Vulnerabilities, Risks and Interplay of Posttraumatic Depression and Epilepsy: Role of Monoaminergic Circuits
Abstract
Traumatic brain injury (TBI) is an increasing concern in both military personnel and in civilians. Epilepsy and depression represent common consequences of TBI, each being a profoundly debilitating disease. Significant number of TBI survivors develop epilepsy and depression concurrently. It has been shown that post-traumatic epilepsy (PTE) and post-traumatic depression (PTD) have bidirectional, mutually exacerbating effects. On the one hand, PTD increases the severity of epilepsy, worsens its prognosis, and is commonly associated with the failure of antiseizure drugs to effectively treat epilepsy. On the other hand, PTE may promote PTD. The result of the PTE-PTD comorbidity is further worsening of the quality of life, in comparison with each disorder developing in isolation. While the connection between PTE and PTD has been well established in people, mechanisms that underlie their mutually detrimental effects remain by and large unknown. This basic research proposal pursues to examine and to understand mechanisms though which PTE and PTD interact and exacerbate each other. The studies under the proposal are performed in the laboratory rat, which is a proven species for modeling both epilepsy and depression. In terms of mechanisms, the project focuses on several brain signaling systems, which play key roles in regulating mood. These systems include three molecules called monoamines, namely, serotonin, norepinephrine, and dopamine, each transmitting neurochemical signals along specific pathways in the brain. Impaired function in each of these monoamines is associated with symptoms of depression (e.g., despair/hopelessness, inability to experience pleasure, and inability to focus). At the same time, these molecules both influence, and are influenced by, brain circuits that are involved in epilepsy. We suggest that mutual detrimental effects of PTE and PTD occur due to the continuous interplay between depression-relevant and epilepsy-relevant brain systems, and the formation of multiple vicious circuits that involve disrupted monoamine signaling. The project consists of several steps. First, normal rats will be examined in neurochemical assays to determine baseline function of brain monoamine systems. Afterwards, TBI will be induced according to a protocol that is well-characterized and produces PTE. During chronic post-TBI period, animals’ behavior will be examined in specialized depression tests, and the animals will be categorized as depressed and not-depressed. Also, during the post-TBI period, the animals will be observed for the development of epileptic seizures and will be categorized as those with and without PTE. During chronic post-TBI period, lasting for 12 months, the severity of PTD and PTE will be analyzed in different categories of rats: those with PTD only, with PTE only, and with PTE-PTD comorbidity. Neurochemical assays to characterize the state of monoamine signaling will be repeatedly performed in all categories of the animals and will be correlated with the severity of PTD and PTE. We expect that in the animals with concurrent PTE and PTD, there will be progressive deterioration of monoamine signaling, which would be significantly worse that the one observed in PTD-only and in PTE-only rats. The projects will have several important implications. It should help understanding mechanisms that may explain the PTE-PTD comorbidity. In turn, understanding these mechanisms should help in developing effective therapies for PTD, which should disrupt the vicious circles, and improve the prognosis of epilepsy. Finally, the findings may help in developing tools for early prediction of depression after TBI, which would allow doctors to take preventive measures even before depression develops. Overall, this should serve to improve the quality of life of those TBI survivors who suffer from concurrent epilepsy and depression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810612
Entities
People
- Aristea S Galanopoulou
Organizations
- Albert Einstein College of Medicine
- United States Army