1,676 research outputs found
Sustainable Capitalism: Full-Employment Flexicurity Growth with Real Wage Rigidities
No full textIn this paper we present a model of flexicurity capitalism that exhibits a second labor market with the government as an employer of first resort, where all workers not employed by firms in the private sector find meaningful employment. We show that the model exhibits a unique interior steady state which is asymptotically stable under real wage adjustment dynamics of the type considered in Blanchard and Katz (1999), and under a type of Okun's Law that links the level of utilization of firms to their hiring and firing decision. The introduction of a company pension fund can be shown to contribute to the viability of the analyzed economic system. However, when credit is incorporated in the model, in place of savings-driven supply side fluctuations in economic activity, investment-driven demand side business cycle fluctuations (of a probably much more volatile type) can take place.Flexicurity, employer of ¯rst resort, Solovian growth, company pension funds, sustainability
Therapeutic effects of deep brain stimulation on antidepressant-link activities in animal models of depression
No full textMore than 264 million people are being treated for depression, but up to 30% of patients suffer from treatment-resistant depression. Deep Brain Stimulation (DBS) is being investigated as a potential treatment option. It involves the implantation of electrodes to electrically stimulate a brain region. While previous studies have shown its effectiveness in reducing depressive-like behaviors, much is still unknown about the mechanism of DBS.
In my thesis, I reviewed the chronic mild stress (CMS) animal model of depression, aiming to address issues with reproducibility and improve reporting protocols. I then discussed clinical and preclinical studies stimulating the subcallosal cingulate, and the rat homolog, medial prefrontal cortex (mPFC), reviewing the mechanisms identified. The role of orexin in depressive-like behaviors is then examined, in both clinical and preclinical studies. I then showed that the environmental effects of light had a significant effect on young rats in certain behavioral tests. I then showed that 1h DBS was able to induce long-term antidepressant effects, and that it was able to increase neurogenesis and neuroplasticity in stressed animals. I then reported that mPFC stimulation at 100 Hz, 200 μA resulted in the strongest antidepressive effect in animals, and showed that stressed animals had reduced orexin levels, and that stimulating the infralimbic or prelimbic (PrL) subregions of the mPFC significantly reduced depressive-like behavior in stressed animals. PrL DBS was able to reverse a knockdown of orexin expression, inducing anti-depressive behavior and rescuing social behavior in rats. Finally, I showed the effects of PrL DBS on orexin was dependent on the dopaminergic circuit in the ventral tegmental area. Taken together, my thesis reports novel mechanisms for DBS and highlights its role in promoting social interaction.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Neuroplasticity and DNA methylation-related mechanism of L-methionine in cognition
No full textRecent studies have shed light on the importance of the dynamic property of DNA methylation in memory formation and maintenance. Methionine is an essential component in one-carbon metabolism, which plays a pivotal role in gene-environment interaction. The disruption of the one-carbon metabolism is implicated in the pathophysiology of various neurodegenerative disorders, for instance age-related dementia and Alzheimer’s disease (AD), in which memory loss is manifested as the core symptom.
In this thesis, I systematically reviewed the neuroepigenetic alterations involved in the pathophysiology of AD seen in literature as an attempt to delineate potential molecular deficits contributing to cognitive impairment. The influence of altered DNA methylation in AD on components involved in neurochemical pathways on memory formation was then examined. I then showed that protracted L-methionine (MET) treatment rescued memory deficits and attenuated amyloid burden through restoring MeCP2-CREB-BDNF and CaN-Akt-GSK3β cascades in 5xFAD transgenic mice. Following the findings that MET effectively normalized certain DNA methylation machinery in AD animal model, I investigated the effect of neuromodulation techniques on certain DNA methylation mechanisms that depend on neuronal activity, and made the case for the said mechanisms as possible memory modulation targets. I then extended the effects of MET on AD identified in the previous chapter to aged animals as a combined treatment paradigm with prelimbic cortical deep brain stimulation (PrL DBS). I showed that while MET alone had no behavioral effect on aged animals, it potentiated the memory-enhancing effect of PrL DBS. MET was able to rescue the global DNA hypomethylation observed in aged animals, and induce expression of plasticity-related genes and proteins in a synergistic manner with PrL DBS. I then showed that inhibition of DNMT in the hippocampus specifically abolished the memory-enhancing effect of PrL DBS, established the integral role of DNMT in mediating the effect of PrL DBS on cognition. Lastly, I proposed the epigenetic regulations of Bdnf gene as the key to memory extinction and BDNF modulation as a potential target for alleviating depression and fear-related anxiety disorders. Overall, my thesis presents evidence demonstrating the important role of DNA methylation in memory disorders and MET as a viable therapeutic in AD and dementia.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Apoptotic factors and pathways across tissues and species in health and Alzheimer's disease
No full textAlzheimer’s disease (AD) is a hard neurodegeneration disease without cure.
One of the provisional mechanisms by which the damage occurs is apoptosis gone aberrant. Both cell-intrinsic and cell-extrinsic factors affect its flow, biochemical as well as physical. A gene that has been attracting intensified attention in relation to both apoptosis and AD, is HNRNP A1, and its link to both was brought to focus.
This work applied the unified set of bioinformatics tools from several angles to study intrinsic apoptosis factors: differential gene expression analysis, SNP and gene transcript analysis, splicing analysis, RNA binding analysis with gene interaction and co-expression with HNRNP A1 gene, and gene ontology analysis. This set was used on various levels: whole-genome, individual cell type, and intra-cell.
Whole-genome sequencing data of murine HNRNP A1 +/- models with AD was clustered with WGCNA, analyzed for differentially expressed genes and splicing events. Following the results of this first stage, the next step of analysis took research to the microglia domain of human specimen from ROSMAP database. 7000 AD risk genes were put through the AD-trained gene embedding. The 16 outcome genes were then analyzed for gene ontology, binding to HNRNP A1, and capability to affect splicing, and also put on a velocity graph as nodes for biological process translation. Finally, meta-analysis of 1654 ROSMAP nervous tissue datasets was investigated for metabolic communication, AD risk genes, and DNA repair hotspots overlapping with BIN1 gene. Additionally, to study what can influence apoptosis extrinsically, caspase, the crucial trigger of apoptosis, was activated optogenetically in vivo, after which cells surviving high caspase activation were investigated to extract other factors they sustained. The results suggested potential role of mechanical force as factor in cell-death decision making.
As a result, gene ontology and marker analysis linked cell types to genetic factors, typical for mechanotransduction processes, and cell communication analysis yielded stages that identify mechanotransduction aberrations. A link between these genetic factors interacting or binding with HNRNP A1 and association with AD was proposed.
HNRNP A1 effect on specific isoforms CSF1 ENSMUST00000156820.1 (pVal = 0.0266, x̄(log2Fold) = 1.8654, σ = 0.9244); MAPK3 ENSMUSE00000477246 (pVal = 0.0379, x̄(log2Fold) = 4.5982, σ = 1.9235); NOS1 ENSMUSE00000689840 (pVal = 0.0166, x̄(log2Fold) = 1.7665, σ = 1.3768); RTN4 ENSMUSE00000279552 (pVal = 0.036, x̄(log2Fold) = 5.0128, σ = 0.4743), ENSMUSE00001278129 (pVal = 0.0128, x̄(log2Fold) = 3.6109, σ = 0.3431), ENSMUSE00001313485 (pVal = 0.0293, x̄(log2Fold) = 1.7891, σ = 0.0979), ENSMUSE00001280062 (pVal = 0.0123, x̄(log2Fold) = 6.5235, σ = 0.8453); SLC39A2 ENSMUSE00000854217 (pVal = 0.0025, x̄(log2Fold) = 3.6789, σ = 1.5867). by AD was highlighted. Role of factors aside from caspase in apoptosis was implicated. RABGAP1L SNP rs114162361 accumulated evidence to be implicated in AD manifestations in microglia through binding to HNRNP A1 (Z = 1.672, with pVal = 4.73e-02). The BIN1 neuronal isoform rs78710909C is significantly downregulated in the AD in microglia-communicating excitatory neurons (beta = –0 .7), highly susceptible to neurodegeneration.
This work opens perspective for novel avenues of research in AD-associated role of HNRNP A1 in apoptosis.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Prelimbic cortical stimulation ameliorates inflammation-induced social behavioural deficits and depressive-like behaviours
No full textDeep brain stimulation (DBS) is a promising neuromodulation therapy for treatment-resistant depression. Previous studies have reported the comorbidity of neuroinflammation and depression, but the underlying mechanisms of the stimulation-induced antidepressive effects on neuroinflammatory elements remain largely unknown. This study aimed to investigate the anti-neuroinflammatory effects of DBS of the prelimbic cortex (PrL-DBS) in rat models of depression. Rats received either electric stimulation or sham stimulation of the prelimbic cortex and then underwent 3 weeks of a chronic unpredictable stress (CUS) paradigm. Rats were subjected to 1 hour of high-frequency stimulation (100 Hz) at 200 µA amplitude prior to testing for social interaction and depressive-like behaviours. Their brains were processed to further elucidate the anti-neuroinflammatory-related mechanisms of DBS-induced antidepressant activity. A further investigation in another animal depression model using a combined CUS and lipopolysaccharide (LPS) treatment paradigm was conducted to examine the anti-neuroinflammatory-dependent and/or -independent mechanisms of DBS-induced antidepressant activity. In both CUS- and CUS plus LPS-induced depression models, we observed increased social interaction and decreased forced swim immobility time in animals with DBS of the prelimbic cortex compared to sham stimulation. Interestingly, the gene expression study found significant neuroinflammatory-related changes after DBS. These results were further supported by the morphological analysis of microglial expression within the prefrontal cortical areas. The study findings demonstrated that PrL-DBS in rats enhanced social interaction and antidepressive-like behaviours. The results also showed that the DBS-induced changes in the neuroinflammatory environment were mediated by both neuroinflammatory-dependent and -independent mechanisms.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
The effects of prelimbic cortex deep brain stimulation on memory and its implications
No full textDeep Brain Stimulation (DBS) is a minimally invasive technique, in which an electrode is implanted in a desired region of the brain. The principle of DBS is to modulate firing of neurons through electrical stimulation supplied via electrodes. Given then ability of DBS to modulate firing of neurons, a key component memory, it is unsurprising that DBS has been investigated as a potential treatment for various neurological and psychiatric diseases, including diseases involving memory such as anxiety disorders and dementia. Despite this, the mechanisms behind how DBS affects memories are still unclear, which has in turn hindered the translational progress. Among the issues that have resulted from the lack of understanding of DBS, an interesting paradox emerges in which the aims of treating dementias and anxiety or addiction seems to be opposite of each other; the aim of treating dementias would be to enhance memory, while treating anxiety or addiction would be to dampen or obliterate maladaptive memories. This somewhat contradictory idea has confused researchers, with some studies showing improvement of memories, while others having shown disruption of memories. Studying the effect of DBS on both models of anxiety and dementia might then hold the key to understanding the effects of DBS on memory and eventually translating DBS to the clinic. In this thesis, I systematically study the effects of DBS on memory in animal models of anxiety and dementia to unravel some of the complexities surrounding the paradoxes seen in the literature, attempting to address these questions holistically by using a multi-disciplinary approach. I first showed that DBS of the prelimbic cortex (PrL) is able to disrupt consolidation of fear memories through dopaminergic modulation. I then showed that chronic PrL DBS is also able to enhance memory function in aged animals, using in-depth microarray analysis to tease out mechanisms. I then tried to make sense of this paradoxical effects using an artificial neural network and modelling in order to overcome current limitations, hypothesizing how PrL DBS can both enhance and disrupt memories. Lastly, I investigated the ethical concerns that emerge from the results and technology that could subsequently eventuate. Overall, I present a comprehensive look into the use of DBS in the modulation of memory.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Elucidation of neuroprotective role of Hericium erinaceus in animal models of depression and cerebellar ataxia
No full textDepression is a severe neuropsychiatric disorder that affects more than 300 million people. It is one of the significant contributors to the global burden of diseases. Although there are many conventional antidepressants, their efficacies are barely adequate, and many have side effects. Therefore, the search for novel antidepressants that potentially has higher efficacy and less side effect is still needed. Hericium erinaceus is a medicinal mushroom that has reported to possess therapeutic potential for depression. This study investigated the antidepressant-like effects of H. erinaceus in restraint-stress induced model of depression. The results showed that 4-weeks of H. erinaceus treatment ameliorates depressive-like behaviours in mice subjected to 14-days of restraint stressed. Temozolomide, a neurogenesis blocker was used to evaluate if the behavioural responses are mediated through neurogenesis-dependent mechanisms. No significant differences were found between all the temozolomide experimental groups, implying that the administration of neurogenesis blocker has completely abolished the antidepressant-like effects of H. erinaceus. This result supported the hypothesis that the underlying mechanism of antidepressant effects by H. erinaceus is through neurogenesis-dependent mechanism. Furthermore, several neurogenesis-related gene and protein expressions including doublecortin, nestin, synaptophysin, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated cAMP response element-binding protein (pCREB) were elevated after 4-weeks of H. erinaceus treatment. These results supported the hypothesis that H. erinaceus potentially rescue the behavioural despair through BDNF-TrkB-CREB signalling mechanism, eventually increases the hippocampal neurogenesis and lead to antidepressant-like effects.
To further investigate the neuroprotective effects of H. erinaceus in neurodegenerative disease, 3-acetylpyridine (3AP)-induced animal model of cerebellar ataxia was used to investigate if H. erinaceus could rescue the motor coordination deficit by protecting the Purkinje cells in the cerebellum of ataxic rats. Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although several studies have demonstrated the neuroprotective effects of H. erinaceus (H. E.), its mechanisms in cerebellar ataxia remain largely unknown. Animals administered 3-AP injection exhibited remarkable impairments in motor coordination and balance. There were no significant effects of 25 mg/kg H.E. on the 3-AP treatment group compared to the 3-AP saline group. Interestingly, there was also no significant difference in the 3-AP treatment group compared to the non-3-AP control, indicating a potential rescue of motor deficits. The results revealed that 25 mg/kg H.E. normalised the neuroplasticity-related gene expression to the level of non-3-AP control. These findings were further supported by increased protein expressions of pERK1/2-pCREB-PSD95 as well as neuroprotective effects on cerebellar Purkinje cells in the 3-AP treatment group compared to the 3-AP saline group. In conclusion, the findings suggest that H. erinaceus potentially rescued behavioural motor deficits through the neuroprotective mechanisms of ERK-CREB-PSD95 in an animal model of 3-AP-induced cerebellar ataxia.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
Smad3 inhibition enhances neurogenesis and antidepressant-like behaviors in mouse models
No full textSmad3 is an important effector of TGF-β function and is implicated in a variety of biological processes involving cell growth. Disruption of Smad3 has been shown to affect neurogenesis, and however, little is known about the mechanism and effect of Smad3 disruption in depressive disorder. The behavior of Smad3 deficient animals were characterized and compared to animal model of depression. Specific Smad3 inhibition in the hippocampus was assessed in a model of rodent depression. Molecular analysis on brain tissues examined the proliferation of BrdU as a marker of neurogenesis and signaling molecules relevant to the TGF-β pathway were analysed. The data showed that Smad3-deficient mice exhibited remarkable antidepressant-like behaviors and pharmacological inhibition of Smad3 had resulted in an increase of BrdU-labelled cells. Interestingly, when localized inhibition of Smad3 was performed in the rostral DG and amygdala, it was found that significant antidepressant-like responses induced by Smad3 inhibition in the DG, but not the amygdala. The results indicated that the antidepressant mechanism of Smad3 inhibition was specifically mediated by the canonical pathway, instead of the non-canonical TGF-β-TAK1-NF-κB signalling mechanism. It is further demonstrated that inhibition of neurogenesis in the hippocampus abolishes the effect of Smad3 inhibition, indicating neurogenesis-dependent mechanism of antidepressant by Smad3 function. In conclusion, inhibition of Smad3 confers resilience against stressors and it is a promising target for further investigation as a potential treatment for depression.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
Therapeutic effects of transcorneal electrical stimulation in animal models of depression and cognitive impairment
No full textDepression and dementia are among the leading causes of global disability, and yet current treatments are often limited by inadequate efficacies. This emphasizes the need to search for novel antidepressants and therapies for cognitive impairment. Transcorneal electrical stimulation (TES) is a non-invasive neuromodulation technique that has shown promising neuroprotective effects in various eye disorders. It has been reported to activate brain regions that are implicated in mood alteration and cognitive decline, which suggests the potential of TES in modulating emotion and cognitive function. To date, the non-visual effects of TES, especially its psychiatric and memory-enhancing effects, remain largely unknown. This study investigated the therapeutic effects of TES on depressive-like behaviors and memory deficits in rodent models of depression and cognitive decline, respectively.
In this thesis, I reviewed findings on the neuroprotective mechanisms underlying the effects of TES in an attempt to develop the hypothesis that TES possesses
antidepressant-like properties. I then showed that long-term TES treatment induced antidepressant-like behaviors in the S334ter-line-3 rat model of retinal degeneration and a rat model of depression induced by chronic unpredictable stress. I found that the antidepressant-like effects of TES partially depended on neurogenesis and involved a normalization of plasma corticosterone level, as well as regulation of gene and protein expression related to neurogenesis, synaptic plasticity, and apoptosis in the hippocampus and amygdala. I further validated the antidepressant- like effects of TES in a chronic restraint stress model (CRS) of depression. I demonstrated that TES ameliorated depressive-like behaviors in the CRS model with efficacy similar to escitalopram treatment. Furthermore, I showed that TES reduced HPA axis hyperactivity, restored glucocorticoid receptor expression, enhanced hippocampal neurogenesis, regulated the oxytocin-GPCR-CREB signaling pathway, and further demonstrated the neurogenesis-dependent effects of TES in hedonic-like behavior and HPA axis response. To better understand the role of hippocampal neurogenesis in the antidepressant effects of neuromodulation treatments, I systematically reviewed studies on the neurogenic and antidepressant outcomes of neuromodulation in depression models. I showed that antidepressant- like effects of neuromodulation were generally accompanied by an increased hippocampal cell proliferation/neurogenesis. Yet, there was insufficient evidence to conclude whether the neuromodulation-induced neurogenesis and antidepressant-like responses were causally related. Finally, I showed that TES improved memory impairment in aged mice and the 5XFAD model of Alzheimer’s disease. I also reported the effects of TES in reducing the hippocampal amyloid burden and restoring postsynaptic protein expression in male 5xFAD mice.
Overall, this thesis presents preclinical findings that support TES as a potential therapeutic tool for depression and cognitive impairment.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
A Theory of the Basal Ganglia and Their Disorders, R. Miller, Publishers CRC Press, Taylor & Francis Group (2008), Price: $164.95, ISBN: 1-4200-5897-5
No full textThis book provides a literature-based theoretical model of the basal ganglia (BG) and their involvement in neuropsychiatric diseases. The author, Robert Miller, has published many articles and also monographs on the brain's functions. He is currently a freelance researcher and has been awarded the New Zealand Order of Merit for his contribution to schizophrenia research. The text of this book can be divided in two major parts. In the first part, the authors focus on the BG physiology and explain that the BG do not only control movement, but also non-movement behaviour such as executive functions and behavioural selection strategies. The mechanisms by which the BG is involved in these functions are explained on the basis of the major inhibitory and excitatory connections between the basal ganglia stuctures, the striatum, pallidal complex (globus pallidus internus and externus), the subthalamic nucleus, and the nigral complex (pars compacta and reticulata), and related synaptic processes, but also input from outside the BG is discussed. The classical idea of the indirect pathway involving the striatum, the external part of the globus pallidus, the subthalamic nucleus and then the basal ganglia output (globus pallidus internus and the substantia nigra pars reticulata) and the direct pathway consisting of the same structures except for the globus pallidus externus and the subthalamic nucleus is highlighted and discussed ...link_to_subscribed_fulltex
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