Adult neurogenesis is a fundamental feature of mammalian nervous systems. Curiously, neurogenesis in the dentate gyrus is typically regarded as homogenous. This thesis challenges that view, and reports the discovery and characterization of a novel region of the dentate gyrus that consistently lacks basal neurogenesis. We demonstrate that this area, referred to as the neurogenically quiescent zone, represents approximately 1.5% of the total volume of the dentate gyrus, and that its location is invariant among animals. This region contains several critical cell types and molecular factors that are known to be critical to the neurogenic niche, including stem cells. We also present data that attempt to conceptualize the existence of this region in the context of early agerelated declines in neurogenesis. Finally, we demonstrate that, under some behavioural conditions, neurogenesis can be induced in this region, suggesting that, under basal conditions, it may simply lack the presence of pro-neurogenic factors. / xvi, 125 leaves : ill. ; 29 cm. --

Fragile-X syndrome (FXS) is the most common form of inherited intellectual impairment. Caused by the transcriptional repression of the Fmr1 gene on the X chromosome, FXS results in the loss of the Fragile-X Mental Retardation Protein (FMRP). Human female patients with FXS are heterozygous for the Fmr1 mutation whereas males are hemizygous. FXS has been studied far less in females than in males due to a generally less severe clinical phenotype. Previous research has implicated the metabotropic glutamate receptor (mGluR) in synaptic plasticity alterations in the cornu ammonis area 1 (CA1) region of the juvenile male Fmr1 knock-out (KO) hippocampus. In contrast, our investigations into the young adult dentate gyrus (DG) subfield of the hippocampus have revealed N-methyl-D-aspartate receptor (NMDAR)-associated impairments in synaptic plasticity. The current study sought to extend these investigations to the young adult female Fmr1 heterozygous (Het) and Fmr1 KO mouse as well as investigate NMDAR- and mGluR-mediated long-term depression (LTD) in the DG and CA1 of the young adult male Fmr1 KO mouse. Input-output curves and paired pulse measures of short-term plasticity were also evaluated in all genotypes. Field electrophysiology revealed a significant impairment in long-term potentiation (LTP) and LTD in male Fmr1 KO and female Fmr1 Het mice that was associated with NMDAR alteration. A more robust synaptic protocol was not able to rescue LTP in the male Fmr1 KO DG. Paired-pulse low-frequency stimulation and (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced mGluR-LTD was intact in all genotypes and brain regions examined. Although further investigation will be required to expand our understanding of FXS and to fully elucidate the mechanisms behind intact synaptic plasticity in the female Fmr1 KO mouse, our results suggest that NMDARs may be poised as important contributors to hippocampal pathophysiology in FXS. / Graduate

The dentate gyrus is a region that hosts most of the hippocampal cells in mammals. Nevertheless, its role in spatial memory remains poorly understood, especially in light of the recently-studied phenomenon of adult hippocampal neurogenesis and its possible role in aging and chronic brain disease. We found that chronic over-expression of transforming growth factor beta1 (TGFbeta1), a cytokine involved in neurodegenerative disease, results in several modifications of brain structure, including volumetric changes and persistent astrogliosis. Furthermore, TGFbeta1 over-expression affects the generation of new neurons, leading to an increased number of neurons in the dentate gyrus and deficits in spatial memory acquisition and storage in aged mice. Nonetheless, reducing neurogenesis via pharmacological treatment impairs spatial memory in juvenile mice but not in adult or aged mice. This suggests that the addition of new cells to hippocampal circuitry, and not the increased plasticity of these cells, is the most relevant role of neurogenesis in spatial memory. We tested this idea by modifying proliferation in the dentate gyrus at several ages using multiple techniques and evaluating the incorporation of newborn neurons into hippocampal circuitry. We found that all granule neurons, recently generated or not, have the same probability of being incorporated. Therefore, the number of new neurons participating in memory circuits is proportional to their availability. Our conclusion is that adult-generated cells have the same functional relevance as those generated during development. Together, our data show that the dentate gyrus is important for memory processing and that adult neurogenesis may be relevant to its functionality by optimizing the number of neurons for memory processing. The equilibrium between neurogenesis and optimal dentate gyrus size is disrupted when TGFbeta1 is chronically increased, which occurs in neurodegenerative pathologies, leading to cognitive impairment in aged animals.

海馬迴不僅在學習與記憶中扮演重要的角色，在許多神經退化性疾病中亦佔有重要的地位。海馬迴的齒迴內側區是哺乳動物大腦中成體幹細胞主要來源區域之一，其所新生的海馬迴粒細胞會往上遷移至海馬迴粒細胞層並與固有神經細胞形成功能性連結。 過去的研究發現太少或過量的壓力荷爾蒙均會造成海馬迴粒細胞的死亡，而一定量濃度的皮質固醇對於維持海馬迴粒細胞的生存亦扮演非常重要的角色。在摘除兩側的腎上腺後，海馬迴粒細胞在幾週後會逐漸死亡且造成認知功能的缺損。本實驗即利用雙側腎上腺摘除術建立動物模式，企圖了解海馬迴粒細胞在凋亡的過程中所產生的生理層面的改變。 壓力荷爾蒙（包含皮質固醇，在老鼠稱為corticosterone，在人類稱為cortisol）為腎上腺皮質分泌激素，已知會參與並調控BK 離子通道的選擇性剪接。BK離子通道的孔道形成α次單元由單一基因 (Slo) 負責轉錄，含有STREX外顯子的剪接變異體之α次單元藉由加速神經細胞的再極化，增強過極化電位以及促進鈉離子通道自去活化狀態中回復可造成神經細胞重複激發，而先前的研究已發現過度的激發會對神經細胞產生興奮性毒殺作用。本實驗即探討BK 鉀離子通道選擇性剪接在海馬迴粒細胞凋亡的過程中所扮演的角色。 實驗結果發現，與對照組相比，雙側腎上腺摘除的老鼠海馬迴細胞中含有STREX外顯子的剪接變異體在mRNA含量上確實有改變，而BK 鉀離子通道蛋白質含量亦有所變化。由上述結果推測，含有STREX外顯子的剪接變異體含量可能與海馬迴粒細胞的凋亡機制有關。 / The hippocampus is a brain region central to learning and memory and is a key target of many neurological diseases that have dramatic cognitive consequences, including Alzheimer’s and other forms of dementia, stroke, epilepsy, and chronic stress. Hippocampal granule cells are one of the two cell pools that contain newborn neurons continuously generated from the subgranular zone in adult mammalian brains. The newborn neurons will migrate to the granule cell layer and integrate into preexisting neuron network. Previous studies have indicated that both an excessive and insufficient levels of stress hormones can lead to neuron death. Corticosterone, an adrenal stress hormone, is essential for the survival of granule cells. Bilateral removal of adrenal glands leads to extensive granule cell death over a period of several weeks and gradually causes cognitive deficits. To understand the mechanisms underlying the granule cell death in the hippocampal formation, adrenalectomy (ADX, removal of adrenal glands) was used to specifically eliminate granule cells in the hippocampus, and the subsequent physiological changes in the hippocampal neurons including dentate granule cells are investigated. Stress hormones (corticosterone in rats and cortisol in human) , secreted from the adrenal cortex regulate the alternative splicing of BK channels (big potassium, calcium-voltage activated potassium channels) in adrenal medulla. An inclusion of STREX (stress axis-regulated exon) exon in pore-forming α subunit encoded by Slo gene promotes repetitive firing by speeding action potential repolarization and augmenting the afterhyperpolarization, as well as facilitating sodium channels de-inactivation. In the present study, the role of BK channel alternative splicing in the ADX-induced granule cell death in the hippocampus was explored. The results indicate that BK channel alternative splicing was regulated by stress hormones in the hippocampus including dentate gyrus. The expression patterns of STREX variant in hippocampus were altered after granule cells death induced by ADX, whilst the expression of total slo gene was changes only in translational level. These observations suggest that the alternation in STREX abundance might be involved in the induction of dentate granule cell death.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Foi realizada a comparação entre os achados de espectroscopia de prótons por ressonância magnética utilizando a sequência PRESS (point resolved spectroscopy), com TE curto (35ms) no cíngulo posterior e hipocampos de 29 pacientes com doença de Alzheimer (leve e moderada) e 15 controles. As relações de metabólitos com melhor sensibilidade e especificidade na diferenciação entre os grupos foram em ordem decrescente: Naa/Cr do cíngulo, mI/Naa do cíngulo, mI/Naa dos hipocampos e mI/Cr dos hipocampos. Não houve vantagens, nesta casuística, na realização da espectroscopia de prótons nos hipocampos, um local tecnicamente mais difícil e demorado em relação ao cíngulo posterior. Observou-se correlação positiva da relação Naa/Cr e negativa da relação mI/Naa do cíngulo posterior com o MMSE / The objective of this study is to compare the findings on Magnetic Resonance Spectroscopy using PRESS (point resolved spectroscopy) technique with short TE (35ms) in the posterior cingulate and hippocampi of 29 patients with Alzheimer's disease (mild and moderate) and 15 controls. The metabolic ratios with highest sensitivity and specificity were (in a decreasing order): posterior cingulate Naa/Cr, posterior cingulate mI/Naa, hippocampi mI/Naa and hippocampi mI/Cr. In the group analised it seems there is no advantage in performing MRS in the hippocampi instead of posterior cingulate, a technically challenging location, usually leading to a longer examination time. In the posterior cingulate we observed a positive correlation with Naa/Cr ratio and a negative correlation with mI/Naa ratio and the MMSE

This report aims to explore if pattern recognition and pattern separation tasks performance degenerate with age. This as there are studies by Brickman et al. (2014) that suggest that these tasks are being performed by the hippocampus in particular, the dentate gyrus part. The tasks used in this report were replicated from a study in which it was assumed that they tested this parts. As both the hippocampus and the dentate gyrus supposedly degenerate with age, the tasks tested this degeneration by looking if the participant’s performance on the tasks changed with age. The performance on the pattern separation task did not change with age while the pattern recognition task did. This preservation of pattern separation might mean that the pattern separation tasks does not measure the dentate gyrus. It might also mean that the hippocampus might not degenerate as previously assumed or that the pattern separation task really test the hippocampus.

This dissertation investigates the mechanisms underlying pattern separation, using rodent models and behavioural tasks that assess the use of representations for similar stimuli. Pattern separation is a theoretical mechanism involving the transformation of inputs into output representations that are less correlated to each other. Because of this orthogonalizing process, similar experiences are stored as discrete non-overlapping representations. Studying pattern separation emphasizes the important but often overlooked fact that successful memory involves more than just remembering events over a period of time, but also differentiating between similar memories. Through a series of experiments this dissertation adds support to the literature that the dentate gyrus (DG) subregion of the hippocampus is important for pattern separation when encoding spatial and contextual inputs. Using the Spontaneous Location Recognition (SLR) task it is shown the brain-derived neurotrophic factor (BDNF) can improve performance by acting via N-methyl-D-aspartate (NMDA) glutamate receptors in the DG and adult-born hippocampal neurons. Manipulating the level of neurogenesis by inhibiting Wnt signalling or by administering acyl-ghrelin systemically is shown to impair and enhance performance on SLR, respectively. Using a novel exposure paradigm in combination with SLR, it is demonstrated for the first time that the relationship between pattern separation and neurogenesis may be reciprocal, such that inhibiting neurogenesis impairs pattern separation, enhancing neurogenesis improves pattern separation, and performing pattern separation enhances the production or survival of adult-born hippocampal neurons. Finally, it is shown that the $TgTau^{P301L}$ mouse model of dementia exhibits spatial and object recognition memory impairments once aged, recapitulating a dementia-like phenotype. Understanding the mechanisms that contribute to effective pattern separation may help elucidate the processes underlying the memory impairment experienced by AD patients. This dissertation concludes with a critical discussion about whether pattern separation can be studied using behavioural paradigms.

Numerous social and educational psychologists propose that intrinsic motivation generated by personal interests and spontaneous satisfactions is qualitatively different from extrinsic types of motivation generated by external compensations and also that intrinsic motivation is more beneficial to learning than extrinsic types of motivation. However, in the field of neuroscience, intrinsic motivation has been little studied while extrinsic types of motivation (e.g., incentive motivation) have been thoroughly studied. The purpose of the present studies was to expand the neural understanding of motivation to include intrinsic motivational processes. To do so, a series of three event-related functional magnetic resonance imaging (fMRI) studies were conducted. Study 1 and Study 2 compared the neural activities when participants decided to act for intrinsic reasons (i.e., self-determined volitional and agentic behavior) versus when they decided to act for extrinsic reasons (i.e., non-self-determined volitional and agentic behavior). Both studies showed that the anterior insular cortex, known to be related to a sense of agency, was more activated during self-determined behavior associated with intrinsic reasons for acting while the posterior parietal regions (e.g., posterior cingulate cortex, angular gyrus), known to be related to a sense of a loss of agency, were more activated during non-self-determined behavior associated with extrinsic reasons for acting. These findings confirm the existence of neural-based intrinsic motivational processes, differentiate intrinsic motivation from incentive motivation, and document the important neural activities which function for generating self-determined agentic action. Study 3 examined these same neural activities as participants engaged in interesting and uninteresting versions of two experimental tasks. Results confirmed the results of the earlier two studies, as the anterior insular cortex was more recruited when participants performed the interesting, but not the uninteresting, version of the tasks. Results also extended the findings from Studies 1 and 2 in an important way in that the ventral striatum, a well-known brain region for reward processing, was more activated when participants performed the interesting, but not the uninteresting, version of the experimental tasks. These findings suggest that intrinsic motivation is generated based on the feeling of intrinsic need satisfaction (from anterior insular cortex activations) and the feeling of reward (from ventral striatum activations). Overall, the present research established three new findings: (1) the neural bases of intrinsic motivation lies largely in increased anterior insular cortical activities; (2) when people made decisions about self-determined intrinsically-motivated behavior, they show enhanced insular cortical activities and suppressed posterior parietal cortical activities; and (3) when people engaged in actual self-determined intrinsically-motivated behavior, they show enhanced insular cortical and ventral striatal activities. In establishing these new findings, the paper introduces a new area of study for motivational neuroscience--namely, intrinsic motivation.

There is a rich literature demonstrating that adults who stutter (AWS) demonstrate atypical functional brain activity during speech production. These differences can be characterized by increased activity in the right inferior frontal gyrus and premotor regions and decreased activity in the left inferior frontal gyrus, premotor area, and bilaterally in the superior temporal gyrus. The process of speech production requires motor movements first be planned and then executed. However, few studies have examined activity related to speech-motor planning independently from speech-motor execution. Additionally, due to methodological limitations, few investigations have examined functional brain activity in children who stutter (CWS). We hypothesized that AWS and CWS would demonstrate atypical brain activity related to both speech-motor planning and execution. Using Near Infrared Spectroscopy (fNIRS), we measured the change in oxygenated hemoglobin concentration (HbO) during speech-motor planning (repetition of nonwords with three repeated or different syllables) and speech-motor execution (covert/overt naming). Results indicated that both AWS and CWS demonstrated cortical activity that was atypical during speech-motor planning processes in the right inferior frontal gyrus and atypical speech-motor execution processes in the left inferior frontal gyrus. Deactivations in the left inferior frontal gyrus may reflect inefficient feedforward mechanisms for speech production. Inefficient feedforward mechanisms will likely result in more variable movements, for which larger feedback correction signals will be necessary. Overactivations in the right inferior frontal gyrus may reflect this increased correction. Additionally, AWS demonstrated atypical speech-motor planning activity in the right middle frontal gyrus, potentially related to the production of prosody. These results are presented within a theoretical framework of two competing theories of stuttering.