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 will 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 which underlie PTSD, and the biology of fear conditioning with a particular focus on the brain derived neurotropic factor (BDNF)-TrkB, GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches may help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.

Corticotropin-Releasing Factor (CRF)-Induced Disruption of Attention in Rats Is Blocked by the κ-Opioid Receptor Antagonist JDTic

“…Interactions between these systems have been thoroughly characterized within the raphe nucleus (Bruchas et al, 2011) but may also occur in other brain regions (Pliakas et al, 2001;Newton et al, 2002;Shirayama et al, 2004;Muschamp et al, 2011b;Knoll et al, 2011). The notion that KOR antagonists block the effects of stress fits well with other evidence that these agents have antidepressant-like (Pliakas et al, 2001;Newton et al, 2002;Mague et al, 2003;Shirayama et al, 2004) and anxiolytic-like effects, including the ability to block acquisition of fear-potentiated startle (Knoll et al, 2007(Knoll et al, , 2011, a procedure often used to study PTSD (Mahan and Ressler, 2012). In addition, KOR agonists can produce key behavioral signs of stress (McLaughlin et al, 2003(McLaughlin et al, , 2006Mague et al, 2003;Todtenkopf et al, 2004).…”

“…The present studies indicate that pretreatment with a KOR antagonist can improve cognitive performance that is typically degraded under stress-like conditions, an effect that would be particularly desirable in humans when stress is accompanied by danger or the potential for harm. Considering prior work showing that pretreatment with this same class of agents has anxiolytic effects and attenuates the development of conditioned fear (Knoll et al, 2007) in a rodent version of a method often used to study PTSD in people (Mahan and Ressler, 2012), these new findings provide further evidence that KOR antagonists can prevent stress-induced processes that may render individuals vulnerable to acute injury and contribute to the development of psychiatric illness.…”

Learning not to Fear: Neural Correlates of Learned Safety

“…Such studies have shown that genetic risk factors increased the probability for major depression and had a higher impact on females than males (Kendler, 2001). Furthermore, specific gene variants (eg serotonin transporter, pituitary adenylate cyclaseactivating polypeptide (PACAP), and PAC1 receptor) have also found to influence the susceptibility as well as resilience to develop mood disorders (Mahan and Ressler, 2012;Uher, 2008). However, whether and how these and other genetic risk factors together with other factors, such as age, sex, and environmental conditions, may also have a role in regulating learned safety remain to be elucidated in future studies.…”

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…The encoding of fear-related memory is well established to involve abnormal plastic changes of information processing in amygdala circuits (Johansen et al, 2011;Mahan and Ressler, 2012). In other brain regions, synaptic plasticity is controlled by the adenosine neuromodulation system (Fredholm et al, 2005), which involves a coordinated action of inhibitory A 1 receptors (A 1 Rs) and facilitatory A 2A receptors (A 2A Rs) to fine tune brain neurotransmission (Cunha, 2008).…”