Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety

Abstract

Stress initiates a series of neuronal responses that prepare an organism to adapt to new environmental challenges. However, chronic stress may lead to maladaptive responses that can result in psychiatric syndromes such as anxiety and depressive disorders. Corticotropin-releasing factor (CRF) has been identified as a key neuropeptide responsible for initiating many of the endocrine, autonomic and behavioral responses to stress. The amygdala expresses high concentrations of CRF receptors and is itself a major extrahypothalamic source of CRF containing neurons. Within the amygdala, the basolateral nucleus (BLA) has an important role in regulating anxiety and affective responses. During periods of stress, CRF is released into the amygdala and local CRF receptor activation has been postulated as a substrate for stress-induced alterations in affective behavior. Previous studies have suggested that synaptic plasticity in the BLA contributes to mechanisms underlying long-term changes in the regulation of affective behaviors. Several studies have shown that acute glutamate receptor-mediated activation, by either GABA-mediated disinhibition or CRF-mediated excitation, induces long-term synaptic plasticity and increases the excitability of BLA neurons. This review summarizes some of the data supporting the hypotheses that stress induced plasticity within the amygdala may be a critical step in the pathophysiology of the development of chronic anxiety states. It is further proposed that such a change in the limbic neural circuitry is involved in the transition from normal vigilance responses to pathological anxiety, leading to syndromes such as panic and post-traumatic stress disorders.

Reduced amygdalar and hippocampal size in adults with generalized social phobia

“…29 Animal studies demonstrated that activation of N-methyl-D-aspartate glutamate receptors inhibits neurogenesis in the hippocampus 30 and increases the excitability of amygdala neurons. 31 In contrast, it can be argued that pre-existing small hippocampal and amygdalar size increases the risk of developing anxiety or affective disorders. A twin study investigating hippocampal size in Vietnam veterans suggested that individuals with smaller hippocampal size were at greater risk for developing PTSD, 10 rendering it likely that genetic factors contribute to the small hippocampal size of individuals with PTSD.…”

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

“…However, more complex auditory stimulation in the PPI paradigm revealed impaired sensory habituation and/or response inhibition. Anxiety levels were increased in VPA-treated offspring, which indicated abnormal amygdala processing (Shekhar et al, 2005).…”

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…Furthermore, for the first time we demonstrate that the activation of Y 1 Rs decreases NMDA-mediated currents, an important new finding with implications for the role of NPY in modulating not only excitability but also synaptic plasticity within the BLA. We have previously shown that CRF-and stress-induced synaptic plasticity within the BLA may be a key component of the pathophysiology of several chronic anxiety disorders, including panic and posttraumatic stress disorder (Rainnie et al, 2004;Shekhar et al, 2005). Stress-induced plasticity within the BLA is mediated by the activation of NMDA receptors and pre-treatment with an NMDA receptor antagonist blocks such plasticity (Rainnie et al, 2004).…”

“…The amygdala is a crucial region in the brain circuitry implicated in many of these psychiatric syndromes and is a well-known component of fear, anxiety, and memory circuits (Fendt and Fanselow, 1999;LeDoux, 2000;Maren and Quirk, 2004;Pare et al, 2004;Shekhar et al, 2005). NPY and its receptors are present in the amygdala (Holmes et al, 2003;Kask et al, 2002;Kishi et al, 2005;Wolak et al, 2003), leading to the hypothesis that the anxiolytic-like effects of NPY are mediated in part by the amygdala.…”