The Neurotransmission Basis of Post-Traumatic Stress Disorders by the Fear Conditioning Paradigm

Abstract

Fear conditioning constitutes the best and most reproducible paradigm to study the neurobiological mechanisms underlying emotions. On the other hand, studies on the synaptic plasticity phenomena underlying fear conditioning present neural circuits enforcing this learning pattern related to post-traumatic stress disorder (PTSD). Notably, in both humans and the rodent model, fear conditioning and context rely on dependent neurocircuitry in the amygdala and prefrontal cortex, cingulate gyrus, and hippocampus. In this review, an overview of the role that classical neurotransmitters play in the contextual conditioning model of fear, and therefore in PTSD, was reported.

Keywords: amygdala; contextual fear conditioning; hippocampus; learning; neurotransmission; post-traumatic stress disorders; prefrontal cortex.

Figure 1

The figure reproduces the human brain, and the areas of the limbic system involved in CFC and PTSD are colored. The classical neurotransmitters discussed in the manuscript are reported. The arrows are intended to highlight the integration and coordination of neurotransmitters in stress and fear responses (created by BioRender).

Figure 2

Schematic representation of the GR pathway (obtained using STRING-db.org, accessed 30 September 2023). YWHAH, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Eta; ARID1A, AT-rich interaction domain 1A; NR3C1, nuclear receptor subfamily 3 group C member 1; PTGES3, Prostaglandin E synthase 3; CALR, calreticulin.

Figure 3

Schematic representation of the GPCR pathway. PIP3, phosphatidylinositol (3,4,5)-trisphosphate; RAC, a subfamily of the Rho family of GTPases; P-REX, Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor; IP3, inositol 1,4,5-trisphosphate; AKT PKB, Ser/Thr kinase AKT, also known as protein kinase B (PKB); IKK, IκB kinase; RHO CEF, Rho GTPase chicken embryo fibroblasts; SRF, Serum Response Factor; cAMP, Cyclic adenosine monophosphate; PKA, protein kinase A; CAEB, Coxiella burnetii effector protein; B-RAF, signal transduction serine/threonine-specific protein kinase; RAP-1, Ras-proximate-1 or Ras-related protein 1; MEK, mitogen-activated protein; ERKs, extracellular signal-regulated kinases; PLCb, Phospholipase C Beta; PIP2, phosphatidylinositol 4,5-bisphosphate; NFAT, nuclear factor of activated T cells (NFAT) protein; NfkB, Nuclear factor kappa-light-chain-enhancer of activated B cells; CARMA1, Caspase recruitment domain-containing protein 11; TAK, Transforming growth factor-β (TGF-β)-activated kinase 1 (created by BioRender).