How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD

Abstract

Exposure to traumatic events that produce extreme fear and horror is all too common in both military and civilian populations, but not all individuals develop posttraumatic stress disorder (PTSD) as a result of the exposure. What mediates risk and resilience in the development of PTSD and other stress-related psychopathology is of paramount importance to our further understanding of trauma-related psychopathology as well as the development of new treatment approaches. Biological factors, such as genotype and neurobiology, interact with environmental factors, such as childhood background and trauma load, to affect vulnerability and resilience in the aftermath of trauma exposure. One of the core symptoms of PTSD is the inability to control fear, which has led some investigators and clinicians to conceptualize PTSD as a disorder of fear or, more importantly, its inhibition. This review focuses on translational methods that have been used to examine fear conditioning and inhibition of fear in PTSD and summarizes genetic and neurobiological factors related to fear inhibition. The authors also discuss different pharmacological approaches that enhance fear inhibition and may improve treatment outcomes for patients with PTSD.

FIGURE 1

Schematic Diagram of Genetic, Neurobiological, and Environmental Interactions That Contribute to Vulnerability or Resilience in Relation to PTSD

FIGURE 2. Conditional Discrimination Paradigm to Measure Inhibition of Learned Fear^a

^aWhile participating in physiological or neural imaging experiments, the subject observes a computer screen with different colored shapes. In the example in panel A, the danger signal (AX+) is represented by the red square and black star. In panel B, the safety signal (BX−) is represented by the blue square and black star. In panel C, the safety transfer test (combination of A and B, where B reduces fear to A) has both A (red square) and B (blue square) presented simultaneously. The aversive unconditioned stimulus (US) is the air blast that occurs only at the end of the AX+ danger signal. In all three conditions, fear-potentiated startle to the conditioned stimulus (CS) is elicited by a 108-dB startle signal, eliciting an eye blink reflex, which is measured with electromyography.

FIGURE 3. Inhibitory Control of Amygdala Regulation of Fear

^aPanel A is a schematic diagram illustrating the interaction of the basolateral nucleus (BLA) and central nucleus (CeA) of the amygdala with modulatory regions such as the medial prefrontal cortex (mPFC). The basolateral nucleus is thought to compare conditioned stimulus (CS) inputs and unconditioned stimulus (US) inputs regulating central nucleus activation of the hardwired fear and stress circuitry, leading to inhibition or activation of the fear response. Panel B illustrates recent research that has begun to determine the role of inhibitory neural circuitry in modulating the fear response at the cellular level (49, 50, 53, 54). Sensory inputs as well as associative inputs from the hippocampus and cortex project directly and indirectly to the central nucleus. “On” and “off” inhibitory circuits within the central nucleus are thought to differentially modulate fear output and extinction of fear. Additionally, direct projections from the infralimbic region of the medial prefrontal cortex activate inhibitory neurons in the intercalated region between the basolateral and central nuclei, serving to inhibit, in a top-down manner, the fear output of the central nucleus.

FIGURE 4. The Developmental Progression of PTSD

^aThe strength and regulation of fearful memories is affected by numerous factors both before and after the traumatic or fearful event occurs. Genetic heritability comprises up to ~40% of the risk for both depression and PTSD, and early childhood abuse is a strong risk factor for all mood and anxiety disorders. Further understanding of the roles of genes and environment may allow enhanced prediction of risk and enhancement of resilience in vulnerable populations. Memories are not permanent at the time of the trauma, and psychological and pharmacological approaches to prevent the initial encoding of the trauma are under study. Memories then undergo a period of consolidation in which they shift from a labile state to a more permanent state. Impairing the consolidation (or even reconsolidation) would be an alternative way to prevent the sequelae of long-term trauma memories. The expression of traumatic memories, which can be the source of symptoms in fear-related disorders, is diminished by the process of extinction when repeated therapeutic exposures to the fear-related cues reduce or inhibit the fear memories over time. In contrast, there is some evidence that in individuals who develop PTSD and other pathology, a combination of avoidance of sufficient exposure with intrusive and uncontrollable memories leads to sensitization of the fear response. Enhancing discrimination and extinction of fear memories is a key aspect of recovery in the psychotherapeutic approaches to treating PTSD.