Brain-Derived Neurotrophic Factor Signaling in the Amygdala: A Role in Anxiety and Alcoholism

Alcoholism is a chronic psychiatric disease that impacts a massive population. The high co-morbidity of anxiety and alcoholism emphasizes the importance of better understandings of the neurobiological basis of anxiety and alcoholism. Brain-derived neurotrophic factor (BDNF) has been shown to play an important role in the regulation of synaptic plasticity and has been implicated in anxiety-like and alcohol-drinking behaviors. However, the specific mechanism by which BDNF and related signaling regulates anxiety and drinking, is not clear. We used three animal models of anxiety to address this critical question: 1) Pharmacological manipulation of BDNF signaling. BDNF infusion into the central nucleus of amygdala (CeA) produced anxiolytic effects in rats, increased CeA Erk1/2 and CREB phosphorylation, Arc mRNA and protein expression. Erk1/2 signaling inhibitor U0126 produced opposite effects. Interestingly, co-infusion of U0126 with BDNF blocked effects of BDNF. Arc antisense oligodeoxynucleotides (ODNs) produced anxiogenic effect in rats, and when co-infused with BDNF it also attenuated the anxiolytic effect of BDNF. 2) Ethanol-withdrawal. Rats undergoing withdrawal had increased anxiety levels and decreased BDNF and Arc expression in the CeA and medial nucleus of amygdala (MeA). The dendritic spine densities (DSD) are decreased in the CeA and MeA of ethanol-withdrawal rats. These deficits in BDNF and Arc expression, and DSD are reversible by histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) treatment. 3) Genetic predisposition. The high alcohol-drinking and low alcohol-drinking (HAD/LAD) rats are selectively bred to have high and low alcohol-drinking behaviors. We found that HAD rats have innately higher anxiety levels, less BDNF and CREB expression, and phosphorylated CREB in CeA and MeA than LAD rats. These data indicates that the deficits in BDNF signaling may be involved in high anxiety levels and alcohol preference. These behavioral changes may be regulated by the BDNF downstream Erk1/2 signaling cascade and its target CREB, which, in turn, controls the expression of synaptic plasticity related genes including BDNF and Arc. Histone acetylation may contribute to the regulation of gene transcription during alcohol dependence because the anxiety-like behaviors and deficits in BDNF and Arc expression and in DSD were reversed by treatment with an HDAC inhibitor.