Explore the vast range of titles available.

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.

Models of cognitive control posit a key modulatory role for the pontine locus coeruleus-norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.

Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be \"switched off\" by the alpha2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary \"fatigue waves\" (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption 1 , 2 . By contrast, oral sodium detection rapidly quenches sodium appetite 3 , 4 , suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste—but not sodium ingestion per se—is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance. Sodium appetite in mice is driven by a neural circuit that is focused on neurons of the pre-locus coeruleus and integrates the sensory detection of sodium and internal signals.

Norepinephrine (NE) modulates cognitive function, arousal, attention, and responses to novelty and stress, and it also regulates neuroinflammation. We previously demonstrated behavioral and immunomodulatory effects of beta-adrenergic pharmacology in mouse models of Alzheimer’s disease (AD). The current studies were designed to block noradrenergic signaling in 5XFAD mice through ( 1 ) chemogenetic inhibition of the locus coeruleus (LC), ( 2 ) pharmacologic blocking of β-adrenergic receptors, and ( 3 ) conditional deletion of β1- or β2-adrenergic receptors (adrb1 or adrb2) in microglia. First, brain-wide AD pathology was mapped in 3D by imaging immunolabeled, cleared 5XFAD brains to assess the overlap between amyloid beta (Aβ) pathology, reactive microglia, and the loss of tyrosine hydroxylase (TH) expression in the catecholaminergic system. To examine the effects of inhibiting the LC NE system in the 5XFAD model, inhibitory (Gi) DREADD receptors were expressed specifically in LC NE neurons. LC NE neurons were chronically inhibited through the subcutaneous pump administration of the DREADD agonist clozapine-N-oxide (CNO). Plasma and brains were collected for assessment of neuroinflammation and pathology. A separate cohort of 5XFAD mice was chronically dosed with the beta-adrenergic antagonist propranolol or vehicle and evaluated for behavior, as well as post-mortem neuroinflammation and pathology. Finally, we used 5XFAD mice with conditional deletion of either adrb1 or adrb2 in microglia to assess neuroinflammation and pathology mediated by β-adrenergic signaling. Using iDISCO+, light sheet fluorescence microscopy, and novel analyses, we detected widespread microgliosis and Aβ pathology, along with modest TH downregulation in fibers across multiple brain regions, in contrast to the spatially limited TH downregulation observed in neurons. Both chemogenetic inhibition of LC adrenergic signaling and pharmacological inhibition of beta-adrenergic receptors potentiated neuroinflammation without altering Aβ pathology. Conditional deletion of adrb1 in microglia did not affect neuroinflammation. Conditional deletion of adrb2 in microglia attenuated inflammation and pathology in females but had no effect in males. Overall, these data support previous observations demonstrating the immunomodulatory effects of beta-adrenergic signaling in the pathophysiology of brain disorders and suggest that adrenergic receptors on cell types other than microglia, such as astrocytes, may mediate some of the disease-modifying effects of β-adrenergic agonists in the brain. Highlights Brain-wide, unbiased detection of amyloid beta, microgliosis, and TH downregulation in somata and fibers in the 5XFAD mouse model of AD. Chemogenetic inhibition of LC potentiates neuroinflammation in 5XFAD mice. Beta-blockers also potentiate neuroinflammation in this mouse model of amyloidosis. Neither chemogenetic inhibition via DREADD nor beta-blockers exacerbate amyloid beta pathology. Genetic deletion of microglial adrb2 attenuates a select set of neuroinflammatory markers in female 5XFAD mice. Female mice have more extensive pathology and neuroinflammation than males in the 5XFAD mouse model of AD.

High levels of locus coeruleus (LC) tonic activity are associated with distraction and poor performance within a task. Adaptive gain theory (AGT; Aston-Jones & Cohen, 2005 ) suggests that this may reflect an adaptive function of the LC, encouraging search for more remunerative opportunities in times of low utility. Here, we examine whether stimulating LC tonic activity using designer receptors (DREADDs) promotes searching for better opportunities in a patch-foraging task as the value of a patch diminishes. The task required rats to decide repeatedly whether to exploit an immediate but depleting reward within a patch or to incur the cost of a time delay to travel to a new, fuller patch. Similar to behavior associated with high LC tonic activity in other tasks, we found that stimulating LC tonic activity impaired task performance, resulting in reduced task participation and increased response times and omission rates. However, this was accompanied by a more specific, predicted effect: a significant tendency to leave patches earlier, which was best explained by an increase in decision noise rather than a systematic bias to leave earlier (i.e., at higher values). This effect is consistent with the hypothesis that high LC tonic activity favors disengagement from current behavior, and the pursuit of alternatives, by augmenting processing noise. These results provide direct causal evidence for the relationship between LC tonic activity and flexible task switching proposed by AGT.

Locus coeruleus-noradrenergic (LC-NA) neurons have been suggested to be involved in the effects of general anesthetics. However, the contribution of LC-NA neurons during propofol anesthesia remains unknown. We aimed to elucidate the mechanism of action of propofol in the LC-NA neurons. LC-NA neurons from adult male mice were identified by targeted expression of fluorescent proteins. Whole-cell patch-clamp recordings were performed to analyze the effects of propofol on action potentials and synaptic transmission. The results showed that propofol induced a concentration-dependent reduction in action potential firing frequency. It also increased the frequency of spontaneous inhibitory postsynaptic currents and prolonged their decay time. The presence of GABA A receptor antagonist bicuculline prevented these effects. Inhibitory tonic currents were evoked only at high concentrations of propofol. In behavioral experiments, bicuculline injection into the LC significantly shortened the return of righting reflex time following propofol anesthesia. We demonstrated that clinically relevant doses of propofol facilitated phasic GABAergic neural currents and acted directly on GABA A receptors in LC-NA neurons. Enhanced GABA A receptor-mediated inhibition in LC-NA neurons likely underlies the anesthetic mechanism of propofol. Whereas previous studies emphasized tonic inhibition as the major mechanism of propofol action, our findings demonstrate that phasic inhibition predominates at clinically relevant concentrations.

Microglia are the brain’s resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of β2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of β2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.