Post-traumatic stress disorder (PTSD) is triggered by a traumatic life event and is characterized by the recurrent retrieval of the traumatic memory in the form of context-induced flashbacks and recurrent nightmares. The amygdala is a critical brain structure involved in both the formation and the extinction of emotional memories. Glucocorticoids, steroid hormones secreted as part of the general stress response, and endocannabinoids, lipid molecules that bind to CB1 receptors in the brain, have been shown to be important for the consolidation and extinction of fear conditioning. Both glucocorticoids and endocannabinoids enhance fear memory formation and extinction via actions within the basolateral amygdaloid complex (BLA). Patients suffering from PTSD typically show low circulating levels of corticosteroids, particularly at the nadir of the diurnal cortisol secretory rhythm, and corticosteroid treatment causes improvement in subjective measures of PTSD symptoms. A recent study showed that the glucocorticoid facilitation of conditioned fear extinction is dependent on CB1 receptor activation in the BLA, linking the actions of glucocorticoids and endocannabinoids in the BLA in conditioned fear extinction. The current study is designed to determine the cellular mechanisms that link glucocorticoid and endocannabinoid effects on fear conditioning in the BLA. We will test the hypothesis that glucocorticoids trigger endocannabinoid synthesis and retrograde release at GABA synapses in the BLA, leading to the suppression of synaptic inhibitory input to BLA neurons.
The specific aims of the proposal are: 1) to test biochemically for a rapid glucocorticoid-induced increase in endocannabinoid synthesis in the BLA and CeA using a liquid chromatography-mass spectrometry approach;and 2) to determine electrophysiologically whether glucocorticoids induce a rapid suppression of GABA synaptic inputs to BLA neurons via activation of a membrane receptor and the retrograde release of endocannabinoids using whole-cell patch clamp recordings in acute in vitro slices of amygdala. Pharmacological and genetic manipulations of glucocorticoid, mineralocorticoid and cannabinoid receptors and intracellular signaling pathways will be employed to characterize the novel molecular interactions between glucocorticoids and endocannabinoids in the BLA. The importance of endocannabinoids and glucocorticoids in the BLA in the consolidation and extinction of fear conditioning, and the relevance of fear conditioning to memory processing in PTSD, suggests that the outcome of this study will provide important insight into, and possible targets for, pharmacological treatment of stress-related disorders such as PTSD.
The proposed research on glucocorticoid-endocannabinoid interactions in the amygdala will provide critical insight into the basic biological mechanisms responsible for emotional memory formation and retention/extinction. The better understanding of emotional memory mechanisms gained from these studies will enhance our ability and improve the tools available to address increasingly prevalent and devastating mental illnesses brought on by stress and trauma, including posttraumatic stress disorder, anxiety disorders and phobias. The link between corticosteroids and endogenous cannabinoids is relevant not only to the basic biology of emotional memory formation, but also to the interaction between illicit drug use and anxiety disorders, as increased drug abuse in certain emotionally disturbed populations may be the result of compensation for a deficit in endogenous psychoactive chemicals involved in the generation of positive emotions.
| Di, Shi; Itoga, Christy A; Fisher, Marc O et al. (2016) Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala. J Neurosci 36:8461-70 |
