RESUMEN
Improvements in imaging technology and the development of powerful machine learning algorithms are revolutionizing the study of animal behavior in the laboratory. These innovations promise to reveal both global and local features of action relevant to understanding how the brain functions. A study in BMC Biology describes one such tool called OptiMouse, which is an open source platform that uses video to capture key features of mouse behavior, including information relevant to olfactory investigation.See research article: 10.1186/s12915-017-0377-3.
Asunto(s)
Algoritmos , Nariz , Animales , Aprendizaje Automático , Ratones , OlfatoRESUMEN
During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this developmental process impacts the development of normal exploratory behaviors of adult mice.
RESUMEN
During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian "fire together, wire together" precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this process impacts the development of normal exploratory behaviors of adult mice.
Asunto(s)
Interneuronas , Somatostatina , Tálamo , Animales , Interneuronas/metabolismo , Somatostatina/metabolismo , Somatostatina/genética , Ratones , Tálamo/metabolismo , Optogenética , Transducción de Señal , Masculino , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/crecimiento & desarrollo , Femenino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.
Asunto(s)
Enfermedad de Huntington/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Muerte Celular , Células Cultivadas , Cuerpo Estriado/citología , Activación Enzimática , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Cuerpos de Inclusión/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fosforilación , Mutación Puntual , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Recombinantes de Fusión/metabolismo , Especificidad por SustratoRESUMEN
The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala)), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry.
Asunto(s)
Proteínas Hedgehog/metabolismo , Bulbo Olfatorio/crecimiento & desarrollo , Vías Olfatorias/crecimiento & desarrollo , Proteoglicanos/metabolismo , Animales , Calbindinas/metabolismo , Proteínas Hedgehog/genética , Inmunohistoquímica , Hibridación in Situ , Ratones Transgénicos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Neurogénesis/fisiología , Neuronas/patología , Neuronas/fisiología , Bulbo Olfatorio/patología , Bulbo Olfatorio/fisiopatología , Proteína Marcadora Olfativa/metabolismo , Vías Olfatorias/patología , Vías Olfatorias/fisiopatología , Tamaño de los Órganos , ARN Mensajero/metabolismo , Transducción de SeñalRESUMEN
The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span.