, 2009). There may be a connection between PKC signaling and the Nedd4-1 regulation of glutamatergic activity, in that PKC-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase Nedd4-2-dependent ubiquitination (García-Tardón et al., 2012). The differences between the outcome of studies described in the two paragraphs above reflect both timing of stress exposure in relation to testing, along with the qualitative nature of the stressors used, and they reveal the biphasic nature of stress responses by the PFC. Since the neurochemical responses, such as the release

of dopamine, during stress exposure are transient, the timing of cognitive testing is a critical factor, in which 4–24 hr may be a time of compensatory reactions. This will be essential to clarify in future studies both in terms of age dependency of both positive and negative effects of stressors as well as Bortezomib timing after stress exposure and the intensity and duration of the stressor. Repeated stress, such as 21 days of chronic restraint stress (CRS), causes functional and structural changes in the prefrontal cortex and amygdala, as well as the hippocampus VE-822 in vivo (McEwen and Gianaros, 2011), though these effects exhibit regional specificity (see Figure 2A). For example, CRS and chronic

immobilization caused dendritic shortening in medial prefrontal cortex (Cerqueira et al., 2007, Cook and Wellman, 2004, Liston et al., 2006 and Radley et al., 2004) but produced dendritic growth in neurons in basolateral amygdala (Vyas et al., 2002), as well as in orbitofrontal cortex (Liston et al., 2006). These actions of stress are reminiscent of recent work on experimenter

versus self-administered morphine and amphetamine, in which different, and sometimes opposite, effects were seen on dendritic spine density in orbitofrontal cortex, medial prefrontal cortex, and hippocampus CA1 (Crombag et al., 2005, Robinson et al., 2001 and Robinson et al., 2002). Indeed, there are clear indications that, besides substance abuse, many other aspects of brain function are subject to structural plasticity, including respiratory and motor control regions during exercise training (Nelson and Iwamoto, 2006 and Nelson et al., 2005), the nucleus accumbens after repeated sodium depletion causing increased salt appetite and enhanced amphetamine self-administration (Roitman et al., 2002), and the ALOX15 hippocampus during hibernation (Magariños et al., 2006 and Popov and Bocharova, 1992). Pyramidal neurons in layer 3 of all three regions of mPFC (AcG, PL, and IL) in male rats are affected by chronic stress, yet as noted below, there are important sex differences in some of these responses. Apical dendritic length shrinks by 20% in male rats, and this shrinkage is most pronounced in the distal apical dendritic branches, whereas the basal dendritic tree is unaffected (Bloss et al., 2010, Bloss et al., 2011, Cook and Wellman, 2004, Radley et al., 2004 and Radley et al., 2008).