Developmental neurotoxicity of MDMA. A systematic literature review summarized in a putative adverse outcome pathway

The increasing use of illegal drugs by pregnant women causes a public health concern because it is associated with health risks for mothers and their developing children. One of such drugs is MDMA (3,4-methylenedioxymethamphetamine) or ecstasy due to its high consumption in relevant age and sex groups and its adverse effects on human and rodent developing brains. To Journal Pre-proof 2 thoroughly review the current knowledge on the developmentally neurotoxic potential of MDMA we systematically collected and summarized articles investigating developmental neurotoxicity (DNT) of MDMA in humans and animals in in vivo and in vitro. In addition, we summarized the findings in a putative adverse outcome pathway (AOP). From an initial 299 articles retrieved from the bibliographic databases Web of Science, PubMed and DART, we selected 39 articles according to inclusion/exclusion criteria for data collection after title/abstract and full text screening. Of these 3 where epidemiological studies, 34 where in vivo studies in mice and rats and 2 were in vitro studies. The three epidemiological studies reported from the same longitudinal study and suggested that MDMA exposure during pregnancy impairs neuromotor function in infants. In rat, postnatal exposure towards MDMA also caused locomotor deficits as well as impaired spatial learning that might be associated with decreased serotonin levels in the hippocampus. In vitro MDMA caused cytotoxicity at high concentrations and effects on the serotonergic and neuritogenic alterations at lower concentrations which are in line with some of the in vivo alterations observed. Considering the adverse outcomes of developmental MDMA described in humans and in rodents we summarized the first putative AOP on developmental compound exposure leading to impaired neuromotor function in children. For generation of this AOP, MDMA exposure was taken as a model compound. In addition, we hypothesized a second AOP involving developmental disturbance of the dopaminergic system. However, further in vitro mechanistic studies are needed to understand the molecular initiating event(s) (MIE) triggering the downstream cascades and obtain consistent evidences causally linking the adverse outcome to effects at the cellular, organ and organism level

Agency Rescues Competition for Credit Assignment Among Predictive Cues from Adverse Learning Conditions

A fundamental assumption of learning theories is that the credit assigned to predictive cues is not simply determined by their probability of reinforcement, but by their ability to compete with other cues present during learning. This assumption has guided behavioral and neural science research for decades, and tremendous empirical and theoretical advances have been made identifying the mechanisms of cue competition. However, when learning conditions are not optimal (e.g., when training is massed), cue competition is attenuated. This failure of the learning system exposes the individual’s vulnerability to form spurious associations in the real world. Here, we uncover that cue competition in rats can be rescued when conditions are suboptimal provided that the individual has agency over the learning experience. Our findings reveal a new effect of agency over learning on credit assignment among predictive cues, and open new avenues of investigation into the underlying mechanisms

Time-dependent phenotypical changes of microglia drive alterations in hippocampal synaptic transmission in acute slices

It is widely acknowledged that microglia actively regulate synaptic function in the brain. Remarkably, much of our understanding regarding the role of microglia in synaptic regulation is derived from studies in acute brain slices. However, it is still uncertain to what extent the preparation and maintenance of acute slices can influence microglial function and whether microglial changes may affect synaptic transmission. In this study, we examined the impact of acute slice resting time on hippocampal CA1 microglia, by assessing morphological and functional parameters at two distinct time intervals. We report that after 4 h from slicing microglia undergo morphological, functional, and transcriptional changes, including a decrease in the number of branches and in their movement speed. Furthermore, microglia acquire a reactive phenotype, characterized by increased amplitude of outward rectifying K+ currents, increased expression of the pro-inflammatory cytokine Tnfα and altered expression of the microglial receptors Cx3cr1 and P2y12r. We also examined time-dependent changes of excitatory synaptic transmission in CA1 pyramidal neurons from acute hippocampal slices, reporting time-dependent decrease in both amplitude and frequency of postsynaptic currents (sEPSCs), along with a decrease in spine density. Noticeably, sEPSCs amplitude decrease was absent in slices prepared from PLX5622 microglia-depleted mice, suggesting that this time-dependent effect on synaptic transmission is microglia-dependent. Our findings highlight possible causal relation between microglia phenotypic changes in the hours following slice preparation and concomitant synaptic changes, pointing to the mechanisms of acute synaptic modulation, whose understanding is crucial for unraveling microglia-neurons interplay in nature. Furthermore, they emphasize the potential issues associated with experimental time windows in ex vivo samples

The 60 pc Environment of FRB 20180916B

Fast Radio Burst FRB 20180916B in its host galaxy SDSS J015800.28+654253.0 at 149 Mpc is by far the closest-known FRB with a robust host galaxy association. The source also exhibits a 16.35-day period in its bursting. Here we present optical and infrared imaging as well as integral field spectroscopy observations of FRB 20180916B with the WFC3 camera on the Hubble Space Telescope and the MEGARA spectrograph on the 10.4-m Gran Telescopio Canarias. The 60-90 milliarcsecond (mas) resolution of the Hubble imaging, along with the previous 2.3-mas localization of FRB 20180916B, allow us to probe its environment with a 30-60 pc resolution. We constrain any point-like star-formation or HII region at the location of FRB 20180916B to have an H$\alpha$ luminosity $L_\mathrm{H\alpha} \lesssim 10^{37}\,\mathrm{erg\,s^{-1}}$ and, correspondingly, constrain the local star-formation rate to be $\lesssim10^{-4}\,\mathrm{M_\odot\,yr^{-1}}$. The constraint on H$\alpha$ suggests that possible stellar companions to FRB 20180916B should be of a cooler, less massive spectral type than O6V. FRB 20180916B is 250 pc away (in projected distance) from the brightest pixel of the nearest young stellar clump, which is $\sim380$\,pc in size (full-width at half maximum). With the typical projected velocities of pulsars, magnetars, or neutron stars in binaries (60-750 km s$^{-1}$), FRB 20180916B would need 800 kyr to 7 Myr to traverse the observed distance from its presumed birth site. This timescale is inconsistent with the active ages of magnetars ($\lesssim10$ kyr). Rather, the inferred age and observed separation are compatible with the ages of high-mass X-ray binaries and gamma-ray binaries, and their separations from the nearest OB associations.Comment: Updated version: Updated Figure 2. 16 pages, 4 figures, 1 table. Published in ApJ Letters. Comments welcom

Time-dependent phenotypical changes of microglia drive alterations in hippocampal synaptic transmission in acute slices

It is widely acknowledged that microglia actively regulate synaptic function in the brain. Remarkably, much of our understanding regarding the role of microglia in synaptic regulation is derived from studies in acute brain slices. However, it is still uncertain to what extent the preparation and maintenance of acute slices can influence microglial function and whether microglial changes may affect synaptic transmission. In this study, we examined the impact of acute slice resting time on hippocampal CA1 microglia, by assessing morphological and functional parameters at two distinct time intervals. We report that after 4 h from slicing microglia undergo morphological, functional, and transcriptional changes, including a decrease in the number of branches and in their movement speed. Furthermore, microglia acquire a reactive phenotype, characterized by increased amplitude of outward rectifying K+ currents, increased expression of the pro-inflammatory cytokine Tnfα and altered expression of the microglial receptors Cx3cr1 and P2y12r. We also examined time-dependent changes of excitatory synaptic transmission in CA1 pyramidal neurons from acute hippocampal slices, reporting time-dependent decrease in both amplitude and frequency of postsynaptic currents (sEPSCs), along with a decrease in spine density. Noticeably, sEPSCs amplitude decrease was absent in slices prepared from PLX5622 microglia-depleted mice, suggesting that this time-dependent effect on synaptic transmission is microglia-dependent. Our findings highlight possible causal relation between microglia phenotypic changes in the hours following slice preparation and concomitant synaptic changes, pointing to the mechanisms of acute synaptic modulation, whose understanding is crucial for unraveling microglia-neurons interplay in nature. Furthermore, they emphasize the potential issues associated with experimental time windows in ex vivo samples

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses

Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence

We recently introduced an animal model to study incubation of drug craving after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Here we studied the role of the nucleus accumbens (NAc) in this model. We trained rats to self-administer a palatable solution (sucrose+maltodextrin 1%, 6 h/day, 6 days) and methamphetamine (6 h/day, 12 days). We then evaluated relapse to methamphetamine seeking after 1 and 15 days of voluntary abstinence, achieved via a discrete choice procedure between the palatable solution and methamphetamine (14 days). We used RNAscope in-situ hybridization to quantify the co-labeling of the neuronal activity marker Fos, and dopamine Drd1- and Drd2-expressing medium spiny neurons (MSNs) in NAc core and shell during the incubation tests. Next, we determined the effect of pharmacological inactivation of NAc core and shell by either GABAA and GABAB agonists (muscimol+baclofen, 50+50 ng/side), Drd1-Drd2 antagonist (flupenthixol, 10 µg/side) or the selective Drd1 or Drd2 antagonists (SCH39166 1.0 µg/side or raclopride 1.0 µg/side) during the relapse tests. Incubated methamphetamine seeking after voluntary abstinence was associated with a selective increase of Fos expression in the NAc core, but not shell, and Fos was co-labeled with both Drd1- and Drd2-MSNs. NAc core, but not shell, injections of muscimol+baclofen, flupenthixol, SCH39166, and raclopride reduced methamphetamine seeking after 15 days of abstinence. Together, our results suggest that dopamine transmission through Drd1 and Drd2 in NAc core is critical to the incubation of methamphetamine craving after voluntary abstinence

Thyroid hormones and fear learning but not anxiety are affected in adult apoE transgenic mice exposed postnatally to decabromodiphenyl ether (BDE-209)

10.1016/j.physbeh.2014.05.013Polybrominated diphenyl ethers (PBDEs) are a family of industrial chemicals used as flame retardants. The fully brominated deca-BDE (BDE-209) is the most used and its potential risk for humans is controversial. The ability of PBDEs to target nervous and endocrine systems suggests multiple enduring effects after perinatal exposure. Cognitive and motor behavior alterations have been reported after developmental exposure to PBDEs, including BDE-209, whereas very little work has been carried out on anxiety and emotional learning. We have previously reported long-term effects of postnatal BDE-209 exposure on spatial memory dependent upon apolipoprotein E (apoE) polymorphism and age. ApoE is involved in lipid transport and its different polymorphisms (e2, e3, e4) confer different vulnerabilities to neurodegeneration, cognitive impairment and anxiety. In the present study we assessed the long term effects of early exposure to BDE-209 on anxiety, fear learning and thyroid hormone levels in mice carrying different apoE polymorphisms (e2, e3, e4). BDE-209 (0, 10 and 30. mg/kg) was orally administered on postnatal day 10 (PND 10). At 4 and 12. months of age mice were tested in an open field (OF) and an elevated zero maze (EZM). Fear conditioning and thyroid hormone levels were evaluated in mice at 5-6. months of age. Postnatal exposure to BDE-209 impaired cued fear learning in apoE2 and apoE3 mice. Levels of thyroid hormones were increased in apoE3 female mice exposed to BDE-209. Our findings indicate long lasting effects of BDE-209 on emotional learning and thyroid hormone levels after a single postnatal exposur