Traits of fear resistance and susceptibility in an advanced intercross line

Abstract

Genetic variability in the strength and precision of fear memory is hypothesized to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalized fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic–pituitary–adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimize false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology.

Cued fear memory generalization increases over time

“…However, overgeneralization of traumatic fear is maladaptive and represents a primary target for the treatment of PTSD and anxiety-related disorders (Lissek 2012;Morey et al 2015;Kaczkurkin et al 2016;Lopresto et al 2016). Indeed, there are now several mouse and rat models (Siegmund and Wotjak 2007;McGuire et al 2013;Coyner et al 2014;Castro-Gomes et al 2016;Sillivan et al 2017) that exhibit fear overgeneralization phenotypes. The preclinical study of auditory cued fear memory generalization in particular may aid our understanding of trauma-related phenotypes, especially in populations with combat-acquired trauma, as traumatic fear memories likely contain a combination of discrete cued (foreground) and contextual (background) elements (Norrholm et al 2014).…”

Characterizing functional and structural brain alterations driven by chronic alcohol drinking: a resting-state fMRI connectivity and voxel-based morphometry analysis

“…MEMRI has allowed us to assess the effects of chronic moderate alcohol consumption on whole brain activity. So far, only a few studies have exploited MEMRI in rodents for identifying neural circuits associated with specific behaviors [44,[97][98][99][100]. Acb activation revealed by MEMRI is also in line with previous attempts to map global brain activation by alcohol using either deoxyglucose metabolic mapping [101] or c-Fos or ΔFosB immunohistochemistry [102][103][104].…”

Fine-mapping QTLs in advanced intercross lines and other outbred populations

“…AILs have also been used to study social behavior (Wiren et al 2009), ocular characteristics (Prashar et al 2009; Chen et al 2011) and gene expression (Ka et al 2013) in chickens, fear-related behavior in mice (McGuire et al 2013) and recombination in yeast (Illingworth et al 2013). However, these studies did not map QTLs and were omitted from the table.…”