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1.
Proc Natl Acad Sci U S A ; 121(21): e2321410121, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38748575

RESUMO

Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.


Assuntos
Prosencéfalo Basal , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neurônios GABAérgicos , Vigília , Animais , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Camundongos , Vigília/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos Transgênicos , Masculino , Sono/fisiologia
2.
Commun Biol ; 5(1): 1211, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357506

RESUMO

LRRK2 mutations are closely associated with Parkinson's disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations-G2019S and R1441C-we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations' impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.


Assuntos
Corpo Estriado , Doença de Parkinson , Camundongos , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Corpo Estriado/metabolismo , Doença de Parkinson/patologia , Dopamina , Mutação
3.
Behav Brain Res ; 281: 69-77, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25513972

RESUMO

Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders.


Assuntos
Medo/psicologia , Hipocampo/metabolismo , Memória/fisiologia , Canais de Cátion TRPC/metabolismo , Animais , Condicionamento Psicológico/fisiologia , Extinção Psicológica/fisiologia , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Canais de Cátion TRPC/deficiência , Canais de Cátion TRPC/genética
4.
Exp Neurol ; 186(2): 212-20, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15026257

RESUMO

The globus pallidus is believed to play a critical role in the normal function of the basal ganglia, and abnormal activity of its neurons may underlie some basal ganglia motor symptoms. A high density of benzodiazepine binding sites on GABAA receptors has been reported in the rat globus pallidus. The present study investigates the effect of activating the benzodiazepine site by the agonist zolpidem. In in vitro slices, 100 nM of zolpidem significantly prolonged the half decay time of both miniature and spontaneous inhibitory postsynaptic currents by 30.1 +/- 3.0% (n=12) and 17.8 +/- 2.4% (n=16), respectively, with no effect on their amplitudes and frequencies. In the behaving animal, when zolpidem was microinjected into the globus pallidus unilaterally, it caused a robust ipsilateral rotation (26.4 +/- 2.4 turns/30 min, n=8), significantly higher than that of control animals receiving vehicle injection (1.3 +/- 1.6 turns/30 min, n=6). This effect was in agreement with the in vitro effect of zolpidem in enhancing the action of GABA on postsynaptic GABAA receptors. All the effects of zolpidem, in vitro or in vivo, were sensitive to the benzodiazepine antagonist flumazenil, confirming the specificity on the benzodiazepine site. This finding on the effect of zolpidem on motor behavior provides a rationale for further investigations into its potential in the treatment of motor disorders originating from the basal ganglia.


Assuntos
Agonistas GABAérgicos/farmacologia , Globo Pálido/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Eletrofisiologia , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Globo Pálido/fisiologia , Técnicas In Vitro , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Zolpidem
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