Moral Lessons from Psychology: Contemporary Themes in Psychological Research and their relevance for Ethical Theory

The thesis investigates the implications for moral philosophy of research in psychology. In addition to an introduction and concluding remarks, the thesis consists of four chapters, each exploring various more specific challenges or inputs to moral philosophy from cognitive, social, personality, developmental, and evolutionary psychology. Chapter 1 explores and clarifies the issue of whether or not morality is innate. The chapter’s general conclusion is that evolution has equipped us with a basic suite of emotions that shape our moral judgments in important ways. Chapter 2 presents and investigates the challenge presented to deontological ethics by Joshua Greene’s so-called dual process theory. The chapter partly agrees with his conclusion that the dual process view neutralizes some common criticisms against utilitarianism founded on deontological intuitions, but also points to avenues left to explore for deontologists. Chapter 3 focuses on Katarzyna de Lazari-Radek and Peter Singer’s suggestion that utilitarianism is less vulnerable to so-called evolutionary debunking than other moral theories. The chapter is by and large critical of their attempt. In the final chapter 4, attention is directed at the issue of whether or not social psychology has shown that people lack stable character traits, and hence that the virtue ethical view is premised on false or tenuous assumptions. Though this so-called situationist challenge at one time seemed like a serious threat to virtue ethics, the chapter argues for a moderate position, pointing to the fragility of much of the empirical research invoked to substantiate this challenge while also suggesting revisions to the virtue-ethical view as such

Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis

Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Rα, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7Rα and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL−/− × IL-7Rα−/− BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7Rα−/− mice, FL−/− × IL-7Rα−/− mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7Rα are indispensable for fetal and adult B cell development

Neuronal and astrocytic differentiation from Sanfilippo C syndrome iPSCs for disease modeling and drug development

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated newneuronal and astrocyticmodels of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients' fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocyticmodels of Sanfilippo syndrome for future studies on disease mechanisms and drug development

Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem Cells

SummaryAvailable methods for differentiating human embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) into neurons are often cumbersome, slow, and variable. Alternatively, human fibroblasts can be directly converted into induced neuronal (iN) cells. However, with present techniques conversion is inefficient, synapse formation is limited, and only small amounts of neurons can be generated. Here, we show that human ESCs and iPSCs can be converted into functional iN cells with nearly 100% yield and purity in less than 2 weeks by forced expression of a single transcription factor. The resulting ES-iN or iPS-iN cells exhibit quantitatively reproducible properties independent of the cell line of origin, form mature pre- and postsynaptic specializations, and integrate into existing synaptic networks when transplanted into mouse brain. As illustrated by selected examples, our approach enables large-scale studies of human neurons for questions such as analyses of human diseases, examination of human-specific genes, and drug screening

Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia

Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development

Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs(1,2). In reprogramming, the same factors are often used to reprogram many different donor cell types3. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors(4,5), it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l)(6) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.Non peer reviewe

Adult Neural Stem Cells-Influence of Stroke, Inflammation and Aging

Neural stem cells (NSCs) in the embryo generate neurons, astrocytes and oligodendrocytes, the principal cells of the central nervous system (CNS), which contribute to the full diversity of the brain. Some NSCs persist in the adult brain and ensures neurogenesis throughout adult life in the subventricular zone (SVZ) and the subgranular zone (SGZ). NSCs in the SGZ generates neurons in the granule cell layer and NSCs in the SVZ generates neuroblasts that migrate trough the rostral migratory stream into the olfactory bulb where they develop into mature neurons. Neurogenesis in the adult brain continues into old age although with reduced capacity. Neurogenesis in SVZ increases after insults to the brain such as stroke and status epilepticus (SE). After stroke proliferation of NSCs increase and newly formed neurons migrate towards the damage where they mature into the same type of neurons that died as a result of the insult. This self-repair mechanism could potentially be of therapeutic value. However, existing neurogenesis as basis for functional recovery after stroke is most likely not sufficient. Therefore, it is extremely important to study regulation of basal and insult induced neurogenesis in order to find ways of optimizing the potential of endogenous NSCs for repair of neurodegenerative disease. In this thesis we have addressed the regulation of adult NSCs and neurogenesis in response to aging, inflammation and stroke using in vivo and in vitro models as well as gene expression analysis. In the first study we explored the influence of aging on intrinsic properties of NSCs and their progeny. We found severely decreased neurogenesis in old mice due to reduced proliferation and loss of NSCs in SVZ. However, when we cultured aged NSC in vitro they could proliferate, differentiate along all three lineages and produce functional neurons similar to their adult counterparts albeit with reduced capacity. In the second study, we investigated the role of inflammation on stroke-induced neurogenesis. More specifically we identified tumor necrosis factor receptor 1 (TNF-R1) as a negative regulator of Stroke-induced NSC proliferation in SVZ. We found increased expression of TNF-α and TNF-R1 in SVZ after stroke. Furthermore we demonstrated a direct negative effect of TNF-α through TNF-R1 on proliferation of NSCs in vitro. In the third study, we identified the adaptor protein Lnk as an insult specific negative regulator of NSC proliferation. Possibly acting by inhibiting growth factor and cytokine signaling. Deletion of Lnk increased the enhanced proliferation in SVZ after stroke but not under basal condition or after SE. We found increased expression of Lnk and growth factors in SVZ after stroke but decreased expression after SE. Furthermore elevated levels of Lnk decreased proliferation and survival while deletion of Lnk increased the proliferation of NSCs in vitro. In summary, we have obtained evidence supporting that brain-repair from endogenous NSCs can work in old age. Furthermore, we have identified two potential therapeutic targets for enhancing neurogenesis after stroke

Past, Present, and Future of Direct Cell Reprogramming

Budding off from the broader developmental biology and stem cell research fields, cellular reprogramming is now established as a prominent discipline in its own right. Direct cell reprogramming is defined as the cell fate conversion of a somatic cell toward another identity without a pluripotent intermediate state. In addition to the opportunity for mechanistic dissection of lineage commitment in human cells, the field offer the promise of diverse applications such as for disease modeling, cell replacement therapy, regenerative medicine, and immunotherapy that have recently spurred innovation and out of the box thinking to unleash the potential of cellular plasticity