Neuroscience
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Focal administration of pharmacological agents during in vivo recordings is a useful technique to study the functional properties of neural microcircuits. However, the lack of visual control makes this task difficult and inaccurate, especially when targeting small and deep regions where spillover to neighboring regions is likely to occur. An additional problem with recording stability arises when combining focal drug administration with in vivo intracellular recordings, which are highly sensitive to mechanical vibrations. ⋯ We applied tetrodotoxin (TTX 10 µM) during whole-cell recordings in the striatum, while simultaneously obtaining extracellular recordings in S1 and M1. The focal application of TTX in the striatum blocked Up states in the recorded striatal neurons, without affecting the cortical activity. We also describe two different approaches for precisely releasing the drugs without unwanted leakage along the pipette approach trajectory.
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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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An understudied symptom of the genetic disorder Neurofibromatosis type 1 (NF1) is chronic idiopathic pain. We used targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin, the protein product of the Nf1 gene, and pain responses. Our study data identified a protein-interaction network with collapsin response meditator protein 2 (CRMP2) as a node and neurofibromin, syntaxin 1A, and the N-type voltage-gated calcium (CaV2.2) channel as interaction edges. ⋯ The data presented here shows that disrupting the CRMP2-neurofibromin interface is sufficient to reverse the dysregulations of voltage-gated ion channels and neurotransmitter release elicited by Nf1 gene editing. As a consequence of these effects, the CNRP1 peptide reversed hyperalgesia to thermal stimulation of the hindpaw observed in Nf1-edited rats. Our findings support future pharmacological targeting of the CRMP2/neurofibromin interface for NF1-related pain relief.
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Increasing evidence has shown that prenatal stress (PS) could cause depression-like behavior in the offspring, which is sex-specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the involvement of tryptophan hydroxylase 2 (Tph2) H3K9 acetylation (H3K9ac) modification on PS-induced depression-like behavior in juvenile offspring rats (JOR). ⋯ However, no significant effects were observed for the female juvenile offspring rats (FJORs). In conclusion, our results showed that the Tph2 H3K9ac modification is only involved in PS-induced depression-like behavior in MJOR, in a sex-specific manner. These findings might contribute to the understanding of the disease pathogenesis and clinical treatment in future.