Neuroanatomical Evidence for a Role of Central Melanocortin-4 Receptors and Oxytocin in the Efferent Control of the Rodent Clitoris and Vagina

IntroductionThe clitoris and the vagina are the main peripheral anatomical structures involved in physiological changes related to sexual arousal and orgasm. Their efferent control and, more particularly, the neurochemical phenotype of these descending neuronal pathways remain largely uncharacterized.AimTo examine if brain neurons involved in the efferent control of the clitoris and the vagina possess melanocortin-4 receptor (MC4-R) and/or contain oxytocin (OT).MethodsNeurons involved in the efferent control of the vagina and clitoris were identified following visualization of pseudorabies virus (PRV) retrograde tracing. PRV was injected into the vagina and clitoris in adult rats in estrous. On the fifth day postinjection, animals were humanely sacrificed, and brains were removed and sectioned, and processed for PRV visualization. The neurochemical phenotype of PRV-positive neurons was identified using double or triple immunocytochemical labeling against PRV, MC4-R, and OT. Double and triple labeling were quantified using confocal laser scanning microscopy.Main Outcome MeasureNeuroanatomical brain distribution, number and percentage of double-labeled PRV/MC4-R and PRV-/OT-positive neurons, and triple PRV-/MC4-R-/OT-labeled neurons.ResultsThe majority of PRV immunopositive neurons which also expressed immunoreactivity for MC4-R were located in the paraventricular and arcuate nuclei of the hypothalamus. The majority of PRV positive neurons which were immunoreactive (IR) for OT were located in the paraventricular nucleus (PVN), medial preoptic area (MPOA), and lateral hypothalamus. PRV positive neurons were more likely to be IR for MC4-R than for OT. Scattered triple-labeled PRV/MC4-R/OT neurons were detected in the MPOA and the PVN.ConclusionThese data strongly suggest that MC4-R and, to a less extent, OT are involved in the efferent neuronal control of the clitoris and vagina, and consequently facilitate our understanding of how the melanocortinergic pathway regulates female sexual function. Gelez H, Poirier S, Facchinetti P, Allers KA, Wayman C, Alexandre L, and Giuliano F. Neuroanatomical evidence for a role of central melanocortin-4 receptors and oxytocin in the efferent control of the rodent clitoris and vagina.     

Crosstalk between PDGF and IGF-I receptors in rat liver myofibroblasts: implication for liver fibrogenesis

Insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF) have been identified as significant mitogens for liver myofibroblasts (LMFs), one of the cell populations playing a role in liver fibrogenesis. In the present work, we aimed to elucidate a possible interaction between PDGF receptor (PDGFR) and IGF-I receptor (IGF-IR) signaling in LMFs. Among different rat liver cells, PDGFR alpha- and beta-subunits were mainly expressed in hepatic stellate cells and LMFs, and were upregulated during their in vitro cultivation. In LMFs, PDGF-BB (10 ng/ml) stimulated DNA synthesis approximately two-fold and this effect was similar to that of IGF-I. IGF-I and PDGF-BB differentially affected IGF-IR and PDGFR signaling. High concentrations of IGF-I decreased levels of IGF-IR and IRS-1 and inhibited the expression and activation of PDGFRalpha. PDGF-BB prevented IGF-I-induced downregulation of the IGF-IR, but did not affect expression of its cognate receptor subunits. Transphosphorylation of PDGFR and IGF-IR was not observed. PDGF effectively activated terminal MAP kinases, PI3 kinase and Akt kinase, whereas IGF-I demonstrated weaker effects. PLCgamma(1) was phosphorylated only in response to PDGF, but not to IGF-I. In rat LMFs, blockade of the IGF-IR via inhibition of the IGF-IR kinase completely abrogated IGF- and PDGF-induced mitogenesis and the ability of PDGF to phosphorylate PLCgamma(1). In conclusion, the presented data demonstrate that the PDGFR signaling requires a functional IGF-IR and that PDGF-BB stabilizes the IGF-IR function through preventing the IGF-I-induced downregulation of the IGF-IR. These interactions might be relevant in vivo for the fibroproliferative response during liver injury.     

Yeast coexpression of human papillomavirus types 6 and 16 capsid proteins

The L1 and L2 capsid proteins of animal and human papillomaviruses (HPVs) can self-assemble into virus-like particles (VLPs) that closely resemble native virions. The use of different animal models shows that VLPs can be very efficient at inducing a protective immune response. However, studies with infectious HPV virions and VLPs of different HPV types indicate that the immune response is predominantly type-specific. We have generated a diploid yeast strain that coexpresses the L1 and L2 capsid proteins of both HPV-6b and HPV-16, and we have purified fully assembled VLPs banding in a cesium chloride gradient at the expected density of 1.29-1.3 mg/ml. Experimental evidence strongly indicated that the four proteins coassembled into VLPs. Western blot analysis, using anti-HPV-6 and anti-HPV-16 L1-specific monoclonal antibodies and type-specific L2 antisera, demonstrated that all four proteins copurified. Most importantly, immunoprecipitation experiments, carried out using type-specific anti-L1 monoclonals and either total yeast cell extracts or purified VLPs, confirmed the interaction and the formation of covalent disulfide bonds between the two L1 proteins. Finally, HPV-6/16 VLPs administered to mice induced conformational antibodies against both L1 protein types. These results suggest that coexpression of different capsid proteins may provide new tools for the induction of antibodies directed against multiple HPV types.     

Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA‐binding protein 43 inclusions) in missense progranulin mutation Cys139Arg

Null mutations in progranulin gene (GRN) reduce the progranulin production resulting in haploinsufficiency and are tightly associated with tau‐negative frontotemporal lobar degeneration with TAR DNA‐binding protein 43‐positive inclusions (FTLD‐TDP). Missense mutations of GRN were also identified, but their effects are not completely clear, in particular unanswered is the question of what neuropathology they elicit, also considering that their occurrence has been reported in patients with typical clinical features of Alzheimer disease. They describe two fraternal twins carrying the missense GRN Cys139Arg mutation affected by late‐onset dementia and we report the neuropathological study of one of them. Both patients were examined by neuroimaging, neuropsychological assessment and genetic analysis of GRN and other genes associated with dementia. The brain of one was obtained at autopsy and examined neuropathologically. One sister presented clinical and MRI features leading to the diagnosis of Alzheimer disease. The other underwent autopsy and the brain showed neuropathological hallmarks of Alzheimer disease with abundant Aβ‐amyloid deposition and Braak stage V of neurofibrillary pathology, in the absence of the hallmark lesions of FTLD‐TDP. Their findings may contribute to better clarify the role of progranulin in neurodegenerative diseases indicating that some GRN mutations, in particular missense ones, may act as strong risk factor for Alzheimer disease rather than induce FTLD‐TDP.     

Phylogenetic analysis of the gag region encoding the matrix protein of small ruminant lentiviruses: comparative analysis and molecular epidemiological applications

Little sequence information exists on the matrix-protein (MA) encoding region of small ruminant lentiviruses (SRLV). Fifty-two novel sequences were established and permitted a first phylogenetic analysis of this region of the SRLV genome. The variability of the MA encoding region is higher compared to the gag region encoding the capsid protein and surprisingly close to that reported for the env gene. In contrast to primate lentiviruses, the deduced amino acid sequences of the N- and C-terminal domains of MA are variable. This permitted to pinpoint a basic domain in the N-terminal domain that is conserved in all lentiviruses and likely to play an important functional role. Additionally, a seven amino acid insertion was detected in all MVV strains, which may be used to differentiate CAEV and MVV isolates. A molecular epidemiology analysis based on these sequences indicates that the Italian lentivirus strains are closely related to each other and to the CAEV-CO strain, a prototypic strain isolated three decades ago in the US. This suggests a common origin of the SRLV circulating in the monitored flocks, possibly related to the introduction of infected goats in a negative population. Finally, this study shows that the MA region is suitable for phylogenetic studies and may be applied to monitor SRLV eradication programs.     

Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat

The effects of melanotan-II, a non-specific agonist of melanocortin receptors, on erection and its possible sites of action were investigated in anesthetized rats. Delivered i.v. (0.1, 0.3 and 1 mg/kg) or within the paraventricular nucleus of the hypothalamus (0.1 and 1 microg), melanotan-II exerted a dose-dependent inducer activity on erection by eliciting erectile events and shortening latency of the first erectile event to occur. Erectile events were of higher amplitude in rats treated with melanotan-II i.t. (0.2 microg) delivered at the L6-S1 level than in animals treated with the vehicle i.t. delivered. Erectile responses elicited by cavernous nerve stimulation were increased after i.v. melanotan-II (1 mg/kg), thereby exerting facilitator effect on erection. In contrast, melanotan-II injected within the corpus cavernosum (1 microg) did not display any facilitator activity. To investigate the neural pathways involved in the facilitator effect of melanotan-II, we performed acute spinalization (T8 level) and differential selective nerve transections. Neither spinalization nor bilateral transection of pelvic nerves or dorsal penile nerves impaired facilitator activity of i.v. melanotan-II (1 mg/kg). Conversely, the facilitator effect of melanotan-II was abolished after acute removal of the lumbar paravertebral sympathetic chain. These results lead to the conclusion that central and peripheral melanocortin pathways are recruited by melanotan-II, depending on its route of delivery, to exert both inducer and facilitator activities on erection.     

Functional asymmetry and interhemispheric cooperation in the perception of emotions from facial expressions

The present study used the redundant target paradigm on healthy subjects to investigate functional hemispheric asymmetries and interhemispheric cooperation in the perception of emotions from faces. In Experiment 1 participants responded to checkerboards presented either unilaterally to the left (LVF) or right visual half field (RVF), or simultaneously to both hemifields (BVF), while performing a pointing task for the control of eye movements. As previously reported (Miniussi et al. in J Cogn Neurosci 10:216-230, 1998), redundant stimulation led to shorter latencies for stimulus detection (bilateral gain or redundant target effect, RTE) that exceeded the limit for a probabilistic interpretation, thereby validating the pointing procedure and supporting interhemispheric cooperation. In Experiment 2 the same pointing procedure was used in a go/no-go task requiring subjects to respond when seeing a target emotional expression (happy or fearful, counterbalanced between blocks). Faster reaction times to unilateral LVF than RVF emotions, regardless of valence, indicate that the perception of positive and negative emotional faces is lateralized toward the right hemisphere. Simultaneous presentation of two congruent emotional faces, either happy or fearful, produced an RTE that cannot be explained by probability summation and suggests interhemispheric cooperation and neural summation. No such effect was present with BVF incongruent facial expressions. In Experiment 3 we studied whether the RTE for emotional faces depends on the physical identity between BVF stimuli, and we set a second BVF congruent condition in which there was only emotional but not physical or gender identity between stimuli (i.e. two different faces expressing the same emotion). The RTE and interhemispheric cooperation were present also in this second BVF congruent condition. This shows that emotional congruency is the sufficient condition for the RTE to take place in the intact brain and that the cerebral hemispheres can interact in spite of physical differences between stimuli.     

Penetrating Aortic Ulcer and Intramural Hematoma

CardioVascular and Interventional Radiology - Acute aortic syndromes include a variety of overlapping clinical and anatomic diseases. Penetrating aortic ulcer (PAU), intramural hematoma (IMH) and...     

Network characteristics in benign epilepsy with centro-temporal spikes patients indicating defective connectivity during spindle sleep: A partial directed coherence study of EEG signals

Objective

To investigate the changes in EEG connectivity in children with the typical presentation of benign epilepsy with centro-temporal spikes (BECTS).