Failla, Michelle
(2014)
Monoaminergic and Neurotrophic Gene Variation Associated with Fronto-Limbic Circuitry affect Mood and Cognitive Recovery Post-TBI.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Following traumatic brain injury (TBI), ~80% of individuals will experience cognitive deficits, and ~50% will experience post-TBI depression (PTD). Identifying individual risk patterns for these complications is important for preventive treatment and early intervention. In uninjured populations, individuals with depression have distinct accompanying cognitive deficits. Importantly, dysregulation of fronto-limbic regions may, in part, explain the co-occurrence of both depressive and cognitive symptoms. The work presented investigates biological factors that influence survival after severe TBI, and among survivors, the presence and severity of PTD and/or cognitive deficits. The scientific framework under which this work was completed proposes targeted interactions between monoaminergic and neurotrophic gene variation that may lead to cognitive deficits and depressive symptoms. In addition to cognition, serotonergic (5-HT) and dopaminergic (DA) signaling both contribute to depressed mood and anhedonia, suggesting genetic variation in their signaling pathways may modulate PTD risk. Brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin involved in neuronal survival and synaptic plasticity, is implicated in depression and cognitive dysfunction, and BDNF interacts with 5-HT/DA signaling in mood and cognitive processes. The work presented examines monoaminergic-neurotrophic biomarkers for predicting PTD risk and cognitive deficits. Serum and cerebrospinal fluid (CSF) BDNF levels, and fronto-limbic atrophy, were examined as possible biomarkers of PTD and cognitive deficits. A battery of targeted genes were examined for their proposed roles in survival, depression, cognition, and/or modulation of fronto-limbic connectivity. The data show variation within monoaminergic genes was associated with PTD incidence (serotonin transporter, 5-HTTLPR) and cognitive deficits post-TBI (dopamine D2 receptor, DRD2 and COMT). When investigating BDNF associations with PTD, we discovered that variation in BDNF interacts with
MONOAMINERGIC AND NEUROTROPHIC GENE VARIATION ASSOCIATED WITH FRONTO-LIMBIC CIRCUITRY AFFECT MOOD AND COGNITIVE RECOVERY POST-TBI
Michelle D. Failla, PhD
University of Pittsburgh, 2014
v
age to influence TBI survival, and acute BDNF levels were consistent biomarkers for TBI survival. Among TBI survivors, acute BDNF levels were associated with chronic cognitive performance and depressive symptoms severity, suggesting early neurotrophic support may facilitate chronic recovery. Investigating fronto-limbic regional brain volumes identified significant relationships to PTD and suggested non-uniform fronto-limbic atrophy patterns that may explain PTD susceptibility. Overall, this work supports that monoaminergic-neurotrophin genetic variability affects individual risk for PTD and related cognitive deficits, possibly through relationships with fronto-limbic circuitry.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
9 December 2014 |
| Date Type: |
Publication |
| Defense Date: |
10 November 2014 |
| Approval Date: |
9 December 2014 |
| Submission Date: |
8 December 2014 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
279 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
traumatic brain injury, genetics, depression, serotonin, dopamine, BDNF |
| Date Deposited: |
09 Dec 2014 13:55 |
| Last Modified: |
19 Dec 2016 14:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/23815 |
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