Substantia Nigra Reticulata Research Articles

Short term plasticity within the basal ganglia - a systems level computational investigation

Striatal direct pathway medium spiny neurons (MSNs) converge, with inhibitory synapses onto output nuclei substantia nigra reticulata (SNr), which keep neurons in the thalamus, superior colliculus and pendunculopontine nuclei under tonic inhibition[1]. Recent experimental findings[2] have found short term facilitation in MSN synapses onto SNr neurons. We investigate the functional consequences of these findings using a basal ganglia system level model, with spiking MSNs modeled according to Izhikevich’s simple model[3] and with facilitating synapses[4] fitted to data in[2]. The model is implemented in the NEST[5] simulator. We quantify how striatal populations of MSNs can control activity in SNr neurons, and to what extent this depends on having weak static, strong static and facilitating synapses between MSNs and SNr neurons. Our simulation experiments predict that facilitating synapses allow baseline firing of presynaptic MSNs without suppressing target SNr neurons, while burst activation of only a few of these presynaptic striatal neurons can suppress the activity of one SNr neuron. This is in accordance with extracellular recordings in awake animals[6], where task dependent activity is transferred from a broad striatal population to a smaller subpopulation, responding increasingly stronger during learning of a task dependent behavior.

Effective inhibition of substantia nigra by deep brain stimulation fails to suppress tonic epileptic seizures

Experimental and clinical data suggest that high-frequency deep brain stimulation (DBS) of different subcortical structures can be used to control or modulate epileptic seizures. Recent studies showed that DBS of the substantia nigra reticulata (SNr) in rats has an anticonvulsant effect on forebrain clonic seizures. The aim of this study was to determine whether DBS of SNr could also suppress tonic epileptic seizures evoked in hindbrain structures. DBS with high frequency often mimics the effects of surgical ablation of a particular area of the brain. However, the optimal parameters of DBS stimulation to induce ablation-like effects on seizures are not well defined. Consequently, in the first experiment we examined the effects of different stimulation frequencies (80, 130, 260 and 390Hz) on neuronal activation induced in SNr, using c-fos immunocytochemistry. The results showed that the stimulation of the SNr with 80Hz has no inhibitory effect while stimulation with 130, 260 and 390Hz produced a remarkable suppressive effect compared with the control unstimulated side. The aim of the second experiment was to determine whether bilateral inhibition of SNr with DBS could suppress tonic seizures induced by electric shock. Statistical analysis showed that the mean tonic seizure scores following SNr stimulation with either 130 or 260Hz were not significantly different from scores following the application of the electrode without current. The data suggest that DBS of the SNr produces neuronal inhibition but fails to suppress tonic seizures. We conclude, therefore, that DBS of SNr with frequencies used in this study might not be effective for treatment of patients who suffer from tonic epileptic seizures.

Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by a deficiency in the lysosomal enzyme glucocerebrosidase (GlcCerase), which results in intracellular accumulation of glucosylceramide (GlcCer). The rare neuronopathic forms of GD are characterized by profound neurological impairment and neuronal cell death, but little is known about the neuropathological changes that underlie these events. We now systematically examine the onset and progression of various neuropathological changes (including microglial activation, astrogliosis and neuron loss) in a mouse model of neuronopathic GD, and document the brain areas that are first affected, which may reflect vulnerability of these areas to GlcCerase deficiency. We also identify neuropathological changes in several brain areas and pathways, such as the substantia nigra reticulata, reticulotegmental nucleus of the pons, cochlear nucleus and the somatosensory system, which could be responsible for some of the neurological manifestations of the human disease. In addition, we establish that microglial activation and astrogliosis are spatially and temporally correlated with selective neuron loss.

The DYT1 carrier state increases energy demand in the olivocerebellar network

DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. To generate high resolution metabolic maps of DYT1 dystonia and pinpoint dysregulated network elements, we performed 2-deoxyglucose autoradiography and cytochrome oxidase (CO) histochemistry in transgenic mice expressing human mutant (hMT1) torsinA and wild-type littermates. In comparison with controls, hMT1 mice showed increased glucose utilization (GU) in the inferior olive (IO) medial nucleus (IOM), IO dorsal accessory nucleus and substantia nigra compacta, and decreased GU in the medial globus pallidus (MGP) and lateral globus pallidus. The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia.

Dopamine–nociceptin/orphanin FQ interactions in the substantia nigra reticulata of hemiparkinsonian rats: Involvement of D 2/D 3 receptors and impact on nigro-thalamic neurons and motor activity

Nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonists proved to be effective in alleviating experimental parkinsonism. Nonetheless, loss of effectiveness or even worsening of parkinsonian symptoms have been observed at high doses. With the aim of clarifying the circuitry underlying the dual action of NOP receptor antagonists and the role of endogenous dopamine, the NOP receptor antagonist 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl]pyrrolidine-2-carboxamide (Compound 24) and the D 2/D 3 receptor antagonist raclopride were used in 6-hydroxydopamine hemilesioned rats. Systemically administered Compound 24 improved motor activity in the 0.1–10 mg/kg dose range being ineffective at 30 mg/kg. To confirm NOP selectivity, Compound 24 improved motor performance in wild-type mice at 1 and 10 mg/kg and inhibited it at 60 mg/kg, being ineffective in NOP receptor knockout mice. To prove that the bell-shaped profile was mediated by nigral NOP receptors, reverse dialysis of Compound 24 (0.03 μM) in substantia nigra reticulata ameliorated akinesia whereas Compound 24 (3 μM) was ineffective. To demonstrate that motor responses were mediated by tuning inhibitory and excitatory inputs to nigro-thalamic neurons, the low concentration elevated GABA and reduced glutamate in substantia nigra, simultaneously reducing GABA levels in ventro-medial thalamus. Conversely, the higher concentration reduced nigral and elevated thalamic GABA, without affecting nigral glutamate levels. Co-perfusion with raclopride (1 μM) abolished the antiakinetic action of Compound 24 (0.03 μM) and turned the ineffectiveness of Compound 24 (3 μM) into an antiakinetic effect. The low concentration reduced nigral but did not affect thalamic GABA whereas the higher concentration elevated nigral and reduced thalamic GABA. Neither concentration affected nigral glutamate. We conclude that dual motor effects of Compound 24 in hemiparkinsonian rats are accomplished through blockade of nigral NOP receptors resulting in opposite modulation of nigro-thalamic neurons. Endogenous dopamine contributes to these responses affecting the level of GABAergic inhibition of the nigral output via D 2/D 3 receptors.

Reduced GABA Content in the Motor Thalamus during Effective Deep Brain Stimulation of the Subthalamic Nucleus

Deep brain stimulation (DBS) of the subthalamic nucleus (STN), in Parkinson's disease (PD) patients, is a well established therapeutic option, but its mechanisms of action are only partially known. In our previous study, the clinical transitions from OFF- to ON-state were not correlated with significant changes of GABA content inside GPi or substantia nigra reticulata. Here, biochemical effects of STN-DBS have been assessed in putamen (PUT), internal pallidus (GPi), and inside the antero-ventral thalamus (VA), the key station receiving pallidothalamic fibers. In 10 advanced PD patients undergoing surgery, microdialysis samples were collected before and during STN-DBS. cGMP, an index of glutamatergic transmission, was measured in GPi and PUT by radioimmunoassay, whereas GABA from VA was measured by HPLC. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in VA (−30%). Simultaneously, cGMP extracellular concentrations were enhanced in PUT (+200%) and GPi (+481%). These findings support a thalamic dis-inhibition, in turn re-establishing a more physiological corticostriatal transmission, as the source of motor improvement. They indirectly confirm the relevance of patterning (instead of mere changes of excitability) and suggest that a rigid interpretation of the standard model, at least when it indicates the hyperactive indirect pathway as key feature of hypokinetic signs, is unlikely to be correct. Finally, given the demonstration of a key role of VA in inducing clinical relief, locally administration of drugs modulating GABA transmission in thalamic nuclei could become an innovative therapeutic strategy.

The effects of chronic levodopa treatments on the neuronal firing properties of the subthalamic nucleus and substantia nigra reticulata in hemiparkinsonian rhesus monkeys

Dopamine replacement therapy with levodopa (LD) is currently the most effective pharmacological treatment for Parkinson's disease (PD), a neurodegenerative disorder characterized by dysfunction of basal ganglia electrophysiology. The effects of chronic LD treatments on the electrophysiological activity of the subthalamic nucleus (STN) and the substantia nigra reticulata (SNR) in parkinsonism are not clear. In the present study we examined the effects of chronic LD treatments on the firing rate and firing pattern of STN and SNR neurons in the stable hemiparkinsonian monkey model of PD. We also evaluated local field potentials of both nuclei before and after LD treatments. In a stable hemiparkinsonian state, STN and SNR had a mean firing rate of 42.6 ± 3.5 Hz (mean ± SEM) and 52.1 ± 5.7 Hz, respectively. Chronic intermittent LD exposure induced marked amelioration of parkinsonism with no apparent drug-induced motor complications. LD treatments did not significantly change the mean firing rate of STN neurons (41.3 ± 3.3 Hz) or bursting neuronal firing patterns. However, LD treatments induced a significant reduction of the mean firing rates of SNR neurons to 36.2 ± 3.3 Hz ( p < 0.05) and a trend toward increased burstiness. The entropy of the spike sequences from STN and SNR was unchanged by LD treatment, while there was a shift of spectral power into higher frequency bands in the LFPs. The inability of chronic LD treatments to reduce the bursty firing patterns in the STN and SNR should be further examined as a potential pathophysiological mechanism for PD symptoms that are refractory to LD treatments.

Decreased Level of Nurr1 in Heterozygous Young Adult Mice Leads to Exacerbated Acute and Long-Term Toxicity after Repeated Methamphetamine Exposure

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals.

Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice

The contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced Parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response because N/OFQ peptide (NOP) receptor knockout (NOP(-/-) ) mice were less susceptible to the hypokinetic action of reserpine than wild-type (NOP(+/+) ) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP(-/-) mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP(+/+) mice, being ineffective in NOP(-/-) mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced Parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release.

L-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata

l-DOPA treatment induces abnormal involuntary movements (AIMs) in Parkinson's patients and experimental animals. We examined the relationship between the development of AIMs (dyskinesia) and changes in [ 3H]-GABA release and cAMP signaling in striatonigral terminals of rats with unilateral 6-OHDA lesions. Analysis of AIMs scores in hemiparkinsonian rats treated with l-DOPA for 20 days was fitted by the sum of two Gaussian distributions showing the presence of two populations: one with mild and the other with severe dyskinesia. cAMP signaling was evaluated in the two populations by determining changes in cAMP formation, Gα olf and adenylyl cyclase type V/VI levels. In animals that were not treated with l-DOPA, all the parameters were significantly increased in the denervated side. In the animals that had mild dyskinesia, l-DOPA treatment normalized these parameters. In contrast, in the animals in which l-DOPA treatment induced severe dyskinesia all the parameters, except for Gα olf levels, were significantly higher in the denervated side. Similarly, D1-stimulated [ 3H]-GABA release was not elevated in l-DOPA-treated animals with mild dyskinesia but was increased in animals with severe dyskinesia. Changes in Gα olf and adenylyl cyclase type V/VI levels in the striatum paralleled the response in the SNr. The linkage between the changes in [ 3H]-GABA release and cAMP activity was further evaluated with the selective adenylyl cyclase V/VI antagonist NKY80. This inhibitor blocked the increases of both [ 3H]-GABA release and cAMP production. These results indicate that increased expression of adenylyl cyclase V/VI is a major determinant of increased GABAergic transmission in the substantia nigra pars reticulata of animals in which l-DOPA induces severe dyskinesia.

Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease

Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine-hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson's disease. In this study, we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine-hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson's disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (-20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be approximately 3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson's disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.

Acute withdrawal from chronic escalating-dose binge cocaine administration alters kappa opioid receptor stimulation of [ 35S] guanosine 5′-O-[gamma-thio]triphosphate acid binding in the rat ventral tegmental area

There is evidence that the kappa opioid system plays an important role in cocaine addiction and that chronic cocaine administration and withdrawal from chronic cocaine alter kappa opioid receptor (KOPr) density. The present study employed in situ [ 35S]guanosine 5′-O-[gamma-thio]triphosphate acid (GTPγS) binding autoradiography to measure KOPr-stimulated activation of G-protein in the caudate putamen, nucleus accumbens core and shell, lateral hypothalamus, basolateral amygdala, substantia nigra compacta, substantia nigra reticulata and ventral tegmental area (VTA), in response to chronic cocaine administration or acute and chronic withdrawal from chronic cocaine. Male Fischer rats were injected i.p. with saline or cocaine three times daily at 1 h intervals in an escalating-dose paradigm for 14 days (from 3×15 mg/kg/injection on days 1–3 up to 3×30 mg/kg/injection on days 10–14). Identically treated separate groups were withdrawn from cocaine or saline for 24 h or 14 days. No significant change in KOPr agonist U-69593-stimulated [ 35S]GTPγS was found in the seven regions studied 30 min or 14 days after chronic 14 days escalating-dose binge cocaine administration. However there was an increase in KOPr -stimulated [ 35S]GTPγS binding in the VTA ( P<0.01) of rats withdrawn for 24 h from chronic cocaine. Our results show a cocaine withdrawal induced increase of KOPr signaling in the VTA, and suggest that the KOPr may play a role in acute withdrawal from cocaine.

MPTP treatment increases expression of pre-pro-nociceptin/orphanin FQ mRNA in a subset of substantia nigra reticulata neurons

Antagonists selectively inhibiting activation of the nociceptin/orphanin FQ (N/OFQ) receptor reduce motor symptoms in experimental models of Parkinson's disease, and genetic deletion of the ppN/OFQ gene offers partial protection of mid-brain dopamine neurons against the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased ppN/OFQ mRNA expression in the substantia nigra (SN). We have evaluated the temporal relationship of dopamine cell loss to increased ppN/OFQ mRNA expression in the substantia nigra after MPTP treatment, and characterized the cellular locations in which increased ppN/OFQ mRNA expression was observed after MPTP treatment. MPTP increased by about 5-fold the number of neurons expressing ppN/OFQ mRNA in the pars reticulata of SN (SNr) by 24 h after treatment and the elevation remained significant for at least 7 days. This period coincided with the timing of the loss of dopamine neurons from the pars compacta of substantia nigra (SNc) after MPTP. The increased expression of ppN/OFQ mRNA co-localized with a neuronal marker in the SNr. MPTP treatment resulted in a small increase in the numbers of neurons expressing ppN/OFQ in the SNc in mice from one mouse colony but the increase did not reach statistical significance in mice from another colony. No changes in ppN/OFQ-mRNA expression were observed in the ventral tegmental area (VTA), the caudate-putamen, the subthalamic nucleus, or in two other brains areas. These results demonstrate that increased N/OFQ expression in the SNr is closely associated with the MPTP-induced loss of dopamine neurons in the SNc in a widely used animal model of Parkinson's disease.

Structural abnormalities in the substantia nigra and neighbouring nuclei in Tourette’s syndrome

Although midbrain nuclei (substantia nigra, ventral tegmental area, and periaqueductal grey) are considered candidate loci of pathology in Tourette's syndrome (TS), few imaging studies have examined midbrain structure. The objective of this study was to evaluate the presence of subtle structural abnormalities in the midbrain of patients with TS. High-field magnetic resonance imaging (MRI) (1.5- and 3-T) was used in 23 patients with TS and in 20 age- and sex-matched normal control subjects. Tics symptoms were rated using the Yale Global Tic Severity Scale and comorbid neuropsychiatric disorders were evaluated with standardised psychiatric rating scales. MRI scans revealed subtle structural abnormalities consistent with expanded perivascular spaces (EPVS) in the substantia nigra (compacta and reticulata) and neighbouring nuclei in 6 (26%) patients with TS, but in none of the normal control subjects (P = 0.045). Stereotyped movements were more frequent (P = 0.017) amongst TS patients with midbrain EPVS than in TS patients with normal MRI. Parkinsonism, posttraumatic stress disorder and autistic spectrum disorders exclusively occurred in TS patients with midbrain EPVS. There were no significant between-group differences in other comorbid neuropsychiatric disorders and in tics. Although EPVS are generally viewed as incidental findings, our results suggest that when EPVS are located in the midbrain they may be symptomatic. These abnormalities would reduce the actual number of neurons in specific midbrain nuclei (e.g., substantia nigra) and disrupt their connectivity with limbic, associative, and motor circuits.

Endogenous nociceptin/orphanin FQ (N/OFQ) contributes to haloperidol-induced changes of nigral amino acid transmission and parkinsonism: a combined microdialysis and behavioral study in naïve and nociceptin/orphanin FQ receptor knockout mice

The contribution of endogenous nociceptin/orphanin FQ (N/OFQ) to neuroleptic-induced parkinsonism has been evaluated in haloperidol-treated mice. Pharmacological blockade of N/OFQ receptors (NOP) via systemic administration of 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397, 0.01–10 mg/kg i.p.) or central injection of [Nphe 1,Arg 14,Lys 15]N/OFQ-NH 2 (UFP-101, 10 nmol i.c.v.) attenuated (0.8 mg/kg) haloperidol-induced motor deficits as evaluated by a battery of behavioral tests providing complementary information on motor parameters: the bar, drag and rotarod tests. A combined neurochemical and behavioral approach was then used to investigate whether the substantia nigra reticulata could be involved in antiakinetic actions of J-113397. Microdialysis combined to the bar test revealed that haloperidol (0.3 and 0.8 mg/kg i.p.) caused a dose-dependent and prolonged elevation of immobility time (i.e. akinesia) which was associated with an increase in nigral glutamate and a reduction in GABA release. Conversely, J-113397 (1 mg/kg) alone reduced glutamate and elevated nigral GABA release, and when challenged against haloperidol, counteracted its behavioral and neurochemical effects. Microdialysis coupled to behavioral testing also demonstrated that NOP receptor knockout mice were resistant to haloperidol (0.3 mg/kg) compared to wild-type mice, lack of response being associated with a reversal of glutamate release facilitation into inhibition and no change in nigral GABA release. This study provides pharmacological and genetic evidence that endogenous N/OFQ contributes to haloperidol-induced akinesia and changes of amino acid transmission in mice. Moreover, it confirms the view that NOP receptor antagonists are capable of reversing akinesia across species and genotypes and may prove effective in relieving neuroleptic-induced parkinsonism.

The pharmacological blockade of medial forebrain bundle induces an acute pathological synchronization of the cortico-subthalamic nucleus-globus pallidus pathway.

Pathological oscillations characterize the firing discharge of different basal ganglia (BG) stations in rat models of Parkinson's disease. Most recent literature focused on the prominence of the beta frequency band in awake rats. Yet, in 6-hydroxydopamine-lesioned animals, the firing discharge of the globus pallidus (GP) and the substantia nigra reticulata are in phase with urethane-induced slow wave cortical activity. The neuronal basis of this pathological synergy at low frequency is widely debated. In order to understand the role of substantia nigra pars compacta (SNc) signalling in the development of pathological synchronization, we performed a pharmacological inactivation of the medial forebrain bundle (MFB) through tetrodotoxin (TTX), which led to a dramatic, but reversible, reduction of the dopamine content in the striatum. This procedure caused a significant contralateral akinesia, detectable as soon as anaesthesia vanished, and lasting about 3-4 h. We sought to determine the electrophysiological counterpart of this transient Parkinsonian-like hypokinetic syndrome. Hence, we obtained the electrocorticogram (ECoG) and single unit recordings from GP and subthalamic nucleus (STN) in normal rats before and after the TTX injection in MFB. Intriguingly, the TTX-mediated inactivation of MFB induced a fast developing coherence between cortex and GP and a significant increase of the cortex/STN synchronization. The intra-GP iontophoretic delivery of haloperidol or the GABA(A) receptor antagonist bicuculline induced a short term cortex/GP synchronization. Strikingly, STN inactivation by local muscimol reversed both haloperidol- and TTX-mediated coherence between cortex and GP. Our data show that an abnormal cortical/BG synchronization, at low frequency, can be reproduced also without SNc neuronal loss and striatal cytoarchitectonic alterations. In addition, our results, which represent an acute and reversible Parkinsonism based upon impaired cable properties, seem compatible with the interpretation of acute changes of the functional interplay between cortex and the STN-GP pathway as a key factor mechanism underlying the fast deep brain stimulation-induced acute Off-On transitions.

The novel delta opioid receptor agonist UFP-512 dually modulates motor activity in hemiparkinsonian rats via control of the nigro-thalamic pathway

The present study aimed to characterize the ability of the novel delta opioid peptide (DOP) receptor agonist H-Dmt-Tic-NH-CH(CH 2–COOH)-Bid (UFP-512) to attenuate motor deficits in 6-hydroxydopamine (6-OHDA) hemilesioned rats. Lower doses (0.1–10 μg/kg) of UFP-512 administered systemically (i.p.) stimulated stepping activity in the drag test and overall gait abilities in the rotarod test whereas higher doses (100–1000 μg/kg) were ineffective or even worsened Parkinsonism. Microdialysis coupled to an akinesia test (bar test) was then used to determine the circuitry involved in the motor actions of UFP-512. An antiakinetic dose of UFP-512 (10 μg/kg) decreased GABA in globus pallidus (GP) as well as GABA and glutamate (GLU) release in substantia nigra reticulata (SNr). On the other hand, a pro-akinetic dose (1000 μg/kg) of UFP-512 increased pallidal GABA, simultaneously producing a decrease in GABA and an increase in nigral GLU release. Moreover, to test the hypothesis that changes in motor behavior were associated with changes in nigro–thalamic transmission, amino acid release in ventromedial thalamus (VMTh, a target of nigro–thalamic GABAergic projections) was also measured. The anti-akinetic dose of UFP-512 reduced GABA and increased thalamic GLU release while the pro-akinetic dose increased GABA without affecting thalamic GLU release. Finally, regional microinjections were performed to investigate the brain areas involved in motor actions of UFP-512. UFP-512 microinjections into GP increased akinesia whereas UFP-512 microinjections into SNr reduced akinesia. Furthermore, the selective DOP receptor antagonist naltrindole (NTD) increased akinesia when injected into either area, GP being more sensitive. We conclude that UFP-512, depending on dose, improves or worsens motor activity in hemiparkinsonian rats by acting differentially as a DOP receptor agonist in SNr and a DOP receptor antagonist in GP, ultimately decreasing or increasing the activity of nigro–thalamic GABAergc output neurons, respectively.

Exploration of the lamprey pallidal neurons – a combined computational and experimental study

The cortex-basal ganglia-thalamic loops are critical for the selection and initiation of motor actions[1]. The output stage of the basal ganglia, Globus Pallidus interna (GPi) and Substantia Nigra reticulata (SNr) in primates, plays an important role by providing tonic inhibition to motor centers in the brain stem and thalamus. GPi/SNr are controlled by input from the striatum, the input stage of the basal ganglia and also by other basal ganglia nuclei, Globus Pallidus externa (GPe) and Subthalamic nucleus (STN). In the present combined experimental and computational study, we investigate the membrane properties and the synaptic control of the neurons in the lamprey basal ganglia output stages. We have combined electrophysiological and immunohistochemical studies to investigate morphology and physiology properties. Using patch clamp techniques, we have recorded spontaneous activity and membrane properties [unpublished data].

Striatal neuroprotection with methylene blue

Recent literature indicates that low-dose Methylene Blue (MB), an autoxidizable dye with powerful antioxidant and metabolic enhancing properties, might prevent neurotoxin-induced neural damage and associated functional deficits. This study evaluated whether local MB may counteract the anatomical and functional effects of the intrastriatal infusion of the neurotoxin rotenone (Rot) in the rat. To this end, stereological analyses of striatal lesion volumes were performed and changes in oxidative energy metabolism in the striatum and related motor regions were mapped using cytochrome oxidase histochemistry. The influence of MB on striatal levels of oxidative stress induced by Rot was determined, and behavioral tests were used to investigate the effect of unilateral MB coadministration on motor asymmetry. Rot induced large anatomical lesions resembling “metabolic strokes,” whose size was greatly reduced in MB-treated rats. Moreover, MB prevented the decrease in cytochrome oxidase activity and the perilesional increase in oxidative stress associated with Rot infusion in the striatum. MB also prevented the indirect effects of the Rot-induced lesion on cytochrome oxidase activity in related motor regions, such as the striatal regions rostral and caudal to the lesion, the substantia nigra compacta and reticulata, and the pedunculopontine nucleus. At a network level, MB maintained a global strengthening of functional connectivity in basal ganglia–thalamocortical motor circuits, as opposed to the functional decoupling observed in Rot-alone subjects. Finally, MB partially prevented the behavioral sensorimotor asymmetries elicited by Rot. These results are consistent with protective effects of MB against neurotoxic damage in the brain parenchyma. This study provides the first demonstration of the anatomical, metabolic and behavioral neuroprotective effects of MB in the striatum in vivo, and supports the notion that MB could be a valuable intervention against neural damage associated with oxidative stress and energy hypometabolism.

Infusions of acetaldehyde into the arcuate nucleus of the hypothalamus induce motor activity in rats

Aims The hypothalamic arcuate nucleus (ARH) is one of the brain regions with the highest levels of catalase expression. Acetaldehyde, metabolized from ethanol in the CNS through the actions of catalase, has a role in the behavioral effects observed after ethanol administration. In previous studies acetaldehyde injected in the lateral ventricles or in the substantia nigra reticulata (SNR) mimicked the behavioral stimulant effects of centrally administered ethanol. Main methods In the present study we assessed the effects of acetaldehyde administered either into the ARH into a dorsal control or into the third ventricle on locomotion and rearing observed in 30 min sessions in an open field. Key findings Acetaldehyde injected into the ARH induced horizontal locomotion and rearing for 20 min. In contrast, administration of acetaldehyde into a control site dorsal to the ARH did not have any effect on locomotion. Although acetaldehyde administration into the third ventricle also induced locomotion, the time course for the effect in this area was different from the time course following ARH injections. Acetaldehyde in the ARH produced a long lasting induction of locomotion, while with intraventricular injections the effects disappeared after 5 min. Significance The present results are consistent with previous studies demonstrating that acetaldehyde is an active metabolite of ethanol, which can have locomotor stimulant properties when administered in the ventricular system of the brain or into specific brain nuclei. Some brain nuclei rich in catalase (i.e.; SNR and ARH) could be mediating some of the locomotor stimulant effects of ethanol through its conversion to acetaldehyde.