Individual Differences in Vulnerability to Maladaptive Fear in Rats and Humans: Behavioral and Neural Correlates.
dc.contributor.author | Prater, Katherine E. | |
dc.date.accessioned | 2016-09-13T13:51:58Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2016-09-13T13:51:58Z | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/133306 | |
dc.description.abstract | Certain individuals are vulnerable to developing post-traumatic stress disorder (PTSD), but mechanisms underlying this selective vulnerability are unknown. We hypothesize that genetic predisposition, together with environmental modulation, influences this selective vulnerability. One potentially useful model are rat lines selectively bred for high (bHR) or low (bLR) locomotor response to novelty, a model of differential vulnerability to affective pathology. Using a standard fear conditioning and extinction paradigm, we determined that bLRs demonstrated decreased extinction learning and retention, while bHRs displayed faster extinction and greater retention. bLRs, like PTSD patients, may be genetically vulnerable to maladaptive fear behaviors while bHRs remain resilient. We next asked whether this genetic predisposition was modifiable by administering FGF2, a treatment previously shown to facilitate extinction learning. Perinatal FGF2 administration facilitated extinction retention in bHRs, but not bLRs, demonstrating that individual variation is an important determinant of FGF2’s ability to modulate fear behavior. Additionally, we examined how social environment might alter vulnerability in the genetic model. The company of in-group phenotype animals facilitated extinction for bHR and bLR rats. Outbred rats characterized as HRs and LRs responded similarly. To understand how this gene-by-environment interaction might influence neural circuitry, we examined brain region coactivation using cFos after extinction learning. Both bHR and bLR animals displayed different patterns of coactivation from outbred rats. We observed potential compensatory coactivations in areas of the prefrontal cortex in bLRs when they displayed extinction behavior. To extend our findings to humans, we performed a similar analysis using functional magnetic resonance imaging during extinction learning. We observed increased coactivation between the anterior cingulate cortex and the amygdala in individuals with high trait anxiety. Together, these coactivation studies implicate prefrontal cortex – amygdala circuit dysfunction in individuals with high anxiety across species. We conclude that individual differences in emotional responsiveness significantly impact fear extinction learning. Moreover, these differences interact with the efficacy of pharmacological agents and environmental factors to reduce vulnerability to maladaptive fear responses. Importantly, these differences in fear extinction are reflected at the neural level, and the altered circuit function in vulnerable individuals is present in both our rodent model and human subjects. | |
dc.language.iso | en_US | |
dc.subject | Neuroscience | |
dc.subject | Fear Extinction | |
dc.subject | Individual Differences | |
dc.subject | Amygdala | |
dc.subject | Medial prefrontal cortex | |
dc.title | Individual Differences in Vulnerability to Maladaptive Fear in Rats and Humans: Behavioral and Neural Correlates. | |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | |
dc.description.thesisdegreediscipline | Neuroscience | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Akil, Huda | |
dc.contributor.committeemember | Maren, Stephen A | |
dc.contributor.committeemember | Phan, Kinh Luan Dinh | |
dc.contributor.committeemember | Flagel, Shelly Beth | |
dc.contributor.committeemember | Murphy, Geoffrey G | |
dc.subject.hlbsecondlevel | Science (General) | |
dc.subject.hlbsecondlevel | Psychology | |
dc.subject.hlbtoplevel | Science | |
dc.subject.hlbtoplevel | Social Sciences | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/133306/1/keprater_1.pdf | |
dc.identifier.orcid | 0000-0001-8615-207X | |
dc.identifier.name-orcid | Prater, Katherine; 0000-0001-8615-207X | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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