The histofluorescence method developed in the early 1960s allowed the visualization of these nuclei and their projection pathways in the rat brain and revealed a remarkably similar organization in that the cell bodies are found in rather compact nuclei with widespread axonal projections to distant forebrain regions (Dahlstrom and Fuxe, 1964). Cholinergic nuclei in the brainstem (lateral dorsal tegmental nucleus and pedunculopontine nucleus [LDT/PPN]) and basal forebrain area (nucleus basalis of Meynert [NBM]) have similar anatomical organization and are also implicated in the regulation of vigilance and cognitive function (Jones, 2008). In

addition to their distal forebrain projections, the neuromodulatory nuclei have multiple reciprocal connections. The LC has strong Regorafenib datasheet projections to all of the others and receives direct input from its neighbor LDT/PPN and

from DR. The DR also projects to VTA and NBM, thereby influencing both dopamine (DA) and cholinergic input to the cortex (Hervé et al., 1987). To add to the complexity of the situation, these systems interact at the level of axon terminals by reciprocal modulation of release of transmitters. For example, noradrenaline (NA), acting at alpha 2 adrenoceptors located on terminals of all four neuronal types, inhibits release of their transmitters. At the same time, there are mutual increases of release of DA and NA via alpha 1 and D1 receptors, respectively, in selleck chemicals llc the prefrontal cortex (PFC) (Pan et al., 2004) and acetylcholine provokes a calcium-dependent release of both DA and NA via a muscarinic receptor (Rao et al., 2003). Ultimately, an understanding of the concerted action of neuromodulatory systems will reveal how behavioral states influence, promote, or even permit cognitive activity (Briand et al., 2007). Nevertheless, TCL in our view, a great deal has yet to be understood about the relative contribution of each one of these systems in attention,

perception, reward and punishment, learning, and memory. Here, we address the specific role of the noradrenergic nucleus locus coeruleus in modulating forebrain networks mediating cognitive activity. In addition to strongly innervating all of the other neuromodulatory nuclei, the LC sends projections to all cortical regions, as well as to thalamic nuclei, septum, hippocampus, and basal lateral amygdala (Loughlin et al., 1986; Figure 1). Moreover, LC is the sole source of noradrenergic innervation to these structures (Jones and Moore, 1977; Moore and Bloom, 1979; Asan, 1998; Samuels and Szabadi, 2008; Figure 1). Multiple approaches using lesions, pharmacology, and transgenic technology combined with behavioral analysis and in vitro and in vivo electrophysiological recording in target regions have generated a large literature and contributed much to our knowledge of how NA acts in the brain. Noradrenergic action in thalamus and cortex strongly influences arousal and behavioral state (Berridge et al.