Sex differences in behavioral decision-making and the modulation of shared neural circuits

Animals prioritize behaviors according to their physiological needs and reproductive goals, selecting a single behavioral strategy from a repertoire of possible responses to any given stimulus. Biological sex influences this decision-making process in significant ways, differentiating the responses animals choose when faced with stimuli ranging from food to conspecifics. We review here recent work in invertebrate models, including C. elegans, Drosophila, and a variety of insects, mollusks and crustaceans, that has begun to offer intriguing insights into the neural mechanisms underlying the sexual modulation of behavioral decision-making. These findings show that an animal's sex can modulate neural function in surprisingly diverse ways, much like internal physiological variables such as hunger or thirst. In the context of homeostatic behaviors such as feeding, an animal's sex and nutritional status may converge on a common physiological mechanism, the functional modulation of shared sensory circuitry, to influence decision-making. Similarly, considerable evidence suggests that decisions on whether to mate or fight with conspecifics are also mediated through sex-specific neuromodulatory control of nominally shared neural circuits. This work offers a new perspective on how sex differences in behavior emerge, in which the regulated function of shared neural circuitry plays a crucial role. Emerging evidence from vertebrates indicates that this paradigm is likely to extend to more complex nervous systems as well. As men and women differ in their susceptibility to a variety of neuropsychiatric disorders affecting shared behaviors, these findings may ultimately have important implications for human health

Sex-based Differences in C. elegans Responsiveness to Aversive Stimuli

Behavioral differences between sexes are evident across many species. The underlying mechanisms surrounding such differences are not fully elucidated, however, due to the complexities of animal behavior. The nematode Caenorhabditis elegans (C. elegans) is a well-characterized, genetically amenable species with two sexes, hermaphrodites (XX) and males (XO). This makes it an appropriate model system for investigating sex-based behavioral differences. Chemosensation in C. elegans is mediated by exposed ciliated sensory neurons, one of which is ASH. ASH is a polymodal nociceptor that elicits reversal when an animal encounters aversive stimuli. We hypothesized that hermaphrodite and male C. elegans worms respond differently to stimuli detected by ASH such as the bitter tastant quinine, the detergent sodium dodecyl sulfate (SDS), and the heavy metal copper (CuCl2). Wild-type assay-age hermaphrodites and males were picked from a nematode growth media (NGM) plate with E. coli OP50 and kept on an NGM plate without food for 10 minutes prior to assaying. A drop of aversive stimulus was placed in front of a forward-moving animal, and the animal’s response was recorded. A positive response is backwards movement within 4 seconds after contact with the stimulus. Our results reveal a quantifiable difference in how wild-type hermaphrodite and male C. elegans respond to aversive stimuli. Specifically, wild-type males are less responsive than hermaphrodites to quinine, SDS, and CuCl2. Further investigations will be conducted through experiments with C. elegans strains in which hermaphrodites have masculinized, and males have feminized nervous systems or subsets of neurons. Through these experiments, we aim to explore potential sites of difference that lead to these observable differences in responsiveness to aversive stimuli

Multiple doublesex-Related Genes Specify Critical Cell Fates in a C. elegans Male Neural Circuit

In most animal species, males and females exhibit differences in behavior and morphology that relate to their respective roles in reproduction. DM (Doublesex/MAB-3) domain transcription factors are phylogenetically conserved regulators of sexual development. They are thought to establish sexual traits by sex-specifically modifying the activity of general developmental programs. However, there are few examples where the details of these interactions are known, particularly in the nervous system.In this study, we show that two C. elegans DM domain genes, dmd-3 and mab-23, regulate sensory and muscle cell development in a male neural circuit required for mating. Using genetic approaches, we show that in the circuit sensory neurons, dmd-3 and mab-23 establish the correct pattern of dopaminergic (DA) and cholinergic (ACh) fate. We find that the ETS-domain transcription factor gene ast-1, a non-sex-specific, phylogenetically conserved activator of dopamine biosynthesis gene transcription, is broadly expressed in the circuit sensory neuron population. However, dmd-3 and mab-23 repress its activity in most cells, promoting ACh fate instead. A subset of neurons, preferentially exposed to a TGF-beta ligand, escape this repression because signal transduction pathway activity in these cells blocks dmd-3/mab-23 function, allowing DA fate to be established. Through optogenetic and pharmacological approaches, we show that the sensory and muscle cell characteristics controlled by dmd-3 and mab-23 are crucial for circuit function.In the C. elegans male, DM domain genes dmd-3 and mab-23 regulate expression of cell sub-type characteristics that are critical for mating success. In particular, these factors limit the number of DA neurons in the male nervous system by sex-specifically regulating a phylogenetically conserved dopamine biosynthesis gene transcription factor. Homologous interactions between vertebrate counterparts could regulate sex differences in neuron sub-type populations in the brain

Use of complementary nucleobase-containing synthetic polymers to prepare complex self-assembled morphologies in water

YesAmphiphilic nucleobase-containing block copolymers with poly(oligo(ethylene glycol) methyl ether methacrylate) as the hydrophilic block and nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerization and then self-assembled via solvent switch in aqueous solutions. Effects of the common solvent on the resultant morphologies of the adenine (A) and thymine (T) homopolymers, and A/T copolymer blocks and blends were investigated. These studies highlighted that depending on the identity of the common solvent, DMF or DMSO, spherical micelles or bicontinuous micelles were obtained. We propose that this is due to the presence of A–T interactions playing a key role in the morphology and stability of the resultant nanoparticles, which resulted in a distinct system compared to individual adenine or thymine polymers. Finally, the effects of annealing on the self-assemblies were explored. It was found that annealing could lead to better-defined spherical micelles and induce a morphology transition from bicontinuous micelles to onion-like vesicles, which was considered to occur due to a structural rearrangement of complementary nucleobase interactions resulting from the annealing process.European Research Council (ERC), University of Warwick, Engineering and Physical Sciences Research Council (EPSRC), National Science Foundation (U.S.) (NSF

Sex differences in behavioral decision-making and the modulation of shared neural circuits

Abstract Animals prioritize behaviors according to their physiological needs and reproductive goals, selecting a single behavioral strategy from a repertoire of possible responses to any given stimulus. Biological sex influences this decision-making process in significant ways, differentiating the responses animals choose when faced with stimuli ranging from food to conspecifics. We review here recent work in invertebrate models, including C. elegans, Drosophila, and a variety of insects, mollusks and crustaceans, that has begun to offer intriguing insights into the neural mechanisms underlying the sexual modulation of behavioral decision-making. These findings show that an animal's sex can modulate neural function in surprisingly diverse ways, much like internal physiological variables such as hunger or thirst. In the context of homeostatic behaviors such as feeding, an animal's sex and nutritional status may converge on a common physiological mechanism, the functional modulation of shared sensory circuitry, to influence decision-making. Similarly, considerable evidence suggests that decisions on whether to mate or fight with conspecifics are also mediated through sex-specific neuromodulatory control of nominally shared neural circuits. This work offers a new perspective on how sex differences in behavior emerge, in which the regulated function of shared neural circuitry plays a crucial role. Emerging evidence from vertebrates indicates that this paradigm is likely to extend to more complex nervous systems as well. As men and women differ in their susceptibility to a variety of neuropsychiatric disorders affecting shared behaviors, these findings may ultimately have important implications for human health.</p

lep-5: a long noncoding RNA is a novel heterochronic regulator in C. elegans

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2014.A fundamental question in developmental biology is how the temporal aspect of development is controlled. Research in the nematode C. elegans has revealed a set of conserved genetic factors, the so called "heterochronic" genes, that function in a temporal cascade to regulate the temporal identity of a cell and the timing of stage specific events in the worm. In this study, we utilize the morphogenesis of the C. elegans male tail as a unique setting to be able to identify novel heterochronic genes that control late larval development. Through the use of forward genetic screens, we have isolated lep-5, a mutant that disrupts the timing of male tail morphogenesis. We showed that lep-5 controls the timing of tail tip retraction through regulating the temporal expression of dmd-3, a master regulator of tail tip retraction. We confirmed that lep-5 is a novel heterochronic regulator in C. elegans and used epistasis experiments to place lep-5 into the pathway controlling the timing of male tail morphogenesis upstream of known heterochronic genes such as lin-41 and let-7. We found that in addition to regulating tail tip retraction, lep-5 also controls other aspects of the larval to adult transitions such as the cessation of molting. We revealed a role for lep-5 and other members of the heterochronic pathway in regulating the changes in nervous system gene expression and behavior that occur as C. elegans transitions from larva to adult. Finally, we identified the gene disrupted in the mutant as H36L18.2, and found that lep-5 functions not as a protein but instead as a novel long non-coding RNA. Through structure function experiments, we identified portions of the transcript necessary for lep-5 function. This work has identified a novel heterochronic regulator in C. elegans and suggests a new role for long noncoding RNAs in both development and temporal regulation

Sex differences in a C. elegans sensory behavior

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2009.Sex differences in the structure and function of the nervous system exist throughout the animal kingdom. Together with sex-biases in neurological diseases, this highlights the importance of studying how sexual differentiation modifies neural circuits and function. Taking advantage of the unique strengths of the nematode C. elegans, we explore how “neural sex”, the sexual state of a given neuron established by cell-intrinsic sex determination, regulates the function of the “core” neural circuitry composed of neurons common to both sexes. To ask how neural sex influences behavior, we have examined olfaction, well-described in the C. elegans hermaphrodite but previously unstudied in the male. Using a novel assay involving the simultaneous presentation of two attractants, we have observed characteristic and distinct sex differences in olfactory preference behaviors. These sex differences were prominent before sexual maturation and did not require the gonad or germline, suggesting that core neural circuitry itself may be the cellular focus of sexually different shared behavior. To address this directly, we switched the sexual state of subsets of core neurons by cell-type specific expression of sexual regulators. We found that the neural sex of even a single sensory neuron, AWA, can determine the sexual phenotype of olfactory preference, indicating that AWA itself possesses sexually different functional properties. Moreover, at least some of these functional properties arise through sex differences in the expression of the odorant receptor ODR-10, providing a molecular mechanism for the generation of sexually different shared sensory function. This work has revealed a novel pathway for bringing about sex differences in the function of shared neural circuitry, and may shed light on the nature of sexual dimorphisms in the vertebrate nervous system

The Genetic Sex of the Sensory Neuron ADF Confers Pheromone Attraction in C. elegans

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neuroscience Graduate Program, 2017.Sexually dimorphic behaviors are widespread throughout the animal kingdom. Approaches to understand how these differences in behavior arise have focused primarily on the roles of gonadal hormones that infiltrate the nervous system during development to orchestrate sexually dimorphic structural remodeling. But an additional mechanism, controlled by the sex chromosomal content of the nervous system itself, has recently emerged as a contributor to sex differences in behavior. Specifically, the genetic sex of the nervous system is able to autonomously alter functional and structural properties of neural circuits present in both sexes. However, the mechanisms by which this occurs are poorly understood. To better understand how genetic sex modulates shared circuitry to elicit sex differences in behavior, we examined the role of genetic sex in sexually dimorphic attraction to ascaroside sex pheromones in the nematode C. elegans. Previous work demonstrated that hermaphrodite sex pheromone is a complex chemical mixture that can be broadly categorized into two classes of chemicals whose synthesis either requires the enzyme daf-22 (daf-22-dependent) or does not (daf-22-independent). The ascarosides ascr#2, #3, and #8 are daf-22-dependent chemicals and elicit strong attraction in males but weakly repel hermaphrodites. By studying sexually mosaic animals, we discovered that the circuitry eliciting this attraction is present in both sexes but is functionally silent in hermaphrodites. That is, switching the sexual state of shared circuits is sufficient to switch the sexual phenotype of ascaroside attraction behavior. Moreover, we found that sexual state is particularly important in the sensory neuron ADF. Feminizing ADF alone causes a complete loss of male attraction, while masculinizing it is sufficient to generate attraction in hermaphrodites. Consistent with this, ablation of ADF in males eliminates attraction, suggesting that the male state of ADF promotes attraction to ascarosides. Finally, we showed that the inability to detect daf-22-dependent pheromones impairs male mating efficiency. Together, these experiments demonstrate that modulation of sensory function by genetic sex plays a key role in the generation of sexually dimorphic behaviors

Distributed Control of Sex Differences in the Locomotor Behavior of Caenorhabditis elegans

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2010.Coordinated motor behavior requires complex interactions between neuromuscular dynamics and the mechanics of the body. This has led some to propose that adaptive variation in these behaviors may necessitate distributed changes to neural, muscular, and mechanical elements. However, as the mechanistic underpinnings of behavioral variation are poorly understood, there remains limited empirical support for this idea. Here I present evidence that sexual variation in the locomotion of C. elegans arises through the coordinated modification of neural signaling, muscle properties, and body mechanics. I find that the two sexes of C. elegans exhibit characteristic locomotor kinematics, whose development mirrors that of sex differences in body size and geometry. While this suggests that sex differences in the passive mechanics of worms may be sufficient to account for behavioral variation, I also find that targeted sex reversal of the nervous system can enforce opposite sex locomotor frequency in male animals. Interestingly, the production of male-like locomotor frequencies requires that both neurons and muscle are masculine, indicating that muscle properties are also sexually modified. Attempting to define the neural modifications that support sex-specific locomotor kinematics, I have found that the sexual modification of shared sensory neurons is an important determinant of locomotor frequency. Genetic evidence raises the possibility that these modifications may influence how these cells interpret monoaminergic signals. I conclude that sex differences in the locomotor kinematics of C. elegans arise through distributed modifications affecting neural function, muscle properties, and body morphology. Together, my findings support the idea that coordinated adaptations at multiple levels of control are critical to natural variation in motor behavior, and point to neuromodulatory systems as a potential substrate for the adaptive modification of rhythmic behaviors