• MeSH
• imunologické techniky MeSH
• krysa rodu rattus MeSH
• vývojová biologie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• arterioskleróza patologie   MeSH
• bronchitida patologie   MeSH
• diabetes mellitus patologie   MeSH
• encefalitida patologie   MeSH
• věkové faktory MeSH

• MeSH
• kraniocerebrální traumata patologie   MeSH
• nervus oculomotorius MeSH
• postura těla MeSH
• vertigo terapie   MeSH

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

• MeSH
• chování zvířat fyziologie   MeSH
• colliculus inferior anatomie a histologie   fyziologie   MeSH
• ganglion spirale cytologie   fyziologie   MeSH
• mapování mozku MeSH
• mezencefalon embryologie   fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus cochlearis anatomie a histologie   fyziologie   MeSH
• sluch fyziologie   MeSH
• sluchová percepce genetika   fyziologie   MeSH
• těhotenství MeSH
• transkripční faktory bHLH genetika   fyziologie   MeSH
• úleková reakce genetika   fyziologie   MeSH
• vestibulární aparát anatomie a histologie   fyziologie   MeSH
• vnímání výšky zvuku fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

• MeSH
• biologické modely MeSH
• dopaminergní neurony cytologie   metabolismus   MeSH
• lidé MeSH
• mezencefalon cytologie   MeSH
• neurogeneze * genetika   MeSH
• rozvržení tělního plánu genetika   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Modeling central auditory neurons in response to complex sounds not only helps understanding neural processing of speech signals but can also provide insights for biomimetics in neuro-engineering. While modeling responses of midbrain auditory neurons to synthetic tones is rather good, modeling those to environmental sounds is less satisfactory. Environmental sounds typically contain a wide range of frequency components, often with strong and transient energy. These stimulus features have not been examined in the conventional approach of auditory modeling centered on spectral selectivity. To this end, we firstly compared responses to an environmental sound of auditory midbrain neurons across 3 subpopulations of neurons with frequency selectivity in the low, middle and high ranges; secondly, we manipulated the sound energy, both in power and in spectrum, and compared across these subpopulations how their modeled responses were affected. The environmental sound was recorded when a rat was drinking from a feeding bottle (called the 'drinking sound'). The sound spectrum was divided into 20 non-overlapping frequency bands (from 0 to 20 kHz, at 1 kHz width) and presented to an artificial neural model built on a committee machine with parallel spectral inputs to simulate the known tonotopic organization of the auditory system. The model was trained to predict empirical response probability profiles of neurons to the repeated sounds. Results showed that model performance depended more on the strong energy components than on the spectral selectivity. Findings were interpreted to reflect general sensitivity to rapidly changing sound intensities at the auditory midbrain and in the cortex.

• MeSH
• akustická stimulace metody   MeSH
• krysa rodu rattus MeSH
• mezencefalon * fyziologie   MeSH
• neurony fyziologie   MeSH
• řeč MeSH
• zvířata MeSH
• zvuk * MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The midbrain-hindbrain boundary (MHB) is one of the key organizing centers of the vertebrate central nervous system (CNS). Its patterning is governed by a well-described gene regulatory network (GRN) involving several transcription factors, namely, pax, gbx, en, and otx, together with signaling molecules of the Wnt and Fgf families. Here, we describe the onset of these markers in Oryzias latipes (medaka) early brain development in comparison to previously known zebrafish expression patterns. Moreover, we show for the first time that vox, a member of the vent gene family, is expressed in the developing neural tube similarly to CNS markers. Overexpression of vox leads to profound changes in the gene expression patterns of individual components of MHB-specific GRN, most notably of fgf8, a crucial organizer molecule of MHB. Our data suggest that genes from the vent family, in addition to their crucial role in body axis formation, may play a role in regionalization of vertebrate CNS.

• MeSH
• embryo nesavčí metabolismus   MeSH
• genové regulační sítě MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• mezencefalon embryologie   metabolismus   MeSH
• Oryzias embryologie   genetika   MeSH
• rombencefalon embryologie   metabolismus   MeSH
• rybí proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• krysa rodu rattus MeSH
• mezencefalon fyziologie   MeSH
• neurony fyziologie   MeSH
• sluchová percepce genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• elektroencefalografie MeSH
• epilepsie * diagnostické zobrazování   chemicky indukované   MeSH
• implantované elektrody MeSH
• kočky MeSH
• mezencefalon patofyziologie   účinky léků   MeSH
• modely u zvířat MeSH
• peniciliny aplikace a dávkování   MeSH
• retikulární formace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• zvířata MeSH

Hypersensitive pain response is observed in patients with Parkinson's disease (PD). However, the signal pathways leading to hyperalgesia still need to be clarified. Chronic oxidative stress is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role NADPH oxidase (NOX) of the PAG in regulating exaggerated pain evoked by PD. PD was induced by central microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle of rats. Then, Western Blot analysis and ELISA were used to determine NOXs and products of oxidative stress (i.e., 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). Pain responses to mechanical and thermal stimulation were further examined in control rats and PD rats. In results, among the NOXs, protein expression of NOX4 in the PAG of PD rats was significantly upregulated, thereby the products of oxidative stress were increased. Blocking NOX4 pathway in the PAG attenuated mechanical and thermal pain responses in PD rats and this was accompanied with decreasing production of oxidative stress. In addition, inhibition of NOX4 largely restored the impaired GABA within the PAG. Stimulation of GABA receptors in the PAG of PD rats also blunted pain responses. In conclusions, NOX4 activation of oxidative stress in the PAG of PD rats is likely to impair the descending inhibitory GABAergic pathways in regulating pain transmission and thereby plays a role in the development of pain hypersensitivity in PD. Inhibition of NOX4 has beneficial effects on the exaggerated pain evoked by PD.

• MeSH
• bolest farmakoterapie   etiologie   metabolismus   patologie   MeSH
• fasciculus telencephali medialis účinky léků   metabolismus   MeSH
• GABA metabolismus   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• NADPH-oxidasa 4 antagonisté a inhibitory   MeSH
• Parkinsonova nemoc enzymologie   metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• práh bolesti účinky léků   fyziologie   MeSH
• pyrazolony farmakologie   MeSH
• pyridony farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• substantia grisea centralis účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH