Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

At least 469 records · Page 26Linked to original sources

bioRxiv2019

Specific gyrA gene mutations correlate with high prevalence of discordant levofloxacin resistance in Mycobacterium tuberculosis isolates from Beijing, China

Although molecular diagnostics are highly sensitive in the diagnosis of fluroquinolone (FQ)-resistant tuberculosis (TB), the discordant results with the sequential phenotypic drug susceptibility testing (DST) invariably occur. To investigate the prevalence and the cause of discordant results between molecular and phenotypic DST for levofloxacin (LFX), the cases who were determined to be LFX-susceptible using the phenotypic DST but LFX-resistant using the MeltPro assay were retrospectively reviewed in Beijing, China. We measured LFX minimal inhibitory concentrations (MICs) using Middlebrook 7H9 broth. Sanger sequencing was used to determine genotypic characteristics of discordant isolates. Between January and December 2018, 126 (22.1%) out of 571 smear-positive TB patients were identified as LFX-resistant TB by MeltPro assay. Among the 126 LFX-resistant TB, there were 34 isolates identified as LFX-susceptible TB by phenotypical DST. This result demonstrated a discordance prevalence of 27.0%. LFX MICs were majorly centered around the critical concentration, and 7 (21.2%) and 13 (39.4%) had MICs of 2.0 mg/l and 4.0 mg/l, respectively. The most prevalent mutations conferring discordant LFX resistance were the amino acid substitutions of Ser to Leu in 90 codon (13, 39.4%) and Asp to Ala in 94 codon of gyrA (11, 33.3mg/l belonged to Ala90Val and Asp94Ala group. In conclusion, our data demonstrate that more than one quarter of LFX-resistant isolates by molecular method are susceptible to LFX using the phenotypic DST. The high prevalence of discordant LFX resistance is majorly due to the isolates with specific mutations within gyrA gene conferring proximity of MICs to the critical concentration.

microbiology↗

bioRxiv2019

MACS: Rapid aqueous clearing system for three-dimensional mapping of intact organs

Tissue optical clearing techniques have provided important tools for large-volume imaging. Aqueous-based clearing methods are known for good fluorescence preservation and scalable size maintenance, but are limited by either long incubation time, or insufficient clearing performance, or requirements for specialized devices. Additionally, due to the use of high concentration organic solvents or detergents, few clearing methods are compatible with lipophilic dyes while maintaining high clearing performance. To address these issues, we developed a rapid, highly efficient aqueous clearing method with robust compatibility, termed m-xylylenediamine (MXDA)-based Aqueous Clearing System (MACS). MACS can render intact organs highly transparent in a fairly short time and possesses ideal compatibility with multiple probes, especially for lipophilic dyes. Using MACS, we cleared the adult mouse brains within only 2.5 days for three-dimensional (3D) imaging of the neural structures labelled by various techniques. Combining MACS with DiI labelling, we visualized the vascular structures of various organs. MACS provides a useful tool for 3D mapping of intact tissues and is expected to facilitate morphological, physiological and pathological studies of various organs.

bioengineering↗

bioRxiv2019

Selective targeting of an oncogenic KRAS mutant allele by CRISPR/Cas9 induces efficient tumor regression

BackgroundKRAS is one of the most frequently mutated oncogenes in human cancers, but its activating mutations have remained undruggable due to its picomolar affinity for GTP/GDP and its smooth protein structure resulting in the absence of known allosteric regulatory sites. ResultsWith the goal of treating mutated KRAS-driven cancers, two CRISPR systems, CRISPR-SpCas9 genome-editing system and transcription-regulating system dCas9-KRAB, were developed to directly deplete KRAS mutant allele or to repress its transcription in cancer cells, respectively, through guide RNA specifically targeting the mutant but not wild-type allele. The effect of in vitro proliferation and cell cycle on cancer cells as well as in vivo tumor growth was examined after delivery of Cas9 system. SpCas9 and dCas9-KRAB systems with sgRNA targeting the mutant allele both blocked the expression of mutant KRAS gene, leading to an inhibition of cancer cell proliferation. Local adenoviral injections using SpCas9 and dCas9-KRAB systems both suppressed tumor growth in vivo. The gene-depletion system (SpCas9) performed more effectively than the transcription-suppressing system (dCas9-KRAB) on tumor inhibition. Application of both Cas9 systems to wild-type KRAS tumor cells did not affect cell proliferation in vitro and in vivo. Furthermore, through bioinformatic analysis of 31555 SNP mutations of the top 20 cancer driver genes, we showed that our mutant-specific editing strategy could be extended to a list of oncogenic mutations with high editing potentials, and this pipeline can be applied to analyze the distribution of PAM sequence in the genome to survey the best targets for other editing purpose. ConclusionsWe successfully developed both gene-depletion and transcription-suppressing systems to specifically target an oncogenic mutant allele of KRAS which led to significant tumor regression. It provides a promising strategy for the treatment of tumors with driver gene mutations.

genetics↗

bioRxiv2019

Global brain signal in awake rats

Although often used as a nuisance in resting-state functional magnetic resonance imaging (rsfMRI), the global brain signal in humans and anesthetized animals has important neural basis. However, our knowledge of the global signal in awake rodents is sparse. To bridge this gap, we systematically analyzed rsfMRI data acquired with a conventional single-echo (SE) echo planar imaging (EPI) sequence in awake rats. The spatial pattern of rsfMRI frames during peaks of the global signal exhibited prominent co-activations in the thalamo-cortical and hippocampo-cortical networks, as well as in the basal forebrain, hinting that these neural networks might contribute to the global brain signal in awake rodents. To validate this concept, we acquired rsfMRI data using a multi-echo (ME) EPI sequence and removed non-neural components in the rsfMRI signal. Consistent co-activation patterns were obtained in extensively de-noised ME-rsfMRI data, corroborating the finding from SE-rsfMRI data. Furthermore, during rsfMRI experiments we simultaneously recorded neural spiking activities in the hippocampus using GCaMP-based fiber photometry. The hippocampal calcium activity exhibited significant correspondence with the global rsfMRI signal. These data collectively suggest that the global rsfMRI signal contains significant neural components that involve coordinated activities in the thalamo-cortical and hippocampo-cortical networks. These results provide important insight into the neural substrate of the global brain signal in awake rodents.

neuroscience↗

bioRxiv2019

Structural changes in the gut microbiome of short-term and long-term medical workers compared to normal controls

ObjectiveHospital environment has been implicated in enrichment and exchange of pathogens and antibiotic resistances, but its potential in shaping the symbiotic microbial community of the hospital staff is unclear. This study was designed to evaluate the alteration of gut microbiome in medical workers compared to non-medical controls.\n\nDesignProspective cross-sectional cohort study.\n\nSettingIntensive care unit (ICU) and other departments from a center in northeast China.\n\nSubjects175 healthy medical workers (1-3 months short-term workers, n = 80; >1 year long-term workers, n = 95) and 80 healthy normal controls.\n\nInterventionsNone.\n\nMeasurements and Main ResultsFecal samples of all subjects were analyzed using the 16S rRNA gene sequencing. Medical workers exhibited remarkable deviation in gut microbial within-sample diversity and enterotypes stratification, and shift in overall microbial structure. Short-term workers were significantly more abundant in taxa including Lactobacillus, Butyrivibrio, Clostridiaceae_Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter and Desulfovibrio, and with lower abundances of Bacteroides and Blautia compared with the controls. While long-term workers were enriched in taxa including Dialister, Veillonella, Clostridiaceae_Clostridium, Bilophila, Desulfovibrio, Pseudomonas and Akkermansia, with lower abundances of Bacteroides and Coprococcus compared with the controls. In addition, medical workers working years (short-term vs. long-term), hospital department (resident doctor vs. nursing staff) and work position (ICU vs. not-ICU) revealed considerable effects on their gut microbiome. Moreover, by analyzing the environmental samples (n = 9) around the inpatient wards and the hospital, we showed that the gut microbiota of medical workers was closer to environmental microbiota than that of the normal controls, probably in correlation to lasting exposure to the pathogenic taxa (e.g. Pseudomonas) in health workers.\n\nConclusionsOur findings demonstrated structural changes in the gut microbial community of the medical workers. Further studies are proposed for investigating the potentially physiological influence of the altered gut microbiome in medical participants.\n\nIMPORTANCEIn this study, we for the first time focused on the influence of hospital environmental factors on gut microbiota of medical workers. The significance of our study is not limited to revealing the remodeling effect of the hospital environment on the gut microbiota of medical workers. Based on these, we also propose targeted and operational recommendations that can promote the health of hospital staff.

microbiology↗

bioRxiv2019

How brain reacts to attack at a local region

The architecture of brain networks has been extensively studied in multiple species. However, exactly how the brain network reconfigures when a local region stops functioning remains elusive. By combining chemogenetics and resting-state functional magnetic resonance imaging (rsfMRI) in awake rodents, we investigated the causal impact of acutely inactivating a hub region (i.e. dorsal anterior cingulate cortex) on brain network properties. We found that disrupting hub activity profoundly changed the function the default-mode network (DMN), and this change was associated with altered DMN-related behavior. Suppressing hub activity also impacted the topological architecture of the whole-brain network in network resilience, segregation and small worldness, but not network integration. This study has established a system that allows for mechanistically dissecting the relationship between local regions and brain network properties. Our data provide direct evidence supporting the hypothesis that acute dysfunction of a brain hub can cause large-scale network changes. This study opens an avenue of manipulating brain networks by controlling hub-node activity.

neuroscience↗

bioRxiv2019

Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we followed glioma progression in awake Thy1-GCaMP6f mice using in-vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring new biomarkers and therapeutic targets.\n\nHighlights- Glioma disrupts neural synchrony between bilateral cortical regions.\n- WFOM reveals frequent interictal discharges and seizures during glioma progression.\n- Tumor development is accompanied by local changes in neurovascular coupling.\n- Altered neurovascular coupling drives hypoperfusion of the tumor during seizures.

neuroscience↗

bioRxiv2019

Anaerobic degradation of syringic acid by an adapted strain of Rhodopseudomonas palustris

While lignin represents a major fraction of the carbon in plant biomass, biological strategies to convert the components of this heterogenous polymer into products of industrial and biotechnological value are lacking. Syringic acid (3,5-dimethoxy-4-hydroxybenzoic acid) is a byproduct of lignin degradation, appearing in lignocellulosic hydrolysates, deconstructed lignin streams, and other agricultural products. Rhodopseudomonas palustris CGA009 is a known degrader of phenolic compounds under photoheterotrophic conditions, via the benzoyl-CoA degradation (BAD) pathway. However, R. palustris CGA009 is reported to be unable to metabolize meta-methoxylated phenolics such as syringic acid. We isolated a strain of R. palustris (strain SA008.1.07), adapted from CGA009, which can grow on syringic acid under photoheterotrophic conditions, utilizing it as a sole source of organic carbon and reducing power. An SA008.1.07 mutant with an inactive benzoyl-CoA reductase structural gene was able to grow on syringic acid, demonstrating that the metabolism of this aromatic compound is not through the BAD pathway. Comparative gene expression analyses of SA008.1.07 implicated the involvement of products of the vanARB operon (rpa3619-rpa3621), which has been described as catalyzing aerobic aromatic ring demethylation in other bacteria, in anaerobic syringic acid degradation. In addition, experiments with a vanARB deletion mutant demonstrated the involvement of the vanARB operon in anaerobic syringic acid degradation. These observations provide new insights into the anaerobic degradation of meta-methoxylated and other aromatics by R. palustris.\n\nIMPORTANCELignin is the most abundant aromatic polymer on Earth and a resource that could eventually substitute for fossil fuels as a source of aromatic compounds for industrial and biotechnological applications. Engineering microorganisms for production of aromatic-based biochemicals requires detailed knowledge of metabolic pathways for the degradation of aromatics that are present in lignin. Our isolation and analysis of a Rhodopseudomonas palustris strain capable of syringic acid degradation reveals a previously unknown metabolic route for aromatic degradation in R. palustris. This study highlights several key features of this pathway and sets the stage for a more complete understanding of the microbial metabolic repertoire to metabolize aromatic compounds from lignin and other renewable sources.

microbiology↗

bioRxiv2019

Monotonous behavior with 2-propanol converts into reentrant transition with 1-propanol: Higher-order structure of DNA

In the present study, we measured the changes in the higher-order structure of genomic DNA molecules in the presence of alcohols through single-DNA observation by use of fluorescence microscopy, with particular focus on the different effects of 1-propanol and 2-propanol. The results showed that, with an increasing concentration of 1-propanol, DNA exhibits reentrant conformational transitions from an elongated coil to a folded globule, and then to an unfolded state. On the other hand, with 2-propanol, DNA exhibits monotonous shrinkage into a compact state. Thus, DNA molecules are more effectively condensed/precipitated with 2-propanol than with 1-propanol. The propanol isomers also had different effects on the changes in the secondary structure of DNA, as revealed by circular dichroism (CD) measurements. With 1-propanol, DNA maintains a B-form secondary structure. An A-like conformation appears with the addition of 2-propanol.\n\nSTATEMENT OF SIGNIFICANCECurrently, 2-propanol has most often been used as the solvent to extract and purify genomic DNA molecules from living cells, according the protocols in molecular biology and biochemistry. Unfortunately, the reason why usage of 2-propanol is recommended instead of ethanol and 1-propanol has never been explained in a clear manner. We believe that the new insight based on chemical physics point of view would play an important role for the development of current chemical procedures/treatments adapted on an empirical basis.

biophysics↗

bioRxiv2019

An updated analysis of opioids increasing the risk of fractures

ObjectiveTo assess the relationship between opioid therapy for chronic noncancer pain and fracture risk by a meta-analysis of cohort studies and case-control studies.\n\nMethodsThe included cohort studies and case-control studies were identified by searching the PubMed and EMBASE databases from their inception until May 24, 2019. The outcome of interest was a fracture. This information was independently screened by two authors. When the heterogeneity among studies was significant, a random effects model was used to determine the overall combined risk estimate.\n\nResultsIn total, 12 cohort studies and 6 case-control studies were included. We used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included literature, and 14 of the studies were considered high-quality studies. The overall relative risk of opioid therapy and fractures was 1.78 (95% confidence interval (CI) 1.53 - 2.07). Subgroup analyses revealed sources of heterogeneity, sensitivity analysis was stable, and no publication bias was observed.\n\nConclusionsThe meta-analysis showed that the use of opioids significantly increased the risk of fracture.

pharmacology and toxicology↗

bioRxiv2019

Estradiol-inducible AvrRps4 expression reveals distinct properties of TIR-NLR-mediated effector-triggered immunity

Plant nucleotide-binding domain, leucine-rich repeat receptor (NLR) proteins play important roles in recognition of pathogen-derived effectors. However, the mechanism by which plant NLRs activate immunity is still largely unknown. The paired Arabidopsis NLRs RRS1-R and RPS4, that confer recognition of bacterial effectors AvrRps4 and PopP2, are well studied, but how the RRS1/RPS4 complex activates early immediate downstream responses upon effector detection is still poorly understood. To study RRS1/RPS4 responses without the influence of cell-surface receptor immune pathways, we generated an Arabidopsis line with inducible expression of effector AvrRps4. Induction does not lead to hypersensitive cell death response (HR) but can induce electrolyte leakage, which often correlates with plant cell death. Activation of RRS1 and RPS4 without pathogens cannot activate mitogen-associated protein kinase cascades, but still activates upregulation of defense genes, and therefore resistance against bacteria.\n\nHighlightInducible expression of AvrRps4 activates RRS1/RPS4-mediated effector-triggered immunity without the presence of pathogens, allowing us to characterise downstream immune responses triggered by TIR-NLRs without cell-surface receptor-mediated immunity.

plant biology↗

bioRxiv2019

Mapping Vector Field of Single Cells

Single-cell RNA-seq, together with RNA velocity and metabolic labeling, reveals cellular states and transitions at unprecedented resolution. Fully exploiting these data, however, requires dynamical models capable of predicting cell fate and unveiling the governing regulatory mechanisms. Here, we introduce dynamo, an analytical framework that reconciles intrinsic splicing and labeling kinetics to estimate absolute RNA velocities, reconstructs velocity vector fields that predict future cell fates, and finally employs differential geometry analyses to elucidate the underlying regulatory networks. We applied dynamo to a wide range of disparate biological processes including prediction of future states of differentiating hematopoietic stem cell lineages, deconvolution of glucocorticoid responses from orthogonal cell-cycle progression, characterization of regulatory networks driving zebrafish pigmentation, and identification of possible routes of resistance to SARS-CoV-2 infection. Our work thus represents an important step in going from qualitative, metaphorical conceptualizations of differentiation, as exemplified by Waddingtons epigenetic landscape, to quantitative and predictive theories.

systems biology↗

bioRxiv2019

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

ObjectivesThis study aims to assess the relationship between the expression of c-Met and the prognosis of high grade glioma patients.\n\nMethodThe MET proto-oncogene encoded c-Met protein. The gene expression data of 325 patients were downloaded from CGGA. The Oncomine database analysis and the prognosis analysis were conducted. Besides, meta-analysis was also performed to confirm the conclusion.\n\nResultOncomine database was identified and analyzed and results showed that the MET copy number was obviously higher in glioblastoma than normal tissue consistently (p<0.001). The prognostic analysis of 325 high grade glioma samples showed that high c-Met expression patients had poor overall survival (OS) and progression free survival (PFS) than the low c-Met expression patients dramatically (HR, 2.223; 95% CI: 1.662 to 2.974; P<0.0001 and HR, 2.089; 95% CI: 1.578 to 2.770; P<0.0001). 6 studies involving 503 patients were included in the meta-analysis. The pooled results indicated that the high expression of c-Met was not significantly associated with OS (HR =1.01, 95% CI:0.93-1.09), but strongly connected with shorter PFS (HR =1.92, 95% CI:1.42-2.58, p<0.01).\n\nConclusionc-Met overexpression has correlation with poor prognosis of high grade glioma patients.

cancer biology↗

bioRxiv2019

Molecular mechanism for the recognition of sequence-divergent CIF peptides by the plant receptor kinases GSO1/SGN3 and GSO2.

Plants use leucine-rich repeat receptor kinases (LRR-RKs) to sense sequence diverse peptide hormones at the cell surface. A 3.0 [A] crystal structure of the LRR-RK GSO1/SGN3 regulating Casparian strip formation in the endodermis reveals a large spiral-shaped ectodomain. The domain provides a binding platform for 21 amino-acid CIF peptide ligands, which are tyrosine sulfated by the tyrosylprotein sulfotransferase TPST/SGN2. GSO1/SGN3 harbors a binding pocket for sulfotyrosine and makes extended backbone interactions with CIF2. Quantitative biochemical comparisons reveal that GSO1/SGN3 - CIF2 represents one of the strongest receptor-ligand pairs known in plants. Multiple missense mutations are required to block CIF2 binding in vitro, and GSO1/SGN3 function in vivo. Using structure-guided sequence analysis we uncover novel CIF peptides conserved among higher plants. Quantitative binding assays with known and novel CIFs suggest that the homologous LRR-RKs GSO1/SGN3 and GSO2 have evolved unique peptide binding properties to control different developmental processes. A quantitative biochemical interaction screen, a CIF peptide antagonist and genetic analyses together implicate SERK LRR-RKs as essential co-receptor kinases required for GSO1/SGN3 and GSO2 receptor activation. 0ur work provides a mechanistic framework for the recognition of sequence-divergent peptide hormones in plants.\n\nSignificance StatementTwo sequence-related plant membrane receptor kinases and their shape-complementary co-receptors are shown to selectively sense members of a small family of secreted peptide hormones to control formation of an important diffusion barrier in the plant root.

plant biology↗

bioRxiv2019

The YdiU Domain Modulates Bacterial Stress Signaling through UMPylation

Sensing stressful conditions and adjusting cellular metabolism to adapt to the environment is essential for bacteria to survive in variable situations. Here, we describe a new stress-related protein YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine 5-monophosphate to a protein tyrosine/histidine residue--a novel modification defined as UMPylation. Mn2+ serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+-binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. The detailed mechanism is proposed based on Apo-YdiU, YdiU-ATP, YdiU-AMP crystal structures and molecular dynamics simulation models of YdiU-UTP and YdiU-UTP-peptide. In vivo data demonstrate that YdiU effectively protects Salmonella from stress-induced ATP depletion through UMPylation. HighlightsO_LIYdiU involves in stress-resistance of Salmonella. C_LIO_LIYdiU mediates protein UMPylation in a Mn2+-dependent manner. C_LIO_LIStructural insights into YdiU-mediated UMPylation. C_LIO_LIUMPylation of chaperones by YdiU modulates their function. C_LI

biochemistry↗

bioRxiv2019

Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unknown, which hinders the discovery of effective anti-epileptogenic drugs. In this study, we built a systems-level analytic framework which integrates gene meta-signatures, gene coexpression network and cellular regulatory network to unveil the evolution landscape of epileptogenic process and to identify key regulators that govern the transition between different epileptogenesis stages. The time-specific hippocampal transcriptomic profiles from five independent rodent TLE models were grouped into acute, latent and chronic stages of epileptogenesis, and were utilized for generating stage-specific gene expression signatures. 13 cell-type specific functional modules were identified from the epilepsy-context coexpression network, and five of them were significantly associated with the entire epileptogenic process. By inferring the differential protein activity of gene regulators in each stage, 265 key regulators underlying epileptogenesis were obtained. Among them, 122 regulators were demonstrated being associated with high seizure frequency and/or hippocampal sclerosis in human TLE patients. Importantly, we discovered four new gene regulators (ANXA5, FAM107A, SEPT2 and SPARC) whose upregulation may drive the process of epileptogenesis and further lead to chronic recurrent seizures or hippocampal sclerosis. Our findings provide a landscape of the gene network dynamics underlying epileptogenesis and uncovered candidate regulators that may serve as potential targets for future anti-epileptogenic therapy development.

bioinformatics↗

bioRxiv2019

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTAVgat) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTAVgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTAVgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTAVgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTAVgat neurons are centrally positioned to help set an animals (and humans) level of mental and physical activity. Inputs that inhibit VTAVgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTAVgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).

neuroscience↗

bioRxiv2019

Gene - Environment Interaction: A TPH2 polymorphism and early life stress shape brain architecture and anxious avoidant behavior

BackgroundEarly life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2), and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance. MethodsThe present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252). ResultsHigher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes. ConclusionsThe present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

neuroscience↗