Neuroscience
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Molecular and functional diversity within midbrain dopaminergic (mDA) and hindbrain serotonergic (5-HT) neurons has emerged as a relevant feature that could underlie selective vulnerability of neurons in clinical disorders. We have investigated the role of transforming growth factor beta (TGF-β) during development of mDA and 5-HT subgroups. We have generated TβRIIflox/flox::En1cre/+ mice where type II TGF-β receptor is conditionally deleted from engrailed 1-expressing cells and have investigated the hindbrain serotonergic system of these mice together with Tgf-β2-/- mice. ⋯ Moreover, conditional deletion of TGF-β signaling from midbrain and rhombomere 1 leads to inactive TGF-β signaling in cre-expressing cells, impaired development of mouse mDA neuron subgroups and of dorsal raphe 5-HT neuron subgroups in a temporal manner. These results highlight a selective growth factor dependency of individual rostral hindbrain serotonergic subpopulations, emphasize the impact of TGF-β signaling during development of mDA and 5-HT subgroups, and suggest TGF-βs as potent candidates to establish diversity within the hindbrain serotonergic system. Thus, the data contribute to a better understanding of development and degeneration of mDA neurons and 5-HT-associated clinical disorders.
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Type 2 diabetes mellitus (T2DM)-associated oxidative stress contributes to cognitive deficiencies and Alzheimer's disease (AD). Sulforaphane (SFN) is a pharmacological activator of Nrf2 that provokes Nrf2-mediated intracellular defenses, including antioxidant and anti-inflammatory responses, under oxidative stress (OS) conditions. This study investigated the effects of SFN on DM-related cognitive decline and its potential mechanisms. ⋯ Accordingly, immunoblotting and immunohistochemistry analyses showed that SFN decreased the levels of amyloid-β (Aβ) oligomers and Aβ 1-42 plaques as well as phospho-tau at Ser396 and Thr231 in the DM mouse hippocampus. This protective effect of SFN might be due to the activation of Nrf2-regulated antioxidant defense deficiencies in the DM mice, as SFN increased the Nrf2 nuclear accumulation and the downstream expression of the antioxidases HO-1 and NQO1 and reduced the levels of the reactive oxygen/nitrogen species (ROS/RNS) in DM mouse brains. Our results confirm that SFN has potential as a therapeutic agent to protect T2DM patients from cognitive deficiencies and AD-like pathological lesions related to the upregulation of Nrf2-regulated antioxidant defenses.
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The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K+ channels or activation of Na+ and Ca+2 channels to depolarize CO2-sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. ⋯ Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses.
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We previously showed that apelin-13 ameliorates chronic normobaric hypoxia (CNH)-induced anxiety-like behavior in mice, the mechanism, however, is not well known. This study aims to investigate whether SIRT1 is involved in the anxiolytic effect of apelin-13 in CNH-treated mice, and to illustrate the potential underlying mechanism. We showed that apelin-13 treatment reversed a decrease in SIRT1 and an increase in acetylated p65 (lysine 310) proteins' expression in hippocampus of CNH-treated mice, indicating that apelin-13 inhibited NF-κB signaling pathway by activating SIRT1. ⋯ Finally, blockade of NF-κB activity by PDTC diminished CNH-induced anxiety-like behavior, indicating that NF-κB was involved in CNH-induced anxiety-like behavior in mice. In conclusion, this study provides the first evidence that SIRT1 mediates the anxiolytic effect of apelin-13 in CNH-treated mice through the inhibition of NF-κB pathway. These results imply that dysfunction of the apelin-SIRT1-NF-κB axis in hippocampus represents a potential mechanism that results in the induction of neuroinflammation and reduction in neuroprotection, thus induces anxiety-like behavior in CNH-treated mice.
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Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons. Currently, there is no effective drug for ALS. Recent studies in ALS model mice have shown that insulin-like growth factor-1 (IGF1) may be a promising therapeutic drug. ⋯ Furthermore, the results were supported by experiments in which the CRISPR/Cas9 system was used to knock-down IGF1 in ALS mice (mIGF1). Our data indicate that IGF1-mediated suppression of NF-κB activation in microglia is a novel molecular mechanism underlying MN death in ALS. It provides new insight into IGF1 and points toward novel therapeutic targets of IGF1 in ALS.