Assessment of Cognitive Impairment in Subarachnoid Hemorrhage Induced Brain Injury: Neurobehavioral Outcomes in a Murine Model Público

Abstract

A large amount of money is spent on clinical trials for subarachnoid hemorrhage (SAH) treatments and many of them have been unsuccessful. Clinical trials should be pursued after improvements have been shown in clinically accurate animal models. Disability is highly prevalent in SAH survivors. This population has more individuals that fit diagnostic criteria for anxiety and depression than healthy reference populations and 25% of employed SAH survivors leave their jobs. Neurobehavioral deficit is thus a key outcome for animal models of SAH. The two most commonly studied animal models of SAH are either arterial puncture models or blood injection models. Larger animals are generally easier to perform surgical methods, however small rodents are more cost-effective than larger animals. Mice provide opportunity for future transgenic study. Blood injection models are less variable between animals since hemorrhage volume is controlled via injection. In the present study, a blood injection SAH model of mice was evaluated for neurobehavioral deficits using three techniques: Modified Garcia Neurological Score, Elevated Plus Maze, and Morris Water Maze. Degeneration of hippocampal and cortical neurons was also measured with Flouro-Jade-C staining to compare SAH animals with sham controls. Our cisterna magna injection model of SAH did not produce significant deficit in sensorimotor ability, anxiety-related behavior, or spatial learning. Fluoro-Jade-C staining also did not show enhanced neurodegeneration in SAH animals. Failure to show deficit in this model restricts the value of SAH studies in mice given that our blood injection model did not show significant functional deficit. Rat models provide a better opportunity for preclinical SAH research as they have repeatedly been shown to have deficits in our performed tests. Further investigation should be done to show that mice models of SAH that are used in justifying clinical trials do indeed present with functional neurobehavioral deficits.

Table of Contents

1. Introduction/Background. 1

1.1 Subarachnoid Hemorrhage in the Clinical Population. 1

1.2 Epidemiology. 1

1.3 Presentation. 2

1.4 Complications leading to poor outcome. 2

1.4.1 Sudden Death. 2

1.4.2 Vasospasm leading to Delayed Cerebral Ischemia. 3

1.4.3 Inflammation. 3

1.5 SAH survivors: Independently maintaining health, not day-to-day functioning. 4

1.6 SAH Clinical Trials. 8

1.7 Animal Models. 8

1.8 Neurobehavioral Testing in Rodents. 10

1.8.1 Neurological Scoring Systems. 10

1.8.2 Anxiety. 10

1.8.3 Spatial Learning and Memory. 11

1.9 Histological Studies for Neuronal Injury and Degeneration. 13

2. Specific Aims of the Study. 13

3. Hypothesis. 14

4. Methods and Materials. 14

4.1 Animals. 14

4.2 Groups. 14

4.3 Surgical Technique and Post-operative Care. 15

4.4 Assessment of neurobehavioral outcome. 16

4.4.1 Garcia Neurological Score. 16

4.4.2 Elevated Plus Maze (EPM). 18

4.4.3 Morris Water Maze. 19

4.5 Histopathological Study. 20

4.5.1 Transcardiac Perfusion and Harvesting of Tissue. 20

4.5.2 Fluoro-Jade-C staining for quantification of degenerating neurons. 21

4.6 Statistics. 22

5. Results. 22

5.1 Sensory and motor ability unaffected by single injection SAH injury. 22

5.2 Lack of anxiety-associated behavior in SAH animals. 23

5.3 Spatial and Working Memory in MWM. 24

5.4 Neurodegeneration - Fluoro-Jade-C-Staining. 27

6. Discussion. 29

6.1 Summary. 29

6.2 In the Field: SAH Rodent Research. 30

6.2.1 Neurological Score. 30

6.2.2 Anxiety. 31

6.2.3 Spatial Memory and Learning. 32

6.2.4 Neuronal Degeneration in SAH mice. 35

7. Conclusion. 37

8. References. 38

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Surgery Biology, Neuroscience Health Sciences, Medicine and Surgery
Palabra Clave	Neurodegeneration Neurosurgery Subarachnoid Hemorrhage Elevated Plus Maze Spatial Memory Stroke Morris Water Maze Anxiety Murine Model
Committee Chair / Thesis Advisor	Pradilla, Gustavo, Emory University
Committee Members	Manns, Joseph, Emory University Lennard, Paul R, Emory University

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