Locus Coeruleus Activity Research Articles

Sex-specific alterations in corticotropin-releasing factor regulation of coerulear-cortical network activity

The locus coeruleus (LC)-norepinephrine system is a stress responsive system that regulates arousal and cognitive functions through extensive projections, including to the prefrontal cortex. LC-cortical circuits are activated by stressors, and this activation is thought to contribute to stress-induced impairments in executive function. Because corticotropin-releasing factor (CRF) is a mediator of stress-induced LC activation, we examined the effects of CRF administered into the LC of male and female rats on network activity of two functionally distinct regions of the PFC, the medial PFC (mPFC) and the orbitofrontal cortex (OFC). Network activity, measured as local field potentials, was recorded in awake animals before and after intra-LC infusion of aCSF or CRF (2 or 20 ng). CRF had qualitatively distinct effects on network activity in males and females with respect to dose, region and timecourse. CRF (20 ng) produced a prominent theta oscillation (7–9 Hz) selectively in female rats shortly after LC infusion and 20 min later. In contrast, in male rats, CRF (2 and 20 ng) decreased the amplitude of power in the 4–6 Hz range in the mPFC 10 min after injection. Lastly, CRF (20 ng) increased mPFC-OFC coherence in females and decreased mPFC-OFC coherence in males. In sum, these results show sex differences in CRF modulation of the LC-norepinephrine system that regulates prefrontal cortical networks, which may underlie sex differences in cognitive and behavioral responses to stress.

PO010 / #932 NOVELTY-RELATED LOCUS COERULEUS ACTIVATION RESCUES COGNITIVE DECLINE IN A PRETANGLE TAU ALZHEIMER’S DISEASE RAT MODEL: E-POSTER VIEWING

The earliest abnormality associated with Alzheimer’s Disease is the presence of hyperphosphorylated pretangle tau in locus coeruleus neurons [1]. Human brain studies reveal that pretangle tau in locus coeruleus neurons spreads to other brain regions resulting in memory loss and cognitive decline [1]. Locus coeruleus activity occurs in novelty- and stress-related patterns [2], and its neuron numbers and fiber density predict human cognition before death [3, 4, 5]. In an animal model that captures the features of human pretangle tau [6], we ask if locus coeruleus activity influences the effects of pretangle tau.

The locus coeruleus mediates behavioral flexibility

Behavioral flexibility is the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a tactile-based rule-shift detection task in which mice responded to left and right whisker deflections in a context-dependent manner and exhibited varying degrees of switching behavior. Recording spiking activity from optogenetically tagged neurons in the LC at millisecond precision during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation accelerated task switching and improved task performance. Overall, our study provides important evidence to reveal the link between LC activity and behavioral flexibility.

PO020 / #1042 THE ROAD TO REWARD AND AVERSIVE BEHAVIOR: INVOLVEMENT OF THE LOCUS COERULEUS TO THE BASOLATERAL AMYGDALA PATHWAY: E-POSTER VIEWING

Reward-seeking and aversion-deterrence behaviors are mediated in part by the locus coeruleus (LC) [1, 2], a brainstem structure significantly involved in the stress response and learning and memory. The LC signals opposing valences via two different firing modes: tonic and phasic. Specifically, high tonic and phasic LC activation signal negative and positive valence, respectively [1, 2]. The basolateral amygdala (BLA), an important structure downstream of the LC, particularly for the formation of fear memories [2, 3], has been suggested to signal opposing valences [4].

Tonic and phasic effects of reward on the pupil: implications for locus coeruleus function.

The locus coeruleus (LC), a nucleus in the pons of the brainstem, plays a significant role in attention and cognitive control. Here, we use an adapted auditory oddball paradigm and measured the pupil dilation response, to provide a marker of LC activity in humans. In Experiment 1, we show event-related pupil responses to rare auditory events which were further elevated by task relevant. In Experiment 2, by asking participants to silently count the number of oddballs, we demonstrated that the task-relevance elevation was not a result of the generation or execution of the manual response. In Experiment 3, we observed two separate effects of reward on the pupil response. First, we found an overall increase in pupil area in the high compared to the low-reward blocks: a sustained effect reminiscent of the tonic changes that occur in LC. Second, we found elevated event-related pupil responses to behaviourally relevant stimuli in the high-reward condition compared with the low-reward condition, consistent with phasic changes in LC in response to a stimulus. These results highlight the complexity of the relationship between the pupil response and reward, and the inferred role of LC in both top-down and bottom-up cognitive control.

Challenges and Perspectives of Mapping Locus Coeruleus Activity in the Rodent with High-Resolution fMRI.

The locus coeruleus (LC) is one of the most commonly studied brainstem nuclei when investigating brain–behavior associations. The LC serves as a major brainstem relay for both ascending bottom-up and descending top-down projections. Specifically, noradrenergic (NA) LC neurons not only connect globally to higher-order subcortical nuclei and cortex to mediate arousal and attention but also directly project to other brainstem nuclei and to the spinal cord to control autonomic function. Despite the extensive investigation of LC function using electrophysiological recordings and cellular/molecular imaging for both cognitive research and the contribution of LC to different pathological states, the role of neuroimaging to investigate LC function has been restricted. For instance, it remains challenging to identify LC-specific activation with functional MRI (fMRI) in animal models, due to the small size of this nucleus. Here, we discuss the complexity of fMRI applications toward LC activity mapping in mouse brains by highlighting the technological challenges. Further, we introduce a single-vessel fMRI mapping approach to elucidate the vascular specificity of high-resolution fMRI signals coupled to LC activation in the mouse brainstem.

Neural circuit for social authentication in song learning

Social interactions are essential when learning to communicate. In human speech and bird song, infants must acquire accurate vocalization patterns and learn to associate them with live tutors and not mimetic sources. However, the neural mechanism of social reality during vocal learning remains unknown. Here, we characterize a neural circuit for social authentication in support of accurate song learning in the zebra finch. We recorded neural activity in the attention/arousal state control center, the locus coeruleus (LC), of juvenile birds during song learning from a live adult tutor. LC activity increased with real, not artificial, social information during learning that enhanced the precision and robustness of the learned song. During live social song learning, LC activity regulated long-term song-selective neural responsiveness in an auditory memory region, the caudomedial nidopallium (NCM). In accord, optogenetic inhibition of LC presynaptic signaling in the NCM reduced NCM neuronal responsiveness to live tutor singing and impaired song learning. These results demonstrate that the LC-NCM neural circuit integrates sensory evidence of real social interactions, distinct from song acoustic features, to authenticate song learning. The findings suggest a general mechanism for validating social information in brain development.

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent.

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli – context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

Pupil-linked Arousal Signals in the Midbrain Superior Colliculus.

The orienting response evoked by the appearance of a salient stimulus is modulated by arousal; however, neural underpinnings for the interplay between orienting and arousal are not well understood. The superior colliculus (SC), causally involved in multiple components of the orienting response including gaze and attention shifts, receives not only multisensory and cognitive inputs but also arousal-regulated inputs from various cortical and subcortical structures. To investigate the impact of moment-by-moment fluctuations in arousal on orienting saccade responses, we used microstimulation of the monkey SC to trigger saccade responses, and we used pupil size and velocity to index the level of arousal at stimulation onset because these measures correlate with changes in brain states and locus coeruleus activity. Saccades induced by SC microstimulation correlated with prestimulation pupil velocity, with higher pupil velocities on trials without evoked saccades than with evoked saccades. In contrast, prestimulation absolute pupil size did not correlate with saccade behavior. Moreover, pupil velocity correlated with evoked saccade latency and metrics. Together, our results demonstrated that small fluctuations in arousal, indexed by pupil velocity, can modulate the saccade response evoked by SC microstimulation in awake behaving monkeys.

Auditory Target Detection Enhances Visual Processing and Hippocampal Functional Connectivity.

Though dividing one’s attention between two input streams typically impairs performance, detecting a behaviorally relevant stimulus can sometimes enhance the encoding of unrelated information presented at the same time. Previous research has shown that selection of this kind boosts visual cortical activity and memory for concurrent items. An important unanswered question is whether such effects are reflected in processing quality and functional connectivity in visual regions and in the hippocampus. In this fMRI study, participants were asked to memorize a stream of naturalistic images and press a button only when they heard a predefined target tone (400 or 1,200 Hz, counterbalanced). Images could be presented with a target tone, with a distractor tone, or without a tone. Auditory target detection increased activity throughout the ventral visual cortex but lowered it in the hippocampus. Enhancements in functional connectivity between the ventral visual cortex and the hippocampus were also observed following auditory targets. Multi-voxel pattern classification of image category was more accurate on target tone trials than on distractor and no tone trials in the fusiform gyrus and parahippocampal gyrus. This effect was stronger in visual cortical clusters whose activity was more correlated with the hippocampus on target tone than on distractor tone trials. In agreement with accounts suggesting that subcortical noradrenergic influences play a role in the attentional boost effect, auditory target detection also caused an increase in locus coeruleus activity and phasic pupil responses. These findings outline a network of cortical and subcortical regions that are involved in the selection and processing of information presented at behaviorally relevant moments.

A novel link between locus coeruleus activity and amyloid-related cognitive decline

Recent work from Prokopiou, Engels-Domínguez et al. assessed locus coeruleus (LC) activity and its functional connectivity (FC) to forebrain regions during a novelty task in cognitively unimpaired adult individuals with varying degrees of amyloid deposition. Novelty increased LC activity and LC FC, but lower responses on these measures were associated with steeper cognitive decline in amyloid-positive individuals.

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

BackgroundThe noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.MethodsThe Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.ResultsActivation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.ConclusionThese findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Phasic and Tonic Locus Coeruleus Stimulation Associated Valence Learning Engages Distinct Adrenoceptors in the Rat Basolateral Amygdala.

Reward exploitation and aversion are mediated in part by the locus coeruleus (LC), a brainstem structure significantly involved in learning and memory via the release of norepinephrine. Different LC firing patterns are associated with different functions. Previously, we have shown that high tonic and phasic LC activation signal negative and positive valence, respectively, via basolateral amygdala (BLA) circuitry. Tonic LC activation is associated preferentially with BLA-central amygdala (CeA) activation, while phasic LC stimulation preferentially recruits the BLA-nucleus accumbens (NAc) pathway. Here, we ask if phasic and tonic LC activation-associated valence learning requires different adrenoceptors in the BLA, in comparison with the odor valence learning induced by natural reward and aversive conditioning. Using optogenetic activation of the LC and local drug infusions in the BLA, we show that phasic LC activation-induced positive odor valence learning is dependent on both α1 and β-adrenoceptors, whereas tonic LC activation induced-negative odor valence learning depends on β-adrenoceptors only. In parallel, both α1 and β-adrenoceptors were required in the odor valence learning induced by reward while aversive conditioning was dependent on β-adrenoceptors. Phasic stimulation and reward conditioning likewise activated more NAc-projectors of the BLA, in comparison to tonic and aversive conditioning. There was a higher proportion of α1+ cells in the NAc-projectors compared to CeA-projectors in the BLA. Together, these results provide insight into the mechanisms underlying the effects of tonic and phasic activation of the LC, and more generally, negative and positive valence signaling.

Temporal dynamics of locus coeruleus modulation of stress-induced antinociception

Pain and stress are largely interdependent. Targeting stress pathways for pain relief is a novel potential therapeutic strategy. However, to take this approach we need to better understand the mechanisms by which stress influences pain. The locus coeruleus (LC) provides the largest noradrenergic (NE) innervation to the central nervous system and is a major intersection of pain and stress neural circuitry. We seek to determine how stress engages the LC-NE system to alter nociception. Using a cell type-selective inhibitory chemogenetic targeting strategy, we show that inhibition of the LC-NE system reverses acute restraint stress-induced antinociception on a hot plate. However, this chemogenetic strategy lacks the temporal specificity necessary to distinguish whether the LC is required for discrete aspects of stress-induced antinociception, namely the experience of the primary stressor versus noxious stimulus detection and processing. To gain temporal precision for these purposes, we use inhibitory optogenetics to restrict cellular inhibition during either the primary stressor or noxious stimulus only. Our results show that LC activity during the experience of the noxious stimulus is not required to elicit stress-induced antinociception. However, somewhat surprisingly, LC activity is required to maintain normal nociceptive processing in the absence of stress. Given this information, we then sought to characterize endogenous LC activity during our stress-induced antinociception behavioral paradigm using in vivo fiber photometry of global LC calcium activity. In acute restraint stress, we demonstrate that LC calcium activity increases during bouts of struggle against the restraint. Additionally, LC calcium activity is increased during discrete nocifensive responses throughout noxious stimulus detection and processing. Together, our combined chemogenetic, optogenetic, and photometry results suggest the LC tone exerts some level of basal antinociception and that the LC may initiate the process of stress-induced antinociception during the primary stressor rather than during the experience of noxious sensation. Grant support from R01 NS117899-01 F31 NS124301-01.

Investigating the Role of the Locus Coeruleus in Periaqueductal Gray-mediated Antinociception

Activity in the ventrolateral periaqueductal gray (vlPAG) has been shown to be antinociceptive and is considered to be a major component in the expression of opioid drug-induced analgesia. Canonically, opioids disinhibit vlPAG activity, which modulates neuronal responses in the rostroventral medulla (RVM) and ultimately gates spinal outflow of nociceptive information via serotonergic and opioidergic mechanisms in the spinal dorsal horn. Fundamental pharmacological studies, however, indicate that spinal noradrenergic signaling is consistently implicated in opioid antinociception, suggesting that there is a gap in our knowledge of how the vlPAG may control the release of antinociceptive neuromodulators in the dorsal horn through different output regions. Although the locus coeruleus (LC) has been shown to modulate nociception, its role in and recruitment by the canonical descending circuitry is unclear. Using genetically-encoded and anatomically-targeted viral tools, immunohistochemistry, and acute pain behavior assays in conjunction with intrathecal pharmacology in mice, we show that activity in the vlPAG is necessary for the expression of systemic morphine analgesia at low doses, and that both systemic morphine-induced and PAG-driven antinociception require opioidergic and noradrenergic signaling in the spinal cord. Additionally, we find that vlPAG projection neurons send branching axons to both the RVM and LC, which may account for the LC activation we observed in both opioid-induced and PAG-driven antinociception. These findings reveal a previously underappreciated architecture of the descending pain modulatory circuitry and advance our understanding of the circuit mechanisms by which morphine produces analgesia. Grant support from NIDA R00 DA034648, Rita Allen Foundation (non-profit), Klingenstein-Simons Foundation (non-profit).

When the Locus Coeruleus Speaks Up in Sleep: Recent Insights, Emerging Perspectives.

For decades, numerous seminal studies have built our understanding of the locus coeruleus (LC), the vertebrate brain’s principal noradrenergic system. Containing a numerically small but broadly efferent cell population, the LC provides brain-wide noradrenergic modulation that optimizes network function in the context of attentive and flexible interaction with the sensory environment. This review turns attention to the LC’s roles during sleep. We show that these roles go beyond down-scaled versions of the ones in wakefulness. Novel dynamic assessments of noradrenaline signaling and LC activity uncover a rich diversity of activity patterns that establish the LC as an integral portion of sleep regulation and function. The LC could be involved in beneficial functions for the sleeping brain, and even minute alterations in its functionality may prove quintessential in sleep disorders.

Chemogenetic stimulation of tonic locus coeruleus activity strengthens the default mode network.

The default mode network (DMN) of the brain is functionally associated with a wide range of behaviors. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)–releasing noradrenergic neurons in the locus coeruleus (LC) on the mouse DMN. Chemogenetic-induced tonic LC activity decreased cerebral blood volume (CBV) and glucose uptake and increased synchronous low-frequency fMRI activity within the frontal cortices of the DMN. Fiber photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

The Nature of Noradrenergic Volume Transmission From Locus Coeruleus to Brainstem Mesencephalic Trigeminal Sensory Neurons.

Noradrenergic neurons in the locus coeruleus (LC) release noradrenaline (NA) that acts via volume transmission to activate extrasynaptic G-protein coupled receptors (GPCRs) in target cells throughout the brain. As the closest projection, the dorsal LC laterally adjoins the mesencephalic trigeminal nucleus (MTN), in which proprioceptive primary sensory neurons innervating muscle spindles of jaw-closing muscles are exceptionally located. MTN neurons express α2-adrenergic receptors (α2-ARs) and display hyperpolarization-activated cyclic nucleotide-gated (HCN) currents (Ihs), which is downregulated by α2-AR activation. To quantify the activity-dependent outcome of volume transmission of NA from LC to MTN, we investigated how direct LC activation inhibits Ih in MTN neurons by performing dual whole-cell recordings from LC and MTN neurons. Repetition of 20 Hz spike-train evoked with 1-s current-pulse in LC neurons every 30 s resulted in a gradual decrease in Ih evoked every 30 s, revealing a Hill-type relationship between the number of spike-trains in LC neurons and the degree of Ih inhibition in MTN neurons. On the other hand, when microstimulation was applied in LC every 30 s, an LC neuron repeatedly displayed a transient higher-frequency firing followed by a tonic firing at 5–10 Hz for 30 s. This subsequently caused a similar Hill-type inhibition of Ih in the simultaneously recorded MTN neuron, but with a smaller Hill coefficient, suggesting a lower signal transduction efficacy. In contrast, 20 Hz activity induced by a 1-s pulse applied every 5–10 s caused only a transient facilitation of Ih inhibition followed by a forced termination of Ih inhibition. Thus, the three modes of LC activities modulated the volume transmission to activate α2-adrenergic GPCR to differentially inhibit Ih in MTN neurons.

Activation of the Locus Coeruleus Mediated by Designer Receptor Exclusively Activated by Designer Drug Restores Descending Nociceptive Inhibition after Traumatic Brain Injury in Rats.

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.

マウス青斑核ニューロン活動に対するアセトアミノフェンの効果

マウス青斑核ニューロン活動に対するアセトアミノフェンの効果