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To better understand the relationship between input and output connectivity for neurons of interest in specific brain regions, a viral-genetic tracing approach is used to identify input based on a combination of neurons’ projection and cell type, as illustrated in a study of locus coeruleus noradrenaline neurons. Noradrenaline circuit architecture New circuit tracing techniques have steadily increased our knowledge of the connectivity between brain regions and how such links may contribute to function and information processing. Here, Liqun Luo and colleagues expand this toolbox to include TRIO, a new strategy designed to characterize the input–output relationships between genetically specified populations of neurons. As a proof of concept, input–output tracing relationships and projection patterns were completed for the noradrenaline neurons of the locus coeruleus. Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input–output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The ‘tracing the relationship between input and output’ method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input–output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH + ) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH + neurons project more profusely than ventral tegmental area TH + neurons to the hippocampus, optogenetic activation of locus coeruleus TH + neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH + photoactivation are sensitive to hippocampal D 1 /D 5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo . Thus, locus coeruleus TH + neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus. Projections from the locus coeruleus, an area typically defined by noradrenergic signalling, to the hippocampus drive novelty-based memory enhancement through possible co-release of dopamine. Memory consolidation in the locus coeruleus Memory retention can be enhanced when something novel or categorically relevant occurs shortly before or after the time of memory encoding, as in 'flashbulb memory'. Dopamine-based mechanisms originating in the ventral tegmental area have been implicated in the phenomenon. These authors suggest that projections from the locus coeruleus—typically defined by noradrenergic signalling—to the hippocampus drive this novelty-based memory enhancement through the possible local release of dopamine.

The locus coeruleus (LC), or ‘blue spot’, is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.Major compelling questions about the functional role of the locus coeruleus nucleus that had been difficult to answer, given its remote location and diminutive size, have now become accessible via new neuroscience tools. In this Perspective, 14 investigators provide a historical context for recent discoveries and outline new vistas for investigation.

Abstract Background The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. Methods We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. Results We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. Conclusion The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.

A small population of brainstem noradrenaline neurons powerfully modulates global brain function, but how they regulate diverse—and at times opposing—functions is not clear. The authors report that a modular organization in this neuromodulatory system, coupled with context-dependent activation modes, controls the balance between opposing emotional and flexible learning states. Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.

The locus coeruleus (LC) is a nucleus within the brainstem associated with physiological arousal and altered structure and function in the context of neurological conditions. Pathologies related to difficulties with attention have previously been associated with abnormalities in neurotransmitter production and sensitivity, suggesting the possibility of abnormality in neurotransmitter‐producing neural regions. One such region is the LC, associated with norepinephrine production. To examine the possibility that LC alteration is associated with inattentive symptom reporting, regression analyses were performed using neuromelanin contrast ratios and volume in a sample of 141 individuals age‐ranged from 8 to 54. Mediation modeling was subsequently performed to examine the relationship between neuromelanin contrast and volume in regard to inattentive behavior. We found that the structural integrity value of the LC, especially in the right hemisphere, showed a significant negative association with the level of the individual's inattentiveness score. LC volume was also significantly positively associated with inattention, and this finding was also lateralized to the right LC. Interestingly, an inverse association was found between structural integrity and volume. These findings support the relationship between LC and attention‐related behavior through both neuromelanin‐sensitive and structural imaging, with important implications for the association between regional structure and function. To examine the possibility that LC alteration is associated with inattentive symptom reporting, a set of regression and mediation analyses was performed using structural integrity value (neuromelanin contrast ratio) and volume size of the LC in a sample of 141 individuals aged from 8 to 54. We found that the structural integrity value of the LC, especially in the right hemisphere, showed a significant negative association with the level of an individual's inattentiveness score.

Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain.

Phasic activation of locus coeruleus (LC)-norepinephrine (NE) neurons is associated with focused attention and behavioral responses to salient stimuli. We used cell-type–specific optogenetics and single-unit neurophysiology to identify how LC activity influences neural encoding of sensory information. We found that phasic, but not tonic, LC-NE photoactivation generated a distinct event-related potential (ERP) across cortical regions. Salient sensory stimuli (which innately trigger phasic LC activity) produced strong excitatory cortical responses during this ERP window. Application of weaker, nonsalient stimuli produced limited responses, but these responses were elevated to salient stimulus levels when they were temporally locked with phasic LC photoactivation. These results demonstrate that phasic LC activity enhances cortical encoding of salient stimuli by facilitating long-latency signals within target regions in response to stimulus intensity/salience. The LC-driven salience signal identified here provides a measure of phasic LC activity that can be used to investigate the LC’s role in attentional processing across species.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer’s disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [18F]MK6240 and [18F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [18F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t186 = −4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = −0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

Accumulating evidence suggests that α-synuclein aggregates—a defining pathology of Parkinson's disease—display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease. In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons. Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11C-donepezil uptake (−0·322, 95% CI −0·112 to −0·531; p=0·0020), 123I-MIBG heart:mediastinum ratio (−0·508, −0·353 to −0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (−0·059, −0·019 to −0·099; p=0·0028), and putaminal 18F-DOPA uptake (Ki; −0·0023, −0·0009 to −0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11C-donepezil (p=0·39), 123I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001). Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.