Godino, A;Salery, M;Durand-de Cuttoli, R;Estill, MS;Holt, LM;Futamura, R;Browne, CJ;Mews, P;Hamilton, PJ;Neve, RL;Shen, L;Russo, SJ;Nestler, EJ;
PMID: 36889314 | DOI: 10.1016/j.neuron.2023.02.013
The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical-activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction and paves the way for future studies of rexinoid signaling in psychiatric disease states.
Kim, JS;Williams, KC;Kirkland, RA;Schade, R;Freeman, KG;Cawthon, CR;Rautmann, AW;Smith, JM;Edwards, GL;Glenn, TC;Holmes, PV;de Lartigue, G;de La Serre, CB;
PMID: 37380023 | DOI: 10.1016/j.molmet.2023.101764
Obesity is associated with deficits in reward which have been linked to compensatory overeating. The vagus nerve is a direct neural pathway that conveys post-ingestive feedback from the gut to the brain, including the reward regions, and vagal activation causes stereotypical reward behaviors. Chronic high fat (HF) feeding alters vagal signaling potentially dampening food-associated reward. Microbiota composition changes rapidly with HF feeding, and a HF-type microbiota is sufficient to alter vagal structure and function. However, whether microbiota-driven alterations in vagal signaling affect host appetitive feeding behavior is unknown. Here, we investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication. Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats. Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats. We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.
Reiner, BC;Zhang, Y;Stein, LM;Perea, ED;Arauco-Shapiro, G;Ben Nathan, J;Ragnini, K;Hayes, MR;Ferraro, TN;Berrettini, WH;Schmidt, HD;Crist, RC;
PMID: 36075888 | DOI: 10.1038/s41398-022-02135-1
Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.
Caprioli D, Venniro M, Zhang M, Bossert JM, Warren BL, Hope BT, Shaham Y.
PMID: 27980115 | DOI: 10.1523/JNEUROSCI.3091-16.2016
We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral and dorsomedial striatum (DLS, DMS) in this incubation.We trained rats to self-administer palatable food pellets (6 days, 6-h/d) and methamphetamine (12 days, 6-h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/day) for 19 days. We used in situ hybridization to measure co-labeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization co-labeling results, we tested the causal role of DMS D1- and D2-family receptors, and DMS neuronal ensembles in 'incubated' methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively.Methamphetamine seeking was higher after 21 days of voluntary abstinence than after 1 day (incubation of methamphetamine craving). The 'incubated' response was associated with increased Fos expression in DMS but not DLS; Fos was co-labeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21.Results demonstrate a role of DMS dopamine D1 and D2-receptors in incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation.
SIGNIFICANCE STATEMENT:
In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving.
Obstetrics, Gynecology and Reproduction
Yakimova, A;Borovaya, S;Mukhamedshina, V;Datsenko, N;Kucherenko, S;Pozdnyakov, I;Nikitenko, E;
| DOI: 10.17749/2313-7347/ob.gyn.rep.2022.337
Introduction. During the COVID-19 pandemic, the question regarding an effect of related infection on the body of pregnant women and the fetoplacental complex has emerged, with many aspects of this issue still being unknown. At the moment, it has been proven that in some cases the course of COVID-19 can be accompanied by severe systemic inflammatory reaction leading to hypercoagulable state.Aim: to search for evidence of a direct and/or indirect effect of SARS-CoV-2 infection on human placenta structure.Materials and Methods. Taking into account the goal, this review was compiled according to the type of a narrative review of publications on a topic of interest. A search for English-language publications dated of 01.12.2019 till 01.12.2021 in PubMed/MEDLINE, Cochrane, Web of Science databases was made. The search queries included the following keywords: combinations of «coronavirus» and «infection during pregnancy», «placental structure» and «2019-nCoV», «COVID-19 and pregnancy», «SARSCoV-2 and pregnancy». In the process of writing the article, in order to improve the reader's understanding of the essence of debated issue, there was a need to discuss some of the results with literary sources published earlier 2019 that were not directly related to the topic of the new coronavirus infection (there are 6 such sources). We analyzed full-text publications, both reports on original research and meta-analyses on relevant topics. In total, 351 full-text publications met the query criteria, of which 54 were selected as meeting the objectives of the study. The select reports were discussed by the co-authors, duplicates were excluded and 34 of them were included in this review. In those that were excluded from the review, information about the clinical course of pregnancy and its outcome during novel coronavirus infection prevailed, or isolated cases of studying insignificant placental structural changes were discussed. Studies with a small number of observations were selected only in the case of the uniqueness of the published data, the absence of scientific papers where similar studies would have been conducted in larger sample.Results. Pregnancy complicated by COVID-19 may be accompanied by placental structural changes, which represent both a manifestation of compensatory-adaptive reactions and a consequence of the damaging effect to the placenta due to infectious process. In case of late (in the III trimester) disease in pregnant woman with mild COVID-19, placental disorders are predominantly of compensatory-adaptive nature, specific cytological signs of viral cell damage are uncharacteristic. During COVID-19 infection, chronic histiocytic intervillositis and syncytiotrophoblast necrosis occur more often than in average population, and adverse fetal outcomes are characterized by additional marked increase in intervillous fibrinoid deposition. Before COVID-19 pandemic, chronic histiocytic intervillositis was described in about 6 out of 10,000 placentas (0.6 %) in II and III trimesters.Conclusion. The high frequency of chronic histiocytic intervillositis, both in the placenta of paired women with live-born infants infected prenatally due to maternal virus transmission, and in the placentas of stillborn infected infants, allows us to cautiously assume that such placental structural changes are more characteristic for damage by SARS-CoV-2 rather than other infectious agents. It is necessary to study a relationship between placental structural changes occurred at different gestation ages, as well as clinical course and outcome of pregnancy during COVID-19.
Charbogne P, Gardon O, Martín-García E, Keyworth HL, Matsui A, Mechling AE, Bienert T, Nasseef T, Robé A, Moquin L, Darcq E, Hamida SB, Robledo P, Matifas A, Befort K, Gavériaux-Ruff , Harsan LA, Von Everfeldt D, Hennig J, Gratton A, Kitchen I, Bailey A,
PMID: - | DOI: 10.1016/j.biopsych.2016.12.022
Background
Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.
Methods
We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.
Results
Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.
Conclusions
Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.
Immunology and cell biology
Mekhael, O;Revill, SD;Hayat, AI;Cass, SP;MacDonald, K;Vierhout, M;Ayoub, A;Reihani, A;Padwal, M;Imani, J;Ayaub, E;Yousof, T;Dvorkin-Gheva, A;Rullo, A;Hirota, JA;Richards, CD;Bridgewater, D;Stämpfli, MR;Hambly, N;Naqvi, A;Kolb, MR;Ask, K;
PMID: 36862017 | DOI: 10.1111/imcb.12637
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodelling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in IPF patient lung and in CD14+ circulating monocytes obtained from IPF patient blood. After bleomycin administration, the myeloid-specific deletion of Atf6α altered pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. Further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.This article is protected by
Teague, C;Picone, J;Wright, W;Browne, C;Silva, G;Futamura, R;Minier-Toribio, A;Estill, M;Ramakrishnan, A;Martinez-Rivera, F;Godino, A;Parise, E;Schmidt, K;Pulido, N;Lorsch, Z;Kim, J;Shen, L;Neve, R;Dong, Y;Nestler, E;Hamilton, P;
| DOI: 10.1016/j.biopsych.2022.07.022
Background Over the course of chronic drug use, brain transcriptional neuroadaptation are thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within mouse NAc. Methods To query the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified CRISPR/dCas9 constructs, capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. Results We observe that CREB binding to the Zfp189 promoter increases Zfp189 expression and diminishes the reinforcing responses to cocaine. We show further that NAc Zfp189 expression is increased within D1 medium spiny neurons (MSNs) in response to acute cocaine, but increased in both D1 and D2 MSNs in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiates electrophysiological activity of D1 and D2 MSNs - recapitulating the known effect of CREB on these neurons. Lastly, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. Conclusions Together, these findings point to the CREB-Zfp189 interaction within NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.
Garcia-Alonso, L;Lorenzi, V;Mazzeo, CI;Alves-Lopes, JP;Roberts, K;Sancho-Serra, C;Engelbert, J;Marečková, M;Gruhn, WH;Botting, RA;Li, T;Crespo, B;van Dongen, S;Kiselev, VY;Prigmore, E;Herbert, M;Moffett, A;Chédotal, A;Bayraktar, OA;Surani, A;Haniffa, M;Vento-Tormo, R;
PMID: 35794482 | DOI: 10.1038/s41586-022-04918-4
Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries1. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal-mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15+ and TREM2+ fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.
The Journal of clinical investigation
Pan, Y;Cao, S;Tang, J;Arroyo, JP;Terker, AS;Wang, Y;Niu, A;Fan, X;Wang, S;Zhang, Y;Jiang, M;Wasserman, DH;Zhang, MZ;Harris, RC;
PMID: 35499079 | DOI: 10.1172/JCI152391
Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.
Nespoli E, Rizzo F, Boeckers T, Schulze U, Hengerer B.
PMID: 29698507 | DOI: 10.1371/journal.pone.0196515
Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette's syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic-like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype.
Brain Struct Funct. 2019 Jan 2.
Yu Q, Liu YZ, Zhu YB, Wang YY, Li Q, Yin DM.
PMID: 30604007 | DOI: 10.1007/s00429-018-01824-2
The D2 dopamine receptor (Drd2) is implicated in several brain disorders such as schizophrenia, Parkinson's disease, and drug addiction. Drd2 is also the primary target of both antipsychotics and Parkinson's disease medications. Although the expression pattern of Drd2 is relatively well known in mouse brain, the temporal and spatial distribution of Drd2 is lesser clear in rat brain due to the lack of Drd2 reporter rat lines. Here, we used CRISPR/Cas9 techniques to generate two knockin rat lines: Drd2::Cre and Rosa26::loxp-stop-loxp-tdTomato. By crossing these two lines, we produced Drd2 reporter rats expressing the fluorescence protein tdTomato under the control of the endogenous Drd2 promoter. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Drd2 in adult and postnatal rat forebrain. Strikingly, the Drd2 expression pattern differs between Drd2 reporter rats and Drd2 reporter mice generated by BAC transgene in prefrontal cortex and hippocampus. These results provide fundamental information needed for the study of Drd2 function in rat forebrain. The Drd2::Cre rats generated here may represent a useful tool to study the function of neuronal populations expressing Drd2.
