The spinal cord plays a key role in motor behavior. It relays major sensory information, receives afferents from supraspinal centers and integrates movement in the central pattern generators. Spinal motor output is controlled via corticofugal pathways including corticospinal and cortico-subcortical projections. Spinal cord injury damages descending supraspinal as well as ascending sensory pathways. In adult rodent models, plasticity of the spinal cord is thought to contribute to functional recovery. How much spinal cord function depends on cortical input is not well known. Here, we address this question using Celsr3/Foxg1 mice, in which cortico-subcortical connections (including corticospinal tract (CST) and the terminal sensory pathway, the thalamocortical tract) are genetically ablated during early development. Although Celsr3/Foxg1 mice are able to eat, walk, climb on grids and swim, open-field tests showed them to be hyperactive. When compared with normal littermates, mutant animals had reduced number of spinal motor neurons, with atrophic dendritic trees. Furthermore, motor axon terminals were decreased in number, and this was confirmed by electromyography. The number of cholinergic, calbindin, and calretinin-positive interneurons was moderately increased in the mutant spinal cord, whereas that of reelin and parvalbumin-positive interneurons was unchanged. As far as we know, our study provides the first genetic evidence that the spinal motor network does not mature fully in the absence of corticofugal connections, and that some motor function is preserved despite congenital absence of the CST.

Previous studies yielded evidence for an interaction between age and valence in numerous cognitive processes. But, to date, no research has been conducted in the field of motor skills. In this study, we examined the age-related differences in the organization of an emotionally goal-directed locomotion task. Faced with a pleasant, unpleasant, or neutral picture displayed to the side of a stop button, younger and older adults were instructed to walk toward the button (intermediate goal) and push it to turn-off the picture (final goal). Kinematic and ground reaction forces were recorded. The main findings indicated that older adults' response times (RTs) did not differ across the valence picture. The fastest RTs were found in younger adults when faced with pleasant pictures, suggesting that older people may focus either on intermediate or final goals, depending on their value of pleasantness, and prioritize positive goals. We also found that the spatial coding of locomotion (trajectory and final body position) was affected in the same way by the valence of the intermediate goal in both age groups. Taken together, these findings provide new perspectives regarding the potential role of the emotional valence of the intermediate and final goals on the cognitive processes involved in action coding, such as in mental representations of action in older adults.

We used FM imaging to identify neurons that receive sensory feedback from the body wall in a circuit for octopamine (OA)-evoked rhythmic locomotion in the earthworm, Eisenia fetida. We visualized synapses in which postsynaptic neurons receive the sensory feedback, by using FM1-43 dye to label the synapses of both motor and sensory pathways that are associated with locomotion, then clearing the motor pathway synapse labeling, and finally identifying the target synapses by distinguishing physiologically functional synapses through destaining using a high-K(+) solution. A pair of synaptic regions associated with the sensory feedback was found to be located two or three cell body-widths away from the midline, between the anterior parts of the roots of the second lateral nerves (LNs) at the segmental ganglia (SGs). Using conventional intracellular recording and dye loading of the cell bodies surrounding these synaptic regions, we identified a pair of bilateral neurons with cell bodies larger than those of other cells in these regions, and named them "Oscillatory firing neurons Projecting to Peripheral nerves" (OPPs). These had a bipolar shape and projected neurites to the ipsilateral first and third LNs, fired rhythmically, and had a burst timing synchronized with the motor pattern bursts from the ipsilateral first LNs. Current injection into an OPP caused firing in the ipsilateral first LNs, supporting the hypothesis that OPPs functionally project to the peripheral nerves. OPPs also sent neurites to the adjacent anterior and posterior SGs, suggesting connections with the adjacent segments. We conclude that FM imaging can be used to identify neurons involved in specific functions, and that OPPs are the first neurons to be associated with OA-induced locomotion in the earthworm.

Acetylcholine (ACh) is an abundant neurotransmitter and neuromodulator in many species. In Drosophila melanogaster ACh is the neurotransmitter used in peripheral sensory neurons and is a primary excitatory neurotransmitter and neuromodulator within the central nervous system (CNS). The receptors that facilitate cholinergic transmission are divided into two broad subtypes: the ionotropic nicotinic acetylcholine receptors (nAChRs) and the metabotropic muscarinic acetylcholine receptors (mAChRs). This receptor classification is shared in both mammals and insects; however, both the pharmacological and functional characterization of these receptors within the Drosophila nervous system has lagged behind its mammalian model counterparts. In order to identify the impact of ACh receptor subtypes in regulating the performance of neural circuits within the larval CNS, we used a behavioral and electrophysiological approach to assess cholinergic modulation of locomotion and sensory-CNS-motor circuit excitability. We exposed intact and semi-intact 3rd instar larvae to ACh receptor agonists and antagonists to observe their roles in behavior and regulation of neural circuit excitability and to investigate AChR pharmacological properties in vivo. We combined this with targeted AChR RNAi-mediated knockdown to identify specific receptor subtypes facilitating ACh modulation of circuit efficacy. We identify a contribution by both mAChRs and nAChRs in regulation of locomotor behavior and reveal they play a role in modulation of the excitability of a sensory-CNS-motor circuit. We further reveal a conspicuous role for mAChR-A and mAChR-C in motor neurons in modulation of their input-output efficacy.

Preclinical data indicate that ethanol produces behavioral effects that can be regulated by many neurotransmitters and neuromodulators like adenosine (A). The most important receptors with respect to the rewarding effects of ethanol seem to be the A2A receptors. This study used a transgenic strategy, specifically rats overexpressing the A2A receptor, to characterize the neurobiological mechanisms of ethanol consumption as measured by intermittent access to 20% ethanol in a two-bottle choice paradigm. In this model, no change in ethanol consumption was observed in transgenic animals compared to wild type controls during the acquisition/maintenance phase. Following alcohol deprivation, only transgenic rats overexpressing the A2A receptor exhibited escalation of ethanol consumption and drank more (by ca. 90%), but not significantly, ethanol than did the wild type rats. During ethanol withdrawal, the immobility time of rats overexpressing the A2A receptor in the forced swim test was lower than that of wild type rats. Moreover, transgenic rats withdrawn from ethanol, compared to the drug-naive transgenic animals, exhibited an increase above 70% in locomotion. The results indicated that the overexpression of A2A receptors may be a risk factor for the escalation of ethanol consumption despite the reduction in depression-like signs of ethanol withdrawal.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The average age of onset of both sporadic and familial cases is 50-60 years of age. The presence of cytoplasmic inclusions of the RNA-binding protein TAR DNA-binding protein-43 (TDP-43) in the affected neurons is seen in 95% of the ALS cases, which results in TDP-43 nuclear clearance and loss of function. The Drosophila melanogaster ortholog of TDP-43 (TBPH) shares many characteristics with the human protein. Using a TDP-43 aggregation inducer previously developed in human cells, we created a transgenic fly that shows an adult locomotive defect. Phenotype onset correlates with a physiologically age-related drop of TDP-43/TBPH mRNA and protein levels, seen both in mice and flies. Artificial reduction of mRNA levels, in vivo, anticipates the locomotion defect to the larval stage. Our study links, for the first time, aggregation and the age-related, evolutionary conserved reduction of TDP-43/TBPH levels with the onset of an ALS-like locomotion defect in a Drosophila model. A similar process might trigger the human disease.

Excitatory amino acids are known to activate the spinal neural network that organize locomotor activity in various species. In this study, the role of various compounds which alter the functioning of the N-methyl-D-aspartate receptor (glycine, Mg2+ ions and spermine) was investigated during fictive locomotion, using an in vitro isolated spinal cord preparation from neonatal rats. Locomotor-like activity induced by excitatory amino acids was recorded both extra- and intracellularly. 7-chloro-kynurenic acid, an antagonist of the glycine site at the N-methyl-D-aspartate receptor, depressed the N-methyl-D-aspartate component of the synaptic inputs received by the motoneurons. Glycine at low concentrations had no effect on locomotor activity, while 7-chlorokynurenic acid increased the locomotor period and decreased the burst amplitude in a dose-dependent manner. Removal of Mg2+ ions from the saline facilitated the N-methyl-D-aspartate-mediated response, and triggered spontaneous bursting activity, abolished by 2-amino-5-phosphonovaleric acid, an antagonist of the N-methyl-D-aspartate receptor. The polyamine, spermine, did not change the locomotor parameters. On the contrary, arcaine, a putative antagonist of the polyamine site on the N-methyl-D-aspartate receptor, increased locomotor activity. The effects of arcaine were counteracted by spermine. These results suggest that glycine and spermine are present at saturating concentrations on the N-methyl-D-aspartate receptor during ongoing locomotion. Together with Mg2+ ions, these endogenous regulators contribute to control the level of activity of the N-methyl-D-aspartate receptor in the spinal cord of the neonatal rat.

We have expressed A-FOS, an inhibitor of activator protein-1 (AP-1) DNA binding, in adult mouse striatal neurons. We observed normal behavior including locomotion and exploratory activities. Following a single injection of cocaine, locomotion increased similarly in both the A-FOS expressing and littermate controls. However, following repeated injections of cocaine, the A-FOS expressing mice showed increased locomotion relative to littermate controls, an increase that persisted following a week of withdrawal and subsequent cocaine administration. These results indicate that AP-1 suppresses this behavioral response to cocaine. We analyzed mRNA from the striatum before and 4 and 24 h after a single cocaine injection in both A-FOS and control striata using Affymetrix microarrays (430 2.0 Array) to identify genes mis-regulated by A-FOS that may mediate the increased locomotor sensitization to cocaine. A-FOS expression did not change gene expression in the basal state or 4 h following cocaine treatment relative to controls. However, 24 h after an acute cocaine treatment, 84 genes were identified that were differentially expressed between the A-FOS and control mice. Fifty-six genes are down-regulated while 28 genes are up-regulated including previously identified candidates for addiction including brain-derived neurotrophic factor and period homolog 1. Using a random sample of identified genes, quantitative PCR was used to verify the microarray studies. The chromosomal location of these 84 genes was compared with human genome scans of addiction to identify potential genes in humans that are involved in addiction.

Treatment to block the pathophysiological processes triggered by acute spinal injury remains unsatisfactory as the underlying mechanisms are incompletely understood. Using as a model the in vitro spinal cord of the neonatal rat, we investigated the feasibility of neuroprotection of lumbar locomotor networks by the glutamate antagonists 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) and aminophosphonovalerate (APV) against acute lesions induced by either a toxic solution (pathological medium (PM) to mimic the spinal injury hypoxic-dysmetabolic perturbation) or excitotoxicity with kainate. The study outcome was presence of fictive locomotion 24 h after the insult and its correlation with network histology. Inhibition of fictive locomotion by PM was contrasted by simultaneous and even delayed (1 h later) co-application of CNQX and APV with increased survival of ventral horn premotoneurons and lateral column white matter. Neither CNQX nor APV alone provided neuroprotection. Kainate-mediated excitotoxicity always led to loss of fictive locomotion and extensive neuronal damage. CNQX and APV co-applied with kainate protected one-third of preparations with improved motoneuron and dorsal horn neuronal counts, although they failed with delayed application. Our data suggest that locomotor network neuroprotection was possible when introduced very early during the pathological process of spinal injury, but also showed how the borderline between presence or loss of locomotor activity was a very narrow one that depended on the survival of a certain number of neurons or white matter elements. The present report provides a model not only for preclinical testing of novel neuroprotective agents, but also for estimating the minimal network membership compatible with functional locomotor output.

In mammals, the suprachiasmatic nucleus (SCN) is the master circadian pacemaker. Within the caudal hamster SCN, a cluster of neurons containing the calcium binding protein, calbindin-D28K (CB), has been implicated in circadian locomotion. However, calbindin-immunoreactive (CB+) neurons in the calbindin subnucleus (CBsn) do not display a circadian rhythm in spontaneous firing [Eur J Neurosci 16 (2002) 2469]. Previously, we proposed that intercellular communication might be essential in integrating outputs from rhythmic (CB-) neurons and nonrhythmic (CB+) neurons to produce a circadian output in the intact animal. The primary aim of this study is to provide a neuroanatomical framework to better understand intercellular communication within the CBsn. Using reconstructions of previously recorded neurons, we demonstrate that CB+ neurons have significantly more dendrites than CB- neurons. In addition, CBsn neurons have dorsally oriented dendritic arbors. Using double-label confocal microscopy, we show that GABA colocalizes with CB+ neurons and GABA(A) receptor subunits make intimate contacts with neurons in the CBsn. Transforming growth factor alpha (TGFalpha), a substance shown to inhibit locomotion [Science 294 (2001) 2511], is present within the CBsn. In addition, neurons in this region express the epidermal growth factor receptor, the only receptor for TGFalpha. Lastly, we show that CB+ neurons are coupled to CB+ and CB- neurons by gap junctions. The current study provides a structural framework for synaptic communication, electrical coupling, and signaling via a growth factor within the CBsn of the hamster SCN. Our results reveal connections that have the potential for integrating cellular communication within a subregion of the SCN that is critically involved in circadian locomotion.

Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice. Phenotypes have been extensively reported in young adult Ube3a mice. Because symptoms continue throughout life in Angelman syndrome, we tested multiple behavioral phenotypes of male Ube3a mice and WT littermate controls at older adult ages. Social behaviors on both the 3-chambered social approach and male-female social interaction tests showed impairments in Ube3a at 12 months of age. Anxiety-related scores on both the elevated plus-maze and the light ↔ dark transitions assays indicated anxiety-like phenotypes in 12 month old Ube3a mice. Open field locomotion parameters were consistently lower at 12 months. Reduced general exploratory locomotion at this age prevented the interpretation of an anxiety-like phenotype, and likely impacted social tasks. Robust phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Motor deficits may provide the best outcome measures for preclinical testing of pharmacological targets, towards reductions of symptoms in adults with Angelman syndrome.

In Vojta physiotherapy, also known as reflex locomotion therapy, prolonged peripheral pressure stimulation induces complex generalized involuntary motor responses and modifies subsequent behavior, but its neurobiological basis remains unknown. We hypothesized that the stimulation would induce sensorimotor activation changes in functional magnetic resonance imaging (fMRI) during sequential finger opposition. Thirty healthy volunteers (mean age 24.2) underwent two randomized fMRI sessions involving manual pressure stimulation applied either at the right lateral heel according to Vojta, or at the right lateral ankle (control site). Participants were scanned before and after the stimulation when performing auditory-paced sequential finger opposition with their right hand. Despite an extensive activation decrease following both stimulation paradigms, the stimulation of the heel specifically led to an increase in task-related activation in the predominantly contralateral pontomedullary reticular formation and bilateral posterior cerebellar hemisphere and vermis. Our findings suggest that sustained pressure stimulation of the foot is associated with differential short-term changes in hand motor task-related activation depending on the stimulation. This is the first evidence for brainstem modulation after peripheral pressure stimulation, suggesting that the after-effects of reflex locomotion physiotherapy involve a modulation of the pontomedullary reticular formation.

Anabolic steroids are drugs of abuse. However, the potential for steroid reward and addiction remains largely unexplored. This study used i.c.v. testosterone self-administration and controlled infusions of testosterone or vehicle in hamsters to explore central mechanisms of androgen overdose. Forty-two hamsters used nose-pokes to self-administer 1 microg/microl testosterone i.c.v. 4 h/day in an operant chamber. During 1-56 days of androgen self-administration, 10 (24%) hamsters died. Deaths correlated with peak daily intake of testosterone. Of the hamsters that self-administered a peak intake of <20 microg/day, there was 100% survival (10/10). Survival decreased to 86% (19/22) when daily testosterone intake peaked at 20-60 microg/day. Only 30% (three of 10) survived when daily testosterone intake exceeded 60 microg/day. Deaths are not due to volume or vehicle because i.c.v. infusions of 80 mul vehicle had no effect. Testosterone overdose resembles opiate intoxication. When male hamsters received infusions of 40 microg testosterone, locomotion (25.1+/-18.8 grid-crossings/10 min), respiration (72.7+/-5.4 breaths/min) and body temperature (33.5+/-0.4 degrees C) were significantly reduced, compared with males receiving vehicle infusions (186.1+/-8.1 crossings/10 min, 117.6+/-1.0 breaths/min, 35.9+/-0.1 degrees C, P<0.05). However, males developed tolerance to continued daily testosterone infusion. After 15 days, locomotion (170.2+/-6.3 crossings), respiration (118.4+/-1.3 breaths/min), and body temperature (35.3+/-0.3 degrees C) in testosterone-infused males were equivalent to that in vehicle controls (P>0.05). The depressive effects of testosterone infusion are blocked by the opioid antagonist, naltrexone. With naltrexone pre-treatment (10 mg/kg s.c.), locomotion (183.7+/-1.8 crossings/10 min), respiration (116.9+/-0.3 breaths/min), and body temperature (36.1+/-0.4 degrees C) during testosterone infusion were equivalent to vehicle controls. Likewise, naltrexone prevents the reinforcing effects of i.c.v. testosterone self-administration. These results indicate that testosterone at high doses causes central autonomic depression, which may be a factor in deaths during self-administration. As well, the depressive effects of large quantities of testosterone may be mediated, at least in part, by an opioidergic mechanism.

The ventromedial spinal cord of mammals contains a neural network known as the locomotor central pattern generator (CPG) which underlies the basic generation and coordination of muscle activity during walking. To understand how this neural network operates, it is necessary to identify, characterize, and map connectivity among its constituent cells. Recently, a series of studies have analyzed the activity pattern of interneurons that are rhythmically active during locomotion and suggested that they belong to one of two functional levels; one responsible for rhythm generation and the other for pattern formation. Here we use electrophysiological techniques to identify locomotor-related interneurons in the lumbar spinal cord of the neonatal mouse. By analyzing their activity during spontaneous deletions that occur during fictive locomotion we are able to distinguish between those likely to belong to the rhythm-generating and pattern-forming levels, and determine the regional distribution of each. Anatomical tracing techniques are also employed to investigate the morphological characteristics of cells belonging to each level. Results demonstrate that putative rhythm-generating cells are medially located and extend locally projecting axons, while those with activity consistent with pattern formation are located more laterally and send axonal projections to the lateral edge of the spinal cord, in the direction of the motoneuron pools. Results of this study provide insight into the detailed anatomical organization of the locomotor CPG.

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.

The locomotor central pattern generator is a neural network located in the ventral aspect of the caudal spinal cord that underlies stepping in mammals. While many genetically defined interneurons that are thought to comprise this neural network have been identified and characterized, the dI6 cells- which express the transcription factors WT1 and/or DMRT3- are one population that settle in this region, are active during locomotion, whose function is poorly understood. These cells were originally hypothesized to be commissural premotor interneurons, however evidence in support of this is sparse. Here we characterize this population of cells using the TgDbx1Cre;R26EFP;Dbx1LacZ transgenic mouse line, which has been shown to be an effective marker of dI6 interneurons. We show dI6 cells to be abundant in laminae VII and VIII along the entire spinal cord and provide evidence that subtypes outside the WT1/DMRT3 expressing dI6 cells may exist. Retrograde tracing experiments indicate that the majority of dI6 cells project descending axons, and some make monosynaptic or disynaptic contacts onto motoneurons on either side of the spinal cord. Analysis of their activity during non-resetting deletions, which occur during bouts of fictive locomotion, suggests that these cells are involved in both locomotor rhythm generation and pattern formation. This study provides a thorough characterization of the dI6 cells labeled in the TgDbx1Cre;R26EFP;Dbx1LacZ transgenic mouse, and supports previous work suggesting that these cells play multiple roles during locomotor activity.

Robust locomotion is critical to many species' survival, yet the mechanisms by which efficient locomotion is learned and maintained are poorly understood. In mice, a common paradigm for assaying locomotor learning is the rotarod task, in which mice learn to maintain balance atop of an accelerating rod. However, the standard metric for learning in this task is improvements in latency to fall, which gives little insight into the rich kinematic adjustments that accompany locomotor learning. In this study, we developed a rotarod-like task called the RotaWheel in which changes in paw kinematics are tracked using high-speed cameras as mice learn to stay atop an accelerating wheel. Using this device, we found that learning was accompanied by stereotyped progressions of paw kinematics that correlated with early, intermediate, and late stages of performance. Within the first day, mice sharpened their interlimb coordination using a timed pause in the forward swing of their forepaws. Over the next several days, mice reduced their stride length and took shorter, quicker steps. By the second week of training, mice began to use a more variable locomotor strategy, where consecutive overshoots or undershoots in strides were selected across paws to drive forward and backward exploration of the wheel. Collectively, our results suggest that mouse locomotor learning occurs through multiple mechanisms evolving over separate time courses and involving distinct corrective actions. These data provide insights into the kinematic strategies that accompany locomotor learning and establish an experimental platform for studying locomotor skill learning in mice.

Knowledge of how the head moves during locomotion is essential for understanding how locomotion is controlled by sensory systems of the head. We have analyzed head movements of the cat walking along a straight flat pathway in the darkness and light. We found that cats' head left-right translations, and roll and yaw rotations oscillated once per stride, while fore-aft and vertical translations, and pitch rotations oscillated twice. The head reached its highest vertical positions during second half of each forelimb swing, following maxima of the shoulder/trunk by 20-90°. Nose-up rotation followed head upward translation by another 40-90° delay. The peak-to-peak amplitude of vertical translation was ∼1.5cm and amplitude of pitch rotation was ∼3°. Amplitudes of lateral translation and roll rotation were ∼1cm and 1.5-3°, respectively. Overall, cats' heads were neutral in roll and 10-30° nose-down, maintaining horizontal semicircular canals and utriculi within 10° of the earth horizontal. The head longitudinal velocity was 0.5-1m/s, maximal upward and downward linear velocities were ∼0.05 and ∼0.1m/s, respectively, and maximal lateral velocity was ∼0.05m/s. Maximal velocities of head pitch rotation were 20-50°/s. During walking in light, cats stood 0.3-0.5cm taller and held their head 0.5-2cm higher than in darkness. Forward acceleration was 25-100% higher and peak-to-peak amplitude of head pitch oscillations was ∼20°/s larger. We concluded that, during walking, the head of the cat is held actively. Reflexes appear to play only a partial role in determining head movement, and vision might further diminish their role.

Environmental deprivation contributes in important ways to the development of a wide range of psychiatric disorders. Isolation rearing of rodents, a model for environmental deprivation in humans, consistently produces hyperlocomotion, which provides a measurable parameter to study the underlying mechanisms of early adverse psychosocial stressors. Male Sprague-Dawley rat pups were separated from dams at postnatal (PN) day 20 and reared either in groups of three or in isolation. On PN 38, locomotion was assessed in the open field. On PN 46, rats were killed and gene expression patterns examined in the medial prefrontal cortex (mPFC). Isolation-reared rats displayed increased locomotor activity and decreased resting time in the open field. Specific gene expression patterns in the mPFC were associated with both isolation rearing and hyperlocomotive behavior in the open field. Genes involved in these expression patterns included immediate early genes (IEGs) and genes that regulate cell differentiation and apoptosis. The study of these genes could provide important insights into how abnormal early psychosocial events affect brain function and behavior.

The pedunculopontine nucleus (PPN) shows altered electrophysiological and anatomic characteristics in Parkinson's disease (PD), but little is known about the effect of 6-hydroxydopamine (6-OHDA) lesion and levodopa (L-DOPA) therapy on the relationship between spike and local field potential (LFP) activities in the PPN and motor cortex. Aiming to investigate this, synchronous spike and LFP signals in the PPN and primary motor cortex (M1) were recorded. The spike-LFP relationship was evaluated using coherence analysis, phase-lock and spike-field coherence (SFC). The results suggested that 6-OHDA lesion had a significant effect on the spike-LFP relationship between the PPN and M1 in rats under a rest or locomotion state. The significantly altered frequency bands varied across different neuron types and animal activity states. In addition, the altered coherence values between PPN spike and M1 LFP were refractory to long-term L-DOPA therapy although all other changes could be reversed by this drug treatment. All results provided evidence of the spike-LFP relationship between the PPN and M1 in PD, revealing some network mechanisms of the cortico-basal ganglia circuitry and PPN, which might be an underlying candidate for PD pathophysiology and therapy.