Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets – https://www.frontiersin.org/articles/10.3389/fncir.2021.638007/full “The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions, and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE to control arousal, but also in the context of a variety of sensory-motor and behavioral functions. Despite its brain-wide effects, much about the role of LC-NE in behavior and the circuits controlling LC activity is unknown. New evidence suggests that the modular input-output organization of the LC could enable transient, task-specific modulation of distinct brain regions. Future work must further assess whether this spatial modularity coincides with functional differences in LC-NE subpopulations acting at specific times, and how such spatiotemporal specificity might influence learned behaviors. Here, we summarize the state of the field and present new ideas on the role of LC-NE in learned behaviors.”
(in case) FIGURE 1 | Anatomy of the LC-NE system. (A) Anatomy of the outputs originating from the LC nucleus in human and mouse. Shaded areas indicate major sub-regions that potentially send input to LC. In this illustration, we have assumed that input regions identified in mouse are similar in humans (B) Distal inputs to LC-NE neurons obtained by retrograde tracing using rabies virus targeted at LC-NE neurons in mice. Input regions are grouped by: cortex (CTX), striatum (STR), pallidum (PAL), hypothalamus (HY), amygdala (AMY), midbrain (MB), medulla (MY), and cerebellum (CB). The thickness of each line represents the strength of the input from each region. Input strength was calculated by counting the number of cells retrogradely labeled in a specific area and dividing it by the total number of retrogradely labeled neurons. Regions providing less than 0.5% of inputs were left out of this diagram. Local inputs from the pons were also excluded. PFC, prefrontal cortex; MO, motor area; SS, somatosensory area; Acb, nucleus accumbens; CP, caudoputamen; BST, bed nucleus of stria terminalis; MS/NDB, medial septal/diagonal band nucleus; MPO, medial preoptic area; DMH/PVH, dorsomedial/paraventricular nucleus; LHA, lateral hypothalamic area; ZI, zona incerta; PSTN, parasubthalamic nucleus; CEA, central amygdala; SNc, substantia nigra; MRN, midbrain reticular nucleus; IPN, interpeduncular nucleus; PAG, periaqueductal gray; SC, superior colliculus; IC, inferior colliculus; PRP, nucleus prepositus; IRN, intermediate reticular nucleus; GRN, gigantocellular reticular nucleus; SPV, spinal nucleus of the trigeminal; CBX, cerebellar cortex; and CBN, cerebellar nuclei. Data in (B) from Breton-Provencher and Sur (2019) …
Theories of LC Function Two predominating theories attempt to explain the role of the LC in sensory-motor behavior: the adaptive gain theory (Aston-Jones and Cohen, 2005) and the network reset theory (Bouret and Sara, 2005; Yu and Dayan, 2005; Dayan and Yu, 2006). The adaptive gain theory seeks to explain the phasic and tonic modes of LC-NE activity. Phasic activity prevails during optimal behavioral performance, where transient increases in LC-NE activity facilitate task-specific decision processes (Usher et al., 1999; Aston-Jones and Cohen, 2005). In contrast, tonic activity prevails during periods of poor performance, where a general increase in LC-NE activity increases the gain of a network indiscriminately, making targeted circuits more responsive to any stimulus (Usher et al., 1999; Aston-Jones and Cohen, 2005). Thus, through adaptive gain, LC-NE activity optimizes the tradeoff between exploitation and exploration behaviors by switching between phasic and tonic activity, respectively. However, this theory does not explain which environmental stimuli would cue the LC to switch between these two modes. Further, this theory does not offer an explanation for whether different phasic activities exist temporally within tasks, and what the roles of these temporally distinct phasic activations might be. The network reset theory, on the other hand, suggests that contexts requiring a change in behavior transiently activate LC-NE neurons (Bouret and Sara, 2005; Yu and Dayan, 2005; Dayan and Yu, 2006). These activating contexts lead LC-NE neurons to induce widespread cortical arousal and reset network activity in the brain. Similarly, it has been suggested that LC-NE activity signals “unexpected uncertainty,” causing a reset in network activity to enable an updating of priors (Yu and Dayan, 2005; Dayan and Yu, 2006). By signaling the need to update priors, LC-NE would suppress top-down, expectation driven information in favor of bottom-up sensory-induced signals to enable learning and behavioral optimization. However, it is not clear how LC responses during execution would not lead to a network reset, and how phasically induced arousal relates to the commonly described tonic regulation by NE of arousal and internal state.
Though these theories of gain-modulation and network reset are not mutually exclusive, neither alone can fully explain the role of LC-NE in the brain, and little progress has been made in either refining or unifying them in the past 15 years. Recent technological advances and increased tool availability enabling precise measurements and manipulations of LC spiking activity in awake behaving mice present a means of evaluating these theories or advancing alternative proposals. Future studies on the role of LC-NE in learned behavior will require well-designed behavioral experiments to address these dual functions, while also considering the heterogeneous nature of LC activity and potential for spatial modularity of outputs.
.. Conclusions – Despite the diverse roles of the LC in regulating arousal, attention, and facilitating more complex behaviors, our understanding of this nucleus is quite limited. Recent studies, however, are changing our understanding of the LC. What was formerly considered a homogenous nucleus exerting global, uniform influence over its many diverse target regions, is now suggested to be a heterogenous population of NE releasing cells, potentially exhibiting both spatial and temporal modularity that govern its function. These observations, combined with a rapidly expanding neuroscience toolkit, enable updating of existing theories, or potentially forming new ones, to explain the roles of LC-NE in learned behaviors.”
Dopamine and Noradrenaline in the Brain; Overlapping or Dissociate Functions? “Locus Coeruleus has long been identified as a noradrenergic center, where majority of the cells produce noradrenaline from dopamine by expressing dopamine-beta-hydroxylase (Figure 1A)” https://www.frontiersin.org/articles/10.3389/fnmol.2019.00334/full#:~:text=Locus%20Coeruleus%20has%20long%20been,%2Dhydroxylase%20(Figure%201A).
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