Life without a brain: Neuroradiological and behavioral evidence of neuroplasticity necessary to sustain brain function in the face of severe hydrocephalus.

A two-year old rat, R222, survived a life-time of extreme hydrocephaly affecting the size and organization of its brain. Much of the cortex was severely thinned and replaced by cerebrospinal fluid, yet R222 had normal motor function, could hear, see, smell, and respond to tactile stimulation. The hippocampus was malformed and compressed into the lower hindbrain together with the hypothalamus midbrain and pons, yet R222 showed normal spatial memory as compared to age-matched controls. BOLD MRI was used to study the reorganization of R222's brain function showing global activation to visual, olfactory and tactile stimulation, particularly in the brainstem/cerebellum. The results are discussed in the context of neuroadaptation in the face of severe hydrocephaly and subsequent tissue loss, with an emphasis on what is the "bare minimum" for survival.

Characterization of the ovarian and reproductive abnormalities in prepubertal and adult estrogen non-responsive estrogen receptor alpha knock-in (ENERKI) mice.

Estrogen non-responsive estrogen receptor alpha (ERalpha) knock-in (ENERKI) mice have a mutation (glycine 525 to leucine, G525L) in the ligand-binding domain of ERalpha. The mutant ERalpha protein has a significantly lower affinity and response to endogenous estrogens, while not altering growth factor activated ligand-independent pathways. ENERKI females demonstrated signs of early follicle development as determined by a significant increase in antral follicle formation by 20 days of age. Adult ENERKI females were infertile, had hemorrhagic ovarian follicular cysts, and failed to develop corpora lutea in response to a superovulation regimen. These results illustrate the importance of ERalpha ligand-induced signaling for ovarian development and for estrogen feedback on the hypothalamus and pituitary. Although ERalpha ligand-induced signaling by endogenous estrogens is lost in ENERKI females, the ERalpha selective agonist propyl pyrazole triol (PPT), a synthetic nonsteroidal compound, is still able to activate G525L ERalphain vivo to increase uterine weight. To test whether PPT could restore ligand-dependent receptor activation, ENERKI females were treated with PPT and evaluated for spontaneous ovulation, ovarian hemorrhagic cysts, and LH serum levels. Daily PPT treatments beginning on day 4 of life prevented formation of ovarian hemorrhagic cysts in adult ENERKI animals. In accordance with this result, preputial gland weight and LH levels were also lowered in these animals, indicating PPT treatments most likely led to restoration of ERalpha negative feedback of the hypothalamic-pituitary axis.

Stem cell biology in the lung and lung cancers: using pulmonary context and classic approaches.

Classic stem cell biology approaches tailored specifically with lung biology in mind are needed to bring the field of lung stem cell biology up to speed with that in other tissues. The infrequent cellular turnover, the diversity of cell types, and the necessity of daily cell function in this organ must be considered in stem cell studies. Previous work has created a base from which to explore transplantation, label retention, and more sophisticated lineage-tracing schemes to identify and characterize stem cell populations in the normal lung. These approaches are also imperative for building on precedents set in other tissues in the exploration of the cancer stem cell hypothesis in lung cancers. Additionally, recent studies provide key leads to further explore the molecular mechanisms that regulate lung homeostasis. Here, we discuss strategies to advance the field of lung stem cell biology with an emphasis on developing new, lung-specific tools.