Thursday, November 21, 2024
11/21/2024
SUMMARY: The stability of neural connections (synapses) and long-term survival of neurons are critically important to human health, as many neurological and neurodegenerative disorders, including dementia, result in the loss of vital synaptic connections in the brain. These dementia disorders currently affect 28 million people worldwide, a number that will increase precipitously as our population continues to age. The proposed research will explore how synapses are maintained when faced with exposure to extreme environmental stressors with the aim of identifying translatable molecular targets to prevent synaptic loss during the normal aging process and the diseased state. To evaluate synaptic stability in the extremes, we will use an invertebrate species, the tardigrade Hypsibius exemplaris, which has the ability to survive near-complete desiccation, and which I recently found can survive extreme hyper-gravity equivalent to 500,000 times the earth’s gravity for an hour. Mechanisms by which the animal survives desiccation are relatively well understood, in that the animal forms a ‘tun,’ an inanimate state of metabolic suspension which is accompanied by gross morphological changes and the loss of nearly 99% of their water content. In contrast, the mechanisms by which these animals survive the extreme forces exerted by hyper-gravity remain wholly unexplored. Following reanimation from desiccation or return to normal gravity, animals rapidly restore coordinated walking and head motions suggesting that their nervous system remains grossly unperturbed by these phenomenal feats of extremotolerance. A critical question is how the nervous system and synaptic function remain stable under these extraordinary environmentally induced stresses. The proposed research will unveil the underpinnings of tardigrade nervous system survival by testing the hypothesis that tardigrades fortify their nervous system through the stabilization of synapses under extreme environmental insults. We will first explore anatomical changes to synapse density and morphology during desiccation and hyper-gravity by direct visualization of synapses and neurons in the nervous system (Aim 1). We will assess the functional maintenance of synapses throughout desiccation and hyper-gravity via a memory-retention paradigm (Aim 2). Finally, we will identify novel targets by monitoring the dynamic changes in the “proteome” that are triggered by extreme hyper-gravity and desiccation, analyze the functional roles of synaptic proteins via the removal of key synaptic regulatory proteins and ultimately apply our identified target molecules to analysis of an in vitro mouse model of neurodegeneration (Aim 3).
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