Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

Abstract

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

“…These include polymorphisms or expression of BDNF (Krishnan et al, 2007), GABRA2 (Nelson et al, 2009), 5-HT1A receptors, dopamine or serotonin transporters (Segman et al, 2002;Kilpatrick et al, 2007;Stein et al, 2009;Wald et al, 2013), catechol-O-methyl transferase (COMT; Jabbi et al, 2007;Kolassa et al, 2010), glucocorticoid receptors and factors that modulate them such as FK506-binding protein (FKBP5;Binder et al, 2008;Derijk and de Kloet, 2008;McGowan et al, 2009;Sarapas et al, 2011), and methylation of corticotrophin-releasing factor (CRF) receptor DNA (Elliott et al, 2010). Several genetically distinct rodent lines are differentially resistant/vulnerable to the effects of stress (Razzoli et al, 2011;Savignac et al, 2011;Camp et al, 2012;Fuchsl et al, 2014). The amygdala circuits that regulate fear and anxiety are hypothesized to be an important target of some of these genetic differences (Hariri et al, 2002;Smolka et al, 2005;Jovanovic and Ressler, 2010;Mozhui et al, 2010;Alexander et al, 2012;Hermann et al, 2012;White et al, 2012;Rogers et al, 2013;Volman et al, 2013).…”

Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory

“…Administration of SSRIs is a common pharmacological approach to the treatment of mood and anxiety disorders including panic disorder. Recent studies indicate that chronic administration of the SSRI fluoxetine improves extinction retention (22)(23)(24), suggesting a potential mechanism underlying its anxiolytic and antidepressant effects (25). Here, we test whether fluoxetine alters the 5-HTT DPF, which would further implicate the 5-HTT DPF as a mediator of both altered extinction retention and the therapeutic effects of SSRIs.…”

“…To further relate the 5-HTT distal polyadenylation fraction to anxiety-related emotional processing, we treated mice with the selective serotonin reuptake inhibitor (SSRI) fluoxetine, a treatment that facilitates extinction retention (22)(23)(24), alleviates anxiety and depressive symptoms (25), and is the most commonly used pharmacological treatment for panic disorder. Chronic fluoxetine increased the 5-HTT DPF in mouse brain, suggesting that biological factors that increase the 5-HTT DPF are anxiolytic and those that decrease it are anxiogenic.…”

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

“…The dendritic morphology and spine density of neurons in DLS, basolateral amygdala (BLA), and orbitofrontal cortex using Glaser and Van der Loos' modified Golgi stain (61).…”