Sex differences in proliferation and attrition of pubertally born cells in the rat posterior dorsal medial amygdala.

The rodent posterodorsal medial amygdala (MePD) evaluates and assigns valence to social sensory stimuli. The perception of social stimuli evolves during puberty, when the focus of social interactions shifts from kin to peers. Using the cell birthdate marker bromo-deoxyuridine (BrdU), we previously discovered that more pubertally born cells are added to the rat MePD in males than females. Here we addressed several questions that remained unanswered by our previous work. First, to determine whether there are sex differences in cell proliferation within the MePD, we examined BrdU-immunoreactive (-ir) cells at 2 and 4 h following BrdU administration on postnatal day 30 (P30). The density of BrdU-ir cells was greater in males than in females, indicating greater proliferation in males. Proliferation was substantiated by double-label immunohistochemistry showing that MePD BrdU-ir cells colocalize proliferating cell nuclear antigen, but not the cell death marker Caspase3. We next studied longer time points (2-21 days) following BrdU administration on P30 and found that the rate of cell attrition is higher in males. Finally, triple-label immunohistochemistry of P30-born MePD cells revealed that some of these cells differentiate into neurons or astrocytes within three weeks of cell birth, with no discernable sex differences. The demonstration of pubertal neuro- and glio-genesis in the MePD of male and female rats adds a new dimension to developmental plasticity of the MePD that may contribute to pubertal changes in the perception of social stimuli in both sexes.

Pubertal Testosterone Programs Adult Behavioral Adaptations to Sexual Experience through Infralimbic Cortex ΔFosB.

Acquisition of social proficiency entails behavioral adaptations to social experience, including both behavioral flexibility and inhibition of behaviors inappropriate in specific social contexts. Here, we investigated the contributions of testosterone and ΔFosB, a transcription factor linked to experience-dependent neural plasticity, to the adolescent maturation of social proficiency in male-female social interactions. To determine whether pubertal testosterone organizes circuits underlying social proficiency, we first compared behavioral adaptations to sexual experience in male Syrian hamsters that were deprived of testosterone during puberty (prepubertal castration; NoT@P) to those of males deprived of testosterone for an equivalent period of time in adulthood (postpubertal castration; T@P). All males were given testosterone replacement in adulthood for two weeks before sexual behavior testing, where males were allowed to interact with a receptive female once per week for five consecutive weeks. T@P males showed the expected decrease in ectopic (mis-directed) mounts with sexual experience, whereas NoT@P males did not. In addition, sexual experience induced FosB gene products expression in the infralimbic cortex (IL) in T@P, but not NoT@P, males. Overexpression of ΔFosB via an adeno-associated viral (AAV) vector in the IL of NoT@P males prior to sexual behavior testing was sufficient to produce a behavioral phenotype similar to that of experienced T@P males. Finally, overexpression of ΔFosB in IL increased the density of immature spines on IL dendrites. Our findings provide evidence that social proficiency acquired through sexual experience is organized by pubertal testosterone through the regulation of ΔFosB in the IL, possibly through increasing synaptic lability.

Observations regarding failure of cerebrospinal fluid shunts early after implantation.

Despite advances in cerebrospinal fluid (CSF) diversionary techniques, shunt failure due to infection or malfunction remains a persistent problem in hydrocephalus care. The aim of this study was to evaluate the independent predictors of early shunt survival after implantation in a large cohort of patients. The authors retrospectively reviewed the records of all patients who had undergone shunt implantation procedures at their institution during an 8-year period. They analyzed the independent predictors of shunt survival in 116 failed shunt placement procedures (infection or malfunction) by performing univariate and multivariate factorial analyses. Analysis of the 116 failed shunts in the 396 new shunt placement procedures performed revealed that age was a significant independent predictor of shunt survival time in failures due to malfunction (p < 0.05) as well as infection (p < 0.05). In addition, a significant relationship between patient race and shunt survival was also found. As suggested by data in other studies focused on this outcome, early shunt failure occurs sooner in younger patients. Interestingly, this study is one of few whose data have revealed that race may affect shunt failure after implantation. Specifically, shunt failure due to infection resulted in significantly shorter shunt survival time in non-white patients compared with that in white patients. Among the shunts that failed due to malfunction, however, white patients had shorter shunt survival times.

The E box motif CAGGTG enhances somatic hypermutation without enhancing transcription.

The frequency of somatic hypermutations of an Ig kappa transgene with an artificial test insert, RS, is at least 4-fold higher than that of three related transgenes. The four transgenes differ only in the sequence of a 96 bp insert within the variable region. RS is hypermutable over the total 625 nucleotides of the variable/joining region. The RS insert contains two CAGGTG sequences, potential binding sites for basic helix-loop-helix proteins. Changing CAGGTG to AAGGTG reduces the mutability to that of the non-RS transgenes without altering the mutation pattern. The CAGGTG motif enhances somatic hypermutation without enhancing transcription. A DNA probe containing the two CAGGTG sites, but not AAGGTG, binds E47 and gives rise to two specific EMSA bands with nuclear extracts from mutating cells. Possible actions of this enhancer of somatic hypermutation are discussed.

Effects of sequence and structure on the hypermutability of immunoglobulin genes.

Somatic hypermutation (SHM) is investigated in related immunoglobulin transgenes that differ in a short artificial sequence designed to vary the content of hotspot motifs and the potential to form RNA or DNA secondary structures. Mutability depends on hotspots, not secondary structure. Hotspot motifs predict about 50% of the mutations; the rest are in neutral and coldspots. Clusters of mutations and the sequential addition of mutations found in cell pedigrees suggest epigenetic attributes of SHM. Sometime in SHM, an essential factor seems to become limiting. Particular error-prone DNA polymerases appear to create mutations in hotspots on the top and bottom DNA strands throughout the target and the SHM process. One transgene is superhypermutable in all regions, suggesting the presence of a cis-element that enhances SHM.