The locus coeruleus mediates behavioral flexibility

McBurney-Lin, Jim; Vargová, Gréta; Garad, Machhindra; Zagha, Edward; Yang, Hongdian

doi:10.1016/j.celrep.2022.111534

Cited by 13 publications

(18 citation statements)

References 63 publications

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“…Our findings of enhanced RPE encoding and faster reversal learning support conclusions from studies in mice documenting noradrenergic neurons in the locus coeruleus causally support flexible behavioral switching of stimulus -reward associations (McBurney-Lin et al, 2022;Su and Cohen, 2022). In these studies, activity of locus coeruleus neurons were either necessary for faster learning (Su and Cohen, 2022) or were predictive of faster behavioral switches (McBurney-Lin et al, 2022). The results reported here suggests that these noradrenergic signals in the LC are translated into stronger prediction error encoding along the ACC-striatum pathway.…”

Section: Discussionsupporting

confidence: 86%

“…Taken together, these findings suggest that noradrenergic signaling in all three recorded brain areas, ACC, dlPFC, and striatum, supports cognitive flexibility by enhancing prediction error signaling and improving the representation of the target feature in a top-down attention set. This conclusion is consistent with recent causal manipulation studies in rodent (McBurney-Lin et al, 2022; Su and Cohen, 2022), and calls upon a refinement of frameworks that propose a more general involvement of noradrenergic signaling to either enhance working memory for task relevant stimulus representations (Wang et al, 2007), or track the uncertainty (including the unexpecteness of outcomes) of an environment and facilitate exploratory behaviors by reducing uncertainty (Yu and Dayan, 2005; Dayan and Yu, 2006).…”

Section: Discussionsupporting

confidence: 84%

“…Noradrenergic neurons in the locus coeruleus projecting to the frontal cortex of mice show higher firing rates when a choice leads to an unexpected outcome that requires adjusting behavior (Su and Cohen, 2022). Silencing the noradrenergic projections to the frontal cortex in mice impairs behavioral switching (Su and Cohen, 2022), while enhancing noradrenergic neuron activation in the locus coeruleus can increase the speed of behavioral switching in mice (McBurney-Lin et al, 2022). These recent insights suggest that noradrenergic modulation of prefrontal circuits might be a key mechanism in the nonhuman primate (NHP) brain for the flexible switching of complex cognitive states such as the updating of attention sets.…”

Section: Introductionmentioning

confidence: 99%

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Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum

Hassani,

Womelsdorf

2023

Preprint

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The noradrenergic system is implicated to support behavioral flexibility by increasing exploration during periods of uncertainty and by enhancing working memory for goal-relevant stimuli. Possible sources mediating these pro-cognitive effects are alpha-2A adrenoceptors in prefrontal cortex or the anterior cingulate cortex facilitating fronto-striatal learning processes. We tested this hypothesis by selectively stimulating alpha-2ARs using Guanfacine during feature-based attentional set shifting in nonhuman primates. We found that alpha-2A stimulation improved learning from errors and facilitates updating the target feature of an attentional set. Neural recordings in the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (dlPFC), and the striatum showed that alpha-2A stimulation selectively enhanced the neural representation of negative reward prediction errors in neurons of the ACC and of positive prediction errors in the striatum, but not in dlPFC. This modulation was accompanied by enhanced encoding of the feature and location of the attended target across the fronto-striatal network. Enhanced learning was paralleled by enhanced encoding of outcomes in putative fast-spiking interneurons in the ACC, dlPFC, and striatum but not in broad spiking cells, pointing to an interneuron mediated mechanism of alpha-2AR action. These results illustrate that alpha-2A receptors causally support the noradrenergic enhancement of updating attention sets through an enhancement of prediction error signaling in the ACC and the striatum.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum

Hassani,

Womelsdorf

2023

Preprint

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“…In addition, NE may exert its effects on both neuronal and non-neuronal cells (Paukert et al, 2014; Mu et al, 2019), providing a rich substrate for broadcasting an ascending learning signal across large volumes of cortex. This learning signal may generalize beyond reinforcement learning; artificial excitation of LC changes sensory-driven learning as well (Glennon et al, 2019; Jordan and Keller, 2022; McBurney-Lin et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Two types of locus coeruleus norepinephrine neurons drive reinforcement learning

Cohen

2022

Preprint

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The cerebral cortex generates flexible behavior by learning. Reinforcement learning is thought to be driven by error signals in midbrain dopamine neurons. However, they project more densely to basal ganglia than cortex, leaving open the possibility of another source of learning signals for cortex. The locus coeruleus (LC) contains most of the brain's norepinephrine (NE) neurons and project broadly to cortex. We measured activity from identified mouse LC-NE neurons during a behavioral task requiring ongoing learning from reward prediction errors (RPEs). We found two types of LC-NE neurons: neurons with wide action potentials (type I) were excited by positive RPE and showed an increasing relationship with change of choice likelihood. Neurons with thin action potentials (type II) were excited by lack of reward and showed a decreasing relationship with change of choice likelihood. Silencing LC-NE neurons changed future choices, as predicted from the electrophysiological recordings and a model of how RPEs are used to guide learning. We reveal functional heterogeneity of a neuromodulatory system in the brain and show that NE inputs to cortex act as a quantitative learning signal for flexible behavior.

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“…While photo-tagging, a method that combines electrophysiology and optogenetics to record from genetically identified neuronal populations, 41,42 has been used to record from LC-NA neurons, it only yields a limited number of *Address all correspondence to Vincent Breton-Provencher, vincent.breton-provencher@cervo.ulaval.ca identified neurons per recordings. 12,26,28,32,43,44 Therefore, neurophotonics has democratized research on the LC, making it more accessible to researchers beyond a few specialized labs. In this review, we will discuss two methods that have been applied to record LC-NA activity in the rodent brain and how they have advanced LC research.…”

Section: Introductionmentioning

confidence: 99%

Shining light on the noradrenergic system

Tanguay,

Bouchard,

Lévesque

et al. 2023

Neurophoton.

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Despite decades of research on the noradrenergic system, our understanding of its impact on brain function and behavior remains incomplete. Traditional recording techniques are challenging to implement for investigating in vivo noradrenergic activity, due to the relatively small size and the position in the brain of the locus coeruleus (LC), the primary location for noradrenergic neurons. However, recent advances in optical and fluorescent methods have enabled researchers to study the LC more effectively. Use of genetically encoded calcium indicators to image the activity of noradrenergic neurons and biosensors that monitor noradrenaline release with fluorescence can be an indispensable tool for studying noradrenergic activity. In this review, we examine how these methods are being applied to record the noradrenergic system in the rodent brain during behavior.

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The locus coeruleus mediates behavioral flexibility

Cited by 13 publications

References 63 publications

Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum

Noradrenergic alpha-2a Receptor Stimulation Enhances Prediction Error Signaling in Anterior Cingulate Cortex and Striatum

Two types of locus coeruleus norepinephrine neurons drive reinforcement learning

Shining light on the noradrenergic system

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