Biology subjects

Cai, Q.

Publications and source records attributed to Cai, Q..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Aeromonas hydrophila CobQ is a new type of NAD+- and Zn2+-independent protein lysine deacetylase in prokaryotes

Protein N--lysine acetylation (Kac) modifications play crucial roles in diverse physiological and pathological functions in cells. In prokaryotic cells, there are only two types of lysine deacetylases (KDACs) that are Zn2+- or NAD+-dependent. In this study, we reported a protein, AhCobQ, in Aeromonas hydrophila ATCC 7966 that presents NAD+- and Zn2+-independent KDAC activity. Furthermore, its KDAC activity is located in an unidentified domain (from 195-245 aa). Interestingly, AhCobQ has no homology with current known KDACs, and no homologous protein was found in eukaryotic cells. A protein substrate analysis showed that AhCobQ has specific protein substrates in common with other known KDACs, indicating that these KDACs can dynamically co-regulate the states of Kac proteins. Microbiological methods employed in this study affirmed AhCobQs positive regulation of isocitrate dehydrogenase (ICD) enzymatic activity at the K388 site, implicating AhCobQ in the modulation of bacterial enzymatic activities. In summary, our findings present compelling evidence that AhCobQ represents a distinctive type of KDAC with significant roles in bacterial biological functions. SummaryThe lack of exploration of new lysine acetylases and deacetylases (KDACs) and their protein substrates in prokaryotic cells has become a bottleneck in the functional study of lysine acetylation modifications. In this study, we reported a novel Zn2+- and NAD+-independent KDAC protein, AhCobQ, in Aeromonas hydrophila. Interestingly, this protein does not share homology with current known KDACs, and its KDAC activity is located in an unknown domain for which a homologous protein cannot be found in eukaryotic cells. The following analysis showed that AhCobQ affected the enzymatic activity and protein-protein interaction ability of its protein substrates. In summary, these results extended our understanding of the regulatory mechanism of bacterial lysine acetylation modifications. HighlightsAhCobQ is an NAD+- and Zn2+-independent protein lysine deacetylase. There are no proteins homologous to AhCobQ in eukaryotes. The deacetylase activity of AhCobQ is located in an unknown domain. AhCobQ has specific protein substrates and substrates in common with other lysine deacetylases. AhCobQ positively regulates the enzymatic activity of isocitrate dehydrogenase at its K388 site.

microbiology↗

bioRxiv2024

Mitochondrial bioenergetics stimulates autophagy for pathological tau clearance in tauopathy neurons

Hyperphosphorylation and aggregation of microtubule-associated tau is a pathogenic hallmark of tauopathies and a defining feature of Alzheimers disease (AD). Pathological tau is targeted by autophagy for clearance, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic failure has been shown to precede the development of tau pathology, it is unclear whether energy metabolism deficiency is involved in tauopathy-related autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy which, strikingly, leads to enhanced autophagy and pronounced tau clearance. OXPHOS-induced autophagy is attributed to increased ATP-dependent phosphatidylethanolamine biosynthesis in mitochondria. Excitingly, early bioenergetic stimulation boosts autophagy activity and reduces tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of bioenergetic dysfunction in tauopathy-linked autophagy defects and suggests a new therapeutic strategy to prevent toxic tau buildup in AD and other tauopathies.

neuroscience↗

bioRxiv2023

Vagus nerve stimulation by focused ultrasound attenuates acute myocardial ischemia/reperfusion injury predominantly through cholinergic anti-inflammatory pathway

BackgroundThe invasive method using electrically stimulating vagus nerve has been demonstrated to inhibit the inflammatory response against acute myocardial ischemia/reperfusion(I/R) injury. This neuro-regulatory technique used is invasive implantation of electrical stimulators which have the risk of infection and other complications. A non-invasive method of vagus nerve stimulation applying on acute myocardial I/R injury is particularly important and desirable. ObjectivesThis study aimed to test the hypothesis that focused ultrasound stimulation(FUS) of vagus nerve attenuates acute myocardial I/R injury through cholinergic anti-inflammatory pathway. MethodsThis study was completed with two parts. In the first part, ischemia was induced by left anterior descending coronary artery (LAD) occlusion for 30 minutes (min), followed by 2 hours (h) of reperfusion, FUS lasted for 50 min after reperfusion for 10 min. Infammatory markers, arrhythmia score, histopathology, infammatory markers 7 nicotinic acetylcholine receptor (7nAchR) protein were determined. In the second part, ischemia was induced by LAD occlusion for 30 min, followed by 24h of reperfusion, FUS lasted for 50 min after reperfusion for 10 min. Myocardial fibrosis, infarct size, echocardiographic measurements, biomarkers of pro-oxidative stress, antioxidant and myocardial apoptosis were determined. ResultsFUS of vagus nerve significantly decreased the level of infammatory markers in I/R+FUS group compared with the I/R group, I/R+vagotomy group and I/R+vagotomy+FUS group. FUS decreased the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF), while also reduced arrhythmia score in I/R+FUS group compared with the I/R group. These improvements were associated with the inhibition of acute inflammatory reaction through cholinergic anti-inflammatory pathway. FUS limited myocardial fibrosis and infarct size, preserved left ventricular function. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. ConclusionsThe noninvasive method of ultrasonic neuromodulation using FUS of vagus nerve exerted protective effects on acute myocardial I/R injury. Its potential mechanisms involved the suppression of acute inflammatory reaction through cholinergic anti-inflammatory pathway.

neuroscience↗

bioRxiv2023

Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles

Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.

bioengineering↗

bioRxiv2023

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6).

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

cancer biology↗

bioRxiv2023

CaMKII autophosphorylation but not downstream kinase activity is required for synaptic memory

CaMKII plays a critical role in long-term potentiation (LTP), a well-established model for learning and memory through the enhancement of synaptic transmission. Biochemical studies indicate that CaMKII catalyzes a phosphotransferase (kinase) reaction of both itself (autophosphorylation) and of multiple downstream target proteins. However, whether either type of phosphorylation plays any role in the synaptic enhancing action of CaMKII remains hotly contested. We have designed a series of experiments to define the minimal requirements for the synaptic enhancement by CaMKII. We find that autophosphorylation of T286 and further binding of CaMKII to the GluN2B subunit are required both for initiating LTP and for its maintenance (synaptic memory). Once bound to the NMDA receptor, the synaptic action of CaMKII occurs in the absence of kinase activity. Thus, autophosphorylation, together with binding to the GluN2B subunit, are the only two requirements for CaMKII in synaptic memory.

neuroscience↗

bioRxiv2023

Manipulation of Bacterial ROS Production Leads to Self-escalating DNA Damage and Resistance-resistant Lethality for Intracellular Mycobacteria

The high prevalence of drug resistance in mycobacteria calls for antimicrobial mechanisms that suppresses the development of resistance. As a structurally conserved multi-site bio-macromolecule, DNA is presumed to be an ideal candidate for such resistance-resistant drug target. However, survey of marketed and investigational DNA interactors indicates that they are not immune to resistance development. Here, we report our strategy to achieve real resistance-resistant DNA targeting by incurring "catastrophic" DNA damage with an organoruthenium-natural product hybrid. The dual-mode DNA damage, in the form of strong tri-valent binding and concomitant oxidative modification, is achieved by manipulating of bacterias native endogenous ROS production mechanism upon lethal stress (such as DNA binding). Such self-escalating DNA damage, together with precise targeting of intracellular bacteria via vacuole fusion, thus endows the hybrids resistance-resistant lethality against mycobacteria and in vivo efficacy in animal models.

microbiology↗

bioRxiv2023

The effect of circulation rate on the water quality of container-type recirculation aquaculture system under different feeding rates of Schizothorax wangchiachii

As an experimental fish, juvenile Schizothorax wangchiachii were fed different dosages (100, 300, or 500 g), and the changes in water quality in the inlet and outlet of the biofilter and in the aquaculture buckets were measured under different circulation rates (1.5, 3, or 4.5 m3/h; water samples were collected every 2 hours). With 100 g of feed and different circulation rates (1.5, 3, or 4.5 m3/h), the average removal rates of ammonia nitrogen and nitroso nitrogen by the biofilter were 40.4, 36.8, and 27.7% and 43.9, 36.9, and 29.8%, respectively. With 300 g of feed, the average removal rates of ammonia nitrogen and nitroso nitrogen were 42.3, 37.9, and 33.6% and 45.8, 32.7, and 21.7%, respectively. With 500 g of feed, the average removal rates of ammonia nitrogen and nitroso nitrogen by biofilters with different circulation rates were 53.5, 42.6, and 35.7% and 40.3, 26.5, and 18.1%, respectively. Therefore, when the feeding amounts were 100, 300, and 500 g, respectively, the optimal circulation rates were 1.5, 1.5, or 4.5 m3/h, which allowed the best management and reduction in energy consumption of the circulating aquaculture system. This research conclusion provides a reliable scientific reference for the promotion of a low-cost new model of industrial circular water aquaculture.

animal behavior and cognition↗

bioRxiv2023

Small RNAs from fungal pathogen Botrytis cinerea ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis

Small RNAs (sRNAs) of the fungal pathogen Botrytis cinerea can enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate that B. cinerea utilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). The B. cinerea tetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerous Arabidopsis clathrin-coated vesicles (CCVs) around B. cinerea infection sites and the colocalization of B. cinerea EV marker BcPLS1 and Arabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and the B. cinerea-secreted sRNAs are detected in purified CCVs after infection. Arabidopsis knockout mutants and inducible dominant-negative mutants of key components of CME pathway exhibit increased resistance to B. cinerea infection. Furthermore, Bc-sRNA loading into Arabidopsis AGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.

plant biology↗

bioRxiv2023

pan-ECM: live brain extracellular matrix imaging with protein-reactive dye

The brain extracellular matrix (ECM), consisting of proteins and glycosaminoglycans, is a critical scaffold in the development, homeostasis, and disorders of the central nervous system (CNS) and undergoes remodeling in response to environmental cues. Live imaging of brain ECM structure represents a native view of the brain ECM but, until now, remains challenging due to the lack of a robust fluorescent labeling approach. Here, we developed a pan-ECM method for labeling the entire (Greek: pan) brain ECM network by screening and delivering a protein-reactive dye into the brain. pan-ECM enables imaging of ECM compartments in live brain tissue, including the interstitial matrix, basement membrane (BM), and perineuronal nets (PNNs), and even the ECM in glioblastoma and stroke mouse brains. This approach provides access to the structure and dynamics of the ECM and enhances our understanding of the complexities of the brain ECM and its contribution to brain health and disease.

neuroscience↗

bioRxiv2023

A Conserved Requirement for RME-8/DNAJC13 in Neuronal Autolysosome Reformation

Autophagosomes fuse with lysosomes, forming autolysosomes that degrade engulfed cargo. To maintain lysosomal capacity, autolysosome reformation (ALR) must regenerate lysosomes from autolysosomes using a membrane tubule-based process. Maintaining lysosomal capacity is required to maintain proteostasis and cellular health, especially in neurons where lysosomal dysfunction has been repeatedly implicated in neurodegenerative disease. Cell biological studies have linked the DNA-J domain Hsc70 co-chaperone RME-8/DNAJC13 to endosomal coat protein regulation, while human genetics studies have linked RME-8/DNAJC13 to neurological disease, including Parkinsonism and Essential Tremor. We report new analysis of the requirements for the RME-8/DNAJC13 protein in neurons, focusing on C. elegans mechanosensory neurons in the intact animal, and in primary mouse cortical neurons in culture. We find that loss of RME-8/DNAJC13 in both systems results in accumulation of grossly elongated autolysosomal tubules. Further C. elegans analysis revealed a similar autolysosome tubule accumulation defect in mutants known to be required for ALR in mammals, including bec-1/beclin and vps-15/PIK3R4/p150 that regulate type-III PI3-kinase VPS-34, and dyn-1/dynamin that severs ALR tubules. Clathrin is also an important ALR regulator implicated in autolysosome tubule formation and release. In C. elegans we found that loss of RME-8 causes severe depletion of clathrin from neuronal autolysosomes, a phenotype shared with bec-1 and vps-15 mutants. We conclude that RME-8/DNAJC13 plays a conserved but previously unrecognized role in autolysosome reformation, likely affecting ALR tubule initiation and/or severing. Additionally, in both systems, we found that loss of RME-8/DNAJC13 appeared to reduce autophagic flux, suggesting feedback regulation from ALR to autophagy. Our results connecting RME-8/DNAJC13 to ALR and autophagy provide a potential mechanism by which RME-8/DNAJC13 could influence neuronal health and the progression of neurodegenerative disease.

cell biology↗

bioRxiv2023

Botrytis cinerea small RNAs are associated with tomato AGO1 and silence tomato target genes supporting cross-kingdom RNAi between the fungal pathogen B. cinerea and its tomato host

Cross-kingdom or cross-species RNA interference (RNAi) is broadly present in many interacting systems between microbes/parasites and their plant and animal hosts. A recent study by Qin et al. (2022) performed correlation analysis using global sRNA- and mRNA-deep sequencing data of cultured B. cinerea and B. cinerea-infected tomato leaves and claimed that cross-kingdom RNAi may not occur in B. cinerea-tomato interaction (Qin et al., 2022). Here, we use experimental evidence and additional bioinformatics analysis of the datasets produced by Qin et al. (2022) to identify the key reasons why a discrepancy between the conclusion of Qin et al. 2022 and previously published findings occurred. We also provided additional experimental evidence to support the presence of cross-kingdom RNAi between tomato and B. cinerea. We believe it is important to clarify the basic concept and mechanism of cross-kingdom/cross-species sRNA trafficking and illustrate proper bioinformatics analyses in this regard for all the scientists and researchers in this field.

plant biology↗

bioRxiv2022

Neural signatures of second language proficiency in narrative processing.

Making sense of speech in a second language relies on multiple abilities. Differences in brain activity related to proficiency in language tasks have often been attributed to processing demands. However, during naturalistic narrative comprehension, listeners at different proficiency levels may form different representations of the same speech. We hypothesized that the synchronization of these representations across people could thus be used to measure second-language proficiency. Using a searchlight shared response model, we found that highly proficient participants showed synchronization in regions similar to those of native speakers, including in the default mode network and in the lateral prefrontal cortex. In contrast, participants with low proficiency showed more synchronization in auditory cortex and word-level semantic processing areas in the temporal lobe. Moderate proficiency showed the greatest neural diversity, suggesting lower consistency in the source of this partial proficiency. Based on these synchronization differences, we were able to reliably classify the proficiency level or predict behavioral performance on an independent English test in held-out participants, suggesting the identified neural systems represented proficiency-sensitive information that was generalizable to other individuals. These findings suggest higher second-language proficiency leads to a more native-like neural processing of naturalistic language, including in systems beyond the cognitive control network or the core language network. HighlightsO_LINeural synchronization in second-language speech processing reflects proficiency. C_LIO_LIHigh-proficiency individuals neurally resemble native speakers. C_LIO_LILow-proficiency individuals are synchronized in perceptual and word semantics areas. C_LIO_LIProficiency level can be predicted using neural synchronization signatures. C_LI

neuroscience↗

bioRxiv2022

Neural mechanisms of musical syntax and tonality, and the effect of musicianship.

The neural basis for the processing of musical syntax has previously been examined almost exclusively in classical tonal music, which is characterized by strictly organized hierarchical structure. The present study investigated the neural mechanisms for processing musical syntax across genres varying in tonality - classical, impressionist, and atonal music - and, in addition, examined how musicianship modulates such processing. Results showed that, first, the dorsal stream, including bilateral inferior frontal gyrus and superior temporal gyrus, plays a key role in the perception of tonality. Second, right fronto-temporal regions were crucial in allowing musicians to outperform non-musicians in musical syntactic processing; musicians also benefit from a cortical-subcortical network including pallidum and cerebellum, suggesting more auditory-motor interaction in musicians than in non-musicians. Third, left pars triangularis carries out on-line computations independently of tonality and musicianship, whereas right pars triangularis is sensitive to tonality and partly dependent on musicianship. Finally, unlike tonal music, processing of atonal music could not be differentiated from that of scrambled notes, both behaviorally and neurally, even among musicians. The present study highlights the importance of studying varying music genres and experience levels, and provides a better understanding of musical syntax and tonality processing and how such processing is modulated by music experience.

neuroscience↗

bioRxiv2022

Exosome-derived lncRNA HOXA-AS3 promotes castration resistance and progression of prostate cancer via the miR-29b-3p/Mcl-1/STAT3 axis

Prostate cancer is one of the leading causes of cancer-related deaths in men. While endocrine therapy is effective in the early stage of metastasis, significantly inhibits the progression of metastatic prostate cancer, most patients eventually develop CRPC. Tumor microenvironment are involved in the progression of prostate cancer as an "accomplice", cancer cell-secreted exosomes were identified as crucial messengers can carry lncRNAs to participate in intercellular communication. we revealed PC-3-derived exosomes promote androgen resistance in LNCaP cells. HOXA-AS3 as a ceRNA of miRNA-29b-3p affects the proliferation and invasion ability of prostate cancer cells. A series of molecular experiments, cell experiments and clinical tissue verification experiments confirmed that HOXA-AS3 participates in the castration resistance and progression of prostate cancer through regulating the miR-29b-3p/Mcl-1/STAT3/Cytochrome C/caspases-9 pathway. Dysregulation of HOXA-AS3 is observed in many cancer types, and this study shows the importance of this lncRNA in controlling prostate cancer cell progression, thus highlighting it as a potential biomarker for inhibiting prostate cancer progression and a target for immunotherapy.

genomics↗

bioRxiv2022

Role of mPFC DUSP1 in regulating the sensitivity to cocaine in adolescent cocaine-exposed mice of adulthood

Adolescent cocaine abuse increases the risk for developing addiction in later life, which remains a big public health concern, but the underlying molecular mechanism is poorly understood. Here, adolescent cocaine-exposed (ACE) male mice models were established by administrating cocaine during adolescent period. When growing to adult age, mice were subjected to conditioned place preference (CPP) to evaluate the sensitivity to cocaine, then potential molecule of dual specificity phosphatase 1 (DUSP1) were screened out by transcriptomic sequencing. Subthreshold dose of cocaine (sdC), that is insufficient to produce CPP, was used to induce CPP in adulthood. The sdC treatment effectively induced CPP in ACE mice during adulthood, accompanied with the more triggered CaMKII-positive neurons, and induced higher Dusp1 gene, lower DUSP1 protein, lower DUSP1 activity and lower DUSP1 expression on CaMKII-positive neurons (DUSP1CaMKII) in medial prefrontal cortex (mPFC). Overexpressing DUSP1CaMKII suppressed CaMKII-positive neuronal activation, and ultimately blocked sdC-induced CPP in ACE mice during adulthood. While, knocking-down DUSP1CaMKII activated more CaMKII-positive neurons, and aggravated sdC-preferred behavior in ACE mice during adulthood. ERK1/2 might be potential subsequent signal for DUSP1 in the process. Collectively, our findings reveal a novel molecular mechanism underlying adolescent drug abuse-induced susceptibility to addiction during adulthood, and mPFC DUSP1CaMKII is a promising pharmacological target to predict or treat addiction, especially caused by adolescent substance use. SummaryAdolescent cocaine exposure causes higher cocaine-preferred behaviors during adulthood, along with evoked mPFC activity in response to cocaine challenge. Locally overexpressing but not knocking-down the dual specificity phosphatase 1 (DUSP1) on CaMKII-positive neurons (DUSP1CaMKII) suppresses mPFC activation, and ultimately rescues the higher sensitivity to cocaine during adulthood.

neuroscience↗

bioRxiv2022

β1-adrenergic receptor on pyramidal neurons of mPFC regulates METH-preferred behaviors in METH-sired male mice

Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naive female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH, insufficient to induce CPP normally, were used in F1 (METHF1). Selective antagonist (betaxolol) for {beta}1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired METHF1-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without METHF1, but strongly evoked after METHF1 treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without METHF1, which was kept at higher levels after METHF1 treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed METHF1-evoked mPFC acyivation, and ultimately blocked METHF1-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and {Delta}FosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKII mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction. HIGHLIGHTSO_LIPaternal methamphetamine (METH) exposure induces higher sensitivity to METH in male F1 during adulthood, accompanied with higher ADRB1 level in mPFC. C_LIO_LIMETH use in F1 (METHF1) evokes more CaMKII-positive neurons in mPFC of METH-sired than saline-sired male F1. C_LIO_LIInhibiting ADRB1 function or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) efficiently suppresses METHF1-evoked mPFC activation, and ultimately rescues transgenerational susceptibility to addiction in male F1. C_LI

neuroscience↗

bioRxiv2022

Activation of Cerebellar Lobule VI PCTH+boxhMed Pathway Selectively blocks METH-induced Conditioned Place Preference in mice

The cerebellum is implicated in drug addiction. However, the cerebellar neuronal circuitry underlying addiction, especially classic pathway of Purkinje cells (PCs) to deep cerebellar nuclei (DCN), are largely unknown. Here, tracing experiments showed robust projections from the cerebellar lobule VI tyrosine hydroxylase (TH)-positive PCs (PCTH+) to CaMKII-positive glutamatergic neurons in medial cerebellar nucleus (MedCaMKII), forming PCTH+-MedCaMKII pathway. Then, mice were subjected to methylamphetamine (METH)-induced conditioned place preference (CPP), showing that METH exposure excited MedCaMKII and inhibited PCTH+. Silencing MedCaMKII by tettox suppressed the formation and expression of METH-induced CPP, but produced serious motor coordination deficits. Chemogenetic activation of lobule VI PCTH+-Med pathway during METH CPP training blocked the formation and expression of METH-induced CPP without affecting motor coordination, locomotor activity and sucrose reinforcements in mice. Our findings revealed a novel cerebellar lobule VI PCTH+-MedCaMKII pathway and pointed out is critical role in encoding METH-preferred behaviors.

neuroscience↗