PI4KIIIß-Mediated Phosphoinositides Metabolism Regulates Function of the VTA Dopaminergic Neurons and Depression-Like Behavior.

Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel, and transporter activity. Phosphatidylinositol 4-kinases (PI4K) are essential enzymes in regulating the turnover of phosphoinositides. However, the functional role of PI4Ks and mediated phosphoinositide metabolism in the central nervous system has not been fully revealed. In this study, we demonstrated that PI4KIIIß, one of the four members of PI4Ks, is an important regulator of VTA dopaminergic neuronal activity and related depression-like behavior of mice by controlling phosphoinositide turnover. Our findings provide new insights into possible mechanisms and potential drug targets for neuropsychiatric diseases, including depression. Both sexes were studied in basic behavior tests, but only male mice could be used in the social defeat depression model.

Effects of differentially expressed microRNAs induced by rootstocks and silicon on improving chilling tolerance of cucumber seedlings (Cucumis sativus L.).

BACKGROUND: Rootstocks can improve the chilling tolerance of grafted cucumbers, but their effectiveness varies. Rootstocks with strong de-blooming capacity may result in lower chilling tolerance of grafted cucumbers compared to those with weak de-blooming capacity, while also reducing the silicon absorption. However, it remains unclear whether this reduction in chilling tolerance is due to differences in rootstock genotypes or the reduction in silicon absorption. RESULTS: The chilling tolerance of cucumber seedlings was improved by using rootstocks and silicon nutrition. Rootstocks had a more significant effect than silicon nutrition, and the weak de-blooming rootstock 'Yunnan figleaf gourd' was superior to the strong de-blooming rootstock 'Huangchenggen No. 2'. Compared to self-rooted cucumber, twelve miRNAs were regulated by two rootstocks, including seven identical miRNAs (novel-mir23, novel-mir26, novel-mir30, novel-mir37, novel-mir46, miR395a and miR398a-3p) and five different miRNAs (novel-mir32, novel-mir38, novel-mir65, novel-mir78 and miR397a). Notably, four of these miRNAs (novel-mir38, novel-mir65, novel-mir78 and miR397a) were only identified in 'Yunnan figleaf gourd'-grafted cucumbers. Furthermore, six miRNAs (miR168a-5p, miR390a-5p, novel-mir26, novel-mir55, novel-mir67 and novel-mir70) were found to be responsive to exogenous silicon. Target gene prediction for 20 miRNAs resulted in 520 genes. Functional analysis of these target genes showed that 'Yunnan figleaf gourd' improves the chilling tolerance of cucumber by regulating laccase synthesis and sulfate metabolism, while 'Huangchenggen No. 2' and exogenous silicon reduced chilling stress damage to cucumber by regulating ROS scavenging and protein protection, respectively. CONCLUSION: Among the identified miRNAs, novel-mir46 and miR398a-3p were found in cucumbers in response to chilling stress and two types of rootstocks. However, no identical miRNAs were identified in response to chilling stress and silicon. In addition, the differential expression of novel-mir38, novel-mir65, novel-mir78 and miR397a may be one of the important reasons for the differences in chilling tolerance of grafted cucumbers caused by two types of rootstocks.

Transcriptome and Physiological Analysis of Rootstock Types and Silicon Affecting Cold Tolerance of Cucumber Seedlings.

Cucumbers grafted on rootstocks with different de-blooming capacity show varying levels of cold tolerance. The content of fruit bloom correlates with its silicon-metabolizing capacity, and rootstock grafting can alter not only the cold tolerance but also the silicon-metabolizing capacity of the scion. The molecular mechanisms responsible for resistance due to rootstocks and silicon and the pathway that affects cold tolerance, however, remain poorly understood. Therefore, we performed physiological and transcriptome analysis to clarify how rootstock types and silicon affect cold tolerance in cucumber seedlings. Then, we randomly selected eight differentially expressed genes (DEGs) for quantitative real time PCR (qRT-PCR) analysis to proof the reliability of the transcriptome data. The results showed that silicon can enhance the cold tolerance of cucumbers by boosting the phenylpropanoid metabolism, and rootstock grafting can boost the active oxygen scavenging ability and synthesis level of hormones in cucumbers and maintain the stability of the membrane structure to enhance cold tolerance. The difference in cold tolerance between the two rootstocks is because the cold-tolerant one has stronger metabolic and sharp signal transduction ability and can maintain the stability of photosynthesis, thereby contributing to the stability of the cellular system and enhancing tolerance to cold.

Activation of parabrachial nucleus - ventral tegmental area pathway underlies the comorbid depression in chronic neuropathic pain in mice.

Depression symptoms are often found in patients suffering from chronic pain, a phenomenon that is yet to be understood mechanistically. Here, we systematically investigate the cellular mechanisms and circuits underlying the chronic-pain-induced depression behavior. We show that the development of chronic pain is accompanied by depressive-like behaviors in a mouse model of trigeminal neuralgia. In parallel, we observe increased activity of the dopaminergic (DA) neuron in the midbrain ventral tegmental area (VTA), and inhibition of this elevated VTA DA neuron activity reverses the behavioral manifestations of depression. Further studies establish a pathway of glutamatergic projections from the spinal trigeminal subnucleus caudalis (Sp5C) to the lateral parabrachial nucleus (LPBN) and then to the VTA. These glutamatergic projections form a direct circuit that controls the development of the depression-like behavior under the state of the chronic neuropathic pain.

Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour.

BACKGROUND AND PURPOSE: The mesolimbic dopamine system originating in the ventral tegmental area (VTA) is involved in the development of depression, and firing patterns of VTA dopaminergic neurons are key determinants in this process. Here, we describe a crucial role for the M-type Kv 7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice. EXPERIMENTAL APPROACH: We used Kv 7.4 channel knockout mice and a social defeat model of depression in combination with electrophysiological techniques (patch clamp recording and in vivo single-unit recordings), immunohistochemistry, single-cell PCR and behavioural analyses (social interaction time and glucose preference tests) to investigate VTA circuits involved in the development of depression-like behaviour. KEY RESULTS: Among the Kv 7 channels, Kv 7.4 channels are selectively expressed in dopaminergic neurons of the VTA. Using a newly identified selective Kv 7.4 channel activator, fasudil, and Kv 7.4 channel knockout mice, we demonstrate that these channels are a dominant modulator of excitability of VTA dopaminergic neurons, in vitro and in vivo. Down-regulation of Kv 7.4 channels could be a causal factor of the altered excitability of VTA dopaminergic neurons and depression-like behaviour. The selective Kv 7.4 channel activator, fasudil, strongly alleviated depression-like behaviour in the social defeat mouse model of depression. CONCLUSION AND IMPLICATIONS: Because expression of Kv 7.4 channels in the CNS is limited, selectively targeting this M channel subunit is likely to produce less on-target side effects than non-selective M channel modulators. Thus, Kv 7.4 channels may offer alternative targets in treatment of depression.