Browsing by Subject "Prosencephalon"

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    Behaviourally driven gene expression reveals song nuclei in hummingbird brain.
    (Nature, 2000-08-10) Jarvis, ED; Ribeiro, S; da Silva, ML; Ventura, D; Vielliard, J; Mello, CV
    Hummingbirds have developed a wealth of intriguing features, such as backwards flight, ultraviolet vision, extremely high metabolic rates, nocturnal hibernation, high brain-to-body size ratio and a remarkable species-specific diversity of vocalizations. Like humans, they have also developed the rare trait of vocal learning, this being the ability to acquire vocalizations through imitation rather than instinct. Here we show, using behaviourally driven gene expression in freely ranging tropical animals, that the forebrain of hummingbirds contains seven discrete structures that are active during singing, providing the first anatomical and functional demonstration of vocal nuclei in hummingbirds. These structures are strikingly similar to seven forebrain regions that are involved in vocal learning and production in songbirds and parrots--the only other avian orders known to be vocal learners. This similarity is surprising, as songbirds, parrots and hummingbirds are thought to have evolved vocal learning and associated brain structures independently, and it indicates that strong constraints may influence the evolution of forebrain vocal nuclei.
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    Characterization of the ubiquitin-modified proteome regulated by transient forebrain ischemia.
    (Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014-03) Iwabuchi, Masahiro; Sheng, Huaxin; Thompson, J Will; Wang, Liangli; Dubois, Laura G; Gooden, David; Moseley, Marthur; Paschen, Wulf; Yang, Wei
    Ubiquitylation is a posttranslational protein modification that modulates various cellular processes of key significance, including protein degradation and DNA damage repair. In animals subjected to transient cerebral ischemia, ubiquitin-conjugated proteins accumulate in Triton-insoluble aggregates. Although this process is widely considered to modulate the fate of postischemic neurons, few attempts have been made to characterize the ubiquitin-modified proteome in these aggregates. We performed proteomics analyses to identify ubiquitylated proteins in postischemic aggregates. Mice were subjected to 10 minutes of forebrain ischemia and 4 hours of reperfusion. The hippocampi were dissected, aggregates were isolated, and trypsin-digested after spiking with GG-BSA as internal standard. K-ɛ-GG-containing peptides were immunoprecipitated and analyzed by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. We identified 1,664 peptides to 520 proteins containing at least one K-ɛ-GG. Sixty-six proteins were highly ubiquitylated, with 10 or more K-ɛ-GG peptides. Based on selection criteria of greater than fivefold increase and P<0.001, 763 peptides to 272 proteins were highly enriched in postischemic aggregates. These included proteins involved in important neuronal functions and signaling pathways that are impaired after ischemia. Results of this study could serve as an important platform to uncover the mechanisms linking insoluble ubiquitin aggregates to the functions of postischemic neurons.
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    Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.
    (Experimental neurology, 2020-04) Wang, Ya-Chao; Galeffi, Francesca; Wang, Wei; Li, Xuan; Lu, Liping; Sheng, Huaxin; Hoffmann, Ulrike; Turner, Dennis A; Yang, Wei

    Background and purpose

    Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.

    Methods

    We generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.

    Results

    Detailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.

    Conclusions

    Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.
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    Neuron-specific SUMO knockdown suppresses global gene expression response and worsens functional outcome after transient forebrain ischemia in mice.
    (Neuroscience, 2017-02) Zhang, Lin; Liu, Xiaozhi; Sheng, Huaxin; Liu, Shuai; Li, Ying; Zhao, Julia Q; Warner, David S; Paschen, Wulf; Yang, Wei
    Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) plays key roles in neurologic function in health and disease. Neuronal SUMOylation is essential for emotionality and cognition, and this pathway is dramatically activated in post-ischemic neurons, a neuroprotective response to ischemia. It is also known from cell culture studies that SUMOylation modulates gene expression. However, it remains unknown how SUMOylation regulates neuronal gene expression in vivo, in the physiologic state and after ischemia, and modulates post-ischemic recovery of neurologic function. To address these important questions, we used a SUMO1-3 knockdown (SUMO-KD) mouse in which a Thy-1 promoter drives expression of 3 distinct microRNAs against SUMO1-3 to silence SUMO expression specifically in neurons. Wild-type and SUMO-KD mice were subjected to transient forebrain ischemia. Microarray analysis was performed in hippocampal CA1 samples, and neurologic function was evaluated. SUMOylation had opposite effects on neuronal gene expression before and after ischemia. In the physiological state, most genes regulated by SUMOylation were up-regulated in SUMO-KD compared to wild-type mice. Brain ischemia/reperfusion significantly modulated the expression levels of more than 400 genes in wild-type mice, with a majority of those genes upregulated. The extent of this post-ischemic transcriptome change was suppressed in SUMO-KD mice. Moreover, SUMO-KD mice exhibited significantly worse functional outcome. This suggests that suppression of global gene expression response in post-ischemic brain due to SUMO knockdown has a negative effect on post-ischemic neurologic function. Together, our data provide a basis for future studies to mechanistically link SUMOylation to neurologic function in health and disease.
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    Profiling of experience-regulated proteins in the songbird auditory forebrain using quantitative proteomics.
    (Eur J Neurosci, 2008-03) Pinaud, Raphael; Osorio, Cristina; Alzate, Oscar; Jarvis, Erich D
    Auditory and perceptual processing of songs are required for a number of behaviors in songbirds such as vocal learning, territorial defense, mate selection and individual recognition. These neural processes are accompanied by increased expression of a few transcription factors, particularly in the caudomedial nidopallium (NCM), an auditory forebrain area believed to play a key role in auditory learning and song discrimination. However, these molecular changes are presumably part of a larger, yet uncharacterized, protein regulatory network. In order to gain further insight into this network, we performed two-dimensional differential in-gel expression (2D-DIGE) experiments, extensive protein quantification analyses, and tandem mass spectrometry in the NCM of adult songbirds hearing novel songs. A subset of proteins was selected for immunocytochemistry in NCM sections to confirm the 2D-DIGE findings and to provide additional quantitative and anatomical information. Using these methodologies, we found that stimulation of freely behaving birds with conspecific songs did not significantly impact the NCM proteome 5 min after stimulus onset. However, following 1 and 3 h of stimulation, a significant number of proteins were consistently regulated in NCM. These proteins spanned a range of functional categories that included metabolic enzymes, cytoskeletal molecules, and proteins involved in neurotransmitter secretion and calcium binding. Our findings suggest that auditory processing of vocal communication signals in freely behaving songbirds triggers a cascade of protein regulatory events that are dynamically regulated through activity-dependent changes in calcium levels.
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    Rudimentary substrates for vocal learning in a suboscine.
    (Nat Commun, 2013) Liu, Wan-chun; Wada, Kazuhiro; Jarvis, Erich D; Nottebohm, Fernando
    Vocal learning has evolved in only a few groups of mammals and birds. The key neuroanatomical and behavioural links bridging vocal learners and non-learners are still unknown. Here we show that a non-vocal-learning suboscine, the eastern phoebe, expresses neural and behavioural substrates that are associated with vocal learning in closely related oscine songbirds. In phoebes, a specialized forebrain region in the intermediate arcopallium seems homologous to the oscine song nucleus RA (robust nucleus of arcopallium) by its neural connections, expression of glutamate receptors and singing-dependent immediate-early gene expression. Lesion of this RA-like region induces subtle but consistent song changes. Moreover, the unlearned phoebe song unexpectedly develops through a protracted ontogeny. These features provide the first evidence of forebrain vocal-motor control in suboscines, which has not been encountered in other avian non-vocal-learners, and offer a potential configuration of brain and behaviour from which vocal learning might have evolved.
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    Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice.
    (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020-11) Yu, Shu; Galeffi, Francesca; Rodriguiz, Ramona M; Wang, Zhuoran; Shen, Yuntian; Lyu, Jingjun; Li, Ran; Bernstock, Joshua D; Johnson, Kory R; Liu, Shuai; Sheng, Huaxin; Turner, Dennis A; Wetsel, William C; Paschen, Wulf; Yang, Wei
    Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1-3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal-based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long-term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.