Reverse engineering the lordosis behavior circuit

Reverse engineering takes the facts we know about a device or a process and reasons backwards to infer the principles underlying the structure–function relations. The goal of this review is to apply this approach to a well-studied hormone-controlled behavior, namely the reproductive stance of female rodents, lordosis. We first provide a brief overview on the considerable amount of progress in the analysis of female reproductive behavior. Then, we propose an analysis of the mechanisms of this behavior from a reverse-engineering perspective with the goal of generating novel hypotheses about the properties of the circuitry elements. In particular, the previously proposed neuronal circuit modules, feedback signals, and genomic mechanisms are considered to make predictions in this manner. The lordosis behavior itself appears to proceed ballistically once initiated, but negative and positive hormonal feedback relations are evident in its endocrine controls. Both rapid membrane-initiated and slow genomic hormone effects contribute to the behavior\u27s control. We propose that the value of the reverse-engineering approach is based on its ability to provide testable, mechanistic hypotheses that do not emerge from either traditional evolutionary or simple reductionistic perspectives, and several are proposed in this review. These novel hypotheses may generalize to brain functions beyond female reproductive behavior. In this way, the reverse-engineering perspective can further develop our conceptual frameworks for behavioral and systems neuroscience

Chromatin remodeling and control of cell proliferation by progestins via cross talk of progesterone receptor with the estrogen receptors and kinase signaling pathways

Transcription from the mouse mammary tumor virus (MMTV) promoter can be induced by glucocorticoids or progestins. Progesterone treatment of cultured cells carrying an integrated single copy of an MMTV transgene leads to recruitment of progesterone receptor (PR), SWI/SNF, and SNF2h-related complexes to MMTV promoter. Recruitment is accompanied by selective displacement of histones H2A and H2B from the nucleosome B. In nucleosomes assembled on promoter sequences, SWI/SNF displaces histones H2A and H2B from MMTV nucleosome B, but not from other MMTV nucleosomes or from an rDNA promoter nucleosome. Thus, the outcome of nucleosome remodeling by purified SWI/SNF depends on the DNA sequence. On the other hand, 5 min after hormone treatment, the cytoplasmic signaling cascade Src/Ras/Erk is activated via an interaction of PR with the estrogen receptor, which activates Src. As a consequence of Erk activation PR is phosphorylated, Msk1 is activated, and a ternary complex PR-Erk-Msk1 is recruited to MMTV nucleosome B. Msk1 phosphorylates H3 at serine 10, which is followed by acetylation at lysine 14, displacement of HP1gamma, and recruitment of Brg1, PCAF, and RNA polymerase II. Blocking Erk activation or Msk1 activity prevents induction of the MMTV transgene. Thus, the rapid nongenomic effects of progestins are essential for their transcriptional effects on certain progestin target genes. In rat endometrial stromal cells, picomolar concentrations of progestins trigger the cross talk of PR with ERbeta that activates the Erk and Akt kinase pathways leading to cell proliferation in the absence of direct transcriptional effects of the ligand-activated PR. Thus, depending on the cellular context rapid kinase activation and transcriptional effect play different roles in the physiological response to progestins.Fil: Vicent, Guillermo P.. Universitat Pompeu Fabra; EspañaFil: Ballare, Cecilia. Universitat Pompeu Fabra; EspañaFil: Zaurin, Roser. Universitat Pompeu Fabra; EspañaFil: Saragueta, Patricia Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Beato, Miguel. Universitat Pompeu Fabra; Españ

CNS-Specific Ablation of Steroidogenic Factor 1 Results in Impaired Female Reproductive Function

The ventromedial hypothalamic nucleus (VMH) regulates a variety of homeostatic processes including female sexual behavior and reproduction. In the current study, we assessed the roles of steroidogenic factor 1 (SF-1) on reproductive function in the VMH using central nervous system-specific SF-1 knockout (SF-1 KOnCre;F/−) mice. Here we show that SF-1 KOnCre;F/− females exhibited marked impairment in female reproduction. Although male mice appeared to be normal in all aspects studied, including sexual behavior, SF-1 KOnCre;F/− females showed infertility or subfertility. Although adult SF-1 KOnCre;F/− females showed decreased or lacked corpora lutea, exogenous administration of gonadotropins induced the formation of multiple corpora lutea and induced normal ovulation, demonstrating that the ovaries are functionally intact. In addition, SF-1 KOnCre;F/− females stimulated with a synthetic GnRH agonist after priming exhibited markedly reduced LH secretion compared with wild-type littermates, arguing that disorganization in and around the VMH caused by SF-1 ablation interferes with the GnRH priming process or gonadotrope LH capacity. Furthermore, the SF-1 KOnCre;F/− females primed with estrogen benzoate and progesterone failed to induce steroid receptors around the VMH, consistent with impaired lordosis behavior in the SF-1 KOnCre;F/− females. Collectively, our results highlight that SF-1 in the VMH plays crucial roles in regulation of female reproductive function, presumably by organizing a precise neuronal connection and communication in and around the VMH