| Exposure to stress is unavoidable. However, the impact it has on individuals varies markedly. While stressful life events promote depression and other psychiatric disorders in some, others show remarkable resilience and capacity to thrive under challenging circumstances. Understanding the neurobiological mechanisms underlying the impact of stress on mood and motivation is crucial for developing rational pharmacological approaches for the treatment of stress-related mental disorders.;A key element in the biological response to stress is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Following exposure to aversive or threatening stimuli, HPA axis activity is increased, leading to the release of several neuroactive hormones including glucocorticoids (GCs) from the adrenal glands. Cortisol is the primary GC in humans, while corticosterone (CORT) predominates in rodents.;The nucleus accumbens (NAc) is a ventral striatal structure that mediates aspects of mood, motivation, reward, and goal-directed behavior by integrating information from limbic inputs. Glutamatergic afferents from hippocampus, prefrontal cortex (PFC), and the basolateral amygdala (BLA) collectively drive action potential firing in medium spiny neurons (MSNs), the primary output neurons of the NAc. Ascending midbrain dopamine (DA) projections from the ventral tegmental area (VTA) serve a modulatory role in this process. Stress has been shown to affect plasticity in each of these accumbens-projecting structures. Furthermore, stress is known to enhance DA and glutamate release, to induce CRE-mediated transcription, and to increase expression of fos-family immediate early genes (IEGs) selectively in the shell subregion of the NAc.;Using whole-cell patch clamp electrophysiology in an acute mouse brain slice preparation, we observed that two consecutive days of cold water stress increase synaptic strength onto NAc shell MSNs when assessed 18--24hrs after the final stressor. These changes were mediated by enhanced forward trafficking of GluR2-containing &agr;-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors via a CORT and GC-receptor (GR)-dependent mechanism. GluR2 in the NAc shell has been shown to enhance responding to reward and to promote resilience to stress. Therefore, we reasoned that understanding the molecular mechanisms underlying stress and CORT-induced plasticity might reveal novel therapeutic targets for the treatment of stress-related psychiatric disorders.;In order to facilitate pharmacological investigation of the mechanisms of stress-induced NAc plasticity, we developed an in vitro CORT-exposure paradigm that recapitulated some of the aspects of plasticity observed following whole animal stress. Using this preparation, we observed that CORT selectively enhanced synaptic strength in DA receptor type-1 (D1R)-expressing NAc shell MSNs within 1hr. These changes required activation of GRs, D1Rs, N-methyl-D-aspartate (NMDA) receptors, and the mitogen-activated protein kinase (MAPK) pathway. Contrary to our expectations, we observed that these initial rapid changes were mediated by GluR2-lacking AMPA receptors (AMPARs), likely GluR1 homomers or GluR1/3 heteromers. Increased NAc shell GluR1 levels induce decreased responding to reward, and activate proteins and genes associated with anhedonia, depression, and anxiety.;Insertion of new GluR1-containing AMPARs is followed by subsequent replacement with GluR2-containing receptors. We hypothesize that these data reveal a novel plasticity process in the NAc that contributes to both the negative affective properties of stress as well as the ensuing adaptive processes that promote resilience to environmental challenges. |
