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1.
Int J Nanomedicine ; 14: 7759-7780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576121

RESUMO

Nanomedicine is a medical application of biochemistry incorporated with materials chemistry at the scale of nanometer for the purpose of diagnosis, prevention, and treatment. New models and approaches are typically associated with nanomedicine for precise multifunctional diagnostic systems at molecular level. Hence, employing nanoparticles (NPs) has unveiled new opportunities for efficient therapies and remedy of difficult-to-cure diseases. Among all types of inorganic NPs, lanthanide-doped up-conversion nanoparticles (UCNPs) have shown excellent potential for biomedical applications, especially for multimodal bioimaging including fluorescence and electron microscopy. Association of these visualization techniques plus the capability for transporting biomaterials and drugs make them superior agents in the field of nanomedicine. Accordingly, in this review, we firstly presented a fundamental understanding of physical and optical properties of UCNPs and secondly, we illustrated some of the prominent associations with bioimaging, theranostics, cancer therapy, and optogenetics.


Assuntos
Diagnóstico por Imagem , Nanomedicina , Nanopartículas/química , Humanos , Elementos da Série dos Lantanídeos/química , Nanopartículas/ultraestrutura , Optogenética , Propriedades de Superfície
2.
Hypertension ; 74(5): 1181-1191, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564162

RESUMO

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.


Assuntos
Proteína ADAM17/metabolismo , Angiotensina II/farmacologia , Hipertensão/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/genética , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Hipertensão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Optogenética/métodos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/patologia , Distribuição Aleatória , Sistema Renina-Angiotensina/efeitos dos fármacos
3.
Nat Biotechnol ; 37(10): 1209-1216, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501561

RESUMO

Chemical and optogenetic methods for post-translationally controlling protein function have enabled modulation and engineering of cellular functions. However, most of these methods only confer single-input, single-output control. To increase the diversity of post-translational behaviors that can be programmed, we built a system based on a single protein receiver that can integrate multiple drug inputs, including approved therapeutics. Our system translates drug inputs into diverse outputs using a suite of engineered reader proteins to provide variable dimerization states of the receiver protein. We show that our single receiver protein architecture can be used to program a variety of cellular responses, including graded and proportional dual-output control of transcription and mammalian cell signaling. We apply our tools to titrate the competing activities of the Rac and Rho GTPases to control cell morphology. Our versatile tool set will enable researchers to post-translationally program mammalian cellular processes and to engineer cell therapies.


Assuntos
Proteínas/química , Proteínas/metabolismo , Animais , Linhagem Celular , Técnicas de Química Combinatória , Desenho de Drogas , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Células NIH 3T3 , Optogenética/métodos , Conformação Proteica , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Biologia Sintética/métodos
4.
Nat Neurosci ; 22(10): 1659-1668, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501573

RESUMO

Neuropathic pain can be a debilitating condition with both sensory and affective components, the underlying brain circuitry of which remains poorly understood. In the present study, a basolateral amygdala (BLA)-prefrontal cortex (PFC)-periaqueductal gray (PAG)-spinal cord pathway was identified that is critical for the development of mechanical and thermal hypersensitivity after peripheral nerve injury. It was shown that nerve injury strengthens synaptic input from the BLA onto inhibitory interneurons located in the prelimbic medial PFC, by virtue of reduced endocannabinoid modulation. These augmented synaptic connections mediate a feedforward inhibition of projections from the PFC to the ventrolateral PAG region and its downstream targets. Optogenetic approaches combined with in vivo pharmacology reveal that these BLA-PFC-PAG connections alter pain behaviors by reducing descending noradrenergic and serotoninergic modulation of spinal pain signals. Thus, a long-range brain circuit was identified that is crucial for pain processing and that can potentially be exploited toward targeting neuropathic pain.


Assuntos
Vias Neurais/patologia , Neuralgia/patologia , Neurônios/patologia , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Temperatura Alta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Neuralgia/psicologia , Optogenética , Substância Cinzenta Periaquedutal/patologia , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/psicologia , Estimulação Física , Córtex Pré-Frontal/patologia , Medula Espinal/patologia , Sinapses/patologia
5.
Nat Neurosci ; 22(10): 1649-1658, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451801

RESUMO

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.


Assuntos
Dor Crônica/patologia , Depressão/patologia , Vias Neurais/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Dor Crônica/complicações , Dor Crônica/diagnóstico por imagem , Depressão/complicações , Depressão/diagnóstico por imagem , Núcleo Dorsal da Rafe/diagnóstico por imagem , Núcleo Dorsal da Rafe/patologia , Feminino , Habenula/diagnóstico por imagem , Habenula/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/diagnóstico por imagem , Neuralgia/diagnóstico por imagem , Neuralgia/patologia , Optogenética , Serotonina/metabolismo , Somatostatina/metabolismo
6.
Dokl Biochem Biophys ; 486(1): 184-186, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31367817

RESUMO

To perform optogenetic prosthetics of the retinal ganglion cell receptive field, a bicistronic genetic construct carrying the genes encoding the excitatory (channelrhodopsin-2) and inhibitory (Guillardia theta anion channelrhodopsin GtACR2) rhodopsins was created. A characteristic feature of this construct was the combination of these two genes with a mutant IRES insertion between them, which ensures the exact ratio of expression levels of the first and second genes in each transfected cell. Illumination of the central part of the neuron with light with a wavelength of 470 nm induced the action potential generation in the cell. Stimulation of the peripheral neuronal region with light induced the inhibition of action potential generation. Thus, using optogenetics methods, we simulated the ON-OFF interaction in the retinal ganglion cell receptive field. Theoretically, this construct can be used for optogenetic prosthetics of degenerative retina in the case of its delivery to the ganglion cells with lentiviral vectors.


Assuntos
Channelrhodopsins/genética , Optogenética/métodos , Retina/patologia , Células Ganglionares da Retina/metabolismo , Animais , Luz , Neurônios/citologia , Neurônios/metabolismo , Neurônios/efeitos da radiação , Ratos , Retina/efeitos da radiação , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/efeitos da radiação , Transfecção
7.
Nat Methods ; 16(8): 681, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31363207
8.
Nat Commun ; 10(1): 3075, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300665

RESUMO

The brain has a remarkable capacity to adapt to changes in sensory inputs and to learn from experience. However, the neural circuits responsible for this flexible processing remain poorly understood. Using optogenetic silencing of ArchT-expressing neurons in adult ferrets, we show that within-trial activity in primary auditory cortex (A1) is required for training-dependent recovery in sound-localization accuracy following monaural deprivation. Because localization accuracy under normal-hearing conditions was unaffected, this highlights a specific role for cortical activity in learning. A1-dependent plasticity appears to leave a memory trace that can be retrieved, facilitating adaptation during a second period of monaural deprivation. However, in ferrets in which learning was initially disrupted by perturbing A1 activity, subsequent optogenetic suppression during training no longer affected localization accuracy when one ear was occluded. After the initial learning phase, the reweighting of spatial cues that primarily underpins this plasticity may therefore occur in A1 target neurons.


Assuntos
Córtex Auditivo/fisiologia , Aprendizagem/fisiologia , Localização de Som/fisiologia , Estimulação Acústica , Animais , Córtex Auditivo/citologia , Feminino , Furões , Modelos Animais , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Optogenética
9.
Nat Commun ; 10(1): 2968, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273206

RESUMO

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca2+ signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.


Assuntos
Astrócitos/enzimologia , Hipocampo/fisiologia , Memória de Longo Prazo/fisiologia , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Comportamento Animal/fisiologia , Condicionamento (Psicologia)/fisiologia , Medo/fisiologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Optogenética , Técnicas de Patch-Clamp , Potenciais Sinápticos/fisiologia
10.
Nat Commun ; 10(1): 3099, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308373

RESUMO

The Gram-positive bacterium Bacillus subtilis exhibits complex spatial and temporal gene expression signals. Although optogenetic tools are ideal for studying such processes, none has been engineered for this organism. Here, we port a cyanobacterial light sensor pathway comprising the green/red photoreversible two-component system CcaSR, two metabolic enzymes for production of the chromophore phycocyanobilin (PCB), and an output promoter to control transcription of a gene of interest into B. subtilis. Following an initial non-functional design, we optimize expression of pathway genes, enhance PCB production via a translational fusion of the biosynthetic enzymes, engineer a strong chimeric output promoter, and increase dynamic range with a miniaturized photosensor kinase. Our final design exhibits over 70-fold activation and rapid response dynamics, making it well-suited to studying a wide range of gene regulatory processes. In addition, the synthetic biology methods we develop to port this pathway should make B. subtilis easier to engineer in the future.


Assuntos
Bacillus subtilis/enzimologia , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica/efeitos da radiação , Engenharia Metabólica/métodos , Optogenética/métodos , Fitocromo/genética , Proteínas Quinases/genética , Bacillus subtilis/genética , Proteínas de Bactérias/metabolismo , Luz , Ficobilinas/biossíntese , Ficocianina/biossíntese , Fitocromo/metabolismo , Regiões Promotoras Genéticas/efeitos da radiação , Proteínas Quinases/metabolismo
11.
Nat Commun ; 10(1): 3097, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308381

RESUMO

Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization.


Assuntos
Encéfalo/fisiologia , Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/fisiologia , Memória/fisiologia , Corpos Pedunculados/fisiologia , Recompensa , Acetilcolina/metabolismo , Animais , Apetite/fisiologia , Encéfalo/citologia , Condicionamento Clássico , Retroalimentação Fisiológica , Larva , Modelos Psicológicos , Corpos Pedunculados/citologia , Vias Neurais/fisiologia , Neuropeptídeos/metabolismo , Odorantes , Percepção Olfatória/fisiologia , Optogenética
12.
Chemistry ; 25(54): 12452-12463, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31304989

RESUMO

Light-inducible approaches provide a means to control biological systems with spatial and temporal resolution that is unmatched by traditional genetic perturbations. Recent developments of optogenetic and chemo-optogenetic systems for induced proximity in cells facilitate rapid and reversible manipulation of highly dynamic cellular processes and have become valuable tools in diverse biological applications. New expansions of the toolbox facilitate control of signal transduction, genome editing, "painting" patterns of active molecules onto cellular membranes, and light-induced cell cycle control. A combination of light- and chemically induced dimerization approaches have also seen interesting progress. Herein, an overview of optogenetic systems and emerging chemo-optogenetic systems is provided, and recent applications in tackling complex biological problems are discussed.


Assuntos
Fenômenos Fisiológicos Celulares , Optogenética/métodos , Proteínas/química , Proteínas/metabolismo , Animais , Membrana Celular/metabolismo , Regulação da Expressão Gênica , Humanos , Cinética , Luz , Mutação , Multimerização Proteica , Proteínas/genética
13.
Neuron ; 103(2): 189-201, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319049

RESUMO

The neural basis of defensive behaviors continues to attract much interest, not only because they are important for survival but also because their dysregulation may be at the origin of anxiety disorders. Recently, a dominant approach in the field has been the optogenetic manipulation of specific circuits or cell types within these circuits to dissect their role in different defensive behaviors. While the usefulness of optogenetics is unquestionable, we argue that this method, as currently applied, fosters an atomistic conceptualization of defensive behaviors, which hinders progress in understanding the integrated responses of nervous systems to threats. Instead, we advocate for a holistic approach to the problem, including observational study of natural behaviors and their neuronal correlates at multiple sites, coupled to the use of optogenetics, not to globally turn on or off neurons of interest, but to manipulate specific activity patterns hypothesized to regulate defensive behaviors.


Assuntos
Encéfalo/fisiologia , Mecanismos de Defesa , Vias Neurais/fisiologia , Neurônios/fisiologia , Animais , Extinção Psicológica , Medo/psicologia , Humanos , Individualidade , Optogenética
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 256-261, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257809

RESUMO

OBJECTIVE: To investigate the effects of optical genetic techniques on new neurons through the Wnt/ß-Catenin pathway. METHODS: Neural stem cells (ESCs)were extracted from the cerebral cortex of fetal rat and transfected by lentivirus carrying DCX-ChR2-EGFP gene and the expression of DCX of newborn neurons differentiated from neural stem cells were observed. All cells were divided into 3 groups(n=9): control group, NSCs+EGFP and NSCs+ChR2 groups. The control group was normal cultured NSCs (NSCs group); the neural stem cells in NSCs+EGFP group were transfected with lentivirus carrying EGFP gene. The neural stem cells in NSCs+ChR2 group were infected with lentivirus carrying DCX-ChR2-EGFP gene. After 48 hours of lentivirus infection, 470 nm blue laser irradiation was performed for 3 consecutive days. NeuN+ positive cell density(the maturation of neural stem cells)and the ratio of NeuN+/Hoechst in each group were observed. Western blot was used to detect the expression levels of MAP2, NeuN, Neurog2, NeuroD1 and GluR2. Western blot was used to detect the expressions of ß-catenin and TCF4 associated with Wnt/ß-catenin signaling channel. Verapamil (100 µmol/L, L-type calcium channel blockers) and Dkk1 (50 µg/ml, ß-catenin inhibitor) were used to treat stem cells of the NSCs+ChR2 group and then the expressions of MAP2, NeuN, Neurog2, NeuroD1 and GluR were detected by Western blot. RESULTS: After 3 days of 470 nm blue laser irradiation, NeuN+ positive cell density(the maturation of neural stem cells)and the ratio of NeuN+/Hoechst, the expression levels of the protein MAP2, NeuN, Neurog2, NeuroD1, GluR and the protein ß-catenin and TCF4 associated with Wnt/ß-catenin signaling channel detected by Western blot were significantly increased in the group of NSCs+ChR2, compared with NSCs and NSCs+EGFP groups. The expressions of MAP2, NeuN, Neurog2, NeuroD1 and GluR were remarkably decreased after treated by verapamil and Dkk1 in the group of NSCs+ChR2. It was proved that the opening of ChR2 channel producing cationic influx promoted the maturation of neural stem cells and induced by the Wnt/ß-catenin signaling pathway. CONCLUSION: Optical genetic promoted the maturation of newborn neurons through the Wnt/ß-catenin signaling pathway.


Assuntos
Células-Tronco Neurais/citologia , Neurônios/citologia , Optogenética , Via de Sinalização Wnt , Animais , Células Cultivadas , Ratos , Transfecção
15.
Endocrinology ; 160(10): 2271-2281, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31329247

RESUMO

Extensive efforts have been made to explore how the activities of multiple brain cells combine to alter physiology through imaging and cell-specific manipulation in different animal models. However, the temporal regulation of peripheral organs by the neuroendocrine factors released by the brain is poorly understood. We have established a suite of adaptable methodologies to interrogate in vivo the relationship of hypothalamic regulation with the secretory output of the pituitary gland, which has complex functional networks of multiple cell types intermingled with the vasculature. These allow imaging and optogenetic manipulation of cell activities in the pituitary gland in awake mouse models, in which both neuronal regulatory activity and hormonal output are preserved. These methodologies are now readily applicable for longitudinal studies of short-lived events (e.g., calcium signals controlling hormone exocytosis) and slowly evolving processes such as tissue remodeling in health and disease over a period of days to weeks.


Assuntos
Sinalização do Cálcio/fisiologia , Imagem Óptica/métodos , Hipófise/fisiologia , Vigília , Animais , Hormônio do Crescimento , Luz , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Hipófise/irrigação sanguínea
16.
Cell Mol Life Sci ; 76(23): 4725-4743, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359086

RESUMO

Targeted cell ablation is a powerful approach for studying the role of specific cell populations in a variety of organotypic functions, including cell differentiation, and organ generation and regeneration. Emerging tools for permanently or conditionally ablating targeted cell populations and transiently inhibiting neuronal activities exhibit a diversity of application and utility. Each tool has distinct features, and none can be universally applied to study different cell types in various tissue compartments. Although these tools have been developed for over 30 years, they require additional improvement. Currently, there is no consensus on how to select the tools to answer the specific scientific questions of interest. Selecting the appropriate cell ablation technique to study the function of a targeted cell population is less straightforward than selecting the method to study a gene's functions. In this review, we discuss the features of the various tools for targeted cell ablation and provide recommendations for optimal application of specific approaches.


Assuntos
Bacteriocinas/metabolismo , Ácido Clodrônico/química , Toxina Diftérica/genética , Optogenética/métodos , Simplexvirus/fisiologia , Animais , Ácido Clodrônico/toxicidade , Toxina Diftérica/metabolismo , Humanos , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Neurônios/fisiologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Simplexvirus/enzimologia
17.
Nat Neurosci ; 22(8): 1223-1234, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332372

RESUMO

Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Giro do Cíngulo/patologia , Proteínas do Tecido Nervoso/genética , Comportamento Social , Animais , Dioxóis/farmacologia , Modelos Animais de Doenças , Ácido Glutâmico , Asseio Animal , Giro do Cíngulo/fisiopatologia , Relações Interpessoais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Optogenética , Piperidinas/farmacologia , Células Piramidais/patologia , Receptores de AMPA/agonistas , Sinapses/patologia
18.
Biochemistry (Mosc) ; 84(5): 479-490, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234763

RESUMO

The review discusses the prospects of using rhodopsin as an optogenetic tool for prosthetics of degenerative (blind) eye retina and the principles of optogenetic techniques. Retinal-containing proteins that depolarize/hyperpolarize the plasma membrane of nerve cells and, accordingly, excite/inhibit physiological activity of neurons, are described. The problem of what cells of the degenerative retina can be treated with what particular rhodopsins is discussed in detail. Viruses and promoters required for the rhodopsin gene delivery into the degenerative retina cells are described. In conclusion, main concepts and tasks associated with the optogenetic prosthetic treatment of degenerative retina employing rhodopsins are presented.


Assuntos
Optogenética/métodos , Degeneração Retiniana/patologia , Animais , Terapia Genética , Humanos , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Degeneração Retiniana/terapia , Células Ganglionares da Retina/metabolismo , Rodopsina/genética , Rodopsina/metabolismo
19.
Nat Commun ; 10(1): 2654, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201326

RESUMO

Animal locomotion requires spatiotemporally coordinated contraction of muscles throughout the body. Here, we investigate how contractions of antagonistic groups of muscles are intersegmentally coordinated during bidirectional crawling of Drosophila larvae. We identify two pairs of higher-order premotor excitatory interneurons present in each abdominal neuromere that intersegmentally provide feedback to the adjacent neuromere during motor propagation. The two feedback neuron pairs are differentially active during either forward or backward locomotion but commonly target a group of premotor interneurons that together provide excitatory inputs to transverse muscles and inhibitory inputs to the antagonistic longitudinal muscles. Inhibition of either feedback neuron pair compromises contraction of transverse muscles in a direction-specific manner. Our results suggest that the intersegmental feedback neurons coordinate contraction of synergistic muscles by acting as delay circuits representing the phase lag between segments. The identified circuit architecture also shows how bidirectional motor networks could be economically embedded in the nervous system.


Assuntos
Retroalimentação Fisiológica , Locomoção/fisiologia , Rede Nervosa/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Interneurônios/fisiologia , Larva/fisiologia , Microscopia Eletrônica , Modelos Animais , Contração Muscular/fisiologia , Músculos/inervação , Músculos/fisiologia , Optogenética
20.
Nat Commun ; 10(1): 2637, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201332

RESUMO

The brain stores and recalls memories through a set of neurons, termed engram cells. However, it is unclear how these cells are organized to constitute a corresponding memory trace. We established a unique imaging system that combines Ca2+ imaging and engram identification to extract the characteristics of engram activity by visualizing and discriminating between engram and non-engram cells. Here, we show that engram cells detected in the hippocampus display higher repetitive activity than non-engram cells during novel context learning. The total activity pattern of the engram cells during learning is stable across post-learning memory processing. Within a single engram population, we detected several sub-ensembles composed of neurons collectively activated during learning. Some sub-ensembles preferentially reappear during post-learning sleep, and these replayed sub-ensembles are more likely to be reactivated during retrieval. These results indicate that sub-ensembles represent distinct pieces of information, which are then orchestrated to constitute an entire memory.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Animais , Mapeamento Encefálico/métodos , Feminino , Hipocampo/citologia , Microscopia Intravital/métodos , Proteínas Luminescentes/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Modelos Animais , Imagem Óptica/métodos , Optogenética/métodos , Sono/fisiologia
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