The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is clearly a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. highlighted this area with red ovals. The structure name AAPK-25 is on page 341 and is presented as Figure 4 (Figura quarta, p 340) in Table 10 (Tabula decima, p 339). Figure provided by N.K.T. and Stefan Hirschberg. In the 1960s and 1970s, with the advent of a histochemical reaction that caused catecholamines to fluoresce yellow-green (Falck et al., 1962; Dahlstroem and Fuxe, 1964), as well as a fluorescent antibody for the noradrenaline synthesis enzyme (Hartman, 1973), and autoradiographic methods (Jones and Moore, 1977; Jones et al., 1977), these pigmented neurons were shown to be noradrenergic and to project broadly, even globally, ascending across nearly the entire forebrain and descending, too, into brainstem and spinal cord (Swanson and Hartman, 1975; Grzanna et al., 1977; Fallon et al., 1978; Morrison et al., 1979). OPD2 This led to the concept of the LC as being part of the central arousal system, preparing the brain for effortful cognitive action. Given its diffuse projections, it came as no surprise, then, that this small brainstem nucleus was involved in myriad brain functions. Subsequent electrophysiology and lesion studies demonstrated activation of the LC in the contexts of wakefulness (Foote et al., 1980; Aston-Jones and Bloom, 1981), the orienting reflex (Foote et al., 1980; Grant et al., 1988; Aston-Jones et al., 1994; Bouret and Sara, 2004), flexible cognition involving shifting attention (Aston-Jones et al., 1994), sensory gating (Waterhouse and Woodward, 1980; Waterhouse et al., 1990, 1998; Devilbiss and Waterhouse, 2004), invigorating of goal-directed activity (Anlezark et al., 1973), analgesia (Hirschberg et al., 2017), pain and tension (Igarashi et al., 1979; Elam et al., 1986; Valentino et al., 1991; Aston-Jones and Hirata, 1994; Grace and Mana, 1997; Sajedianfard et al., 2005; Hickey et al., 2014; McCall et al., 2015), and dread conditioning aswell as dread extinction learning (Mueller et al., 2008; Uematsu et al., 2017; Giustino et al., 2019). A central query that LC study has oft regarded as is what sort of broadly projecting nucleus could influence any singular function without influencing them all. For instance, LC activation causes awakening and arousal (Carter et al., 2010; Hayat et al., 2019), which can be associated with improved sensory discrimination (Aston-Jones et al., 1994; Froemke and Martins, 2015) and AAPK-25 reduced sensory neuron response thresholds (Waterhouse et al., 1990, 1998; Edeline and Manunta, 1998, 2004; Bouret and Sara, 2002; Devilbiss and Waterhouse, 2004; Devilbiss et al., 2006; Edeline et al., 2011; Navarra et al., 2013), but this rests at odds using the observation that LC activation can be connected with suppression of nociceptive sensory inputs (analgesia). This obvious paradox is easily demonstrable in attentional analgesia paradigms in human beings where LC activity can be from the discussion between interest (increased AAPK-25 visible sensory discrimination) and analgesia (reduced nociceptive percept) (Brooks et al., 2017). One perspective, which includes ample support, is that the LC alters global noradrenaline concentration and specific functional consequences are achieved through differences in postsynaptic receptors and regional differences in the spatiotemporal dynamics of noradrenaline reuptake (Berridge and Waterhouse, 2003; Agster et al., 2013; Giustino and Maren, 2018). However, a complementary view is now emerging that suggests that the LC may provide localized neuromodulation via LC neurons that have relatively circumscribed projection targets and synchronous spike timing among only subsets of LC neurons (for review, see Totah et al., 2019). In many ways, this perspective has parallels with the emerging conceptualization of the sympathetic nervous system as having discrete efferent limbs that are organ- or even target-tissue-specific with characteristic patterns of activity (for review, see J?nig, 2006) but that also has the capability to act as a unified whole (Farmer et al., 2019). Similar parallels may be drawn with the dopaminergic system which, over the past decade, has become parcellated by cell type and by cell-specific afferents and efferents that allow this diffuse neuromodulatory system to contribute highly informative.