RESUMEN
Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson's disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or KATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing.
Asunto(s)
Neuronas Dopaminérgicas/patología , Regulación hacia Abajo , Mesencéfalo/patología , Núcleo Subtalámico/patología , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Activación del Canal Iónico/efectos de los fármacos , Canales KATP/metabolismo , Masculino , Mesencéfalo/efectos de los fármacos , Mesencéfalo/fisiopatología , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/fisiopatologíaRESUMEN
The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.
Asunto(s)
Corteza Cerebral/fisiología , Cuerpo Estriado/fisiología , Neuronas Dopaminérgicas/fisiología , Globo Pálido/fisiología , Núcleo Subtalámico/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Neuronas Dopaminérgicas/metabolismo , Técnicas de Silenciamiento del Gen , Locomoción/efectos de los fármacos , Locomoción/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Transgénicos , Inhibición Neural/fisiología , Vías Nerviosas/fisiología , Oxidopamina , Enfermedad de Parkinson/fisiopatología , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course.
Asunto(s)
Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Núcleo Subtalámico/patología , Núcleo Subtalámico/fisiopatología , Animales , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Ratones , Ratones Transgénicos , Mitocondrias/fisiología , Neuronas/fisiología , Estrés Oxidativo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Toadfishes are among the best-known groups of sound-producing (vocal) fishes and include species commonly known as toadfish and midshipman. Although midshipman have been the subject of extensive investigation of the neural mechanisms of vocalization, this is the first comprehensive, quantitative analysis of the spectro-temporal characters of their acoustic signals and one of the few for fishes in general. Field recordings of territorial, nest-guarding male midshipman during the breeding season identified a diverse vocal repertoire composed of three basic sound types that varied widely in duration, harmonic structure and degree of amplitude modulation (AM): 'hum', 'grunt' and 'growl'. Hum duration varied nearly 1000-fold, lasting for minutes at a time, with stable harmonic stacks and little envelope modulation throughout the sound. By contrast, grunts were brief, ~30-140 ms, broadband signals produced both in isolation and repetitively as a train of up to 200 at intervals of ~0.5-1.0 s. Growls were also produced alone or repetitively, but at variable intervals of the order of seconds with durations between those of grunts and hums, ranging 60-fold from ~200 ms to 12 s. Growls exhibited prominent harmonics with sudden shifts in pulse repetition rate and highly variable AM patterns, unlike the nearly constant AM of grunt trains and flat envelope of hums. Behavioral and neurophysiological studies support the hypothesis that each sound type's unique acoustic signature contributes to signal recognition mechanisms. Nocturnal production of these sounds against a background chorus dominated constantly for hours by a single sound type, the multi-harmonic hum, reveals a novel underwater soundscape for fish.