Locus coeruleus: a new look at the blue spot

Poe, Gina R.; Foote, Stephen L.; Eschenko, O; Johansen, Joshua P.; Bouret, Sébastien; Aston‐Jones, Gary; Harley, Carolyn W.; Manahan‐Vaughan, Denise; Weinshenker, David; Valentino, Rita J.; Berridge, Craig W.; Chandler, Daniel J.; Waterhouse, Barry D.; Sara, Susan J.

doi:10.1038/s41583-020-0360-9

Cited by 411 publications

(453 citation statements)

References 226 publications

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“…Alzheimer's disease (AD) is presently an incurable neurodegenerative disease leading to dementia with the number of worldwide cases predicted to triple over the next thirty years (Alzheimer's Disease International, 2019;Canter, Penney, & Tsai, 2016;World Health Organization, 2004). Post-mortem studies indicate that abnormally phosphorylated tau, an indicator of AD, begins to appear early in life in the locus coeruleus (LC), the primary source of cortical norepinephrine (Braak, Thal, Ghebremedhin, & Del Tredici, 2011;Ehrenberg et al, 2017;Poe et al, 2020;Stratmann et al, 2016;Theofilas, Dunlop, Heinsen, & Grinberg, 2015).…”

Section: Introductionmentioning

confidence: 99%

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Dahl

Mather

Werkle‐Bergner

et al. 2020

Preprint

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Abnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

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Section: Introductionmentioning

confidence: 99%

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Dahl

Mather

Werkle‐Bergner

et al. 2020

Preprint

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“…The locus coeruleus (LC) is the sole source of norepinephrine (NE) for >90% of the brain, and is critical for attention, behavioral flexibility, spatial navigation, and learning and memory (for review see (1)). LC degeneration, predominantly caused by hyperphosphorylated tau (pTau) deposition (2–5), is tightly associated with the transition from cognitively intact to amnestic mild cognitive impairment (aMCI) (2–4, 6) to dementia in AD patients (3, 6, 7).…”

Section: Introductionmentioning

confidence: 99%

Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

Goodman

Langner

Jackson

et al. 2020

Preprint

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The central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened β-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.Significance StatementThe locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer’s disease pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.

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“…Second, consistent with the idea that effort represents resource mobilization (Hockey, G. Robert 1997), decisions may require an estimation of the energization needed to ensure that the action under consideration can be successfully achieved (Paravlic et al 2018). A sizeable literature indicates that locus coeruleus noradrenergic (LC-NA) activity plays an important role in changing arousal states (Pfaff, Martin, and Faber 2012;Takahashi et al 2010;Poe et al 2020) by providing neuromodulatory input to the entire neocortex (Porrino and Goldman-Rakic 1982;Chandler, Lamperski, and Waterhouse 2013;Schwarz et al 2015), thereby facilitating energization (Varazzani et al 2015;Jahn et al 2018). NA activity can directly influence pupil size and is tightly linked to changes in pupil dilation (Joshi et al 2016;Reimer et al 2016;Gelbard-Sagiv et al 2018), making phasic, task-related pupil an accurate indicator of brain arousal states (Yüzgeç et al 2018;McGinley et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Anticipatory energization revealed by pupil and brain activity guides human effort-based decision making

Kurniawan

Grueschow

Ruff

2020

Preprint

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17An organism's behavioral success is determined by its ability to mobilize resources to overcome 18 challenges. This ability involves the noradrenergic system, indicated by the finding that pupil-size 19 increases proportionally with currently exerted effort. However, humans can deliberate in advance 20 whether to engage in effort in the future. It remains unclear how effort is represented in such an 21 anticipatory fashion during decision-making. We investigated this by measuring pupil responses while 22 participants decided whether to accept or reject rewards that required effort execution after the 23 experiment. We found a faster rate of pupillary dilation in decisions to accept high-effort rewards. This 24 was accompanied by stronger fMRI activity in anterior cingulate cortex (ACC) and anterior insula: When 25 accepting high-effort rewards, individuals with faster pupil dilation showed larger activity in these areas. 26Our results identify a brain process instantiating anticipatory arousal when humans prepare for a 27 physical challenge, potentially reflecting simulated energization. 28 30 31Should I go to the gym tonight or should I skip training? The ability to select actions by considering their 32 costs and benefits is crucial for survival in most animals 1 . Relatively unique to humans, however, is 33 the remarkable ability to take such choices in a purely anticipatory fashion, deciding about potential 34 future actions for which the potential benefits and costs are out of sight 2 . This ability is important for 35 planning as it allows us to deliberate for sequences of actions whether the effort of overcoming all 36 subsequent costs will be worth the associated rewards. 37Indeed, humans constantly simulate future rewards to make decisions. Cues associated with 38 reward trigger more vivid imagination of future events than neutral ones do 3 . There is also evidence 39 that we make better decisions by thinking about future events so vividly as if we were experiencing the 40 pleasure of the imagined rewards 4,5 . A decision to go to the gym might result from a mental simulation 41 of rewarding experiences such as the thrill from getting yelled at by that energetic spinning instructor 42 or the relaxing shower after the workout. Overwhelming evidence shows that both experienced and 43 anticipated rewards are signalled by activity in the dopaminergic (DA) system 6 , which also comprises 44 the core brain reward circuitry including the ventral striatum and ventromedial prefrontal cortex (vmPFC 45 7 ). These reward signals are thought to reflect learned associations between reward cues and 46 reinforcers 6 . But what is remarkable from this wealth of research is the consensus that DA not only 47 signals experienced but also purely anticipated rewards, confirming its pivotal role in decision making. 48By contrast, very little is known about how simulation of physical effort could guide choice. Here 49 two possible scenarios have been proposed. First, a prevailing idea from the effort discounting literature...

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Locus coeruleus: a new look at the blue spot

Cited by 411 publications

References 226 publications

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

Anticipatory energization revealed by pupil and brain activity guides human effort-based decision making

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