, 2003). Stressful experiences exert biphasic, time-dependent effects upon the prefrontal cortex, as shown in animal models. In

3- to 4-week-old rats, diverse acute stressors (forced swim, restraint, elevated platform) facilitate both PFC-dependent behavior, as well as long-term potentiation (LTP), tested 4 hr after stress exposure. Adrenal steroids mediate these effects and facilitate LTP, as well as behaviors known to depend on mPFC via mechanisms dependent not only on glucocorticoid receptors (GRs), but also on signaling pathways involving serum- and glucocorticoid-inducible kinase (SGK) and Rab4-mediated recycling of NMDA and AMPA receptors (NMDARs and AMPARs, respectively) (Yuen et al., 2009 and Yuen et al., 2011a). Yet, at this same age, chronic unpredictable stress

or restraint I-BET-762 molecular weight stress for 7 days impaired temporal order recognition memory in rats, a cognitive process controlled by the mPFC and caused reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression in mPFC (Yuen et al., 2012). All these effects relied on activation of glucocorticoid receptors and the subsequent enhancement of ubiquitin/proteasome-mediated degradation SCH772984 molecular weight of GluR1 and NR1 subunits, which was controlled by the E3 ubiquitin ligase Nedd4-1 and Fbx2, respectively. Inhibition of proteasomes or knockdown of Nedd4-1 and Fbx2 in PFC prevented the loss of glutamatergic responses and recognition memory in stressed animals. Thus, repeated stress dampens PFC glutamatergic transmission by facilitating glutamate receptor turnover. Indeed, the effects of chronic stress carry over to older ages Forskolin research buy since, in adult

rats, 21 days of chronic restraint stress impaired working memory and caused spine loss and debranching of dendrites on mPFC neurons (Hains et al., 2009), as will be discussed further below. However, in adult rats, acute mild stress impairs working memory during and immediately after stress exposures and does so via excessive stimulation of dopaminergic and noradrenergic receptors (Arnsten, 2009b). This acute stress effect on working memory and working memory-related activity in dlPFC monitored by fMRI is reported in volunteer subjects viewing movie clips with extremely aversive material (Qin et al., 2009). Intracellular signaling pathways activated by stress exposure have feedforward interactions that rapidly impair PFC-dependent cognitive function. High levels of dopamine (DA) D1-receptor stimulation and noradrenaline (NA) β1-receptor stimulation activate adenylyl cyclases (ACs) to produce cyclic AMP (cAMP); cAMP opens hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN channels) on dendritic spines to produce the h current (Ih), which weakens network inputs and decreases delay-related firing. High levels of NA also stimulate α1-receptors, which activate phosphatidylinositol biphosphate (PIP2)-protein kinase C (PKC) signaling (Arnsten, 2009b).