Investigating Sex-Specific Responses in a Preclinical Model of Traumatic Brain Injury: Development of Chronic Depression-Like Behavior and Glutamatergic Protein Changes
| dc.contributor.author | Talty, Caiti-Erin Teresa | en |
| dc.contributor.committeechair | VandeVord, Pamela | en |
| dc.contributor.committeemember | Hodes, Georgia E. | en |
| dc.contributor.committeemember | Chiu, Pearl Huh | en |
| dc.contributor.committeemember | Swanger, Sharon Ann | en |
| dc.contributor.committeemember | Costa, Blaise M. | en |
| dc.contributor.department | Graduate School | en |
| dc.date.accessioned | 2025-01-10T09:01:56Z | en |
| dc.date.available | 2025-01-10T09:01:56Z | en |
| dc.date.issued | 2025-01-09 | en |
| dc.description.abstract | Concussion is the most common form of brain injury, comprising over 80% of traumatic brain injuries (TBIs) occurring in the United States and around the world. While many individuals are able to fully recover in the weeks following a concussion, an estimated 50% of patients go on to suffer from persistent symptoms that may range from months to years in duration. Among the most common complaints of those with persistent symptoms is sadness or depression, and significantly elevated rates of suicide have been reported in this population. Females are more likely to develop persistent symptoms and have reported higher rates of neuropsychiatric symptoms than males following injury. Altered glutamatergic neurotransmission has been implicated as a possible cause of depression following concussion due to similarities in glutamatergic changes that occur following concussion and during depression, independently of brain injury. Excitotoxicity is known to occur following TBI, resulting in neuronal death, and dysfunction in the cells that survive. Glutamatergic dysfunction occurring in regions such as the hippocampus, prefrontal cortex or amygdala, may be a driver of depressed mood or major depressive disorder (MDD) in concussed individuals as these regions, among others, have previously been linked to MDD. There are currently no approved pharmacological treatments for TBI symptoms. Therefore, gaining insight into chronic pathophysiology underlying TBI symptoms, including depression, is essential to support the development of therapeutic approaches for patients. The glutamate system represents a promising avenue of investigation in the context of chronic TBI pathophysiology. Using a clinically-relevant rodent model of concussion, this work sought to elucidate chronic glutamatergic changes occurring in the brain in association with the development of depression-like behavior following injury. Delayed-onset deficits in social and self-care behaviors were observed in association with region-specific changes in N-methyl-D-aspartate (NMDA) receptor and glutamate transporter expression in injured male animals. Females responded differently to injury, showing disinhibition and compulsive behaviors in conjunction with upregulation of glutamatergic signaling proteins. Further, this work aimed to investigate chronic sex-specific responses to TBI. Direct comparisons of behavioral changes in injured males and females demonstrated differences in both the emergence and nature of behavioral deficits. Examinations of hippocampal subregions showed deeper specificity in expressional changes in glutamatergic markers with both region- and sex-specific alterations observed at a chronic time point. Additionally, proteomic analysis was employed to evaluate widespread protein-level changes in the injured frontal cortex, and results revealed significant dysregulation in pathways involved in excitatory neurotransmission and calcium signaling. However, the dysregulated proteins within these pathways differed in a sex-dependent manner, indicating a sexual dimorphism in chronic TBI pathophysiology. Potential drug targets were also identified for investigation in future studies. The fundamental work presented in these studies provides strong evidence of dynamic, sex-specific modifications in the glutamate system in association with chronic TBI deficits in a translational model, ultimately providing a foundation for future development of therapeutic options to improve the lives of patients suffering with persistent symptoms. | en |
| dc.description.abstractgeneral | Concussion is the most common form of brain injury, comprising over 80% of traumatic brain injuries (TBIs) occurring in the United States and around the world. While many individuals are able to fully recover in the weeks following a concussion, an estimated 50% of patients go on to suffer from persistent symptoms that may range from months to years in duration. Among the most common complaints of those with persistent symptoms is sadness or depression, and significantly elevated rates of suicide have been reported in this population. Females are also more likely to develop persistent concussion symptoms and tend to experience more severe symptoms than males, but the reasons for this are not known. Changes in important signaling proteins, which allow neurons to properly communicate with one another, have been observed in the brains of concussed patients. Changes in the same proteins have been reported in depressed patients, leading to the belief that these signaling proteins may be involved in the development of depression after a brain injury. These proteins are involved in glutamate signaling, and glutamate is the main excitatory neurotransmitter in the brain. Excitatory neurotransmission is responsible for activating receptors which can lead to the firing of neurons, hence its importance in neuron communication. There are currently no approved treatments for TBI symptoms. Therefore, gaining insight into the chronic biological changes underlying TBI symptoms, including depression, is essential to support the development of therapies for patients. Using a rodent model of concussion, this work identified long-term changes in important glutamate signaling proteins in injured animals which were observed alongside depression-like behaviors. Injured male rodents were less social and were less motivated to take care of themselves, similar to humans with major depressive disorder (MDD). Female rodents showed different changes in depression-like behaviors and also developed behaviors similar to humans with obsessive compulsive disorder (OCD). This work demonstrated the development of sex-specific symptoms in injured animals, and these were accompanied by different changes in key glutamate signaling proteins, which suggests problems in neuron communication due to injury. These protein changes were detected in regions of the brain linked to MDD. The fundamental work presented in these studies provides strong evidence of dynamic, sex-specific modifications in the glutamate system in association with chronic TBI symptoms, ultimately providing a foundation for future development of therapeutic options to improve the lives of patients suffering with persistent symptoms. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:42066 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/124090 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | traumatic brain injury | en |
| dc.subject | depression | en |
| dc.subject | glutamate | en |
| dc.subject | NMDA receptor | en |
| dc.subject | chronic | en |
| dc.subject | females | en |
| dc.subject | proteomics | en |
| dc.title | Investigating Sex-Specific Responses in a Preclinical Model of Traumatic Brain Injury: Development of Chronic Depression-Like Behavior and Glutamatergic Protein Changes | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Translational Biology, Medicine and Health | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |