The locus coeruleus(LC),a norepinephrine nucleus governing arousal states through tonic activity,requires precise regulatory mechanisms to maintain its dynamic activation levels.However,the neural circuitry underlying...The locus coeruleus(LC),a norepinephrine nucleus governing arousal states through tonic activity,requires precise regulatory mechanisms to maintain its dynamic activation levels.However,the neural circuitry underlying LC activity maintenance remains unclear.Here,we identify a glutamatergic projection from the ventrolateral periaqueductal gray(vlPAG)to the LC in mice as a critical regulator of arousal dynamics.Fiber photometry recordings revealed stress-induced Ca^(2+)dynamics in vlPAGCaMKIIα-LC axon terminals across diverse threat paradigms.Slice electrophysiology demonstrated that this pathway mediates LC-norepinephrine(LC-NE)neuronal activity via glutamatergic transmission.Low-frequency pathway activation(1 Hz)mainly induced anxiety-like behaviors,whereas high-frequency stimulation(10 Hz)evoked more panic-like hyperlocomotion,establishing a frequency-dependent continuum of arousal states.Conversely,pathway inhibition reduced pupil size,a reliable biomarker for arousal,concurrently suppressing threat avoidance behaviors and alleviating anxiety-related behaviors without altering environmental preference.These findings reveal that the vlPAGCaMKIIα-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.展开更多
Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have...Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.展开更多
Objective To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD). Methods 2 and 4 weeks after unilateral lesion of the nigrostri...Objective To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD). Methods 2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording. Results The firing rate of LC noradrenergic neurons increased sig...展开更多
The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.T...The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.The present study was designed to address whether stimulation of Phox2 b-expressing LC(Phox2 b~(LC)) neurons affects breathing and to reveal the putative circuit mechanism.A Cre-dependent viral vector encoding a Gqcoupled human M3 muscarinic receptor(hM3 Dq) was delivered into the LC of Phox2 b-Cre mice.The hM3 Dqtransduced neurons were pharmacologically activated while respiratory function was measured by plethysmography.We demonstrated that selective stimulation of Phox2 b~(LC) neurons significantly increased basal ventilation in conscious mice.Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses.Moreover,stimulation of Phox2 b~(LC) neurons enhanced the activity of preBotzinger complex neurons.Finally,axons of Phox2 b~(LC) neurons projected to the preBotzinger complex.Collectively,Phox2 b~(LC) neurons contribute to the control of breathing most likely via an LC-preBotzinger complex circuit.展开更多
The locus coeruleus(LC) has been studied in major depressive disorder(MDD) and bipolar disorder(BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytoche...The locus coeruleus(LC) has been studied in major depressive disorder(MDD) and bipolar disorder(BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin.We found significantly increased tyrosine hydroxylase(TH) in the LC of MDD patients—thus validating the method—but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.展开更多
Mice carrying mutant amyloid precursor protein and presenilin-1 genes （APP/PS1 double trans- genic mice） have frequently been used in studies of Alzheimer＇s disease; however, such studies have focused mainly on hip...Mice carrying mutant amyloid precursor protein and presenilin-1 genes （APP/PS1 double trans- genic mice） have frequently been used in studies of Alzheimer＇s disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer＇s disease is known to correlate with the amount of amyloid-13 protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age： young mice （5-6 months old） and aged mice （16-17 months old）. Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase （a marker of catecholaminergic neurons in the locus coeruleus） revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine hy- droxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.展开更多
In present work,the effects of acupuncturing Renzhong（GV 26）and Zusanli（ST 36）on the neuronal activity of Locus Coeruleus（LC）in rats were observed and compared.The resultsindicated that the central mechanism o...In present work,the effects of acupuncturing Renzhong（GV 26）and Zusanli（ST 36）on the neuronal activity of Locus Coeruleus（LC）in rats were observed and compared.The resultsindicated that the central mechanism of promoting blood pressure（BP）by acupuncturing Renzhongwas related to the activity of LC;the influence of acupuncturing Renzhong on neuronal activity of LC was more obvious than that of acupuncturing Zusanli;and there was relative speciality between the acupoints.展开更多
Robo-pigeons,a novel class of hybrid robotic systems developed using brain–computer interface technology,hold marked promise for search and rescue missions due to their superior load-bearing capacity and sustained fl...Robo-pigeons,a novel class of hybrid robotic systems developed using brain–computer interface technology,hold marked promise for search and rescue missions due to their superior load-bearing capacity and sustained flight performance.However,current research remains largely confined to laboratory environments,and precise control of their flight behavior,especially flight altitude regulation,in a large-scale spatial range outdoors continues to pose a challenge.Herein,we focus on overcoming this limitation by using electrical stimulation of the locus coeruleus(LoC)nucleus to regulate outdoor flight altitude.We investigated the effects of varying stimulation parameters,including stimulation frequency(SF),interstimulus interval(ISI),and stimulation cycles(SC),on the flight altitude of robo-pigeons.The findings indicate that SF functions as a pivotal switch controlling the ascending and descending flight modes of the robo-pigeons.Specifically,60 Hz stimulation effectively induced an average ascending flight of 12.241 m with an 87.72% success rate,while 80 Hz resulted in an average descending flight of 15.655 m with a 90.52% success rate.SF below 40 Hz did not affect flight altitude change,whereas over 100 Hz caused unstable flights.The number of SC was directly correlated with the magnitude of altitude change,enabling quantitative control of flight behavior.Importantly,electrical stimulation of the LoC nucleus had no significant effects on flight direction.This study is the first to establish that targeted variation of electrical stimulation parameters within the LoC nucleus can achieve precise altitude control in robo-pigeons,providing new insights for advancing the control of flight animal–robot systems in real-world applications.展开更多
Background Degeneration of the locus coeruleus(LC)noradrenergic system contributes to clinical symptoms in Alzheimer’s disease(AD)and Parkinson’s disease(PD).Diffusion magnetic resonance imaging(MRI)has the potentia...Background Degeneration of the locus coeruleus(LC)noradrenergic system contributes to clinical symptoms in Alzheimer’s disease(AD)and Parkinson’s disease(PD).Diffusion magnetic resonance imaging(MRI)has the potential to evaluate the integrity of the LC noradrenergic system.The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.Methods Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD,14 PD,and 8 control brain donors.Fractional anisotropy(FA)and mean diffusivity were derived from the LC,and from tracts between the LC and the anterior cingulate cortex,the dorsolateral prefrontal cortex(DLPFC),the primary motor cortex(M1)or the hippocampus.Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase(DBH)to quantify noradrenergic cell density and fiber load.Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.Results The AD and PD cases showed loss of LC noradrenergic cells and fibers.In the cortex,the AD cases showed increased DBH+immunoreactivity in the DLPFC compared to PD cases and controls,while PD cases showed reduced DBH+immunoreactivity in the M1 compared to controls.Higher FA within the LC was found for AD,which was correlated with loss of noradrenergic cells and fibers in the LC.Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group,whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group.The tract alterations were not correlated with cortical DBH+immunoreactivity.Conclusions In AD and PD,the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC,rather than noradrenergic changes in the cortex.展开更多
The effects of stimulating locus coeruleus (LC) on neuronal activity of cerebellar fastigial nucleus (FN) was investigated. Stimulation of LC elicited inhibitory, excitatory and biphasic (inhibition-excitation) respon...The effects of stimulating locus coeruleus (LC) on neuronal activity of cerebellar fastigial nucleus (FN) was investigated. Stimulation of LC elicited inhibitory, excitatory and biphasic (inhibition-excitation) responses from FN cells. The majority of responsive cells showed an inhibitory response with a latency of less than 10 ms. Injection of α adrenoreceptor antagonists phentolamine (ⅳ) could block the inhibitory response of FN cells to the LC stimulation, but propranolol (ⅳ), a β adrenoreceptor antagonist, could not. These results suggest that LC-cerebellar noradrenergic afferent fibers may be involved in the cerebellar sensorimotor integration process by exerting their modulatory action on the cerebellar nuclear cells’ activities.展开更多
In the structure of brain the medial preoptic area (MPO) and ventromedial nucleus of hypothalamus (VMN)are the two parts where the estrogen receptors concentrate but have opposite effects on sexual behavior. Recently ...In the structure of brain the medial preoptic area (MPO) and ventromedial nucleus of hypothalamus (VMN)are the two parts where the estrogen receptors concentrate but have opposite effects on sexual behavior. Recently estrogen receptors have been known to be located in the locus coeruleus(LC), where noradrenergic(NE) fibres terminate in the hypothalamus arising from cell bodies. The discharge rate of NE-ergic neurons in LC can be increased by electrical stimulation of MPO in a female rat at estrus stage, and decreased at diestrus stage. These studies help us to infer that VMN might have some modulation influence on NE-ergic neurons in LC. In order to study the pattern activities展开更多
Several studies showed that sex hormone receptors are in close relationship with classical neurotransmitter neurons especially catecholaminergic(CA) neurons. There are many gonadotrophin releasing hormone (GnRH) neuro...Several studies showed that sex hormone receptors are in close relationship with classical neurotransmitter neurons especially catecholaminergic(CA) neurons. There are many gonadotrophin releasing hormone (GnRH) neurons in hypothalamus and the medial preoptic area (MPO). Electrical stimulation of MPO can cause a rise in secretion展开更多
Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression....Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression.Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the brain.However,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant.Contrary to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant.In addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of MDD.Moreover,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC neurons.These inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD.In this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD.We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.展开更多
Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in ...Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals.Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons.Astrocytes,outnumbering neurons by nearly fivefold,support and regulate neuronal and synaptic function.Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling.This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep,wakefulness,and arousal levels,exploring the involvement of noradrenaline signaling,ion channels,and glutamatergic signaling in different cortical states.These findings highlight the significant impact of astrocytes on large-scale neuronal networks,influencing brain activity and responsiveness.Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation.More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states,requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep-and arousal-related disorders.展开更多
BACKGROUND： Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions： the ventral tegmental area, the nuc...BACKGROUND： Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions： the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE： To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 （Gi2） in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING： A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA （Shanghai, China） between September 2002 and March 2004. MATERIALS： Thirty-six, healthy, male, Sprague-Dawley （SD） rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory （China）; naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory （China）; and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc （USA）. METHODS： Thirty-six SD rats were randomly divided into six groups （n = 6）： （1） acute morphine-dependent group, （2） acute abstinent group, （3） acute control group, （4） chronic morphine-dependent group, （5） chronic abstinent group, and （6） chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine （5 mg/kg）, one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone （5 mg/kg）. Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20：00, which increased by 5 mg/kg at 8：00, 12：00, and 20：00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone （5 mg/kg） at 8：00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES： The concentration of Gi2 protein in the five brain regions （ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus） was detected by immunohistochemistry. RESULTS： In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group （P 〈 0.01）, while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus （P 〈 0.01 ） compared to the chronic control group. CONCLUSION： Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.展开更多
Background:Rapid eye movement sleep(REMS)loss affects almost all physiological processes,while it itself is affected in disorders.REMS maintains optimum level of noradrenaline(NA)in a healthy individual,while increase...Background:Rapid eye movement sleep(REMS)loss affects almost all physiological processes,while it itself is affected in disorders.REMS maintains optimum level of noradrenaline(NA)in a healthy individual,while increased NA during disturbed REMS is associated with diseases.The synthesis,release,and degradation of neurotransmitter are modulated by biomolecules,which are genetically encoded.The aim of this study is to understand the transcriptional and translational changes of those biomolecules in locus coeruleus(LC)and pedunculo-pontine tegmentum(PPT)in association with REMS and its loss,which is expected to help us explain associated acute and chronic pathophysiological changes.Methods:In this study,male inbred Wistar rats were deprived of REMS for 96 h using classical flowerpot method;free-moving-,large platform-and recoverycontrol sets were also conducted(n=5 per group).Brain areas related to REMS regulation,namely the LC and PPT,as well as an area unrelated to REMS regulation,namely the hippocampus,were dissected out for evaluation.Animals were grouped based on similar traits(age,weight,etc.)and then randomly by random table assigned within those matched sets.Dopamineβ-hydroxylase(DBH),tyrosine hydroxylase(TH),and monoamine oxidase-A(MAO-A)protein,their gene expressions and associated histone modifications were evaluated using western blot analysis,quantitative polymerase chain reaction(qPCR)and chromatin immunoprecipitation(ChlP)assays,respectively.One-way analysis of variance(ANOVA)followed by Holm Sidak multiple comparison test was applied to evaluate the significance level between the experimental and control groups using GraphPad Prism(version 9.0.0;GraphPad Software,San Diego,California,USA,www.graphpad.com)and Sigma Stat Statistical Software(version 12;Jandel Scientific Software,CA,USA).Results:Upon rapid eye movement sleep deprivation(REMSD),although TH and DBH protein expressions altered significantly in all the brain areas,the latter was highest in LC(F(5,30)=11.320,p<0.001);MAO-A decreased in LC(F(5,30)=9.286,p<0.001).In LC,DBH(F(8,44)=7.138,p<0.001)and TH(F(8,44)=5.813,p<0.001)gene expressions and histone H3 at lysine 14(H3K14)-acetylation of TH(F(11,59)=25.290,p<0.001)and DBH(F(11,59)=11.610,p<0.001)increased,while lysine K9 in histone H3(H3K9)-dimethylation tended to decrease,whereas opposite modifications were seen in MAo-A gene expression(F(11,59)=16.970,p<0.001).The altered gene-and proteinexpressions returned or tended to return to normal levels after recovery,as in post-REMSD prazosin treated rat brains.Conclusion:The differential expressions of the genes and corresponding proteins(enzymes)responsible for synthesis and degradation of NA support sustained increase in NA upon REMSD that explains underlying causes of REMSD associated chronic effects,which may be exploited for amelioration of REMSD-associated disorders.展开更多
Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with...Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.展开更多
In stressful or anxiety-provoking situations,most people with Parkinson’s disease(PD)experience a general worsening of motor symptoms,including their gait impairments.However,a proportion of patients actually report ...In stressful or anxiety-provoking situations,most people with Parkinson’s disease(PD)experience a general worsening of motor symptoms,including their gait impairments.However,a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations.Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight(USA)and ParkinsonNEXT(NL)cohorts,we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment.Crucially,these strategies differ along an axis of arousal-some act to heighten,whereas others diminish,overall sympathetic tone.Together,our observations suggest that arousal may act as a double-edged sword for gait control in PD.We propose a theoretical,neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals,while alleviating them in others.Specifically,we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system:namely,that arousal is related to task performance by an inverted u-shaped curve(the so-called Yerkes and Dodson relationship).We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression,by regulating arousal and by mediating network-level functional integration across the brain.The ability of the locus coeruleus to facilitate dynamic‘cross-talk’between distinct,otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD.In the presence of suboptimal arousal,compensatory networks may be too segregated to allow for adequate compensation.Conversely,with supraoptimal arousal,increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional.Because the locus coeruleus degenerates with disease progression,finetuning of this delicate balance becomes increasingly difficult,heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub-or supraoptimal state of arousal to improve gait performance.Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.展开更多
基金supported by grants from the National Natural Science Foundation of China(32171014 and 32000706)the National Science and Technology Major Project(2024ZD0530200)+5 种基金research funding by the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2023-PT310-01)the Fundamental Research Funds for Central Universities(226-2024-00133)Nanhu Brain-computer Interface Institute(010904004)the Zhejiang Provincial Natural Science Foundation of China(LMS25C090004)The Fundamental Research Funds for Central Universities(2025ZFJH01-01)the China Postdoctoral Science Foundation(2020M681828 and 2023TQ0280).
文摘The locus coeruleus(LC),a norepinephrine nucleus governing arousal states through tonic activity,requires precise regulatory mechanisms to maintain its dynamic activation levels.However,the neural circuitry underlying LC activity maintenance remains unclear.Here,we identify a glutamatergic projection from the ventrolateral periaqueductal gray(vlPAG)to the LC in mice as a critical regulator of arousal dynamics.Fiber photometry recordings revealed stress-induced Ca^(2+)dynamics in vlPAGCaMKIIα-LC axon terminals across diverse threat paradigms.Slice electrophysiology demonstrated that this pathway mediates LC-norepinephrine(LC-NE)neuronal activity via glutamatergic transmission.Low-frequency pathway activation(1 Hz)mainly induced anxiety-like behaviors,whereas high-frequency stimulation(10 Hz)evoked more panic-like hyperlocomotion,establishing a frequency-dependent continuum of arousal states.Conversely,pathway inhibition reduced pupil size,a reliable biomarker for arousal,concurrently suppressing threat avoidance behaviors and alleviating anxiety-related behaviors without altering environmental preference.These findings reveal that the vlPAGCaMKIIα-LC pathway maintains baseline arousal while dynamically scaling threat-induced hyperarousal.
基金supported by the Canadian Institutes of Health Research Project grant (PJT-169197) to QYsupported by a CGS-M fellowship from the Canadian Institutes of Health Research
文摘Alzheimer’s disease(AD)remains an incurable neurodegenerative disorder with devastating societal and personal impacts.Despite decades of intensive research,therapeutic efforts targeting the clinical stages of AD have largely failed to halt or reverse disease progression.This has prompted a critical shift in focus toward the earlier,preclinical stages of AD,where interventions may hold greater promise for altering the disease trajectory.
基金supported by the Foundation of Science and Technological Program of Shaanxi Province,China (No. 2007K15-G1).
文摘Objective To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD). Methods 2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording. Results The firing rate of LC noradrenergic neurons increased sig...
基金supported by the National Natural Science Foundation of China(31971058 and 31571174)the Youth Fund for Scientific and Technological Research in Higher Education Institutions of Hebei Province(QN2019019)the Youth Science and Technology Talent Support Program of Natural Science in Hebei Medical University(CYQD201907)。
文摘The locus coeruleus(LC) has been implicated in the control of breathing.Congenital central hypoventilation syndrome results from mutation of the paired-like homeobox 2 b(Phox2 b) gene that is expressed in LC neurons.The present study was designed to address whether stimulation of Phox2 b-expressing LC(Phox2 b~(LC)) neurons affects breathing and to reveal the putative circuit mechanism.A Cre-dependent viral vector encoding a Gqcoupled human M3 muscarinic receptor(hM3 Dq) was delivered into the LC of Phox2 b-Cre mice.The hM3 Dqtransduced neurons were pharmacologically activated while respiratory function was measured by plethysmography.We demonstrated that selective stimulation of Phox2 b~(LC) neurons significantly increased basal ventilation in conscious mice.Genetic ablation of these neurons markedly impaired hypercapnic ventilatory responses.Moreover,stimulation of Phox2 b~(LC) neurons enhanced the activity of preBotzinger complex neurons.Finally,axons of Phox2 b~(LC) neurons projected to the preBotzinger complex.Collectively,Phox2 b~(LC) neurons contribute to the control of breathing most likely via an LC-preBotzinger complex circuit.
基金supported by the National Key R&D Program of China (2016YFC1306700)the National Natural Science Foundation of China (91332102 and 31271130)
文摘The locus coeruleus(LC) has been studied in major depressive disorder(MDD) and bipolar disorder(BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin.We found significantly increased tyrosine hydroxylase(TH) in the LC of MDD patients—thus validating the method—but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.
基金supported by the National Natural Science Foundation of China, No. 81100663the Scientific Research Funds of the Health Department of Hunan Province, No.120303+1 种基金Hunan Provincal Natural Science Foundation of China, No. 13JJ3058a grant from the Scientific Research Program of Hunan Provincial Higher Education Institutes, No. 11C0829
文摘Mice carrying mutant amyloid precursor protein and presenilin-1 genes （APP/PS1 double trans- genic mice） have frequently been used in studies of Alzheimer＇s disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer＇s disease is known to correlate with the amount of amyloid-13 protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age： young mice （5-6 months old） and aged mice （16-17 months old）. Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase （a marker of catecholaminergic neurons in the locus coeruleus） revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine hy- droxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.
文摘In present work,the effects of acupuncturing Renzhong（GV 26）and Zusanli（ST 36）on the neuronal activity of Locus Coeruleus（LC）in rats were observed and compared.The resultsindicated that the central mechanism of promoting blood pressure（BP）by acupuncturing Renzhongwas related to the activity of LC;the influence of acupuncturing Renzhong on neuronal activity of LC was more obvious than that of acupuncturing Zusanli;and there was relative speciality between the acupoints.
基金supported by the Research Fund of State Key Laboratory of Mechanics and Control for Aerospace Structures(grant no.1005-IZD2300225)the Scientific Research Starting Foundation of Chinese Academy of Sciences(no.E3J1230201)+1 种基金the National Key Research and Development Program of China(no.2020YFB1313504)the Science and Technology Cooperation Project of the China Electronics Technology Group Corporation.
文摘Robo-pigeons,a novel class of hybrid robotic systems developed using brain–computer interface technology,hold marked promise for search and rescue missions due to their superior load-bearing capacity and sustained flight performance.However,current research remains largely confined to laboratory environments,and precise control of their flight behavior,especially flight altitude regulation,in a large-scale spatial range outdoors continues to pose a challenge.Herein,we focus on overcoming this limitation by using electrical stimulation of the locus coeruleus(LoC)nucleus to regulate outdoor flight altitude.We investigated the effects of varying stimulation parameters,including stimulation frequency(SF),interstimulus interval(ISI),and stimulation cycles(SC),on the flight altitude of robo-pigeons.The findings indicate that SF functions as a pivotal switch controlling the ascending and descending flight modes of the robo-pigeons.Specifically,60 Hz stimulation effectively induced an average ascending flight of 12.241 m with an 87.72% success rate,while 80 Hz resulted in an average descending flight of 15.655 m with a 90.52% success rate.SF below 40 Hz did not affect flight altitude change,whereas over 100 Hz caused unstable flights.The number of SC was directly correlated with the magnitude of altitude change,enabling quantitative control of flight behavior.Importantly,electrical stimulation of the LoC nucleus had no significant effects on flight direction.This study is the first to establish that targeted variation of electrical stimulation parameters within the LoC nucleus can achieve precise altitude control in robo-pigeons,providing new insights for advancing the control of flight animal–robot systems in real-world applications.
文摘Background Degeneration of the locus coeruleus(LC)noradrenergic system contributes to clinical symptoms in Alzheimer’s disease(AD)and Parkinson’s disease(PD).Diffusion magnetic resonance imaging(MRI)has the potential to evaluate the integrity of the LC noradrenergic system.The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.Methods Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD,14 PD,and 8 control brain donors.Fractional anisotropy(FA)and mean diffusivity were derived from the LC,and from tracts between the LC and the anterior cingulate cortex,the dorsolateral prefrontal cortex(DLPFC),the primary motor cortex(M1)or the hippocampus.Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase(DBH)to quantify noradrenergic cell density and fiber load.Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.Results The AD and PD cases showed loss of LC noradrenergic cells and fibers.In the cortex,the AD cases showed increased DBH+immunoreactivity in the DLPFC compared to PD cases and controls,while PD cases showed reduced DBH+immunoreactivity in the M1 compared to controls.Higher FA within the LC was found for AD,which was correlated with loss of noradrenergic cells and fibers in the LC.Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group,whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group.The tract alterations were not correlated with cortical DBH+immunoreactivity.Conclusions In AD and PD,the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC,rather than noradrenergic changes in the cortex.
文摘The effects of stimulating locus coeruleus (LC) on neuronal activity of cerebellar fastigial nucleus (FN) was investigated. Stimulation of LC elicited inhibitory, excitatory and biphasic (inhibition-excitation) responses from FN cells. The majority of responsive cells showed an inhibitory response with a latency of less than 10 ms. Injection of α adrenoreceptor antagonists phentolamine (ⅳ) could block the inhibitory response of FN cells to the LC stimulation, but propranolol (ⅳ), a β adrenoreceptor antagonist, could not. These results suggest that LC-cerebellar noradrenergic afferent fibers may be involved in the cerebellar sensorimotor integration process by exerting their modulatory action on the cerebellar nuclear cells’ activities.
文摘In the structure of brain the medial preoptic area (MPO) and ventromedial nucleus of hypothalamus (VMN)are the two parts where the estrogen receptors concentrate but have opposite effects on sexual behavior. Recently estrogen receptors have been known to be located in the locus coeruleus(LC), where noradrenergic(NE) fibres terminate in the hypothalamus arising from cell bodies. The discharge rate of NE-ergic neurons in LC can be increased by electrical stimulation of MPO in a female rat at estrus stage, and decreased at diestrus stage. These studies help us to infer that VMN might have some modulation influence on NE-ergic neurons in LC. In order to study the pattern activities
文摘Several studies showed that sex hormone receptors are in close relationship with classical neurotransmitter neurons especially catecholaminergic(CA) neurons. There are many gonadotrophin releasing hormone (GnRH) neurons in hypothalamus and the medial preoptic area (MPO). Electrical stimulation of MPO can cause a rise in secretion
文摘Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity rate.Stress-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of depression.Lack of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the brain.However,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of antidepressant.Contrary to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of antidepressant.In addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of MDD.Moreover,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC neurons.These inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of MDD.In this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in MDD.We will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.
基金supported by the Corbett Estate Fund(62285-531021-41800,to EW)the Helen Vosburg McCrillus Plummer and Robert Edward Lee Plummer,Jr.Chair Fund(to JHH).
文摘Neuron-astrocyte interactions are vital for the brain’s connectome.Understanding astrocyte activities is crucial for comprehending the complex neural network,particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals.Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons.Astrocytes,outnumbering neurons by nearly fivefold,support and regulate neuronal and synaptic function.Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling.This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep,wakefulness,and arousal levels,exploring the involvement of noradrenaline signaling,ion channels,and glutamatergic signaling in different cortical states.These findings highlight the significant impact of astrocytes on large-scale neuronal networks,influencing brain activity and responsiveness.Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation.More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states,requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep-and arousal-related disorders.
文摘BACKGROUND： Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions： the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE： To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 （Gi2） in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING： A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA （Shanghai, China） between September 2002 and March 2004. MATERIALS： Thirty-six, healthy, male, Sprague-Dawley （SD） rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory （China）; naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory （China）; and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc （USA）. METHODS： Thirty-six SD rats were randomly divided into six groups （n = 6）： （1） acute morphine-dependent group, （2） acute abstinent group, （3） acute control group, （4） chronic morphine-dependent group, （5） chronic abstinent group, and （6） chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine （5 mg/kg）, one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone （5 mg/kg）. Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20：00, which increased by 5 mg/kg at 8：00, 12：00, and 20：00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone （5 mg/kg） at 8：00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES： The concentration of Gi2 protein in the five brain regions （ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus） was detected by immunohistochemistry. RESULTS： In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group （P 〈 0.01）, while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus （P 〈 0.01 ） compared to the chronic control group. CONCLUSION： Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.
文摘Background:Rapid eye movement sleep(REMS)loss affects almost all physiological processes,while it itself is affected in disorders.REMS maintains optimum level of noradrenaline(NA)in a healthy individual,while increased NA during disturbed REMS is associated with diseases.The synthesis,release,and degradation of neurotransmitter are modulated by biomolecules,which are genetically encoded.The aim of this study is to understand the transcriptional and translational changes of those biomolecules in locus coeruleus(LC)and pedunculo-pontine tegmentum(PPT)in association with REMS and its loss,which is expected to help us explain associated acute and chronic pathophysiological changes.Methods:In this study,male inbred Wistar rats were deprived of REMS for 96 h using classical flowerpot method;free-moving-,large platform-and recoverycontrol sets were also conducted(n=5 per group).Brain areas related to REMS regulation,namely the LC and PPT,as well as an area unrelated to REMS regulation,namely the hippocampus,were dissected out for evaluation.Animals were grouped based on similar traits(age,weight,etc.)and then randomly by random table assigned within those matched sets.Dopamineβ-hydroxylase(DBH),tyrosine hydroxylase(TH),and monoamine oxidase-A(MAO-A)protein,their gene expressions and associated histone modifications were evaluated using western blot analysis,quantitative polymerase chain reaction(qPCR)and chromatin immunoprecipitation(ChlP)assays,respectively.One-way analysis of variance(ANOVA)followed by Holm Sidak multiple comparison test was applied to evaluate the significance level between the experimental and control groups using GraphPad Prism(version 9.0.0;GraphPad Software,San Diego,California,USA,www.graphpad.com)and Sigma Stat Statistical Software(version 12;Jandel Scientific Software,CA,USA).Results:Upon rapid eye movement sleep deprivation(REMSD),although TH and DBH protein expressions altered significantly in all the brain areas,the latter was highest in LC(F(5,30)=11.320,p<0.001);MAO-A decreased in LC(F(5,30)=9.286,p<0.001).In LC,DBH(F(8,44)=7.138,p<0.001)and TH(F(8,44)=5.813,p<0.001)gene expressions and histone H3 at lysine 14(H3K14)-acetylation of TH(F(11,59)=25.290,p<0.001)and DBH(F(11,59)=11.610,p<0.001)increased,while lysine K9 in histone H3(H3K9)-dimethylation tended to decrease,whereas opposite modifications were seen in MAo-A gene expression(F(11,59)=16.970,p<0.001).The altered gene-and proteinexpressions returned or tended to return to normal levels after recovery,as in post-REMSD prazosin treated rat brains.Conclusion:The differential expressions of the genes and corresponding proteins(enzymes)responsible for synthesis and degradation of NA support sustained increase in NA upon REMSD that explains underlying causes of REMSD associated chronic effects,which may be exploited for amelioration of REMSD-associated disorders.
基金This work was supported by the Natural Science Foundation of Beijing Municipality(No.7212156,China)CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1–026,China)National Natural Science Foundation of China,China(82373852).
文摘Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.
基金supported by an Academy Van Leersum grant of the Academy Medical Sciences Fund,Royal Netherlands Academy of Arts&Sciencessupported by a Parkinson Canada New Investigator grant,as well as a Natural Sciences and Engineering Research Council of Canada Discovery grant.RCH was supported by a research grant(VIDI,#09150172010044)from the Netherlands Organization for Scientific Research+4 种基金He has acted as consultant for UCB(unrelated to this work)supported by a grant from the European Regional Development Fund(ERDF/EFRO,grant number PROJ-00928)outside the submitted worksupported by the National Health and Medical Research Council(1193857)supported by the Australian Government Research Training Program(RTP)Scholarship.GW reports no disclosures.SJGL was supported by a National Health and Medical Research Council Leadership Fellowship(1195830)supported by a ZonMW Veni grant(16.196.022).
文摘In stressful or anxiety-provoking situations,most people with Parkinson’s disease(PD)experience a general worsening of motor symptoms,including their gait impairments.However,a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations.Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight(USA)and ParkinsonNEXT(NL)cohorts,we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment.Crucially,these strategies differ along an axis of arousal-some act to heighten,whereas others diminish,overall sympathetic tone.Together,our observations suggest that arousal may act as a double-edged sword for gait control in PD.We propose a theoretical,neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals,while alleviating them in others.Specifically,we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system:namely,that arousal is related to task performance by an inverted u-shaped curve(the so-called Yerkes and Dodson relationship).We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression,by regulating arousal and by mediating network-level functional integration across the brain.The ability of the locus coeruleus to facilitate dynamic‘cross-talk’between distinct,otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD.In the presence of suboptimal arousal,compensatory networks may be too segregated to allow for adequate compensation.Conversely,with supraoptimal arousal,increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional.Because the locus coeruleus degenerates with disease progression,finetuning of this delicate balance becomes increasingly difficult,heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub-or supraoptimal state of arousal to improve gait performance.Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.
