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- All Subjects: Neuroscience
- Creators: School of Life Sciences
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the deterioration of upper and lower motor neurons in the brain, brain stem, and spinal cord. Multiple missense mutations have been connected to familial ALS, including those in the Matrin-3 protein. Matrin-3 is an RNA and DNA-binding protein encoded by the MATR3 gene. Normally found in the nuclear matrix, Matrin-3 plays several roles vital to RNA metabolism, including splicing, RNA degradation, mRNA transport, mRNA stability, and transcription. Mutations in MATR3 leading to familial ALS include P154S and S85C, but the mechanisms through which these mutations contribute to ALS pathology remain unknown. This makes mouse models particularly useful in elucidating pathology mechanisms, ultimately having the potential to serve as preclinical models for therapeutic drugs. Because of the importance of animal models, we worked to create ALS mouse models for the MATR3 P154S and S85C mutations. We specifically generated two CRISPR/Cas9 mediated knock-in mouse models containing the MATR3 P154S or S85C mutation expressed under the control of the endogenous promoter. Both the homozygous and heterozygous P154S mice developed no physical or motor defects or shortening of lifespan compared to the wildtype mice. They also exhibited no ALS-like pathology in either the muscle or spinal cord up to 24 months. In contrast, the homozygous S85C mice exhibited significant physical and motor differences, including smaller weight, impaired gait, and shortening of lifespan. Some ALS-like pathology was observed in the muscle, but pathology remained limited in the spinal cord of the homozygous mice up to 12 months. In conclusion, our data suggests that the MATR3 P154S mutation alone does not cause ALS in vivo, while the MATR3 S85C mutation induces significant motor deficits, with pathology in the spinal cord potentially beginning at older ages not examined in our study.
This paper provides a multidisciplinary analysis of the relationship between beauty and addiction, with a focus on the emerging field of neuroaesthetics. Neuroaesthetics investigates the neural mechanisms that underlie aesthetic experiences and how the brain cognitively processes beauty. Since there is a biological foundation of this report, I will predominantly discuss neuroanatomy, neurological studies, and the overlap in neural circuitry between beauty and addiction. In addition, I will discuss the philosophical roots of beauty, as well as the environmental elements involved. Chapter 1 begins by explaining the history of beauty and its importance. I discuss the main constituents of beauty and differentiate between key terms involved in the beauty experience. In order to understand the link between beauty and addiction, it is essential to have a knowledgeable background on what beauty is. Next, I discuss the neurobiology of addiction. The main component of this chapter involves the mesolimbic and mesocortical reward pathways. I also describe neuroanatomical terms involved in addiction. The last chapter considers the implications of neuroaesthetics in various studies, which primarily involve the use of fMRIs. I discuss the sensory evaluations of beauty and the brain regions involved in the beauty experience. From this, I found that the experience of beauty activates these main brain regions: PFC, amygdala, striatum, NAcc, cingulate, VTA, and most remarkably, field A1 of the mOFC. By combining the neurological studies with studies of aesthetics, I reached the conclusion that there is an overlap in the neural pathways during the experience of beauty and during addiction. Although it is necessary for further research to be conducted to properly declare this, I discovered that the pursuit of beauty can lead to addictive behaviors, as the reward centers of the brain are activated by aesthetic experiences.
Environmental and genetic factors influence schizophrenia risk. Individuals who have direct family members with schizophrenia have a much higher incidence. Also, acute stress or life crisis may precede the onset of the disease. This study aims to understand the effects of environment on genes related to schizophrenia risk. It investigates the impact of sleep deprivation as an acute environmental stressor on the expression of Htr2a in mice, a gene that codes for the serotonin 2A receptor (5-HT2AR). HTR2A is associated with schizophrenia risk through genetic association studies and expression is decreased in post-mortem studies of patients with the disease. Furthermore, sleep deprivation as a stressor in human trials has been shown to increase the binding capacity of 5-HT2AR. We hypothesize that sleep deprivation will increase the number of cells expressing Htr2a in the mouse anterior prefrontal cortex when compared to controls. Sleep deprived that mice express EGFP under control of the Htr2a promoter displayed anteroposterior gradients of expression across sagittal sections, with concentrations seen most densely within the prefrontal cortex as well as the anterior pretectal nucleus, thalamic nucleus, as well as the cingulate gyrus. Htr2a-EGFP expression was most densely visualized in cortical layer V and VI pyramidal neurons within the lateral prefrontal cortex of coronal sections. Furthermore, the medial prefrontal cortex contained significantly cells expressing Htr2a¬-EGFP than the lateral prefrontal cortex. Ultimately, the hypothesis was not supported and sleep deprivation did not result in more ¬Htr2a-EGFP expressing cells compared to basal levels. However, expressing cells appeared visibly brighter in sleep-deprived animals when compared to controls, indicating that the amount of intracellular Htr2a-GFP expression may be higher. This study provides strong visual representations of expression gradients following sleep deprivation as an acute stressor and paves the way for future studies regarding 5H-T2AR’s role in schizophrenia.
Neurological manifestations may be more prominent and have a larger role in ankylosing spondylitis than previously thought. Ankylosing Spondylitis is a rheumatic disease primarily identified by its autoinflammatory characteristics and is highly associated with the HLA-B27 gene. While it’s cause is not yet fully understood and it’s symptoms widely vary, neurological impairment is not uncommon. The neurological manifestations of Ankylosing Spondylitis include but are not limited to pain sensitization, altered brain phenotype, and disrupted cardiac conduction. Central and peripheral nervous system involvement may be more significant than previously thought and have the potential to cause demyelinating diseases, spinal cord, and nerve root injuries. Altered connectivity throughout various regions within the brain further exemplify the need for a better understanding of the disease and better treatment development. Higher instances of depression and dementia were also reported and coincide with not only a less active lifestyle, but altered brain activity. Studies on cardiac conduction and arrhythmias in AS patients revealed parasympathetic and sympathetic nervous system dysregulation. These studies have explored the possibility of new targets for treatment involving cardiac mechanisms. Treatments for diseases of a similar suspected pathology, new prospective targets for therapy, and a more thorough understanding of current treatments for the disease may be the key in providing more substantial relief. By further investigation in the role of the nervous system in Ankylosing Spondylitis, the disease may become more manageable for patients and greatly increase quality of life in the future.