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Monoaminergic and Neurotrophic Gene Variation Associated with Fronto-Limbic Circuitry affect Mood and Cognitive Recovery Post-TBI

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 (Unpublished)

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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
Michelle D. Failla, PhD
University of Pittsburgh, 2014
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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Failla, Michellemdc56@pitt.eduMDC56
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairErickson, Kirk Ikiericks@pitt.eduKIERICKS
Thesis AdvisorWagner, Amywagnerak@upmc.eduAKW4
Committee MemberConley, Yvette P.yconley@pitt.eduYCONLEY
Committee MemberSibille, Etienneets7@pitt.eduETS7
Committee MemberDixon, C.
Committee Member,
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


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