Noradrenergic Research Articles

Use of clonidine in the management of opiate withdrawal in community patients

AimsClonidine has been used to alleviate symptoms of opiate withdrawal. No validated prescribing schedules exist for the use of Clonidine in opiate detoxification in community patients. We have devised a Clonidine prescribing schedule for adult outpatients seeking opiate detoxification.BackgroundOpiate cessation following prolonged use produces a central noradrenergic (NA) response in the locus coeruleus (LC), causing symptoms that can result in reinstatement of use. Pharmacotherapies for withdrawal are thought to work through decreased NA release in the LC by agonising pre-synaptic alpha-2 adrenoceptors. Clonidine has been used since the 1970s. However, it is off-license in the UK, and superseded by Lofexidine. Though both cause hypotension, this is less marked with Lofexidine, which may be anxiolytic and considered better tolerated. Lofexidine is no longer available in the UK. Specialists may need to resort to Clonidine for those seeking opiate detoxification.MethodWe performed a feasibility study with the primary outcome being tolerability of an outpatient clonidine schedule. Patients (n = 7) were aged between 18 and 65 years (mean 32). Six were prescribed buprenorphine as opiate substitution (OST), and one methadone.Exclusion criteria were in keeping with BNF contraindications.An ECG was obtained for each patient before treatment. A urine drug screen and Clinical Opiate Withdrawal Scale were taken to confirm opiate dependence and withdrawal. Patients self-monitored withdrawal using the Subjective Opiate Withdrawal Scale and daily blood pressure measurements. Standard adjuvants for withdrawal were prescribed.A test dose of 100mcg Clonidine was given to assess for hypotension. If tolerant they received 100mcg QDS, reducing over eight days.Patients were contacted by their recovery worker twice during the period.ResultFive of the seven completed the course, two dropped out due to hypotension. No other adverse effects warranting discontinuation were encountered. Patients reported fatigue and light-headedness as their most troublesome side-effects. Of 3 patients who returned SOWS scores, 2 reported decline by 21/64 and 14/64 respectively. One reported an increase of 49/64 over 8 days. 3 of the 5 subjects who completed the course were not abstinent at completion, citing opiate withdrawal symptoms as causative.ConclusionThere is scope for the safe use of clonidine in the community for motivated individuals. Adequate monitoring of heart rate and blood pressure is required. Starting doses at 100mcg QDS appear well tolerated. Prescribers may wish to reduce this over a longer period to encourage completion and improve tolerability. Further research is needed.

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease.

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

030 The sleeping brain switches from frontal-subcortical working memory to hippocampal episodic memory processing during NREM sleep

Abstract Introduction Working memory (WM) and long-term memory (LTM) serve separate functions. The former is a control process for planning and carrying out behavior that is information-independent, whereas the latter is an information-dependent vast store of knowledge and record of prior events. Both domains benefit from sleep. The overall picture emerging is that NREM sleep supports improvement in WM via strengthening of prefrontal-subcortical control networks, as well as the formation of LTM via thalamocortical sigma activity. Prior research suggests a potential antagonistic relation between the two neural processes during NREM sleep. Yet, how the sleeping brain performs both of these feats remain unknown. Methods Thirty-eight adults (age = 20.85 ± 2.97 years, 19 Females) were enrolled. We used a double-blind, placebo-controlled, within-subject design to investigate the role of autonomic and central activity on sleep-dependent LTM and WM improvement. We administered zolpidem, a GABA-A agonist, during PSG-recorded night and tested overnight LTM (word-paired-associates) and WM memory (operation-span) changes. We used effective connectivity to explore the causal information flow between central and autonomic sleep features and tested if the magnitude of this influence predicts the trade-off between overnight LTM and WM improvement. Results The intervention selectively suppressed vagal cardiac autonomic activity and increased sleep spindle sigma activity (12-15Hz) during non-rapid eye movement sleep (NREM). Behaviorally, the changes in sigma were associated with increased LTM and decreased WM improvement. Effective connectivity demonstrated a significantly decreased communication from autonomic to central regions with zolpidem compared with placebo, and this decrease in causal influence predicted the behavioral trade-off between LTM and WM. Conclusion Our results suggest evidence for a sleep switch that toggles between spindle-dependent and vagal-dependent processes during NREM. This switch supports enhancement of both LTM and WM during sleep via separate mechanisms. These results are consistent with prior studies reporting an antagonistic relation between neuromodulators governing the two systems, thalamocortical GABA and noradrenergic (NE) activity, respectively. Support (if any):

The Role of Noradrenergic and Glutamatergic Signaling in Noradrenergic Neurons in Respiratory Control

Central noradrenergic (NA) neurons are a critical component of the brainstem respiratory network that maintains blood CO2 and O2 levels through respiratory chemoreflexes. NA dysfunction is implicated in numerous developmental respiratory disorders such as the fatal Sudden Infant Death Syndrome (SIDS), Rett Syndrome, and Congenital Central Hypoventilation Syndrome (CCHS), in which abnormal chemosensory function is implicated. However, which NA neurons modulate respiratory chemoreflexes and the underlying mechanisms are still not fully understood. Previous studies in our lab utilizing intersectional chemogenetic (hM4D and hM3D DREADD mediated) inhibition and excitation identified multiple rhombomere (transient genetically-defined hindbrain segments arising during early development) specific NA populations that play a role in the adult hypercapnic chemoreflex. NA neurons are typically thought to communicate with synaptic partners through noradrenaline as their primary neurotransmitter. However, the excitatory neurotransmitter, glutamate, is also expressed in subpopulations of NA neurons including those derived from rhombomeres playing a role in the hypercapnic reflex. Prior studies have implicated NA derived glutamatergic signaling in respiratory control. Thus, we seek to determine the relative roles of noradrenergic and glutamatergic signaling in rhombomeric NA populations that are involved in adult respiratory chemoreflexes. To determine the requirement of noradrenergic signaling in the hypercapnic reflex, we aim to conditionally ablate noradrenergic signaling in rhombomeric NA sub-populations by crossing rhombomere specific Credrivers with the THflox/flox(tyrosine hydroxylase) allele to remove dopamine and downstream (nor) adrenaline production in targeted neurons. We also aim to determine if the glutamate producing NA neurons represented a larger functional cohort in breathing control. We therefore used our intersectional strategy to target and chemogenetically activate (hM3D) or inhibite (hM4De) glutamate co-expressing NA neurons (defined by partially overlapping Vglut2Cre; DBHFLPo activity) which are expected to comprise a super-set of rhombomere specific NA neurons that play a role in respiratory chemoreflexes. Whole-body barometric plethysmography was used to measure the respiratory function of the mice under room air (21%O2,79%N2) and hypercapnia (21%O2, 74%N2, 5% CO2). Our preliminary data suggests that removing noradrenergic signaling in a key rhombomeric NA subpopulation does not inhibit the hypercapnic reflex while DREADD mediated inhibition does reduce the hypercapnic reflex. Acute inhibition of glutamate-expressing NA neurons shows a reduction in the hypercapnic ventilatory reflex while acute activation of these same neurons shows a significantly enhanced reflex. Altogether, these preliminary data suggest that glutamate production may delineate a functionally specific NA subpopulation in the hypercapnic reflex and offers additional clues to the respective roles of noradrenaline and glutamatergic signaling in the noradrenergic system.

Psychiatric Considerations in Pediatric Chronic Pain

Features| May 2021 Psychiatric Considerations in Pediatric Chronic Pain Souraya Torbey, MD; Souraya Torbey, MD Search for other works by this author on: This Site PubMed Google Scholar Gaëlle Rached, MD, MSc; Gaëlle Rached, MD, MSc Search for other works by this author on: This Site PubMed Google Scholar Dimitri Fiani; Dimitri Fiani Search for other works by this author on: This Site PubMed Google Scholar M-Irfan Suleman, MD, FAAP, FASA M-Irfan Suleman, MD, FAAP, FASA Search for other works by this author on: This Site PubMed Google Scholar ASA Monitor May 2021, Vol. 85, 25–26. https://doi.org/10.1097/01.ASM.0000751508.64877.83 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Search Site Citation Souraya Torbey, Gaëlle Rached, Dimitri Fiani, M-Irfan Suleman; Psychiatric Considerations in Pediatric Chronic Pain. ASA Monitor 2021; 85:25–26 doi: https://doi.org/10.1097/01.ASM.0000751508.64877.83 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll PublicationsASA Monitor Search Advanced Search Topics: chronic pain, pediatrics, psychiatry, pain Chronic pain can greatly affect a patient's daily functioning and significantly impact health-related quality of life (Pain 2005;119:1-4). Undertreated or untreated chronic pain in children can be especially burdensome to families by disrupting routines, restricting the child's daily activities, and increasing risk of long-term disability (Paediatr Drugs 2002;4:737-46). Therefore, it is not unusual for chronic pain to be highly comorbid with psychiatric disorders. This association is mediated by significant overlap in biological pathways. First, central and peripheral noradrenergic (NA) and serotoninergic (5-HT) pathways are affected in both pain and mood disorders (Prog Neuropsychopharmacol Biol Psychiatry 2018;87B:290-7; J Psychiatry Neurosci 2001;26:21-9). A pathway involving serotonergic neurons in the dorsal raphe nucleus has been implicated in chronic pain as well as depression (Nat Neurosci 2019;22:1612-4). Both NA and 5-HT brainstem-spinal descending systems... © 2021 American Society of Anesthesiologists (ASA), All Rights Reserved.2021 You do not currently have access to this content.

Noradrenergic correlates of chronic cocaine craving: neuromelanin and functional brain imaging

Preclinical studies have implicated noradrenergic (NA) dysfunction in cocaine addiction. In particular, the NA system plays a central role in motivated behavior and may partake in the regulation of craving and drug use. Yet, human studies of the NA system are scarce, likely hampered by the difficulty in precisely localizing the locus coeruleus (LC). Here, we used neuromelanin imaging to localize the LC and quantified LC neuromelanin signal (NMS) intensity in 44 current cocaine users (CU; 37 men) and 59 nondrug users (NU; 44 men). We also employed fMRI to investigate cue-induced regional responses and LC functional connectivities, as quantified by generalized psychophysiological interaction (gPPI), in CU. Imaging data were processed by published routines and the findings were evaluated with a corrected threshold. We examined how these neural measures were associated with chronic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ). Compared to NU, CU demonstrated higher LC NMS for all probabilistic thresholds defined of 50–90% of the peak. In contrast, NMS of the ventral tegmental area/substantia nigra (VTA/SN) did not show significant group differences. Drug as compared to neutral cues elicited higher activations of many cortical and subcortical regions, none of which were significantly correlated with CCQ score. Drug vs. neutral cues also elicited “deactivation” of bilateral parahippocampal gyri (PHG) and PHG gPPI with a wide array of cortical and subcortical regions, including the ventral striatum and, with small volume correction, the LC. Less deactivation of the PHG (r = 0.40, p = 0.008) and higher PHG-LC gPPI (r = 0.44, p = 0.003) were positively correlated with the CCQ score. In contrast, PHG-VTA/SN connectivity did not correlate with the CCQ score. Together, chronic cocaine exposure may induce higher NMS intensity, suggesting neurotoxic effects on the LC. The correlation of cue-elicited PHG LC connectivity with CCQ score suggests a noradrenergic correlate of chronic cocaine craving. Potentially compensating for memory functions as in neurodegenerative conditions, cue-elicited PHG LC circuit connectivity plays an ill-adaptive role in supporting cocaine craving.

The Dopaminergic and Acetylcholinergic Supplements to Freudian Structural Theory of Psychoanalysis

For the Freudian topographic theory of psychoanalysis, it has recently been supplemented the reticular noradrenergic (NA), serotonergic (5-HT) and acetylcholinergic (ACh) systems to demonstrate the differential regulation of unconscious/preconscious/conscious in waking and sleep, applicable to depression and anxiety. For the Freudian structural theory of id/ego/super-ego, it is keen to depict the personal social psychology with selfishness, applicable to schizophrenia. Herein, it is analogously added the neglected reticular dopaminergic (DA) and ACh systems to regulate the id, ego, and super-ego, corresponding to the bodily instincts including motivation, selfish behaviors including skills, and social knowledge including law, respectively. For DA, predominantly it is selective on super-ego, excitatory to id and beneficial to ego; while for ACh, predominantly it is excitatory to super-ego, depressive to id, and restrictive to ego. It is the hyperactivation of DA and downregulation of ACh that results in schizophrenia and dementia, respectively. It is accordingly reconciled the structural theory of psychoanalysis with the present pathological and pharmacological achievements.

Structural basis for noradrenergic regulation of neural circuits in the mouse olfactory bulb.

Olfactory input is processed in the glomerulus of the main olfactory bulb (OB) and relayed to higher centers in the brain by projection neurons. Conversely, centrifugal inputs from other brain regions project to the OB. We have previously analyzed centrifugal inputs into the OB from several brain regions using single-neuron labeling. In this study, we analyzed the centrifugal noradrenergic (NA) fibers derived from the locus coeruleus (LC), because their projection pathways and synaptic connections in the OB have not been clarified in detail. We analyzed the NA centrifugal projections by single-neuron labeling and immunoelectron microscopy. Individual NA neurons labeled by viral infection were three-dimensionally traced using Neurolucida software to visualize the projection pathway from the LC to the OB. Also, centrifugal NA fibers were visualized using an antibody for noradrenaline transporter (NET). NET immunoreactive (-ir) fibers contained many varicosities and synaptic vesicles. Furthermore, electron tomography demonstrated that NET-ir fibers formed asymmetrical synapses of varied morphology. Although these synapses were present at varicosities, the density of synapses was relatively low throughout the OB. The maximal density of synapses was found in the external plexiform layer; about 17% of all observed varicosities contained synapses. These results strongly suggest that NA-containing fibers in the OB release NA from both varicosities and synapses to influence the activities of OB neurons. The present study provides a morphological basis for olfactory modulation by centrifugal NA fibers derived from the LC.

Mental Effort When Playing, Listening, and Imagining Music in One Pianist's Eyes and Brain.

We investigated “musical effort” with an internationally renowned, classical, pianist while playing, listening, and imagining music. We used pupillometry as an objective measure of mental effort and fMRI as an exploratory method of effort with the same musical pieces. We also compared a group of non-professional pianists and non-musicians by the use of pupillometry and a small group of non-musicians with fMRI. This combined approach of psychophysiology and neuroimaging revealed the cognitive work during different musical activities. We found that pupil diameters were largest when “playing” (regardless of whether there was sound produced or not) compared to conditions with no movement (i.e., “listening” and “imagery”). We found positive correlations between pupil diameters of the professional pianist during different conditions with the same piano piece (i.e., normal playing, silenced playing, listen, imagining), which might indicate similar degrees of load on cognitive resources as well as an intimate link between the motor imagery of sound-producing body motions and gestures. We also confirmed that musical imagery had a strong commonality with music listening in both pianists and musically naïve individuals. Neuroimaging provided evidence for a relationship between noradrenergic (NE) activity and mental workload or attentional intensity within the domain of music cognition. We found effort related activity in the superior part of the locus coeruleus (LC) and, similarly to the pupil, the listening and imagery engaged less the LC–NE network than the motor condition. The pianists attended more intensively to the most difficult piece than the non-musicians since they showed larger pupils for the most difficult piece. Non-musicians were the most engaged by the music listening task, suggesting that the amount of attention allocated for the same task may follow a hierarchy of expertise demanding less attentional effort in expert or performers than in novices. In the professional pianist, we found only weak evidence for a commonality between subjective effort (as rated measure-by-measure) and the objective effort gauged with pupil diameter during listening. We suggest that psychophysiological methods like pupillometry can index mental effort in a manner that is not available to subjective awareness or introspection.

Noradrenaline signaling in the LPBN mediates amylin's and salmon calcitonin's hypophagic effect in male rats

The LPBN (lateral parabrachial nucleus) plays an important role in feeding control. CGRP (calcitonin gene-related peptide) LPBN neurons activation mediates the anorectic effects of different gut-derived peptides, including amylin. Amylin and its long acting analog sCT (salmon calcitonin) exert their anorectic actions primarily by directly activating neurons located in the area postrema (AP). A large proportion of projections from the AP and the adjacent nucleus of the solitary tractNTS to the LPBN, are noradrenergic (NA), and amylin-activated NAAP neurons are critical in mediating amylin's hypophagic effects. Here, we determine the functional role of NAAP amylin activated neurons to activate CGRP and non-CGRP LPBN neurons. To this end, NA was specifically depleted in the rat LPBN through a stereotaxic microinfusion of 6-OHDA, a neurotoxic agent that destroys NA terminals. While amylin (50μg/kg) and sCT (5μg/kg) reduced eating in sham-lesioned rats, no reduction in feeding occurred in NA-depleted animals. Further, the amylin-induced c-Fos response in the LPBN and c-Fos/CGRP colocalization were reduced in NA-depleted animals compared to controls. We conclude that AP→LPBN NA signaling, through the activation of LPBN CGRP neurons, mediates part of amylin's hypophagic effect.

Dopaminergic, Noradrenergic, Adrenal, and Thyroid Abnormalities in Psychotic and Affective Disorders.

BackgroundThis study aimed to assess hypothalamic-pituitary dopaminergic (DA), noradrenergic (NA), thyroid (HPT), and adrenal (HPA) activity in schizophrenia, in schizoaffective disorder, and in bipolar disorder.MethodWe investigated a combined approach of hormone responses to (1) apomorphine (APO), a short-acting DA receptor agonist which decreases prolactin secretion (PRL), and stimulates secretion of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol; (2) clonidine (CLO), an alpha 2-adrenoceptor agonist which stimulates GH secretion; (3) 8 AM and 11 PM protirelin (TRH) which stimulates thyrotropin (TSH) secretion; and (4) dexamethasone which suppresses cortisol secretion, in 13 hospitalized healthy male controls and 39 untreated male inpatients: 13 with DSM-IV paranoid schizophrenia, 13 with DSM-IV schizoaffective disorder (bipolar subtype, depressed at the time of the study), and 13 with DSM-IV bipolar disorder (depressed).ResultsCompared to controls, paranoid schizophrenic patients showed (1) lower APO-induced ACTH and cortisol stimulation, and (2) higher post-dexamethasone cortisol values. Compared to controls, schizoaffective and bipolar patients showed (1) lower ΔΔTSH values (i.e., difference between 11 PM and 8 AM TRH-TSH responses), (2) lower APO-induced PRL suppression, (3) lower CLO-induced GH stimulation, and (4) higher post-dexamethasone cortisol values.ConclusionsAlthough results must be interpreted with caution because of the small sample, this preliminary study suggests that depressed bipolar and schizoaffective patients share common biological dysregulations, distinct from that of paranoid schizophrenic patients. From a pathophysiological viewpoint, paranoid schizophrenic patients can be characterized by hyposensitivity of the hypothalamic DA receptors (possibly resulting from an increase in presynaptic DA release) associated with increased HPA axis activity, while depressed bipolar and schizoaffective patients can be characterized by hyposensitivity of the pituitary TRH and DA-D2 receptors (possibly linked to the activation of the hypothalamic TRH and tuberoinfundibular DA neurons, respectively), together with subsensitive postsynaptic α2-adrenoreceptors at the hypothalamic level (possibly secondary to an erratic release of NA) and increased HPA axis activity.

Involvement of noradrenergic and serotonergic systems in risk-based decisions between options of equivalent expected value in rats

Risk perception is an important factor that may mediate risk-based decision-making processes regulated by noradrenergic (NA) and serotonergic (5-HT) systems. Most risk-based decision-making models involve complex factors, such as risk perception or reward value, such that the final decision is the result of the interactions among these factors. However, the contribution of risk perception per se in risk decisions has remained unclear. Therefore, in the present study, we made some modifications to the classical probabilistic discounting task (PDT) to focus on the impact of risk perception and noradrenergic/serotonergic systems on decision-making behavior. Meanwhile, we conducted an elevated plus-maze (EPM) test to detect the correlation between anxiety and choice behavior. In the current study, rats had to choose between a “certain” lever that delivered a certain number of pellets and a “risky” lever that delivered eight pellets in a probabilistic manner (descending: 50%, 25%, 12.5% or ascending 12.5%, 25%, 50% of the time). The long-term rewarding values of the two levers were always identical in each block within each session. According to their baseline performances in choosing the risky lever, rats were divided into the risk-prefer group and risk-averse group. The results showed that there was a significant correlation between open arm time in EPM and risky choice for both descending order and ascending order, indicating that highly anxious rats more often preferred the safe option under risk. Pharmacological stimulation of α2-adrenergic receptors via dexmedetomidine (0.01 mg/kg) decreased the preference of probabilistic rewards in the risk-prefer group, while blocking α2 receptors by atipamezole (0.3 mg/kg) also reduced risky choices. The NA reuptake inhibitor, atomoxetine, increased the preference for risky choices in the risk-prefer group, the effect of which was attained via multiple superimposed doses. Administration of the 5-HT2A receptor agonist, DOI (0.1 mg/kg), increased risk-taking behavior in the risk-prefer group. Taken together, these results suggest that NA may be more inclined to process negative information such as loss or uncertainty in the regulation of risk-related decision making, whereas 5-HT may function primarily to increase risk-taking behavior. Our findings may help to further elucidate how noradrenergic and serotonergic systems differentially affect individuals with different risk preferences in terms of regulating risk perception in risk-related decision making.

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer's disease pathogenesis.

Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of the central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, LC terminals provide dense innervation of brain intraparenchymal arterioles/capillaries, and NA modulates astrocyte functions. The term neurovascular unit (NVU) defines the strict anatomical/functional interaction occurring between neurons, glial cells, and brain vessels. NVU plays a fundamental role in coupling the energy demand of activated brain regions with regional cerebral blood flow, it includes the blood-brain barrier (BBB), plays an active role in neuroinflammation, and participates also to the glymphatic system. NVU alteration is involved in AD pathophysiology through several mechanisms, mainly related to a relative oligoemia in activated brain regions and impairment of structural and functional BBB integrity, which contributes also to the intracerebral accumulation of insoluble amyloid. We review the existing data on the morphological features of LC-NA innervation of the NVU, as well as its contribution to neurovascular coupling and BBB proper functioning. After introducing the main experimental data linking LC with AD, which have repeatedly shown a key role of neuroinflammation and increased amyloid plaque formation, we discuss the potential mechanisms by which the loss of NVU modulation by LC might contribute to AD pathogenesis. Surprisingly, thus far not so many studies have tested directly these mechanisms in models of AD in which LC has been lesioned experimentally. Clarifying the interaction of LC with NVU in AD pathogenesis may disclose potential therapeutic targets for AD.

Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats.

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α2 adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats.

Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications.

The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task-related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC-NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I-INs) located in the peri-LC. We also observe that inhibition of peri-LC I-INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri-LC I-INs and LC-NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri-LC I-INs. Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task-related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC-NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation-pause profile observed in animals. The activity was referred to as phasic-like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory-inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I-INs) in the medial part of the peri-LC that exerted feedforward inhibition of LC-NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri-LC I-INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri-LC I-INs and LC-NA neurons. These observations demonstrate functional roles of peri-LC I-INs in integrating inputs of the frontal cortex onto LC-NA neurons and gating the phasic LC output.

Ghrelin signaling contributes to fasting-induced attenuation of hindbrain neural activation and hypophagic responses to systemic cholecystokinin in rats.

In rats, overnight fasting reduces the ability of systemic cholecystokinin-8 (CCK) to suppress food intake and to activate cFos in the caudal nucleus of the solitary tract (cNTS), specifically within glucagon-like peptide-1 (GLP-1) and noradrenergic (NA) neurons of the A2 cell group. Systemic CCK increases vagal sensory signaling to the cNTS, an effect that is amplified by leptin and reduced by ghrelin. Since fasting reduces plasma leptin and increases plasma ghrelin levels, we hypothesized that peripheral leptin administration and/or antagonism of ghrelin receptors in fasted rats would rescue the ability of CCK to activate GLP-1 neurons and a caudal subset of A2 neurons that coexpress prolactin-releasing peptide (PrRP). To test this, cFos expression was examined in ad libitum-fed and overnight food-deprived (DEP) rats after intraperitoneal CCK, after coadministration of leptin and CCK, or after intraperitoneal injection of a ghrelin receptor antagonist (GRA) before CCK. In fed rats, CCK activated cFos in ~60% of GLP-1 and PrRP neurons. Few or no GLP-1 or PrRP neurons expressed cFos in DEP rats treated with CCK alone, CCK combined with leptin, or GRA alone. However, GRA pretreatment increased the ability of CCK to activate GLP-1 and PrRP neurons and also enhanced the hypophagic effect of CCK in DEP rats. Considered together, these new findings suggest that reduced behavioral sensitivity to CCK in fasted rats is at least partially due to ghrelin-mediated suppression of hindbrain GLP-1 and PrRP neural responsiveness to CCK.

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function.

The Role of Noradrenergic and Glutamatergic Signaling in Noradrenergic Neurons in Respiratory Control

Central noradrenergic (NA) neurons are a critical component of the brainstem respiratory network that maintains blood CO2 and O2 levels through respiratory chemoreflexes. NA dysfunction is implicated in numerous developmental respiratory disorders such as the fatal Sudden Infant Death Syndrome (SIDS), Rett Syndrome, and Congenital Central Hypoventilation Syndrome (CCHS), in which abnormal chemosensory function is implicated. However, which NA neurons modulate respiratory chemoreflexes and the underlying mechanisms are still not fully understood. Previous studies in our lab utilizing intersectional chemogenetic (hM4D and hM3D DREADD mediated) inhibition and excitation identified multiple rhombomere (transient genetically‐defined hindbrain segments arising during early development) specific NA populations that play a role in the adult hypercapnic chemoreflex. NA neurons are typically thought to communicate with synaptic partners through noradrenaline and adrenaline as their primary neurotransmitter. However, the excitatory neurotransmitter, glutamate, is also expressed in subpopulations of NA neurons including rhombomeric NA neurons playing a role in the hypercapnic reflex. Prior studies have implicated NA derived glutamatergic signaling in respiratory control. Thus, we seek to determine the relative roles of noradrenergic and glutamatergic signaling in rhombomeric NA populations that are involved in adult respiratory chemoreflexes. To determine the requirement of noradrenergic signaling in the hypercapnic reflex, we aim to conditionally ablate noradrenergic signaling in rhombomeric NA sub‐populations by crossing rhombomere specific Credrivers with the THflox/flox(tyrosine hydroxylase) allele to remove dopamine and downstream (nor) adrenaline production in targeted neurons. We also aim to determine if the glutamate producing NA neurons represent a larger functional cohort in breathing control. We therefore used our intersectional strategy to target and chemogenetically activate (hM3D) or inhibite (hM4De) glutamate co‐expressing NA neurons (defined by partially overlapping Vglut2Cre; DBHFLPo activity) which are expected to comprise a super‐set of rhombomere specific NA neurons that play a role in respiratory chemoreflexes. Whole‐body barometric plethysmography was used to measure the respiratory function of the mice under room air (21%O2, 79%N2) and hypercapnia (21%O2, 74%N2, 5% CO2). Our preliminary data suggests that removing noradrenergic signaling in a key rhombomeric NA subpopulation does not inhibit the hypercapnic reflex while DREADD mediated inhibition does reduce the hypercapnic reflex. Acute inhibition of glutamate‐expressing NA neurons shows a reduction in the hypercapnic ventilatory reflex while acute activation of these same neurons shows a significantly enhanced reflex. Altogether, these preliminary data suggest that glutamate production may delineate a functionally specific NA subpopulation in the hypercapnic reflex and offers additional clues to the respective roles of noradrenaline and glutamatergic signaling in the noradrenergic system.Support or Funding InformationR01HL153505

Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development.

Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.

Neuroimmunomodulation by estrogen in health and disease.

Systemic homeostasis is maintained by the robust bidirectional regulation of the neuroendocrine-immune network by the active involvement of neural, endocrine and immune mediators. Throughout female reproductive life, gonadal hormones undergo cyclic variations and mediate concomitant modulations of the neuroendocrine-immune network. Dysregulation of the neuroendocrine-immune network occurs during aging as a cumulative effect of declining neural, endocrine and immune functions and loss of compensatory mechanisms including antioxidant enzymes, growth factors and co-factors. This leads to disruption of homeostasis and sets the stage for the development of female-specific age-associated diseases such as autoimmunity, osteoporosis, cardiovascular diseases and hormone-dependent cancers. Ovarian hormones especially estrogen, play a key role in the maintenance of health and homeostasis by modulating the nervous, endocrine and immune functions and thereby altering neuroendocrine-immune homeostasis. Immunologically estrogen's role in the modulation of Th1/Th2 immune functions and contributing to pro-inflammatory conditions and autoimmunity has been widely studied. Centrally, hypothalamic and pituitary hormones influence gonadal hormone secretion in murine models during onset of estrous cycles and are implicated in reproductive aging-associated acyclicity. Loss of estrogen affects neuronal plasticity and the ensuing decline in cognitive functions during reproductive aging in females implicates estrogen in the incidence and progression of neurodegenerative diseases. Peripherally, sympathetic noradrenergic (NA) innervations of lymphoid organs and the presence of both adrenergic (AR) and estrogen receptors (ER) on lymphocytes poise estrogen as a potent neuroimmunomodulator during health and disease. Cyclic variations in estrogen levels throughout reproductive life, perimenopausal surge in estrogen levels followed by its precipitous decline, concomitant with decline in central hypothalamic catecholaminergic activity, peripheral sympathetic NA innervation and associated immunosuppression present an interesting study to explore female-specific age-associated diseases in a new light.