Mating induces pronounced changes in female reproductive behavior, typically including a dramatic reduction in sexual receptivity. In Drosophila, postmating behavioral changes are triggered by sex peptide (SP), a male seminal fluid peptide that acts via a receptor (SPR) expressed in sensory neurons (SPSNs) of the female reproductive tract. Here, we identify second-order neurons that mediate the behavioral changes induced by SP. These SAG neurons receive synaptic input from SPSNs in the abdominal ganglion and project to the dorsal protocerebrum. Silencing SAG neurons renders virgin females unreceptive, whereas activating them increases the receptivity of females that have already mated. Physiological experiments demonstrate that SP downregulates the excitability of the SPSNs, and hence their input onto SAG neurons. These data thus provide a physiological correlate of mating status in the female central nervous system and a key entry point into the brain circuits that control sexual receptivity.

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IntroductionAcute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous subclassifications displaying a wide spectrum of phenotypes. 1,2 The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission. [6][7][8] The tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors, RARs, with the subsequent binding of this complex to the retinoic acid response element (RARE) consensus sequences located in the regulatory regions of retinoid-responsive genes. 9 The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique promyelocytic leukemia (PML)-RAR␣ fusion product that results in the subsequent maturation arrest of these cells at the promyelocyte stage [10][11][12] ; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RAR␣ fusion product, with subsequent maturation of the APL cells. [13][14] Unfortunately, the other AML subtypes as classified by the French-American-British (FAB) classification demonstrate inherent resistance to tRA-mediated differentiation and induction of apoptosis. 15,16 We and others have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN/CD437), which is a potent inducer of apoptosis in a variety of cell types and which displays resistance to tRA-mediated differentiation and apoptosis. [17][18][19][20][21] The mechanistic pathways by which AHPN induces apoptosis in malignant cells are not clearly defined. AHPN binds and transactivates both the RAR␤ and RAR␥ receptors. 22,23 The roles of these retinoid nuclear receptors in AHPN-mediated apoptosis are controversial. While some studies have suggested that binding and transactivation of RAR␥ are essential for AHPN/CD437-mediated apoptosis, 24,25 others have indicated that neither the RARs nor the retinoid X receptors (RXRs) to which AHPN does not bind or transactivate are involved. 20,21,26 bloodjournal.org FromIn the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA. The 3-C...

How do descending inputs from the brain control leg motor circuits to change how an animal walks? Conceptually, descending neurons are thought to function either as command-type neurons, in which a single type of descending neuron exerts a high-level control to elicit a coordinated change in motor output, or through a population coding mechanism, whereby a group of neurons, each with local effects, act in combination to elicit a global motor response. The Drosophila Moonwalker Descending Neurons (MDNs), which alter leg motor circuit dynamics so that the fly walks backwards, exemplify the command-type mechanism. Here, we identify several dozen MDN target neurons within the leg motor circuits, and show that two of them mediate distinct and highly-specific changes in leg muscle activity during backward walking: LBL40 neurons provide the hindleg power stroke during stance phase; LUL130 neurons lift the legs at the end of stance to initiate swing. Through these two effector neurons, MDN directly controls both the stance and swing phases of the backward stepping cycle. These findings suggest that command-type descending neurons can also operate through the distributed control of local motor circuits.

To perform most behaviors, animals must send commands from higher-order processing centers in the brain to premotor circuits that reside in ganglia distinct from the brain, such as the mammalian spinal cord or insect ventral nerve cord. How these circuits are functionally organized to generate the great diversity of animal behavior remains unclear. An important first step in unraveling the organization of premotor circuits is to identify their constituent cell types and create tools to monitor and manipulate these with high specificity to assess their function. This is possible in the tractable ventral nerve cord of the fly. To generate such a toolkit, we used a combinatorial genetic technique (split-GAL4) to create 195 sparse driver lines targeting 198 individual cell types in the ventral nerve cord. These included wing and haltere motoneurons, modulatory neurons, and interneurons. Using a combination of behavioral, developmental, and anatomical analyses, we systematically characterized the cell types targeted in our collection. Taken together, the resources and results presented here form a powerful toolkit for future investigations of neural circuits and connectivity of premotor circuits while linking them to behavioral outputs.

How do descending inputs from the brain control leg motor circuits to change the way an animal walks? Conceptually, descending neurons are thought to function either as command-type neurons, in which a single type of descending neuron exerts a high-level control to elicit a coordinated change in motor output, or through a more distributed population coding mechanism, whereby a group of neurons, each with local effects, act in combination to elicit a global motor response. The Drosophila Moonwalker Descending Neurons (MDNs), which alter leg motor circuit dynamics so that the fly walks backwards, exemplify the command-type mechanism. Here, we identify several dozen MDN target neurons within the leg motor circuits, and show that two of them mediate distinct and highly-specific changes in leg muscle activity during backward walking: LIN156 neurons provide the hindleg power stroke during stance phase; LIN128 neurons lift the legs at the end of stance to initiate swing. Through these two effector neurons, MDN directly controls both the stance and swing phases of the backward stepping cycle. MDN exerts these changes only upon the hindlegs; the fore- and midlegs follow passively through ground contact. These findings suggest that command-type descending neurons can also operate through the distributed control of local motor circuits.

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