Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article, we review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components that underlie PTSD, and the biology of fear conditioning with a particular focus on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB), GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches might help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.

Box 1 Figure I

Genetic and environmental factors influence the risk for developing PTSD in certain individuals, as well as the severity of PTSD symptoms.

Figure 1. A schematic of the human brain illustrating how the limbic system is involved in PTSD

The PFC and the hippocampus both have dense connections to the amygdala, which is important for conditioned fear and associative emotional learning. The PFC is thought to be responsible for reactivating past emotional associations and is decreased in both responsiveness and density ^{, , ,} . The hippocampus is thought to play a role in explicit memories of the traumatic events and in mediating learned responses to contextual cues, and in PTSD the hippocampus is decreased in volume and responsiveness to traumatic stimuli ^, . The top down control of the amygdala by the hippocampus and PFC may result in the increased activation of the amygdala, as is observed in subjects with PTSD [7,8,14,15]. The end result of these neuroanatomical alterations is increased stress sensitivity, generalized fear responses and impaired extinction. Other regions including the anterior cingulate cortex, the orbitofrontal cortex, the parahippocampal gyrus, the thalamus and the sensorimotor cortex also play a secondary role in the regulation of fear and PTSD .

Figure 2. Disordered fear regulation in PTSD

Individuals with PTSD typically show increased sensitization to stress, overgeneralization of fear to irrelevant stimuli, and impaired extinction of fear memories. Individuals who demonstrate resilience to PTSD, and/or who recover from traumatic/stressful experiences, are able to discriminate between fearful and non-fearful stimuli, as well as displaying normal extinction of fear memories.

Figure 3. BDNF – TrkB induced signaling pathway

BDNF binds to the TrkB receptor, resulting in the phosphorylation of two tyrosine sites (Y515 and Y816) on the intracellular domain of the TrkB receptor. Phosphorylation of the Y515 residue allows recruitment of Shc/FRS-2, which subsequently activates the Ras/MAPK and PI3K pathways. In contrast, phosphorylation of the Y816 residue allows recruitment of PLC, which activates the CAMK/CREB signaling pathway. Point mutations of the Y515 residue produce deficits in consolidation but not acquisition of fear conditioning . Point mutations of the Y816 residue, on the other hand, produce deficits in acquisition . Evidence exists for a role of BDNF signaling in the amygdala, hippocampus and PFC with respect to both the consolidation and extinction of fear conditioning.

Figure 4. Schematic diagram illustrating the key amygdala nuclei involved in fear conditioning

Microcircuits within the amygdala demonstrate multiple levels of regulation with response to fear consolidation, extinction, and the expression of fear. Initially, it was thought that the BLA complex was solely responsible for fear acquisition and was the main recipient of thalamic and cortical inputs. The central amygdala was thought to be crucial only for the expression of conditioned fear responses via activation of downstream neural structures (see ^, for reviews). Now significant evidence supports the idea that the lateral division of the central amgydala (CeL) is also critical for acquisition of fear and also receives cortical and thalamic inputs. In addition, intercalated neurons may regulate firing of central amgydala output neurons and the expression of extinction. The intercalated neurons receive projections from the infralimbic cortex (a region critical for extinction) and project GABAergic inhibitory neurons onto the medial division of the central amygdala (CeM).