Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor.

Progestogens [progesterone (P(4)) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P(4) metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P(4), in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP's role and mechanisms to enhance affective and motivated processes is essential.

A screen for dominant modifiers of the irreC-rst cell death phenotype in the developing Drosophila retina.

Programmed cell death (PCD) in the Drosophila retina requires activity of the irregular chiasmC-roughest (irreC-rst) gene. Loss-of-function mutations in irreC-rst block PCD during retinal development and lead to a rough eye phenotype in the adult. To identify genes that interact with irreC-rst and may be involved in PCD, we conducted a genetic screen for dominant enhancers and suppressors of the adult rough eye phenotype. We screened 150,000 mutagenized flies and recovered 170 dominant modifiers that localized primarily to the second and third chromosomes. At least two allelic groups correspond to previously identified death regulators, Delta and dRas1. Examination of retinae from homozygous viable mutants indicated two major phenotypic classes. One class exhibited pleiotropic defects while the other class exhibited defects specific to the cell population that normally undergoes PCD.

Programmed cell death and patterning in Drosophila.

Selective cell death provides developing tissues with the means to precisely sculpt emerging structures. By imposing patterned cell death across a tissue, boundaries can be created and tightened. As such, programmed cell death is becoming recognized as a major mechanism for patterning of a variety of complex structures. Typically, cell types are initially organized into a fairly loose pattern; selective death then removes cells between pattern elements to create correct structures. In this review, we examine the role of selective cell death across the course of Drosophila development, including the tightening of embryonic segmental boundaries, head maturation, refining adult structures such as the eye and the wing, and the ability of cell death to correct for pattern defects introduced by gene mutation. We also review what is currently known of the relationship between signals at the cell surface that are responsible for tissue patterning and the basal cell death machinery, an issue that remains poorly understood.

A widespread and early requirement for a novel Notch function during Drosophila embryogenesis.

The Notch pathway plays a key role in the formation of many tissues and cell types in Metazoans. We recently showed that Notch acts in two pathways to determine muscle precursor fates. The first is the "standard" Notch pathway, in which Delta activates the Notch receptor, which then translocates into the nucleus in conjunction with Su(H) to reprogram transcription patterns and bring about changes in cell fates. The second pathway is poorly defined, but known to be independent of the ligands and downstream effectors of the standard pathway. The standard pathway is required in many different developmental contexts and we wondered if there was also a general requirement for the novel pathway. Here we show that the novel Notch pathway is required for the development of each of five examined cell types. These results indicate that the novel pathway is a widespread and fundamental component of Notch function. We further show that both Notch pathways operate in the differentiation of the same cell types. In such cases, the novel pathway acts first and appears to set up or limit the size of equivalence groups. The standard pathway then acts within the equivalence groups to limit individual cell fates.

The pore-forming and cytoplasmic domains of the neurogenic gene product, BIG BRAIN, are conserved between Drosophila virilis and Drosophila melanogaster.

The Drosophila BIG BRAIN (BIB) protein functions critically in the determination of neuroblasts in the embryonic ectoderm and many other cell types. BIB is a member of the MIP family of transmembrane channel proteins. The conserved channel domain of BIB is flanked by amino- and carboxy-terminal cytoplasmic domains of unique sequence, which comprise over two-thirds of the protein. To determine whether the cytoplasmic domains of BIB are important for BIB function, we have cloned and sequenced the bib gene of D. virilis and compared it with that of D. melanogaster. Here we report that the channel domain and both cytoplasmic domains are highly conserved between the two species. The conservation of the cytoplasmic domains indicates that they are critical to BIB function. bib transcripts are found in similar patterns in both species, indicating that the developmental function(s) of BIB have also been conserved.

Evidence for a novel Notch pathway required for muscle precursor selection in Drosophila.

The Notch pathway mediates cell fate choice in many species and developmental contexts. In the Drosophila mesoderm, phenotypic differences were observed when different components of the pathway were defective. To determine if these differences reflect variations in the signaling pathway or in the persistence of wild-type maternal products, we examined muscle precursors in embryos that lacked both maternally- and zygotically-derived gene products, called holonull embryos. Most holonull neurogenic embryos have the same number and arrangement of extra muscle precursors, but in Notch holonull embryos many additional cells also become muscle precursors. Thus Notch is active in cells where its known ligands and downstream effectors are not. These results indicate that Notch acts in two pathways to determine cell fates in mesoderm: the Delta-to-Notch-to-Suppressor of Hairless-to-Enhancer of split signaling pathway previously defined, and a second pathway that acts independently.