Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

Abstract

Stress exposure enhances glutamatergic signaling in the BLA-L2/3plPFC reciprocal circuit… .. 36 Endocannabinoid signaling broadly inhibits glutamatergic input from the BLA to the plPFC .... 41 Stress impairs 2-AG-mediated inhibition of the BLA-plPFC reciprocal glutamatergic circuits ..

Sleep and Wellbeing, Now and in the Future

“…Recent developments in endocannabinoid signalling, which has a key role in the regulation of stress responses and emotional learning [30], may signpost and prioritise research opportunities in this field. The signalling molecule 2-arachidonoylglycerol (2-AG) appears to protect against stress [31]. In the presence of acute stress exposure, the failure of 2-AG signalling would result in the strengthening of anxiety-producing connections between the amygdala and prefrontal corticies [31].…”

“…The signalling molecule 2-arachidonoylglycerol (2-AG) appears to protect against stress [31]. In the presence of acute stress exposure, the failure of 2-AG signalling would result in the strengthening of anxiety-producing connections between the amygdala and prefrontal corticies [31]. This mouse model research is very encouraging, since the identification of anxiety-producing signalling pathways may provide an insight into future treatment possibilities.…”

The endocannabinoid system in modulating fear, anxiety, and stress

“…42 Deletion of the 2-AG synthesizing enzyme DAGLα in PFC strengthens glutamatergic activity in a BLA-PFC-BLA circuit that facilitates stress-induced anxiety-like behavior. 43 These data show that facilitating synthesis or inhibiting degradation of anandamide and 2-AG have overlapping consequences, suggesting the therapeutic potential of these enzyme modulators for the treatment of stress-related disorders. The redundancy exhibited by 2-AG and anandamide could potentially be exploited to design drug combinations with lower doses of active ingredients and may be useful to tackle different aspects of chronic stress disorders at once.…”

“…Prelimbic PFC glutamatergic neurons are active after threat exposure, as demonstrated by recent optogenetic and cell-specific gene deletion experiments. 43 A traumatic experience (foot-shock) in mice facilitates 2-AG depletion and subsequent enhancement of glutamatergic neurotransmission in this BLA-PFC-BLA pathway to trigger anxiety-like behavior. 43 The relevance of this circuitry is reflected in clinical studies showing that the anxiolytic effects of THC are associated with reduced activity and disrupted connectivity between these two brain areas.…”

Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure

“…In the BLA, CB1 receptor mRNA is highly expressed in a sparsely distributed population of cholecystokinin positive (CCK+) GABAergic interneurons that synapse locally onto projection PNs (Katona et al 2001;Jasnow et al 2009;Yoshida et al 2011). At these sites, reciprocal functional interactions between presynaptic CB1 and postsynaptic mGlu5 receptors produces transient disinhibition of PNs which serves to maintain tight regulatory control over the excitability of bidirectional PL and IL targeting BLA outputs (Zhu and Lovinger 2005;Vogel et al 2016;Marcus et al 2020). In the PSS model, we have found increased CB1 receptor expression in the amygdala of stress-resilient rats relative to both unstressed controls and stress-susceptible rats (Schwendt et al 2018).…”