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1.
Netw Neurosci ; 8(1): 260-274, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562296

RESUMO

The zona incerta (ZI) is a subthalamic structure that has been implicated in locomotion, fear, and anxiety. Recently interest has grown in its therapeutic efficacy in deep brain stimulation in movement disorders. This efficacy might be due to the ZI's functional projections to the other brain regions. Notwithstanding some evidence of anatomical connections between the ZI and the inferior olive (IO) and the pontine nuclei (PN), how the ZI modulates the neuronal activity in these regions remains to be determined. We first tested this by monitoring responses of single neurons in the PN and IO to optogenetic activation of channelrhodopsin-expressing ZI axons in wild-type mice, using an in vivo awake preparation. Stimulation of short, single pulses and trains of stimuli at 20 Hz elicited rapid responses in the majority of recorded cells in the PN and IO. Furthermore, the excitatory response of PN neurons scaled with the strength of ZI activation. Next, we used in vitro electrophysiology to study synaptic transmission at ZI-IO synapses. Optogenetic activation of ZI axons evoked a strong excitatory postsynaptic response in IO neurons, which remained robust with repeated stimulation at 20 Hz. Overall, our results demonstrate a functional connection within ZI-PN and ZI-IO pathways.

2.
Nat Neurosci ; 27(3): 497-513, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272967

RESUMO

Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show, in mice, that Cb-SNc projections form monosynaptic glutamatergic synapses with dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation of Cb-SNc axons in the SNc is associated with increased SNc activity, elevated striatal dopamine levels and increased locomotion. During behavior, Cb-SNc projections are bilaterally activated before ambulation and unilateral lever manipulation. Cb-SNc projections show prominent activation for water reward and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor and reward processing.


Assuntos
Dopamina , Substância Negra , Camundongos , Animais , Dopamina/metabolismo , Substância Negra/fisiologia , Locomoção , Cerebelo , Água/metabolismo
3.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868164

RESUMO

Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations in SGCE and characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgce in the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like, jerking movements in mice that improved after administration of ethanol. Acute knockdown of Sgce in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.


Assuntos
Distúrbios Distônicos/genética , Distúrbios Distônicos/mortalidade , Sarcoglicanas/genética , Sarcoglicanas/metabolismo , Animais , Córtex Cerebelar/metabolismo , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Distonia , Distúrbios Distônicos/induzido quimicamente , Distúrbios Distônicos/patologia , Etanol/efeitos adversos , Feminino , Gânglios/metabolismo , Predisposição Genética para Doença/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Interferente Pequeno
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