母體在懷孕期間受到感染已被定義為一些神經發育精神疾病如：精神分裂症及自閉症的風險因子之一。此外， 越來越多的實驗證據顯示不良的生活經驗如：早期社會隔離會與這些精神病的發生息息相關。因此，我們想要研究兩個精神疾病的風險因子──產前感染及社交隔離，是否會互相作用，從而引發成年子代的行為異常及其中腦─前額葉多巴胺系統中神經元的改變。在本篇實驗中，我們對C57BL/6 背景的懷孕母鼠在其懷孕第九天時分別施打20mg/kg的polyriboinosinic: polyribocytidilic acid (poly I:C)以模擬產前病毒感染，待其生下後代並在其後代離乳後(約出生後30天)，分為兩個組別，一組為集體飼養(3-5隻一籠)，另一組為個別隔離飼養(1隻一籠)以模擬社交隔離，飼養一個月後，進行實驗去檢測四個組別的表現型。在行為方面，我們發現產前poly I:C處理小鼠在曠野實驗(open field test)中呈現活動力下降的情形，然而是否有社交隔離對此並沒影響。另一方面，與對照組相比，產前poly I:C處理及單獨飼養小鼠的短期記憶及前脈衝抑制 (Prepulse inhibition ; PPI) 有缺失的情況，顯示產前感染及社交隔離會對子代成年時期的行為造成影響。在組織學上，我們發現經過poly I:C處理的小鼠其腹側被蓋區 (Ventral tegmental area ; VTA) 中多巴胺神經細胞密度顯著增加，表示poly I:C處理後，後代的多巴胺系統出現異常。然而，抑制性神經細胞在前額葉皮質中的密度則只有在社交隔離小鼠上有顯著減少的情狀，代表產前感染及社交隔離分別影響後代不同的大腦系統。在神經形態方面，我們發現所有實驗組別的小鼠，其中前額葉皮質中第二、三層錐體神經元的基底樹突複雜性有所改變且其樹突棘的密度有顯著下降。總括以上實驗結果，產前感染結合社交隔離的小鼠出現認知功能下降及中前額葉皮質神經元結構上的改變，因此可以作為神經發育相關的精神疾病的動物模型。

Maternal infection during pregnancy is a noticed risk factor for neurodevelopment psychiatric disorders, such as schizophrenia and autism. Accumulating evidence suggests that adverse life experiences such as social isolation have been associated with the onset of psychosis. Therefore, our study aimed to test whether prenatal infection could interact with postweaning social isolation to induce behavioral deficits and neuronal alterations in the mesocortical dopamine system. In the present study, we treated the pregnant mice of C57BL/6 background with a single injection of polyriboinosinic: polyribocytidilic acid (Poly I:C, 20 mg/kg, i.p.) at gestation day 9 to mimic prenatal infection. After weaning at postnatal day P30, male offspring were reared individually to mimic social isolation or in group (3-5). Phenotypes were characterized in various aspects after P60. In the behavioral aspect, only poly I:C-offspring exhibited hypolocomotor activity in a novel open field but not in isolated-mice. Notably, impairment of short-term memory function tested in novel-object recognition task and prepulse inhibition deficits were found in all experiment groups compared to the control group. The number of dopaminergic neurons in the ventral tegmental area (VTA) was increased in poly I:C-offspring whereas the number of parvalbumin-expressing neurons in the medial prefrontal cortex (mPFC) was decreased in isolated-offspring. Histologically, the dendritic architecture of the layer II/III pyramidal neurons in the mPFC was examined. Alterations in dendritic complexity and reduced spine density were present in all experiment groups. Together, our data demonstrated that prenatal infection combined with postweaning social isolation lead to cognitive deficits and neuronal alteration, thus, it could be a model for neurodevelopment psychiatric disorders.

中文摘要 i
Abstract iii
Contents v
List of Figures viii
List of Tables ix
Abbreviations x

Chapter 1 Introduction 1
1.1 Schizophrenia and its causes 1
1.2 Dopamine hypotheses of Schizophrenia 2
1.3 Animal model of Schizophrenia 4
1.3.1 Animal model: Prenatal infection 4
1.3.2 Animal model: Social isolation 6

Chapter 2 Materials and Methods 8
2.1 Animals 8
2.2 Behavioral tests 9
2.2.1 Open field test (OFT) 9
2.2.2 Novel object recognition test (NORT) 10
2.2.3 Social Interaction test 11
2.2.4 Prepulse inhibition test (PPI) 12
2.3 Histology 14
2.3.1 Perfusion 14
2.3.2 Immunohistochemistry (IHC) 14
2.3.3 Golgi-Cox impregnation and morphometric analyses 17
2.4 Statistical analysis 18

Chapter 3 Results 19
3.1 Behavior Tests 19
3.1.1 Poly I:C-offspring exhibited hypolocomotor activity but not in isolated mice 19
3.1.2 Poly I:C-isolated mice exhibited impaired short-term memory function in novel object recognition test 20
3.1.3 No significant difference in social affiliation and sociability between four groups 21
3.1.4 Effects of prenatal infection and social isolation on sensorimotor
gating 22
3.2 Histology 23
3.2.1 Independent effects of prenatal infection and social isolation on dopamine neurons in the VTA 23
3.2.2 Independent effects of prenatal infection and social isolation on Parvalbumin-expressing interneurons in the mPFC 24
3.2.3 No effects of prenatal infection and social isolation on mature oligodendrocytes in the mPFC 24
3.3 Morphological analysis 21
3.3.1 Effects of prenatal infection and social isolation on the dendritic architectures of layer II/III mPFC pyramidal neurons 25
3.3.2 Effects of prental infection and social isolation on spine density in neurons of the mPFC 26

Chapter 4 Discussion 27

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