, 2010). We have postulated that DNC mechanisms weaken recurrent connections during fatigue (inadequate NE α2A-AR stimulation) or hunger (inadequate glucose) in order to reduce neuronal firing

and reserve energy stores (Arnsten et al., 2010). Recurrent firing is a very energy intensive process—PFC neurons have more mitochondria than do their sensory cortex counterparts (Chandrasekaran et al., 1992)—and the weakening of synaptic connections with a build-up of Ca+2 and/or cAMP would dampen dlPFC activity OSI-906 chemical structure to save energy. These mechanisms also serve as negative feedback on NMDA recurrent excitatory circuits to prevent seizures, and indeed, genetic insults to cAMP-PKA opening of KCNQ channels are associated with epilepsy (Schroeder et al., 1998). These protective mechanisms prevent seizures and save energy, but they likely constrain mental capability. The same feedback mechanisms appear to be actively generated during exposure to uncontrollable stress, when high levels of catecholamine release rapidly increase Ca+2 and cAMP signaling Selleck Raf inhibitor (e.g., via α1-AR and D1R stimulation) to take dlPFC

“off-line” and switch control of behavior to more primitive systems (Arnsten, 2009). More subtle changes in neuromodulation during nonstressed waking may serve to shape the contents of working memory, for example, focusing network firing on events associated with reward. The NE system has been studied most extensively, both in terms of LC firing patterns during sleep, waking, and stress (see above) and in terms of its effects on dlPFC Megestrol Acetate function. Varying levels of NE release engage different types of receptors and thus can act as a neurochemical switch to alter brain state. As the NE innervation to dlPFC is quite delicate (e.g., compared to thalamus), moderate levels of phasic NE release during alert waking engage those receptors with the highest affinity for NE, the α2-AR, while

high levels of NE release during stress engage the lower affinity receptors, α1-AR and β-AR (Arnsten, 2000; Li and Mei, 1994). Thus, α2A-AR stimulation strengthens network connections for the neurons’ preferred direction and increases neuronal firing to relevant stimuli (Figure 6A), while higher levels of NE reduce dlPFC firing and impair working memory via α1-AR-Ca+2-PKC actions (Birnbaum et al., 2004) and possibly β1-AR effects (Ramos et al., 2005); these receptors are not shown in Figure 3, as immunoEM has not yet determined their subcellular location on dlPFC neurons. Figure 6A shows a hypothetical representation of network connections for a dlPFC delay neuron throughout the range of arousal conditions. During sleep, there is little or no NE release, and the dlPFC shows reduced levels of neuronal firing (M.J.W., unpublished data) or BOLD response (Boly et al., 2008). Low levels of catecholamine receptor stimulation (α2A-AR and D1R) during the drowsy/fatigued state would weakly excite the neuron in a generalized manner.