Locus Coeruleus Activation Patterns Differentially Modulate Odor Discrimination Learning and Odor Valence in Rats

The locus coeruleus (LC) produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence encoding of sensory information are unknown. Here, we show bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 ms or 10 s accelerated acquisition of a similar odor discrimination. Similar odor discrimination learning was impaired by noradrenergic blockade in the piriform cortex (PC). However, 10-Hz phasic light-mediated learning facilitation was prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting a LC–VTA–PC dopamine circuitry involvement. Ten-hertz tonic stimulation did not alter odor discrimination acquisition, and was ineffective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced conditioned odor aversion, whereas 10-Hz phasic stimulations produced an odor preference. Both conditionings were prevented by noradrenergic blockade in the basolateral amygdala (BLA). Cholera Toxin B retro-labeling showed larger engagement of nucleus accumbens-projecting neurons in the BLA with 10-Hz phasic activation, and larger engagement of central amygdala projecting cells with 25-Hz tonic light. These outcomes argue that the LC activation patterns differentially influence both target networks and behavior

An interaction between locus coeruleus activation modes and heterogeneous adrenoceptor expression in the basolateral amygdala for valence signaling

The locus coeruleus (LC) is a neuromodulatory brainstem nucleus which signals arousal via the release of norepinephrine (NE) throughout the central nervous system. Norepinephrine facilitates adaptive behavioural responding, perception, and learning and memory via enhancing the signal-to-noise ratio at downstream structures. The LC has recently been suggested to be involved in positive and negative valence signaling via two distinct activation modes, phasic and tonic. This effect has been shown to depend on adrenoceptor engagement in the basolateral amygdala (BLA). Here, we sought to determine whether phasic and tonic modes of LC activation differentially engage functionally distinct subpopulations of the BLA and whether naturally-produced valence recruits the same circuitry. Finally, we investigated the adrenoceptor profile of these subpopulations, as our valence effects may depend on their unique adrenoceptor expressions. Phasic and tonic LC photostimulation preferentially recruited nucleus accumbens (NAc)- and central amygdala (CeA)-projecting subpopulations of the BLA in the presence of an odor, respectively. Natural reward and aversive learning showed patterns of BLA activation similar to that of phasic and tonic LC photostimulation, respectively. Immunohistochemistry revealed differences in adrenoceptor expression across BLA subpopulations. These findings offer a mechanism underlying the differential valence effects of phasic and tonic LC activation

Phasic and Tonic Locus Coeruleus Stimulation Associated Valence Learning Engages Distinct Adrenoceptors in the Rat Basolateral Amygdala

Reward exploitation and aversion are mediated in part by the locus coeruleus (LC), a brainstem structure significantly involved in learning and memory via the release of norepinephrine. Different LC firing patterns are associated with different functions. Previously, we have shown that high tonic and phasic LC activation signal negative and positive valence, respectively, via basolateral amygdala (BLA) circuitry. Tonic LC activation is associated preferentially with BLA-central amygdala (CeA) activation, while phasic LC stimulation preferentially recruits the BLA-nucleus accumbens (NAc) pathway. Here, we ask if phasic and tonic LC activation-associated valence learning requires different adrenoceptors in the BLA, in comparison with the odor valence learning induced by natural reward and aversive conditioning. Using optogenetic activation of the LC and local drug infusions in the BLA, we show that phasic LC activation-induced positive odor valence learning is dependent on both α1 and β-adrenoceptors, whereas tonic LC activation induced-negative odor valence learning depends on β-adrenoceptors only. In parallel, both α1 and β-adrenoceptors were required in the odor valence learning induced by reward while aversive conditioning was dependent on β-adrenoceptors. Phasic stimulation and reward conditioning likewise activated more NAc-projectors of the BLA, in comparison to tonic and aversive conditioning. There was a higher proportion of α1+ cells in the NAc-projectors compared to CeA-projectors in the BLA. Together, these results provide insight into the mechanisms underlying the effects of tonic and phasic activation of the LC, and more generally, negative and positive valence signaling