A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor α in the Hippocampus and Cortex of Adult Female Rats

Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor α (ERα) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERα expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17β-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15–17 weeks of age, half of each group received a subcutaneous injection of 5 μg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17–19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 μg estradiol benzoate injection, and western blots used to determine ERα expression. A significant decrease in ERα expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERα in the hippocampus.     

Deviance-Related Responses along the Auditory Hierarchy: Combined FFR,MLR and MMN Evidence

The mismatch negativity (MMN) provides a correlate of automatic auditory discrimination in human auditory cortex that is elicited in response to violation of any acoustic regularity. Recently, deviance-related responses were found at much earlier cortical processing stages as reflected by the middle latency response (MLR) of the auditory evoked potential, and even at the level of the auditory brainstem as reflected by the frequency following response (FFR). However, no study has reported deviance-related responses in the FFR, MLR and long latency response (LLR) concurrently in a single recording protocol. Amplitude-modulated (AM) sounds were presented to healthy human participants in a frequency oddball paradigm to investigate deviance-related responses along the auditory hierarchy in the ranges of FFR, MLR and LLR. AM frequency deviants modulated the FFR, the Na and Nb components of the MLR, and the LLR eliciting the MMN. These findings demonstrate that it is possible to elicit deviance-related responses at three different levels (FFR, MLR and LLR) in one single recording protocol, highlight the involvement of the whole auditory hierarchy in deviance detection and have implications for cognitive and clinical auditory neuroscience. Moreover, the present protocol provides a new research tool into clinical neuroscience so that the functional integrity of the auditory novelty system can now be tested as a whole in a range of clinical populations where the MMN was previously shown to be defective.     

Inorganic sulfur oxidizing system in green sulfur bacteria

Green sulfur bacteria use various reduced sulfur compounds such as sulfide, elemental sulfur, and thiosulfate as electron donors for photoautotrophic growth. This article briefly summarizes what is known about the inorganic sulfur oxidizing systems of these bacteria with emphasis on the biochemical aspects. Enzymes that oxidize sulfide in green sulfur bacteria are membrane-bound sulfide-quinone oxidoreductase, periplasmic (sometimes membrane-bound) flavocytochrome c sulfide dehydrogenase, and monomeric flavocytochrome c (SoxF). Some green sulfur bacteria oxidize thiosulfate by the multienzyme system called either the TOMES (thiosulfate oxidizing multi-enzyme system) or Sox (sulfur oxidizing system) composed of the three periplasmic proteins: SoxB, SoxYZ, and SoxAXK with a soluble small molecule cytochrome c as the electron acceptor. The oxidation of sulfide and thiosulfate by these enzymes in vitro is assumed to yield two electrons and result in the transfer of a sulfur atom to persulfides, which are subsequently transformed to elemental sulfur. The elemental sulfur is temporarily stored in the form of globules attached to the extracellular surface of the outer membranes. The oxidation pathway of elemental sulfur to sulfate is currently unclear, although the participation of several proteins including those of the dissimilatory sulfite reductase system etc. is suggested from comparative genomic analyses.     

Design and synthesis of novel 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group as superior AMPA receptor antagonists with good physicochemical properties

We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of alpha-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h (KRP-199), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties, including stability to light and good solubility in aqueous solutions.     

Neurons important for the photoperiodic control of diapause in the bean bug, <Emphasis Type="Italic">Riptortus pedestris</Emphasis>

The morphology and functions of the brain neurons projecting to the retrocerebral complex were examined in terms of photoperiodic control of adult diapause in the bean bug, Riptortus pedestris. Backfills through the nervi corporis cardiaci stained 15-20 pairs of somata in the pars intercerebralis (PI) with contralateral axons, and 14-24 pairs in the pars lateralis (PL) with ipsilateral axons to the nervi corporis cardiaci. In the PL, two clusters of somata, PL-d and PL-v, were found. Forwardfills showed neurons in the PI terminated in the aorta, and those in the PL at the corpus cardiacum, corpus allatum, and aorta. Removal of the PI did not cause effects on diapause incidence both under short-day (12 h:12 h, light:dark) and long-day conditions (16 h:8 h, light:dark) at 25 degrees C. Under short-day conditions, diapause incidence was significantly lower than the controls after removal of the PL. Either removal of PL-d or PL-v did not reduce diapause incidence. It decreased only when both the PL-d and PL-v were ablated. The PI is not indispensable for diapause in R. pedestris, and both PL-d and PL-v neurons are suggested to be involved in photoperiodic inhibition of ovarian development.     

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

The solution structure of the growth factor receptor-bound protein 2 (Grb2) SH2 domain complexed with a high-affinity inhibitor containing a non-phosphorus phosphate mimetic within a macrocyclic platform was determined by nuclear magnetic resonance (NMR) spectroscopy. Unambiguous assignments of the bound inhibitor and intermolecular NOEs between the Grb2 SH2 domain and the inhibitor was accomplished using perdeuterated Grb2 SH2 protein. The well-defined solution structure of the complex was obtained and compared to those by X-ray crystallography. Since the crystal structure of the Grb2 SH2 domain formed a domain-swapped dimer and several inhibitors were bound to a hinge region, there were appreciable differences between the solution and crystal structures. Based on the binding interactions between the inhibitor and the Grb2 SH2 domain in solution, we proposed a design of second-generation inhibitors that could be expected to have higher affinity.