Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment

Abstract

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role. Significance StatementBurst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations.

Target detection increases pupil diameter and enhances memory for background scenes during multi-tasking

“…Though the orienting response likely includes multiple systems 26,27 one potential neurophysiological mechanism underlying both temporal selection and the orienting response is phasic activity in the locus coeruleus (LC) system 14,23,24,28,29 . Whereas tonic levels of LC activity regulate wakefulness, arousal, and task engagement 28,30–32 , phasic increases in LC activity are involved in responding to behaviorally relevant stimuli, such as targets, and in adapting to changes in the current situation 33–36 . Growing evidence suggests that increases in LC activity are indexed by increases in pupil diameter 30,37,38 .…”

Estimates of locus coeruleus function with functional magnetic resonance imaging are influenced by localization approaches and the use of multi-echo data

“…This circuitry allows the LC to regulate autonomic states and task engagement to influence how neural systems respond to behaviorally relevant events (Aston- Jones, Rajkowski, & Cohen, 1999;Glennon et al, 2019;Greene, Bellgrove, Gill, & Robertson, 2009;Nieuwenhuis, Van Nieuwpoort, Veltman, & Drent, 2007;Mohanty, Gitelman, Small, & Mesulam, 2008). Although the precise mechanisms by which LC activity accomplishes this task are still being investigated (Mather, Clewett, Sakaki, & ESTIMATES OF LC FUNCTION 5 Harley, 2016;Uematsu, Tan, & Johansen, 2015;Schwarz & Luo, 2015), NE changes the signalto-noise ratio in brain regions involved in perceptual processing (Foote, Freedman, & Oliver, 1975;Berridge & Waterhouse, 2003), promotes memory consolidation and retrieval (Sara, 2009;Grella et al, 2019;Swallow, Jiang, & Riley, 2019), and may influence the integration of networks across brain regions (Shine et al, 2016). The importance of the LC for basic cognitive processing has been further reinforced by findings that there is an estimated 40% decline in cell number in the LC over the lifespan (Vijayashankar & Brody, 1979) which is accompanied by a decline in cognitive performance .…”

Neuromodulated attention and goal-driven perception in uncertain domains

“…2) A neural network reset was implemented to rapidly re-adapt when a goal changes. Empirical evidence suggests that the noradrenergic system facilitates this reset in the brain [5,6].…”

“…The noradrenergic system responds to surprises or large violations of priors. When the noradrenergic system responds phasically, where the neural activity rapidly and transiently increases, it causes a network reset (e.g., re-initializing weights or connections) that allows rapid adaptation and relearning under novel conditions [5,6].We modified a c-EB network for use in a goal-driven perception task, where the system had to increase attention to the intended goal object and decrease attention to the distractor. Specifically, we presented to the network pairs of noisy MNIST digits.…”

“…The noradrenergic system responds to surprises or large violations of priors. When the noradrenergic system responds phasically, where the neural activity rapidly and transiently increases, it causes a network reset (e.g., re-initializing weights or connections) that allows rapid adaptation and relearning under novel conditions [5,6].…”