An Examination of Hippocampal and Prefrontal Contributions to Spatial Learning and Memory using Immediate Early Gene Imaging

The hippocampus and medial prefrontal cortex are two brain regions which have repeatedly been linked to spatial learning and memory processing; however, the precise roles of individual sub-regions within these areas continue to be debated. The Morris water maze is a well-known behavioural task used to measure spatial memory. Despite its popularity, the type of spatial information animals encode and ultimately rely on for accurate navigation in this task remains unclear. Therefore, the primary objectives of this thesis were to conduct an in-depth investigation into the use of navigation strategies during memory encoding and retrieval in the water maze, and to characterise the specific contributions of the hippocampus and medial prefrontal cortex to these processes using Immediate Early Genes (IEG) imaging. In addition, we investigated the mechanisms underlying neuronal activation by inhibiting ionotropic glutamate receptors (NMDA and AMPA) during or after spatial learning. We found novel evidence that the salience (or noticeability) of environmental cues significantly impacted the type of learning strategy used (i.e. simple or complex), and that increased training led to more flexible responding (i.e. strategy switching). We also discovered that NMDA receptor-mediated activation in area CA1 (indexed by Zif268) was tightly linked to learning-related plasticity, and activation in CA3, prelimbic and anterior cingulate cortices was strongly associated with flexible spatial memory recall (i.e. pattern completion). Finally, we revealed that spatial memory deficits induced by NMDA receptor blockade could be partially prevented by extended environmental experience

Boswell: Citizen of the World, Man of Letters

These eleven original essays by well-known eighteenth-century scholars, five of them editors of James Boswell’s journal or letters, commemorate the bicentenary of Boswell’s death on May 19, 1795. The volume illuminates both the life and the work of one of the most important literary figures of the age and contributes significantly to the scholarship on this rich period. In the introduction, Irma S. Lustig sets the tone for the volume. She reveals that the essays examining Boswell as “Citizen of the World are deliberately paired with those that analyze his artistic skills, to emphasize that “Boswell’s sophistication as a writer is inseparable from his cosmopolitanism. The essays in Part I focus on the relationship of the Enlightenment, at home and abroad, to Boswell’s personal development. Marlies K. Danziger restores to significant life the continental philosophers and theologians Boswell consulted in his search for religious certainty. Peter Perreten examines Boswell’s enraptured study of Italian antiquity and his responses to the European landscape. Richard B. Sher and Perreten document the personal and aesthetic influence of Henry Home, Lord Kames, Scottish jurist and leading Enlightenment figure, on Boswell. Michael Fry discusses Boswell’s relationship with Henry Dundas, political manager for Scotland, and Thomas Crawford examines Boswell’s long-standing interest in the volatile political issues of the period, including the French Revolution, through his correspondence with William Johnson Temple. In evaluation Boswell’s performance as Laird of Auchinleck, John Strawhorn documents his efforts to improve the estate by use of new agricultural methods. The essays in Part II study aspects of Boswell’s artistry in Life of Johnson, the magnum opus that set a standard for biography. Carey McIntosh examines Boswell’s use of rhetoric, and William P. Yarrow offers a close scrutiny of metaphor. Isobel Grundy invokes Virginia Woolf in demonstrating Boswell’s acceptance of uncertainty as a biographer. John B. Radner reveals Boswell’s self-assertive strategies in his visit with Johnson at Ashbourne in September 1777, and, finally, Lustig examines as a “subplot” of the biography Johnson’s patient efforts to win the friendship of Margaret Montgomerie Boswell. An appendix by Hitoshi Suwabe serves scholars by providing the most exact account to date of Boswell’s meetings with Johnson. Irma S. Lustig is Research Associate in English at the University of Pennsylvania and a member of the editorial board of the Yale Editions of the Private Papers of James Boswell. She is the author of more than thirty articles and review essays on Boswell, Johnson, and their circle. Lustig\u27s collection of essays successfully supports the claims that Boswell\u27s Life of Johnson is more than a memory. As conscious artistry, it is a noble creation that evolves from the James Boswell who was a citizen of the world, a man of letters, and a product of the Enlightenment. —Albion These essays set the standard against which future examinations of Boswell\u27s prose should be measured. —British Journal for Eighteenth-Century Studieshttps://uknowledge.uky.edu/upk_english_language_and_literature_british_isles/1014/thumbnail.jp

Place cell physiology in a transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairments (Selkoe, 2001). Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. This PhD project aims to clarify the mechanisms responsible for the cognitive deficits in AD at the hippocampal network level, by examining place cell physiology in a transgenic mouse model of AD. I have recorded place cells in tg2576 mice, and found that aged (16 months) but not young (3 months) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Additionally, pilot data show that physiological changes of the hippocampus in tg2576 mice seem to start as early as 3 months, when no pathological and behavioural deficits are present. However, these changes are not obvious at the neuronal level, but only at the hippocampal network level, which represent hippocampal responses to environmental changes. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies

Thomas Erastus and the Palatinate

Utilizing Erastus’s correspondence, this book offers a synthetic treatment of Erastus’s career in the Palatinate including his role in the territory’s conversion, the Heidelberg Catechism, the church discipline controversy, as well as his refutation of Paracelsus and Johann Weyer. Readership: All those interested in intellectual history, Reformed Protestantism, Calvinism, the Second Reformation, the Heidelberg Catechism, church discipline, church and state in early modern Europe, Erastianism, Paracelsianism, Renaissance medicine, demonology, and witchcraft

Constructing One Another: Philodemus and Paul on Interdependence in Moral Formation

In this thesis, I argue that one gains fresh perspective on Paul’s understanding of believers’ interdependence in ‘constructing’ each other in 1 Corinthians by comparison with Philodemus’ vision for interdependence in reciprocal ‘therapy’. Pauline construction and Philodemean therapy are analogous instances of interdependent moral formation, both in concept and practice. Beyond previous comparisons, however, such a pairing is only fruitful if it is methodologically reoriented to both similarities and differences. This reorientation requires expanding the comparison to include additional dimensions of both figures’ perspectives, namely, their socio-economic locations (including their views of economic interdependence) and their theologies. In the first half (chs. two to four), I examine Philodemus’ socio-economic location and theology in the course of describing interdependence in reciprocal moral therapy via frank criticism among friends (drawing from his treatise On Frank Criticism). In the second half (chs. five to seven), I examine Paul’s socio-economic location and theology in the course of describing interdependence in reciprocal construction among believers in 1 Cor 8n10 and 12n14. In the final chapter (ch. 8), I bring Paul and Philodemus into comparative perspective. I argue that, alongside their similarities (esp. in the practices of reciprocal formation), the two have qualitatively different understandings of moral formation and moral interdependence among community members. For Philodemus, one grows out of one’s need to receive formation from others into moral self-sufficiency. This trajectory correlates with the assumed economic self-sufficiency of Epicurean friends, and the moral self-sufficiency of the gods, which Epicureans can reach by means of perfected human character. For Paul, however, believers constantly depend on one another for moral formation, as they also do for economic support in their poverty. Paul cannot champion Philodemus’ moral self-sufficiency, because the moral life of a believer is one of interactive relationship with God, who continually reveals himself through other believers for their formation, yet always transcends all human moral character

The role of GLI2 in human basal cell carcinoma tumourigenesis

PhDAbnormal Sonic Hedgehog (SHH) signalling leads to increased transcriptional activation of its downstream effector, GLI2, which is implicated in the pathogenesis of a variety of human tumours, including human basal cell carcinoma (BCC). However, little is known about the molecular mechanisms underlying the tumourigenic role of GLI2 in human skin keratinocytes. This study examines the effects of inducible and stable expression of constitutively active GLI2 (GLI2:N) oncogenic transcription factor, on immortalised human epidermal keratinocytes. It is shown here that GLI2:N overexpressing N/TERT keratinocytes display gene expression patterns and phenotypic characteristics reminiscent of those observed in human BCC in vivo. It is also shown for first time, that expression of GLI2:N in N/TERT keratinocytes is sufficient to induce accumulation of binucleated/tetraploid cells as evidenced by an increase in G2/M phase of the cell cycle and binucleate cell counting, and to promote polyploidy and aneuploidy, in the absence of increased cell death or apoptosis. This cell cycle deregulation is accompanied by strong activation of anti-apoptotic protein BCL-2 and simultaneous suppression of important cell-cycle regulators such as 14-3-3σ and CDK inhibitor p21WAF1/CIP1, with no change in p53 protein levels, indicating uncontrolled proliferation of cells with ploidy abnormalities and/or DNA damage. Consistently, it is shown that p21WAF1/CIP1 protein is also absent in human BCC tumours and that forced overexpression of GLI2:N renders human keratinocytes resistant to apoptosis mediated by ultraviolet B (UVB, 290-320 nm), one of the most important etiological factors in BCC formation. Karyotype analysis of GLI2:N N/TERT keratinocytes further demonstrates that overexpression of GLI2:N induces numerical (tetraploidy, polyploidy, aneuploidy) and structural instability in N/TERT keratinocytes including chromosomal translocations and double minute chromosomes. Furthermore, β-catenin activation is the most common alteration observed during aberrant WNT signalling, and is often implicated in the development of human carcinogenesis and metastasis. In this study it is shown that GLI2:N induction induces nuclear accumulation of β-catenin in keratinocyte cell culture and in the basal layer of organotypic skin rafts, similar to human BCCs. In addition, several WNT genes were found to be upregulated upon GLI2:N induction, while β-catenin transcriptional activity is increased upon stable and conditional expression of GLI2:N. Overall these data give new insights for the possible mechanisms that mediate the tumourigenic potential of GLI2

Pennsylvania Folklife Vol. 15, No. 3

• Stitching for Pretty • New Light on Mountain Mary • The Newspaper and Folklife Studies • Pennsylvania Limekilns • Mennonite Maids • The Eighteenth-Century Emigration from the Palatinate: New Documentationhttps://digitalcommons.ursinus.edu/pafolklifemag/1023/thumbnail.jp

Thomas Erastus and the Palatinate

Utilizing Erastus’s correspondence, this book offers a synthetic treatment of Erastus’s career in the Palatinate including his role in the territory’s conversion, the Heidelberg Catechism, the church discipline controversy, as well as his refutation of Paracelsus and Johann Weyer. Readership: All those interested in intellectual history, Reformed Protestantism, Calvinism, the Second Reformation, the Heidelberg Catechism, church discipline, church and state in early modern Europe, Erastianism, Paracelsianism, Renaissance medicine, demonology, and witchcraft