Hindbrain Double-Negative Feedback Mediates Palatability-Guided Food and Water Consumption.

Hunger and thirst have distinct goals but control similar ingestive behaviors, and little is known about neural processes that are shared between these behavioral states. We identify glutamatergic neurons in the peri-locus coeruleus (periLCVGLUT2 neurons) as a polysynaptic convergence node from separate energy-sensitive and hydration-sensitive cell populations. We develop methods for stable hindbrain calcium imaging in free-moving mice, which show that periLCVGLUT2 neurons are tuned to ingestive behaviors and respond similarly to food or water consumption. PeriLCVGLUT2 neurons are scalably inhibited by palatability and homeostatic need during consumption. Inhibition of periLCVGLUT2 neurons is rewarding and increases consumption by enhancing palatability and prolonging ingestion duration. These properties comprise a double-negative feedback relationship that sustains food or water consumption without affecting food- or water-seeking. PeriLCVGLUT2 neurons are a hub between hunger and thirst that specifically controls motivation for food and water ingestion, which is a factor that contributes to hedonic overeating and obesity.

Brain mechanisms of insomnia: new perspectives on causes and consequences.

While insomnia is the second most common mental disorder, progress in our understanding of underlying neurobiological mechanisms has been limited. The present review addresses the definition and prevalence of insomnia and explores its subjective and objective characteristics across the 24-hour day. Subsequently, the review extensively addresses how the vulnerability to develop insomnia is affected by genetic variants, early life stress, major life events, and brain structure and function. Further supported by the clear mental health risks conveyed by insomnia, the integrated findings suggest that the vulnerability to develop insomnia could rather be found in brain circuits regulating emotion and arousal than in circuits involved in circadian and homeostatic sleep regulation. Finally, a testable model is presented. The model proposes that in people with a vulnerability to develop insomnia, the locus coeruleus is more sensitive to-or receives more input from-the salience network and related circuits, even during rapid eye movement sleep, when it should normally be sound asleep. This vulnerability may ignite a downward spiral of insufficient overnight adaptation to distress, resulting in accumulating hyperarousal, which, in turn, impedes restful sleep and moreover increases the risk of other mental health adversity. Sensitized brain circuits are likely to be subjectively experienced as "sleeping with one eye open". The proposed model opens up the possibility for novel intervention studies and animal studies, thus accelerating the ignition of a neuroscience of insomnia, which is direly needed for better treatment.

Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus.

The locus coeruleus (LC) is a small nucleus in the pons from which ascending and descending projections innervate major parts of the central nervous system. Its major transmitter is norepinephrine (NE). This system is evolutionarily conserved, including in humans, and its functions are associated with wakefulness and related to disorders, such as depression. Here, we performed single-cell ribonucleic acid-sequencing (RNA-seq) to subdivide neurons in the LC (24 clusters in total) into 3 NE, 17 glutamate, and 5 γ-aminobutyric acid (GABA) subtypes, and to chart their neuropeptide, cotransmitter, and receptor profiles. We found that NE neurons expressed at least 19 neuropeptide transcripts, notably galanin (Gal) but not Npy, and >30 neuropeptide receptors. Among the galanin receptors, Galr1 was expressed in ~19% of NE neurons, as was also confirmed by in situ hybridization. Unexpectedly, Galr1 was highly expressed in GABA neurons surrounding the NE ensemble. Patch-clamp electrophysiology and cell-type-specific Ca2+-imaging using GCaMP6s revealed that a GalR1 agonist inhibits up to ~35% of NE neurons. This effect is direct and does not rely on feed-forward GABA inhibition. Our results define a role for the galanin system in NE functions, and a conceptual framework for the action of many other peptides and their receptors.

Cell-type-specific optogenetic stimulation of the locus coeruleus induces slow-onset potentiation and enhances everyday memory in rats.

Memory formation is typically divided into phases associated with encoding, storage, consolidation, and retrieval. The neural determinants of these phases are thought to differ. This study first investigated the impact of the experience of novelty in rats incurred at a different time, before or after, the precise moment of memory encoding. Memory retention was enhanced. Optogenetic activation of the locus coeruleus mimicked this enhancement induced by novelty, both when given before and after the moment of encoding. Optogenetic activation of the locus coeruleus also induced a slow-onset potentiation of field potentials in area CA1 of the hippocampus evoked by CA3 stimulation. Despite the locus coeruleus being considered a primarily noradrenergic area, both effects of such stimulation were blocked by the dopamine D1/D5 receptor antagonist SCH 23390. These findings substantiate and enrich the evidence implicating the locus coeruleus in cellular aspects of memory consolidation in hippocampus.

Role of the Locus Coeruleus Arousal Promoting Neurons in Maintaining Brain Criticality across the Sleep-Wake Cycle.

Sleep control depends on a delicate interplay among brain regions. This generates a complex temporal architecture with numerous sleep-stage transitions and intermittent fluctuations to micro-states and brief arousals. These temporal dynamics exhibit hallmarks of criticality, suggesting that tuning to criticality is essential for spontaneous sleep-stage and arousal transitions. However, how the brain maintains criticality remains not understood. Here, we investigate θ- and δ-burst dynamics during the sleep-wake cycle of rats (Sprague-Dawley, adult male) with lesion in the wake-promoting locus coeruleus (LC). We show that, in control rats, θ- and δ-bursts exhibit power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, as well as power-law long-range temporal correlations (LRTCs)-typical of non-equilibrium systems self-organizing at criticality. Furthermore, consecutive θ- and δ-bursts durations are characterized by anti-correlated coupling, indicating a new class of self-organized criticality that emerges from underlying feedback between neuronal populations and brain areas involved in generating arousals and sleep states. In contrast, we uncover that LC lesion leads to alteration of θ- and δ-burst critical features, with change in duration distributions and correlation properties, and increase in θ-δ coupling. Notably, these LC-lesion effects are opposite to those observed for lesions in the sleep-promoting ventrolateral preoptic (VLPO) nucleus. Our findings indicate that critical dynamics of θ- and δ-bursts arise from a balanced interplay of LC and VLPO, which maintains brain tuning to criticality across the sleep-wake cycle-a non-equilibrium behavior in sleep micro-architecture at short timescales that coexists with large-scale sleep-wake homeostasis.

Noradrenergic alterations in Parkinson's disease: a combined 11C-yohimbine PET/neuromelanin MRI study.

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease.

Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease.

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the association of reduced LC norepinephrine signaling with brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8-12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is strongest in fronto-motor cortices, where alpha activity is inversely related to attention scores. Using neurochemical colocalization analyses with normative atlases of neurotransmitter transporters, we also show that this effect is more pronounced in regions with high densities of norepinephrine transporters. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15-29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity is related to dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.

Microstructural associations between locus coeruleus, cortical, and subcortical regions are modulated by astrocyte reactivity: a 7T MRI adult lifespan study.

The locus coeruleus-norepinephrine system plays a key role in supporting brain health along the lifespan, notably through its modulatory effects on neuroinflammation. Using ultra-high field diffusion magnetic resonance imaging, we examined whether microstructural properties (neurite density index and orientation dispersion index) in the locus coeruleus were related to those in cortical and subcortical regions, and whether this was modulated by plasma glial fibrillary acidic protein levels, as a proxy of astrocyte reactivity. In our cohort of 60 healthy individuals (30 to 85 yr, 50% female), higher glial fibrillary acidic protein correlated with lower neurite density index in frontal cortical regions, the hippocampus, and the amygdala. Furthermore, under higher levels of glial fibrillary acidic protein (above ~ 150 pg/mL for cortical and ~ 145 pg/mL for subcortical regions), lower locus coeruleus orientation dispersion index was associated with lower orientation dispersion index in frontotemporal cortical regions and in subcortical regions. Interestingly, individuals with higher locus coeruleus orientation dispersion index exhibited higher orientation dispersion index in these (sub)cortical regions, despite having higher glial fibrillary acidic protein levels. Together, these results suggest that the interaction between locus coeruleus-norepinephrine cells and astrocytes can signal a detrimental or neuroprotective pathway for brain integrity and support the importance of maintaining locus coeruleus neuronal health in aging and in the prevention of age-related neurodegenerative diseases.

Spatial contextual recognition memory updating is modulated by dopamine release in the dorsal hippocampus from the locus coeruleus.

Detecting novelty is critical to consolidate declarative memories, such as spatial contextual recognition memory. It has been shown that stored memories, when retrieved, are susceptible to modification, incorporating new information through an updating process. Catecholamine release in the hippocampal CA1 region consolidates an object location memory (OLM). This work hypothesized that spatial contextual memory updating could be changed by decreasing catecholamine release in the hippocampal CA1 terminals from the locus coeruleus (LC). In a mouse model expressing Cre-recombinase under the control of the tyrosine hydroxylase (TH) promoter, memory updating was impaired by photoinhibition of the CA1 catecholaminergic terminals from the LC (LC-CA1) but not from the ventral tegmental area (VTA-CA1). In vivo microdialysis confirmed that the extracellular concentration of both dopamine (DA) and noradrenaline (NA) decreased after photoinhibition of the LC-CA1 terminals (but not VTA-CA1) during the OLM update session. Furthermore, DA D1/D5 and beta-adrenergic receptor antagonists disrupted behavior, but only the former impaired memory updating. Finally, photoinhibition of LC-CA1 terminals suppressed long-term potentiation (LTP) induction in Schaffer's collaterals as a plausible mechanism for memory updating. These data will help understand the underpinning mechanisms of DA in spatial contextual memory updating.

Distinct ensembles in the noradrenergic locus coeruleus are associated with diverse cortical states.

The noradrenergic locus coeruleus (LC) is a controller of brain and behavioral states. Activating LC neurons en masse by electrical or optogenetic stimulation promotes a stereotypical "activated" cortical state of high-frequency oscillations. However, it has been recently reported that spontaneous activity of LC cell pairs has sparse yet structured time-averaged cross-correlations, which is unlike the highly synchronous neuronal activity evoked by stimulation. Therefore, LC population activity could consist of distinct multicell ensembles each with unique temporal evolution of activity. We used nonnegative matrix factorization (NMF) to analyze large populations of simultaneously recorded LC single units in the rat LC. NMF identified ensembles of spontaneously coactive LC neurons and their activation time courses. Since LC neurons selectively project to specific forebrain regions, we hypothesized that distinct ensembles activate during different cortical states. To test this hypothesis, we calculated band-limited power and spectrograms of local field potentials in cortical area 24a aligned to spontaneous activations of distinct LC ensembles. A diversity of state modulations occurred around activation of different LC ensembles, including a typical activated state with increased high-frequency power as well as other states including decreased high-frequency power. Thus­in contrast to the stereotypical activated brain state evoked by en masse LC stimulation­spontaneous activation of distinct LC ensembles is associated with a multitude of cortical states.

Prostaglandin E2 Induces Long-Lasting Inhibition of Noradrenergic Neurons in the Locus Coeruleus and Moderates the Behavioral Response to Stressors.

Neuronal activity is modulated not only by inputs from other neurons but also by various factors, such as bioactive substances. Noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons) are involved in diverse physiological functions, including sleep/wakefulness and stress responses. Previous studies have identified various substances and receptors that modulate LC-NA neuronal activity through techniques including electrophysiology, calcium imaging, and single-cell RNA sequencing. However, many substances with unknown physiological significance have been overlooked. Here, we established an efficient screening method for identifying substances that modulate LC-NA neuronal activity through intracellular calcium ([Ca2+]i) imaging using brain slices. Using both sexes of mice, we screened 53 bioactive substances, and identified five novel substances: gastrin-releasing peptide, neuromedin U, and angiotensin II, which increase [Ca2+]i, and pancreatic polypeptide and prostaglandin D2, which decrease [Ca2+]i Among them, neuromedin U induced the greatest response in female mice. In terms of the duration of [Ca2+]i change, we focused on prostaglandin E2 (PGE2), since it induces a long-lasting decrease in [Ca2+]i via the EP3 receptor. Conditional knock-out of the receptor in LC-NA neurons resulted in increased depression-like behavior, prolonged wakefulness in the dark period, and increased [Ca2+]i after stress exposure. Our results demonstrate the effectiveness of our screening method for identifying substances that modulate a specific neuronal population in an unbiased manner and suggest that stress-induced prostaglandin E2 can suppress LC-NA neuronal activity to moderate the behavioral response to stressors. Our screening method will contribute to uncovering previously unknown physiological functions of uncharacterized bioactive substances in specific neuronal populations.SIGNIFICANCE STATEMENT Bioactive substances modulate the activity of specific neuronal populations. However, since only a limited number of substances with predicted effects have been investigated, many substances that may modulate neuronal activity have gone unrecognized. Here, we established an unbiased method for identifying modulatory substances by measuring the intracellular calcium signal, which reflects neuronal activity. We examined noradrenergic (NA) neurons in the locus coeruleus (LC-NA neurons), which are involved in diverse physiological functions. We identified five novel substances that modulate LC-NA neuronal activity. We also found that stress-induced prostaglandin E2 (PGE2) may suppress LC-NA neuronal activity and influence behavioral outcomes. Our screening method will help uncover previously overlooked functions of bioactive substances and provide insight into unrecognized roles of specific neuronal populations.

Effects of Adult Age and Functioning of the Locus Coeruleus Norepinephrinergic System on Reward-Based Learning.

Age-related impairments in value representations and updating during decision-making and reward-based learning are often related to age-related attenuation in the catecholamine system such as dopamine (DA) and norepinephrine (NE). However, it is unclear to what extent age-related declines in NE functioning in humans affect reward-based decision-making. We conducted a probabilistic decision-making task and applied a Q-learning model to investigate participants' anticipatory values and value sensitivities. Task-related pupil dilations and locus coeruleus (LC) magnetic resonance imaging (MRI) contrast, which served as a potential window of the LC-NE functions, were assessed in younger and older adults. Results showed that in both choice and feedback phases, younger adults' (N = 42, 22 males) pupil dilations negatively correlated with anticipatory values, indicating uncertainty about outcome probabilities. Uncertainty-evoked pupil dilations in older adults (N = 41, 27 males) were smaller, indicating age-related impairments in value estimation and updating. In both age groups, participants who showed a larger uncertainty-evoked pupil dilation exhibited a higher value sensitivity as reflected in the ß parameter of the reinforcement Q-learning model. Furthermore, older adults (N = 34, 29 males) showed a lower LC-MRI contrast than younger adults (N = 25, 15 males). The LC-MRI contrast positively correlated with value sensitivity only in older but not in younger adults. These findings suggest that task-related pupillary responses can reflect age-related deficits in value estimation and updating during reward-based decision-making. Our evidence with the LC-MRI contrast further showed the age-related decline of the LC structure in modulating value representations during reward-based learning.SIGNIFICANCE STATEMENT Age-related impairments in value representation and updating during reward-based learning are associated with declines in the catecholamine modulation with age. However, it is unclear how age-related declines in the LC-NE system may affect reward-based learning. Here, we show that compared with younger adults, older adults exhibited reduced uncertainty-induced pupil dilations, suggesting age-related deficits in value estimation and updating. Older adults showed a lower structural MRI of the LC contrast than younger adults, indicating age-related degeneration of the LC structure. The association between the LC-MRI contrast and value sensitivity was only observed in older adults. Our findings may demonstrate a pioneering model to unravel the role of the LC-NE system in reward-based learning in aging.

Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.

In Vivo Photoadduction of Anesthetic Ligands in Mouse Brain Markedly Extends Sedation and Hypnosis.

Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi-m-propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology.SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action.

In search of the locus coeruleus: guidelines for identifying anatomical boundaries and electrophysiological properties of the blue spot in mice, fish, finches, and beyond.

Our understanding of human brain function can be greatly aided by studying analogous brain structures in other organisms. One brain structure with neurochemical and anatomical homology throughout vertebrate species is the locus coeruleus (LC), a small collection of norepinephrine (NE)-containing neurons in the brainstem that project throughout the central nervous system. The LC is involved in nearly every aspect of brain function, including arousal and learning, which has been extensively examined in rats and nonhuman primates using single-unit recordings. Recent work has expanded into putative LC single-unit electrophysiological recordings in a nonmodel species, the zebra finch. Given the importance of correctly identifying analogous structures as research efforts expand to other vertebrates, we suggest adoption of consensus anatomical and electrophysiological guidelines for identifying LC neurons across species when evaluating brainstem single-unit spiking or calcium imaging. Such consensus criteria will allow for confident cross-species understanding of the roles of the LC in brain function and behavior.

Response of nitrergic system in the brain of rat conditioned to intracranial self-stimulation.

The role of nitrergic system in modulating the action of psychostimulants on reward processing is well established. However, the relevant anatomical underpinnings and scope of the involved interactions with mesolimbic dopaminergic system have not been clarified. Using immunohistochemistry, we track the changes in neuronal nitric oxide synthase (nNOS) containing cell groups in the animals conditioned to intracranial self-stimulation (ICSS) via an electrode implanted in the lateral hypothalamus-medial forebrain bundle (LH-MFB) area. An increase in the nNOS immunoreactivity was noticed in the cells and fibers in the ventral tegmental area (VTA) and nucleus accumbens shell (AcbSh), the primary loci of the reward system. In addition, nNOS was up-regulated in the nucleus accumbens core (AcbC), vertical limb of diagonal band (VDB), locus coeruleus (LC), lateral hypothalamus (LH), superficial gray layer (SuG) of the superior colliculus, and periaqueductal gray (PAG). The brain tissue fragments drawn from these areas showed a change in nNOS mRNA expression, but in opposite direction. Intracerebroventricular (icv) administration of nNOS inhibitor, 7-nitroindazole (7-NI) showed decreased lever press activity in a dose-dependent manner in ICSS task. While an increase in the dopamine (DA) and 3, 4-dihydroxyphenylacetic acid (DOPAC) efflux was noted in the microdialysates collected from the AcbSh of ICSS rats, pre-administration of 7-NI (icv route) attenuated the response. The study identifies nitrergic centers that probably mediate sensory, cognitive, and motor components of the goal-directed behavior.

Indole induces anxiety-like behaviour in mice mediated by brainstem locus coeruleus activation.

The gut microbiota produces metabolites that enrich the host metabolome and play a part in host physiology, including brain functions. Yet the biological mediators of this gut-brain signal transduction remain largely unknown. In this study, the possible role of the gut microbiota metabolite indole, originating from tryptophan, was investigated. Oral administration of indole to simulate microbial overproduction of this compound in the gut consistently led to impaired locomotion and anxiety-like behaviour in both C3H/HeN and C57BL/6J mice. By employing c-Fos protein expression mapping in mice, we observed a noticeable increase in brain activation within the dorsal motor nucleus of the vagus nerve (DMX) and the locus coeruleus (LC) regions in a dose-dependent manner. Further immune co-labelling experiments elucidated that the primary cells activated within the LC were tyrosine hydroxylase positive. To delve deeper into the mechanistic aspects, we conducted chemogenetic activation experiments on LC norepinephrine neurons with two doses of clozapine N-oxide (CNO). Low dose of CNO at 0.5 mg/kg induced no change in locomotion but anxiety-like behaviour, while high dose of CNO at 2 mg/kg resulted in locomotion impairment and anxiety-like behaviour. These findings support the neuroactive roles of indole in mediating gut-brain communication. It also highlights the LC as a novel hub in the gut-brain axis, encouraging further investigations.

Neuromelanin-sensitive magnetic resonance imaging: Possibilities and promises as an imaging biomarker for Parkinson's disease.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.

Locus coeruleus microstructural integrity is associated with vigilance vulnerability to sleep deprivation.

Insufficient sleep compromises cognitive performance, diminishes vigilance, and disrupts daily functioning in hundreds of millions of people worldwide. Despite extensive research revealing significant variability in vigilance vulnerability to sleep deprivation, the underlying mechanisms of these individual differences remain elusive. Locus coeruleus (LC) plays a crucial role in the regulation of sleep-wake cycles and has emerged as a potential marker for vigilance vulnerability to sleep deprivation. In this study, we investigate whether LC microstructural integrity, assessed by fractional anisotropy (FA) through diffusion tensor imaging (DTI) at baseline before sleep deprivation, can predict impaired psychomotor vigilance test (PVT) performance during sleep deprivation in a cohort of 60 healthy individuals subjected to a rigorously controlled in-laboratory sleep study. The findings indicate that individuals with high LC FA experience less vigilance impairment from sleep deprivation compared with those with low LC FA. LC FA accounts for 10.8% of the variance in sleep-deprived PVT lapses. Importantly, the relationship between LC FA and impaired PVT performance during sleep deprivation is anatomically specific, suggesting that LC microstructural integrity may serve as a biomarker for vigilance vulnerability to sleep loss.

The influence of transcranial direct current stimulation to the trigeminal nerve on attention and arousal.

One mechanism by which transcranial direct current stimulation (tDCS) has been proposed to improve attention is by transcutaneous stimulation of cranial nerves, thereby activating the locus coeruleus (LC). Specifically, placement of the electrodes over the frontal bone and mastoid is thought to facilitate current flow across the face as a path of least resistance. The face is innervated by the trigeminal nerve, and the trigeminal nerve is interconnected with the LC. In this study, we tested whether stimulating the trigeminal nerve impacts indices of LC activity and performance on a sustained attention task. We replicated previous research that shows deterioration in task performance, increases in the rate of task-unrelated thoughts, and reduced pupil responses due to time on task irrespective of tDCS condition (sham, anodal, and cathodal stimulation). Importantly, tDCS did not influence pupil dynamics (pretrial or stimulus-evoked), self-reported attention state, nor task performance in active versus sham stimulation conditions. The findings reported here are consistent with theories about arousal centered on a hypothesized link between LC activity indexed by pupil size, task performance, and self-reported attention state but fail to support hypotheses that tDCS over the trigeminal nerve influences indices of LC function.