Activity Of Noradrenergic Neurons Research Articles

Vagus nerve stimulation with a small total charge transfer improves motor behavior and reduces neuroinflammation in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD.

Cell-specific expression of Cre recombinase in rat noradrenergic neurons via CRISPR-Cas9 system

Noradrenergic neurons play a crucial role in the functioning of the nervous system. They formed compact small clusters in the central nervous system. To target noradrenergic neurons in combination with viral tracing and achieve cell-type specific functional manipulation using chemogenetic or optogenetic tools, new transgenic animal lines are needed, especially rat models for their advantages in large body size with facilitating easy operation, physiological parameter monitoring, and accommodating complex behavioral and cognitive studies. In this study, we successfully generated a transgenic rat strain capable of expressing Cre recombinase under the control of the dopamine beta-hydroxylase (DBH) gene promoter using the CRISPR-Cas9 system. Our validation process included co-immunostaining with Cre and DBH antibodies, confirming the specific expression of Cre recombinase. Furthermore, stereotaxic injection of a fluorescence-labeled AAV-DIO virus illustrated the precise Cre-loxP-mediated recombination activity in noradrenergic neurons within the locus coeruleus (LC). Through crossbreeding with the LSL-fluorescence reporter rat line, DBH-Cre rats proved instrumental in delineating the position and structure of noradrenergic neuron clusters A1, A2, A6 (LC), and A7 in rats. Additionally, our specific activation of the LC noradrenergic neurons showed effective behavioral readout using chemogenetics of this rat line. Our results underscore the effectiveness and specificity of Cre recombinase in noradrenergic neurons, serving as a robust tool for cell-type specific targeting of small-sized noradrenergic nuclei. This approach enhances our understanding of their anatomical, physiological, and pathological roles, contributing to a more profound comprehension of noradrenergic neuron function in the nervous system.

Locus coeruleus activation contributes to masseter muscle overactivity induced by chronic restraint stress in mice.

It is commonly accepted that exposure to stress may cause overactivity in the orofacial muscles, leading to consistent muscle pain, which is the main symptom of temporomandibular disorders. The central neural mechanism underlying this process, however, remains unclear. The locus coeruleus is considered to play an important role in stress-related behavioral changes. Therefore, the present study was designed to examine the role of locus coeruleus neurons in masseter overactivity induced by stress. C57BL/6 mice were subjected to chronic restraint stress for 14 days to establish an animal model. The behavioral changes and the electromyography of the masseter muscle in mice were measured. The expression of Fos in locus coeruleus was observed by immunofluorescence staining to assess neuronal activation. A chemogenetic test was used to inhibit locus coeruleus neuronal activity, and the behavioral changes and electromyography of the masseter muscle were observed again. The results exhibited that chronic restraint stress could induce anxiety-like behavior, overactivity of the masseter muscle, and significant activation of locus coeruleus neurons in mice. Furthermore, inhibition of noradrenergic neuron activity within the locus coeruleus could alleviate stress-induced anxiety behavior and masseter muscle overactivity. Activation of noradrenergic neurons in locus coeruleus induced by stress may be one of the central regulatory mechanisms for stress-induced anxiety-like behaviors and overactivity of masseter muscles.

Circuit mechanism underlying fragmented sleep and memory deficits in 16p11.2 deletion mouse model of autism.

Sleep disturbances are prevalent in children with autism spectrum disorder (ASD) and have a major impact on the quality of life. Strikingly, sleep problems are positively correlated with the severity of ASD symptoms, such as memory impairment. However, the neural mechanisms underlying sleep disturbances and cognitive deficits in ASD are largely unexplored. Here, we show that non-rapid eye movement sleep (NREMs) is highly fragmented in the 16p11.2 deletion mouse model of ASD. The degree of sleep fragmentation is reflected in an increased number of calcium transients in the activity of locus coeruleus noradrenergic (LC-NE) neurons during NREMs. Exposure to a novel environment further exacerbates sleep disturbances in 16p11.2 deletion mice by fragmenting NREMs and decreasing rapid eye movement sleep (REMs). In contrast, optogenetic inhibition of LC-NE neurons and pharmacological blockade of noradrenergic transmission using clonidine reverse sleep fragmentation. Furthermore, inhibiting LC-NE neurons restores memory. Rabies-mediated unbiased screening of presynaptic neurons reveals altered connectivity of LC-NE neurons with sleep- and memory regulatory brain regions in 16p11.2 deletion mice. Our findings demonstrate that heightened activity of LC-NE neurons and altered brain-wide connectivity underlies sleep fragmentation in 16p11.2 deletion mice and identify a crucial role of the LC-NE system in regulating sleep stability and memory in ASD.

Norepinephrine regulates calcium signals and fate of oligodendrocyte precursor cells in the mouse cerebral cortex

Oligodendrocyte precursor cells (OPCs) generate oligodendrocytes, contributing to myelination and myelin repair. OPCs contact axons and respond to neuronal activity, but how the information relayed by the neuronal activity translates into OPC Ca2+ signals, which in turn influence their fate, remains unknown. We generated transgenic mice for concomitant monitoring of OPCs Ca2+ signals and cell fate using 2-photon microscopy in the somatosensory cortex of awake-behaving mice. Ca2+ signals in OPCs mainly occur within processes and confine to Ca2+ microdomains. A subpopulation of OPCs enhances Ca2+ transients while mice engaged in exploratory locomotion. We found that OPCs responsive to locomotion preferentially differentiate into oligodendrocytes, and locomotion-non-responsive OPCs divide. Norepinephrine mediates locomotion-evoked Ca2+ increases in OPCs by activating α1 adrenergic receptors, and chemogenetic activation of OPCs or noradrenergic neurons promotes OPC differentiation. Hence, we uncovered that for fate decisions OPCs integrate Ca2+ signals, and norepinephrine is a potent regulator of OPC fate.

Chemogenetic inhibition of locus coeruleus to rostromedial tegmental nucleus noradrenergic pathway increases light cycle ethanol drinking in male and female mice and blunts ethanol-induced CTA

We recently showed that chemogenetic activation of the locus coeruleus (LC) to the rostromedial tegmental nucleus (RMTg) noradrenergic (NE) pathway significantly blunted binge-like ethanol drinking and induced aversive-like behaviors in mice. The aim of the present study is to determine if silencing this TH + LC → RMTg noradrenergic pathway promotes increased levels of binge-like ethanol intake and reduced ethanol-induced conditioned taste aversion (CTA). To this end, both male and female TH-ires-cre mice on a C57BL/6 J background were cannulated in the RMTg and injected in the LC with rAVV viruses that encode cre-dependent Gi-expressing designer receptor exclusively activated by designer drugs (DREADDs), or its control, to directly control the activity of NE neurons. Inhibition of the LC to RMTg pathway had no effect on the binge-ethanol drinking in a “drinking-in-the-dark” (DID) paradigm. However, when using this paradigm during the light cycle, silencing of this circuit significantly increased ethanol intake without altering sucrose drinking. Moreover, we found that inhibition of this circuit significantly attenuated an ethanol-induced CTA. In addition, when compared to control animals, pairing RMTg-directed Clozapine N-oxide (CNO) with an i.p. injection of 1.5 g/kg ethanol reduced c-Fos activation in the LC, and increased c-Fos expression in the ventral tegmental area (VTA) in Gi-expressing mice. Our data show that inhibition of the TH + LC to the RMTg pathway significantly increased ethanol drinking as well as attenuated ethanol-induced CTA, supporting the involvement of the LC to RMTg noradrenergic circuit as an important protective mechanism against excessive ethanol consumption.

Shining light on the noradrenergic system.

Despite decades of research on the noradrenergic system, our understanding of its impact on brain function and behavior remains incomplete. Traditional recording techniques are challenging to implement for investigating in vivo noradrenergic activity, due to the relatively small size and the position in the brain of the locus coeruleus (LC), the primary location for noradrenergic neurons. However, recent advances in optical and fluorescent methods have enabled researchers to study the LC more effectively. Use of genetically encoded calcium indicators to image the activity of noradrenergic neurons and biosensors that monitor noradrenaline release with fluorescence can be an indispensable tool for studying noradrenergic activity. In this review, we examine how these methods are being applied to record the noradrenergic system in the rodent brain during behavior.

Chemogenetic activation of locus coeruleus neurons ameliorates the severity of multiple sclerosis

BackgroundMost current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology. Drugs that enhance noradrenaline appear to have some beneficial effects in MS, suggesting their potential to dampen the underlying pathology and disease progression.MethodsTherefore, we explored the consequences of chronic LC noradrenergic neurons activation by chemogenetics in experimental autoimmune encephalomyelitis (EAE) mice, the most widely used experimental model of MS. LC activation from the onset or the peak of motor symptoms was explored as two different therapeutic approaches, assessing the motor and non-motor behavioral changes as EAE progresses, and studying demyelination, inflammation and glial activation in the spinal cord and cerebral cortex during the chronic phase of EAE.ResultsLC activation from the onset of motor symptoms markedly alleviated the motor deficits in EAE mice, as well as their anxiety-like behavior and sickness, in conjunction with reduced demyelination and perivascular infiltration in the spinal cord and glial activation in the spinal cord and prefrontal cortex (PFC). When animals exhibited severe paralysis, LC activation produced a modest alleviation of EAE motor symptoms and it enhanced animal well-being, in association with an improvement of the EAE pathology at the spinal cord and PFC level. Interestingly, the reduced dopamine beta-hydroxylase expression associated with EAE in the spinal cord and PFC was reversed through chemogenetic LC activation.ConclusionTherefore, clear anti-inflammatory and neuroprotective effects were produced by the selective activation of LC noradrenergic neurons in EAE mice, having greater benefits when LC activation commenced earlier. Overall, these data suggest noradrenergic LC neurons may be targets to potentially alleviate some of the motor and non-motor symptoms in MS.

An FGF21 fix to get sober.

FGF21-mediated activation of noradrenergic neurons enables recovery from ethanol intoxication in mice.

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. This review on the neurorespiratory toxicity of fentanyl and analogs highlights the need for specific research focused on these agents to better understand the involved mechanisms of toxicity and develop dedicated strategies to limit the resulting fatalities.

Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities

Trigeminal neuralgia is the most common neuropathic pain involving the craniofacial region. Due to the complex pathophysiology, it is therapeutically difficult to manage. Noradrenaline plays an essential role in the modulation of arousal, attention, cognitive function, stress, and pain. The locus coeruleus, the largest source of noradrenaline in the brain, is involved in the sensory and emotional processing of pain. This review summarizes the knowledge about the involvement of noradrenaline in acute and chronic trigeminal pain conditions and how the activity of the locus coeruleus noradrenergic neurons changes in response to acute and chronic pain conditions and how these changes might be involved in pain-related comorbidities including anxiety, depression, and sleep disturbance.

A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances

In our daily life, we are exposed to uncontrollable and stressful events that disrupt our sleep. However, the underlying neural mechanisms deteriorating the quality of non-rapid eye movement sleep (NREMs) and REM sleep are largely unknown. Here, we show in mice that acute psychosocial stress disrupts sleep by increasing brief arousals (microarousals [MAs]), reducing sleep spindles, and impairing infraslow oscillations in the spindle band of the electroencephalogram during NREMs, while reducing REMs. This poor sleep quality was reflected in an increased number of calcium transients in the activity of noradrenergic (NE) neurons in the locus coeruleus (LC) during NREMs. Opto- and chemogenetic LC-NE activation in naïve mice is sufficient to change the sleep microarchitecture similar to stress. Conversely, chemogenetically inhibiting LC-NE neurons reduced MAs during NREMs and normalized their number after stress. Specifically inhibiting LC-NE neurons projecting to the preoptic area of the hypothalamus (POA) decreased MAs and enhanced spindles and REMs after stress. Optrode recordings revealed that stimulating LC-NE fibers in the POA indeed suppressed the spiking activity of POA neurons that are activated during sleep spindles and REMs and inactivated during MAs. Our findings reveal that changes in the dynamics of the stress-regulatory LC-NE neurons during sleep negatively affect sleep quality, partially through their interaction with the POA.

Chemogenetic activation of noradrenergic A5 neurons increases blood pressure and visceral sympathetic activity in adult rats.

In mammals, the pontine noradrenergic system influences nearly every aspect of central nervous system function. A subpopulation of pontine noradrenergic neurons, called A5, are thought to be important in the cardiovascular response to physical stressors, yet their function is poorly defined. We hypothesized that activation of A5 neurons drives a sympathetically mediated increase in blood pressure (BP). To test this hypothesis, we conducted a comprehensive assessment of the cardiovascular effects of chemogenetic stimulation of A5 neurons in male and female adult rats using intersectional genetic and anatomical targeting approaches. Chemogenetic stimulation of A5 neurons in freely behaving rats elevated BP by 15 mmHg and increased cardiac baroreflex sensitivity with a negligible effect on resting HR. Importantly, A5 stimulation had no detectable effect on locomotor activity, metabolic rate, or respiration. Under anesthesia, stimulation of A5 neurons produced a marked elevation in visceral sympathetic nerve activity (SNA) and no change in skeletal muscle SNA, showing that A5 neurons preferentially stimulate visceral SNA. Interestingly, projection mapping indicates that A5 neurons target sympathetic preganglionic neurons throughout the spinal cord and parasympathetic preganglionic neurons throughout in the brainstem, as well as the nucleus of the solitary tract, and ventrolateral medulla. Moreover, in situ hybridization and immunohistochemistry indicate that a subpopulation of A5 neurons coreleases glutamate and monoamines. Collectively, this study suggests A5 neurons are a central modulator of autonomic function with a potentially important role in sympathetically driven redistribution of blood flow from the visceral circulation to critical organs and skeletal muscle.

Measurement of Noradrenaline and Serotonin Metabolites With Internal Jugular Vein Sampling: An Indicator of Brain Monoamine Turnover in Depressive Illness and Panic Disorder.

In research spanning three decades we have estimated brain monoamine turnover (approximately equating with synthesis rate) with sampling from the internal jugular veins and measurement of trans-cerebral plasma monoamine metabolite concentration gradients. Here we report indices of brain noradrenaline and serotonin turnover in patients with major depressive illness (MDD) and panic disorder (PD). Brain noradrenaline turnover was assessed from the combined flux into the internal jugular veins of the metabolites dihydroxyphenylglycol (DHPG) and 3-hydroxy-4-methoxyphenylglycol (MHPG), and brain serotonin turnover from the overflow of the primary metabolite, 5-hydroxyindole acetic acid (5HIAA). Comparison was made with matched healthy research participants. In both MD and PD the estimate of brain noradrenaline turnover provided by metabolite overflow was unremarkable. In contrast, in both patient groups the estimate of brain serotonin turnover provided by 5HIAA overflow was increased 3–4-fold (P < 0.01). This neurotransmitter abnormality was normalized in MDD and PD in clinical remission, during selective serotonin reuptake blocker (SSRI) dosing. We cannot be sure if the brain serotonergic abnormality we find in MDD and PD is causal or a correlate. Measurements in PD were not made during a panic attack. The increased estimated serotonin turnover here may possibly be a substrate for panic attacks; serotonergic raphe nuclei participate in anxiety responses in experimental animals. It is puzzling that the findings were identical in MDD and PD, although it may be pertinent that these psychiatric diagnoses are commonly comorbid. It is unlikely that activation of brain serotonergic neurons is driving the sympathetic nervous activation present, which contributes to cardiovascular risk, persistent sympathetic activation in MDD and episodic activation in PD during panic attacks. We have previously demonstrated that the mechanism of activation of human central sympathetic outflow in other contexts (hypertension, heart failure) is activation of noradrenergic brainstem neurons projecting to the hypothalamus and amygdala.

Does smoking affect the prevalence of caffeine use in schizophrenia?

IntroductionCaffeine acts as a competing antagonist of adenosine receptors, increasing the release of norepinephrine and the activation of noradrenergic neurons. Long-standing schizophrenia patients frequently develop a comorbidly high daily caffeine intake. This could be explained by its relationship with smoking [1,2].ObjectivesTo determine caffeine consumption in schizophrenia and predisposing factors.MethodsCross-sectional study designed on a sample of 68 outpatients with a follow-up of at least 5 years at the Mental Health Unit, aged between 18 and 65 years, diagnosed with schizophrenia (ICD-10). Average daily caffeine intake was quantified by reference values for each beverage: coffee (66.7mg/100ml), tea (30mg/100ml), soft or energy drinks (11.5mg/100ml). High intake was defined as a consumption of ≥200mg of caffeine per day. Retrospective review of medical records revealed tobacco use and negative symptoms observed on the PANSS scale. Statistical analysis were performed using SPSS v21.0 (significance p&lt;0.05).Results88.2% of the subjects were daily caffeine consumers with a mean intake of 146.7mg/day (SD=5.8), and a mean consumption time of 6.2 years. Coffee was the predominant beverage in 66.7% of the cases, followed by soft or energy drinks (25%) and tea (0.1%). 45% of participants also had a high caffeine intake of ≥200 mg/day. Comorbid smoking was found in 93% of these patients. Negative symptomatology prevailed among caffeine consumers (PANSS-N= 41.3).ConclusionsXanthine abuse seems to be highly prevalent in people with schizophrenia, and there may be a relationship with smoking and negative psychotic symptoms.DisclosureNo significant relationships.

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

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

Activity of pontine A7 noradrenergic neurons is suppressed during REM sleep

The activity of hypoglossal motoneurons plays an important role in the maintenance of upper airway patency. Both withdrawal of noradrenergic excitatory drive and increase of cholinergic inhibition markedly decrease excitability of hypoglossal motoneurons during sleep and especially during rapid-eye-movement (REM) stage. This leads to increased collapsibility of upper airway during sleep, which is the major neurological factor of obstructive sleep apnea (OSA) pathophysiology. Anatomical and functional data suggest that noradrenergic A7 neurons are the main source of noradrenergic drive to hypoglossal motoneurons. However, it is unknown whether the behavior of A7 neurons during sleep-wake cycle is in accord with their proposed involvement in sleep-related depression of hypoglossal motoneuron activity. Therefore, we sought to assess the behavior of A7 neurons during sleep and wakefulness in naturally sleeping head-restrained rats. We have found that, similar to other pontine noradrenergic neurons, the putative A7 noradrenergic neurons fired with relatively long-lasting action potentials with a low-frequency regular discharge. Importantly, noradrenergic A7 neurons were predominantly silent during REM sleep. The REM-off activity of the A7 neurons supports our hypothesis that these neurons may significantly contribute to the withdrawal of excitatory noradrenergic drive from upper airway motoneurons during REM sleep and, consequently, play an essential role in maintaining upper airway patency and pathophysiology of OSA. Therefore, noradrenergic A7 neurons may serve as an additional target for designing pharmacological approaches to treat OSA.NEW & NOTEWORTHY Noradrenergic A7 neurons are mostly silent during REM sleep. This is in accord with their role in the control of upper airway muscles and important contribution to OSA pathophysiology. Therefore, a modulation of A7 neuron activity can serve as a novel therapeutic target for pharmacological treatment of OSA.

Evidence for Cholinergic Collateral Projections between Sympathetic Neurons in the Murine Stellate Ganglia

Postganglionic neurons of the stellate ganglia (SG) are an integral component of sympathetic regulation of the heart. SG neurons receive preganglionic cholinergic inputs via T‐2 and send noradrenergic projections to the heart via the inferior cardiac nerve (iCN) to influence cardiac activity. SG neurons are thought to receive simple monosynaptic inputs from preganglionic neurons, but early studies have hinted that cholinergic collateral projections may be present in the SG. In culture, SG neurons form noradrenergic and cholinergic synapses between one another, suggesting that SG neurons express dual neurochemical phenotypes. This study tests the hypothesis that cholinergic collateral projections are present between sympathetic neurons of the intact SG in mice.Whole‐cell patch clamp recordings were made of intact SG neurons from male (N=8) and female (N=6) ChATTH+CreERT2/lox mice with and without tamoxifen treatment (N=7 ChAT KO mice and N=7 control mice, respectively). Tamoxifen treatment in ChATTH+CreERT2/lox mice induced the deletion of choline acetyltransferase (ChAT) in tyrosine hydroxylase positive (i.e. noradrenergic) cells. This strategy blocks putative acetylcholine synthesis in SG neurons while leaving preganglionic cholinergic synapses intact. To search for collaterals, the preganglionic nerve trunk, T‐2, was electrically stimulated to evoke excitatory postsynaptic currents (eEPSCs). The amplitude and jitter (i.e. variability in latency) of eEPSCs were examined. Additionally, the postganglionic nerve trunk, the iCN, was electrically stimulated to evoke retrograde action currents (rAC) and the presence of evoked synaptic currents was assessed. The amplitude and frequency of spontaneous EPSCs (sEPSCs) were also examined.ChAT KO significantly reduced the frequency of sEPSCs compared to control mice (1.21±0.559events/s vs. 0.13±0.048events/s, P&lt;0.05 from Student’s unpaired t‐test, N=5‐6 cells) while the amplitude was unaffected (74.4±26.10pA vs. 39.4±10.46pA, P&gt;0.05 from Student’s unpaired t‐test, N=5‐6 cells). This suggests that ChAT KO reduces the presynaptic activity of postganglionic noradrenergic neurons within the SG. In control mice, stimulation of T‐2 evoked high jitter eEPSCs, which was significantly reduced in ChAT KO mice (327.1±92.14μs vs. 39.2±15.69μs, P&lt;0.05 from Student’s unpaired t‐test, N=5‐6 cells) Additionally, the proportion of neurons that exhibited evoked synaptic currents following stimulation of the iCN was significantly reduced in ChAT KO mice (3/4 cells vs. 1/9 cells, P&lt;0.05 from χ² test).Chemical transmission at additional synapses accounts for the high jitter events observed in disynaptic pathways. High jitter responses following T‐2 stimulation and evoked synaptic responses after iCN stimulation in control neurons are both consistent with the collateral hypothesis. The loss of high jitter responses and evoked synaptic currents in ChAT KO mice also suggests these collateral projections are cholinergic. This suggests that collateral synaptic activity contributes to the increased frequency of sEPSCs in control mice. Understanding SG neurocircuitry is critical in deciphering changes in sympathetic activity in many pathophysiological conditions such as myocardial infarction and heart failure and may identify novel therapeutic targets for the treatment of autonomic imbalance.

Insights into the role of noradrenaline in effortful decisions.

To maintain homeostasis, our brain tracks the effort exerted during decision-making. A new study in PLOS Biology shows that the activity of noradrenergic neurons in the locus coeruleus (LC) reflects the effort exerted to face cognitive or physical challenges.

Maturation of Temporal Saccade Prediction from Childhood to Adulthood: Predictive Saccades, Reduced Pupil Size, and Blink Synchronization.

When presented with a periodic stimulus, humans spontaneously adjust their movements from reacting to predicting the timing of its arrival, but little is known about how this sensorimotor adaptation changes across development. To investigate this, we analyzed saccade behavior in 114 healthy humans (ages 6-24 years) performing the visual metronome task, who were instructed to move their eyes in time with a visual target that alternated between two known locations at a fixed rate, and we compared their behavior to performance in a random task, where target onsets were randomized across five interstimulus intervals (ISIs) and thus the timing of appearance was unknown. Saccades initiated before registration of the visual target, thus in anticipation of its appearance, were labeled predictive [saccade reaction time (SRT) < 90 ms] and saccades that were made in reaction to its appearance were labeled reactive (SRT > 90 ms). Eye-tracking behavior including saccadic metrics (e.g., peak velocity, amplitude), pupil size following saccade to target, and blink behavior all varied as a function of predicting or reacting to periodic targets. Compared with reactive saccades, predictive saccades had a lower peak velocity, a hypometric amplitude, smaller pupil size, and a reduced probability of blink occurrence before target appearance. The percentage of predictive and reactive saccades changed inversely from ages 8-16, at which they reached adult-levels of behavior. Differences in predictive saccades for fast and slow target rates are interpreted by differential maturation of cerebellar-thalamic-striatal pathways.SIGNIFICANCE STATEMENT From the first moments of life, humans are exposed to rhythm (i.e., mother's heartbeat in utero), but the timeline of brain development to promote the identification and anticipation of a rhythmic stimulus, known as temporal prediction, remains unknown. Here, we used saccade reaction time (SRT) in the visual metronome task to differentiate between temporally predictive and reactive responses to a target that alternated at a fixed rate in humans aged 6-24. Periods of age-related change varied little by target rate, with matured predictive performance evident by mid-adolescence for fast and slow rates. A strong correlation among saccade, pupil, and blink responses during target prediction provides evidence of oculomotor coordination and dampened noradrenergic neuronal activity when generating rhythmic motor responses.