Conditioned Fear Associated Phenotypes as Robust, Translational Indices of Trauma-, Stressor-, and Anxiety-Related Behaviors

Abstract

Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods.

Fear Memory

“…However, use of the terms fear learning, fear conditioning, fear-motivated learning, fear memory, and fear extinction has become so widespread that many readers interested in these subjects might well skip altogether an article whose title does not contain those words. So they will be used here as they are in most other recent accounts of the subject (95,98,115,116,182,294,296,299,378,403,421,462,463,468,475,501,524,653).…”

“…It can be associated with neutral stimuli that may become CSs, such as a noise, a tone or a light, and become a form of conditioned fear (146,223). In humans it has become standard testing for anxiety related to fear and characteristically increases in patients suffering from fear disorders (PTSD among them) or with other disorders that increase their propensity to suffer fear (95,299,462,463,502).…”

Nicotine Addiction and Psychiatric Disorders

“…Fear conditioning, a behavioral paradigm in which the subject learns an association between a neutral stimulus and an aversive unconditioned stimulus akin to the associations formed during trauma, has been widely utilized as a transitional animal model to study the traumatic experience common for all anxiety disorders (Briscione, Jovanovic, & Norrholm, 2014). Previous studies have identified two types of fear memories: (1) hippocampus dependent (contextual and trace fear conditioning) and (2) hippocampus independent (cued fear conditioning; Clark & Squire, 1998; Logue, Paylor, & Wehner, 1997; McEchron, Bouwmeester, Tseng, Weiss, & Disterhoft, 1998; Phillips & LeDoux, 1992; Solomon, Vander Schaaf, Thompson, & Weisz, 1986).…”

“…Fear extinction has been widely utilized as a translational animal model for the exposure therapies used for anxiety disorders (Briscione et al, 2014; Myers & Davis, 2006; Quirk & Mueller, 2007). In humans, several studies have demonstrated that PTSD patients show impaired fear extinction (Blechert, Michael, Vriends, Margraf, & Wilhelm, 2007; Michael, Blechert, Vriends, Margraf, & Wilhelm, 2007; Milad et al, 2009) as well as difficulty learning safety discrimination, another form of inhibitory learning where the subjects are trained to differentiate between a safe versus dangerous cue or context (Jovanovic, Kazama, Bachevalier, & Davis, 2012; Jovanovic et al, 2010, 2009; Lissek et al, 2005; for a review, see Christianson et al, 2012).…”

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…Variations include examining responses to "contextual" versus discrete CS+ [to examine phasic versus sustained fear responses (Garfinkel et al 2014;Glenn et al 2014;Grillon et al 2006 The short answer is it depends on the measure. PTSD patients exhibit increased potentiated startle responses to discrete fear cues (Briscione et al 2014;Norrholm et al 2011) and contextual fear cues (Grillon et al 2009b); however, increased fear is not consistently detected using other behavioral or physiological measures such as self-report or skin conductance response (SCR) (Glover et al 2011;Milad et al 2008). This difference may be related to specific fear circuitry that is being probed by these behavioral measures, as startle reactivity is thought to reflect "automatic" fear conditioning processes that do not rely on contingency awareness, while SCR and self-report reflect fear processes that require contingency awareness (Jovanovic et al 2006;Tabbert et al 2006).…”