsilateral projection and increased contralateral projection. However, aberrantly crossing axons project to the ipsilateral zone in the dLGN. Given its combination of an aberrant decussation phenotype with a grossly normal targeting phenotype, I used this mutant to explore the relationship between midline choice, tract organization, and targeting. First, remaining ipsilateral axons in the EphB1-/- optic tract largely retain their position in the lateral optic tract, but appear splayed apart, suggestive of aberrant fasciculation. In vitro, EphB1-/- ipsilateral neurites still bundle more than EphB1-/- contralateral neurites, although the magnitude of this difference is less striking than in wild-type retinal explants. Thus, EphB1 may be involved in preferential ipsilateral RGC axon fasciculation. In vivo, the aberrantly crossing axons in the EphB1 mutant grossly maintain their position in the ipsilateral zone of the optic tract (i.e., the lateral aspect), indicating a preservation of ipsilateral segregation in the tract. This is in line with a model in which bundling partners in the tract may help guide axons to the correct zone in the target. The data presented in this thesis detail two organizational modes of RGC axons in the developing optic nerve and tract, eye-specific (typographic) and topographic, and suggest that axon-intrinsic factors mediate ipsilateral-specific self-association. Axon-intrinsic factors likely act alongside extrinsic cellular and molecular cues in the developing retinogeniculate pathway to facilitate pre-target axon organization, which may in turn facilitate accurate formation of synaptic connections in the dLGN.