Varying levels of DA D1R stimulation would correspondingly weaken

nonpreferred connections, sharpening tuning under conditions of salient events (e.g., a rewarding stimulus or pressure from a deadline). The sculpting of network inputs may be optimal for performance of a spatial working memory task in which one is trying to maintain the representation of a small location in space but may be harmful when cognitive demands require more flexible network connections (Arnsten et al., 2009). This may explain why D1R stimulation is needed for spatial working memory but actually impairs attentional set-shifting (Robbins and Arnsten, 2009), even though both functions depend on dlPFC. Thus, the optimal neuromodulatory environment depends on the cognitive demands: insightful solutions to problems or creative endeavors that require Selleck AZD2281 wide network connections would be optimal under relaxed, alert conditions with less D1R sculpting (e.g., in the shower),

while more focused work may be best performed under the conditions that increase DA release (e.g., the pressure of working for a reward) (Arnsten et al., 2009). This may also NVP-AUY922 explain why stimulant medications can be helpful for some schoolwork (e.g., math) but harmful to others (e.g., composing a poem or song). The right side of the inverted U in Figure 6A shows the progressive weakening of network connections and progressive decrease in dlPFC firing with increasing stress (Arnsten, 1998, 2009). Evidence of this phenomenon has been seen in human imaging studies, where a found mild uncontrollable stressor (watching a gory movie) impairs working memory and reduces the BOLD signal over the dlPFC, while disinhibiting activity in the amygdala and default mode network (Qin et al., 2009), consistent with loss of dlPFC regulation and strengthening

of more primitive circuits. Data from animals indicate that that the same neurochemical pathways that take PFC off-line (D1R-cAMP and β1-AR-cAMP, α1-AR-Ca+2-PKC) serve to strengthen subcortical and sensory/motor circuits, switching the brain from a reflective to reflexive mode (Arnsten, 2009). The feed-forward nature of these signaling pathways would promote a very rapid switch to primitive circuits, that is, “Going to Hell in a Handbasket” (Arnsten, 2009). Thus, regulatory interactors, such as DISC1-PDE4A, would serve a critical role to reign in feed-forward Ca+2-cAMPsignaling and restore dlPFC top-down regulation of thought and behavior. Loss of this regulation and/or chronic stress exposure leads to architectural changes in PFC pyramidal cells, with loss of spines and retraction of dendrites (Cook and Wellman, 2004; Liston et al., 2006; Radley et al., 2008). The molecular basis for stress-induced atrophy has just begun to be studied.