RESUMO
The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning.
Assuntos
Apetite/fisiologia , Condicionamento Clássico/fisiologia , Neurônios Dopaminérgicos/fisiologia , Aprendizagem , Núcleo Tegmental Pedunculopontino/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Apetite/efeitos da radiação , Condicionamento Clássico/efeitos da radiação , Sinais (Psicologia) , Neurônios Dopaminérgicos/efeitos da radiação , Glutamatos/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BL , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Recompensa , Área Tegmentar Ventral/efeitos da radiaçãoAssuntos
Relógios Biológicos/fisiologia , Estimulação Encefálica Profunda/métodos , Núcleo Tegmental Pedunculopontino/fisiopatologia , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Animais , Relógios Biológicos/efeitos da radiação , Humanos , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Transtornos dos Movimentos/terapiaRESUMO
Bilateral peduncolopontine nucleus (PPN) and subthalamic nucleus (STN) deep brain stimulation (DBS) was performed in six-advanced Parkinson's disease (PD) patients. We report the effect of both PPN-DBS (25 Hz) and STN-DBS (185 Hz) on patient spinal reflex excitability by utilizing the soleus-Hoffman reflex (HR) threshold. Compared to controls (n = 9), patients showed an increase of HR-threshold, which was scarcely affected by levodopa, but significantly reduced by DBS. In particular, we found that PPN-DBS alone, or plus STN-DBS induced a complete recovery of HR-threshold up to control values. The HR-threshold changes, although do not allow to investigate the contribution of specific intraspinal pathways, suggest that PPN may play a key-role in modulating spinal excitability in PD possibly by improving the basal ganglia-brainstem descending system activity.
Assuntos
Estimulação Encefálica Profunda/métodos , Reflexo H/efeitos dos fármacos , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Medula Espinal/fisiopatologia , Idoso , Estudos de Casos e Controles , Relação Dose-Resposta à Radiação , Feminino , Reflexo H/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Tegmental Pedunculopontino/fisiologiaRESUMO
The symptom of Parkinson's disease that is most disabling and difficult to treat is akinesia. We have previously shown that low-frequency stimulation of the pedunculopontine nucleus can alleviate such akinesia in a macaque rendered Parkinsonian using 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine. Here, we have extended that study to show that adding stimulation of the pedunculopontine nucleus to levodopa treatment in this Parkinsonian monkey increased its motor activity significantly more than levodopa alone. This additivity suggests that pedunculopontine nucleus stimulation may improve movement by acting at a site downstream from where levodopa therapy affects the basal ganglia.
Assuntos
Estimulação Elétrica/métodos , Intoxicação por MPTP/terapia , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Animais , Antiparkinsonianos/uso terapêutico , Comportamento Animal , Dopamina/metabolismo , Relação Dose-Resposta à Radiação , Levodopa/uso terapêutico , Intoxicação por MPTP/fisiopatologia , Macaca mulatta , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Atividade Motora/efeitos da radiaçãoAssuntos
Estimulação Encefálica Profunda/métodos , Atividade Motora/fisiologia , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/terapia , Núcleo Tegmental Pedunculopontino/fisiopatologia , Animais , Antiparkinsonianos/administração & dosagem , Bicuculina/administração & dosagem , Relação Dose-Resposta à Radiação , Feminino , Antagonistas GABAérgicos/administração & dosagem , Humanos , Levodopa/administração & dosagem , Macaca mulatta , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Doença de Parkinson/cirurgia , Transtornos Parkinsonianos/patologia , Núcleo Tegmental Pedunculopontino/anatomia & histologia , Núcleo Tegmental Pedunculopontino/efeitos dos fármacos , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Estudos RetrospectivosRESUMO
We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinson's disease and other akinetic disorders.
Assuntos
Estimulação Encefálica Profunda , Transtornos dos Movimentos/terapia , Transtornos Parkinsonianos/terapia , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Animais , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Lateralidade Funcional/fisiologia , Lateralidade Funcional/efeitos da radiação , Macaca mulatta , Masculino , Movimento/efeitos dos fármacos , Movimento/efeitos da radiação , Transtornos dos Movimentos/etiologia , Transtornos Parkinsonianos/complicaçõesRESUMO
We have previously reported that electrical stimulation delivered to the ventral part of the pedunculopontine tegmental nucleus (PPN) produced postural atonia in acutely decerebrated cats [Neuroscience 119 (2003) 293]. The present study was designed to elucidate synaptic mechanisms acting on motoneurons during postural atonia induced by PPN stimulation. Intracellular recording was performed from 72 hindlimb motoneurons innervating extensor and flexor muscles, and the changes in excitability of the motoneurons following the PPN stimulation were examined. Repetitive electrical stimulation (20-50 microA, 50 Hz, 5-10 s) of the PPN hyperpolarized the membrane potentials of both the extensor and flexor motoneurons by 2.0-12 mV (6.0 +/- 2.3 mV, n = 72). The membrane hyperpolarization persisted for 10-20 s even after termination of the stimulation. During the PPN stimulation, the membrane hyperpolarization was associated with decreases in the firing capability (n = 28) and input resistance (28.5 +/- 6.7%, n = 14) of the motoneurons. Moreover the amplitude of Ia excitatory postsynaptic potentials was also reduced (44.1 +/- 13.4%, n = 14). After the PPN stimulation, these parameters immediately returned despite that the membrane hyperpolarization persisted. Iontophoretic injections of chloride ions into the motoneurons reversed the polarity of the membrane hyperpolarization during the PPN stimulation. The polarity of the outlasting hyperpolarization however was not reversed. These findings suggest that a postsynaptic inhibitory mechanism, which was mediated by chloride ions, was acting on hindlimb motoneurons during PPN-induced postural atonia. However the outlasting motoneuron hyperpolarization was not due to the postsynaptic inhibition but it could be due to a decrease in the activity of descending excitatory systems. The functional role of the PPN in the regulation of postural muscle tone is discussed with respect to the control of behavioral states of animals.
Assuntos
Membro Posterior/fisiologia , Neurônios Motores/fisiologia , Tono Muscular/fisiologia , Núcleo Tegmental Pedunculopontino/efeitos da radiação , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/efeitos da radiação , Animais , Gatos , Cloretos/farmacologia , Colina O-Acetiltransferase/metabolismo , Relação Dose-Resposta à Radiação , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Imuno-Histoquímica/métodos , Potenciais da Membrana/efeitos da radiação , Microinjeções/métodos , Neurônios Motores/classificação , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/efeitos da radiação , Tono Muscular/efeitos da radiação , Inibição Neural/efeitos dos fármacos , Inibição Neural/efeitos da radiação , Núcleo Tegmental Pedunculopontino/fisiologiaRESUMO
The pedunculopontine tegmental nucleus appears to influence striatal dopamine activity via cholinergic and glutamatergic afferents to dopaminergic cells of the substantia nigra pars compacta. We measured changes in striatal dopamine oxidation current (dopamine efflux) in response to electrical stimulation of the pedunculopontine tegmental nucleus using in vivo electrochemistry in urethane-anaesthetized rats. Pedunculopontine tegmental nucleus stimulation evoked a three-component change in striatal dopamine efflux, consisting of: (i) an initial rapid increase of 2 min duration; followed by (ii) a decrease below prestimulation levels of 9 min duration; then by (iii) a prolonged increase lasting 35 min. Intra-nigral infusions of the ionotropic glutamate receptor antagonist kynurenate (10 microg/ microL) or the nicotinic cholinergic receptor antagonist mecamylamine (5 microg/0.5 microL) selectively attenuated the rapid first component, while systemic injections of the muscarinic cholinergic antagonist scopolamine (5 mg/kg, i.p.) diminished the second and third components. In addition, intra-pedunculopontine tegmental nucleus infusions of the M2 muscarinic antagonist methoctramine (50 microg/ microL) selectively abolished the inhibitory second component, while intranigral infusions of scopolamine (200 microg/ microL) selectively abolished the prolonged third component. Intra-nigral infusions of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (2 microg/ microL) had no effect on pedunculopontine tegmental nucleus-elicited striatal dopamine efflux. These results suggest that the pedunculopontine tegmental nucleus utilizes nicotinic and ionotropic glutamate receptors in the substantia nigra to mediate rapid activation, M2-like muscarinic autoreceptors in the pedunculopontine tegmental nucleus to mediate decreased activation, and muscarinic receptors in the substantia nigra (probably of the M5 subtype) to mediate prolonged activation, of the nigrostriatal dopaminergic system.