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

Abstract

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 msec or 10 sec 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, while 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.

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

“…LC optogenetic input patterns result in different functional outcomes, in part at least, by recruiting different target structure microcircuits. This is clearly reflected in c-fos intersectional studies [ 13 , 36 ]. Differences in response to target receptor antagonists for stress effects produced with the same LC input frequency, as seen with place-associated anxiety and place-associated avoidance [ 14 ], also provide evidence for different target effects with the same LC placements.…”

“…Neither group avoided the center of the testing cage. These activity differences may relate to greater rearing as reported with phasic patterns in rats [ 13 ], but rearing was not assessed here. Neither group displayed anxiogenic behavior consistent with the results of McCall et al discussed in (3) when lower tonic rates and similar phasic rates of LC activation were assessed for aversive responses in mice [ 14 ].…”

“…Differential effects of phasic and tonic activation patterns in rats can be understood in terms of differential recruitment of output microcircuits [ 13 ].…”

“…Working with rats and using bilateral activation of LC, Ghosh et al, 2021 [ 13 ] compared the effects of phasic and tonic LC activations from the same sites on spontaneous and learned behaviors. In the open field, phasic activation (10 Hz, 10 pulses/30 s) or tonic activation (10 Hz) increased rearing duration suggesting both inputs enhanced exploration, while 25 Hz tonic activation increased freezing suggesting stress, as seen earlier with lower frequencies in mice [ 14 ].…”

“…The differences in stress-related optogenetic frequencies with lower frequencies inducing stress in mice (McCall et al, 2015 [ 14 ]) and only higher frequencies being effective in rats (Ghosh et al, 2021 [ 13 ]) may reflect a species difference or may relate to the spatial extent of LC activation. In rats, Hirschberg et al, 2017 [ 32 ] used chemogenetics to activate LC and reported increased anxiety with LC firing ~15 Hz.…”