MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR34c could be a suitable therapy.

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulingrowth factor 2 (Igf2) and downregulation of insulingrowth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinctioninduced IGF2/IGFBP7 signalling promotes the survival of 17-19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.

Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ‐oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD‐related pathology that should be investigated further.

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Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB 1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/ Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.

Background: Ectopic pregnancy is still a global problem for women of reproductive age with increasing burden of the disease and increasing mortality especially for women living developing world like Africa. In Ghana studies evaluating the burden of ectopic pregnancy have been conducted in major centres like Korle-Bu and KATH but few in other centres. This study tends to evaluate the prevalence, clinical presentation and finding of ectopic pregnancy in a referral hospital in the Volta region of Ghana. Methodology: This was a 3 years (2013)(2014)(2015)(2016) retrospective review of all gynaecological admission in the Volta regional hospital. All ectopic pregnancy cases/ record were identified, retrieved and information on the socio-demographics, clinical presentations, intraoperative findings and outcome of surgery were all extracted for analysis. Result: A prevalence of 2.05% (53/2582) was recorded over the study period. 58.5% (31/53) of the women were married and between the age group of 21 -30. 47.2% (25/53) had primary school education. Lower abdominal pain was common in 98.1% (52//53), 69.2% (37/53) had vaginal bleeding while 96.4% (51/53). Fallopian tube pregnancy was seen in 96.2% (51/53) while 3.8% (2/53) were abdominal pregnancy. Tubal rupture and heamoperitoneum were seen in 73.6% (39/53) of the women. 78.4% (40/51) of the fallopian tube pregnancy occurred at the ampulla. All the women in this study were successfully managed with radical surgery. Conclusion: There is still the need to evaluate the prevalence of ectopic pregnancy in the region. Proper education of women of reproductive age and provision of equipment and skills to enable early diagnosis of ectopic pregnancy is very necessary in ensuring less radical and traumatic management with less implication on fertility of women post-surgery.

SummaryIntroductionVulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident‐intruder confrontations to study the brain corticostriatal‐function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB 1 receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures.Aims and methodsThe investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid‐like molecules and changes in the transcriptome.ResultsStressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N‐arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicotinic alpha 6. The cannabinoid agonist WIN55212.2 diminished locomotor activity while the inverse agonist increased the distance travelled in the center of the open field. Upon CB 1 activation, N‐oleoylethanolamide and N‐palmitoylethanolamide, two AEA congeners that do not interact directly with cannabinoid receptors, were enhanced in the striatum. The co‐administration with both cannabinoids induced an up‐regulation of striatal FK506 binding protein 5. The inverse agonist in controls reversed the effects of WIN55212.2 on motor activity. When Rimonabant was injected under stress, the cortical levels of 2‐arachidonoylglycerol were maximum. The agonist and the antagonist influenced the cortical expression of cholinergic receptor nicotinic alpha 6 and serotonin transporter neurotransmitter type 4 in opposite directions, while their co‐administration tended to produce a null effect under stress.ConclusionsThe endocannabinoid system had a direct effect on serotoninergic neurotransmission and glucocorticoid signaling. Cholinergic receptor nicotinic alpha‐6 was shown to be deregulated in response to stress and following synthetic cannabinoid drugs thus could confer vulnerability to cannabis addiction and psychosis. Targeting the receptors of endocannabinoids and endocannabinoid‐like mediators might be a valuable option for treating stress‐related neuropsychiatric symptoms.

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