The Oren Lab

From Genes to Circuits:
How Sex Shapes Brain Design, Behavior & Vulnerability

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Research

The Oren lab investigates how sexually dimorphic patterns in the brain emerge, from synapse formation to animal behavior

Sexual dimorphisms in brain structure and behavior are widespread across the animal kingdom, yet the mechanisms by which shared neurons generate sex-specific circuit function remain poorly understood. The Oren-Suissa lab investigates how genetic sex shapes neuronal circuits, from synapse formation and circuit topology to behavior and neuronal health.

Using the nematode Caenorhabditis elegans as a primary model system, we combine genetics, connectomics, single-cell transcriptomics, and behavioral analysis to uncover the design principles that allow shared neural circuits to generate distinct behaviors in males and females. Our work has shown that small sex-specific differences in synaptic connectivity and neuromodulatory signaling can profoundly bias information flow through neural circuits and produce robust behavioral divergence.

More recently, we have expanded this framework to examine how the same mechanisms that stabilize sex-specific circuits can also create vulnerabilities. Our research identified a conserved pathway involving the Netrin receptor DCC/UNC-40 that controls synapse stability and can trigger sexually dimorphic neurodegeneration in dopaminergic neurons when dysregulated. To investigate whether similar principles operate in mammals and humans, we are extending our studies to mouse models and human induced pluripotent stem cell-derived dopaminergic neurons.

Together, these approaches allow us to study sexual dimorphism across multiple levels- from genes and synapses to circuits, behavior, and disease,revealing how sex-specific optimization of neural circuits shapes both adaptive behaviors and neuronal vulnerability.

Research page

Mechanism of sex-specific synapse elimination

Elucidate the development and function of sexually dimorphic neuronal circuits

Synaptic organization in health and disease

Modeling sex differences in human neurons

Evolution of sexual motivation circuits

Selected Publications

A panoramic view of the expression and function of the Doublesex/DMRT gene family in C. elegans

Wang 王琛 C., Salzberg Y., Oren-Suissa M. & Hobert O. (2026) Science advances. 12, 16, eaef1478.

Throughout the animal kingdom, sex determination and sexual differentiation are orchestrated by a strikingly diverse set of regulatory factors. The only type of molecules consistently deployed during sexual differentiation are members of the Doublesex/MAB-3-related transcription factor (DMRT) family. Although each animal genome codes for a multitude of DMRT family members, in no species has the full array of DMRT genes been comprehensively analyzed across the entire animal, in all sexes and throughout development. Hence, the extent of deployment of DMRT genes in sexual differentiation remains unknown. We describe here a genome- and nervous system-wide expression and functional analysis of all members of the DMRT gene family. Leveraging genome-engineered reporter alleles of all 10 DMRT genes of the nematode Caenorhabditis elegans, we find that 6 DMRTs display sexually dimorphic expression in somatic and/or reproductive tissues, including in cell and tissue types not previously known to be sexually dimorphic. In the nervous system, DMRT protein expression covers many, although not all, known sexually dimorphic neuron types. Analyses of DMRT null mutant alleles reveal a suite of neuronal differentiation defects, ranging from altered neurotransmitter identities and switched neuropeptide signatures to impaired glia-to-neuron transdifferentiation. Several DMRT proteins do not exhibit sexually dimorphic expression, indicating roles beyond sexual differentiation. Similar comprehensive analyses of DMRT genes in other organisms may help to better understand the extent and regulation of sex-specific cellular differentiation programs.

Cold and lithium delay forgetting of olfactory memories in Caenorhabditiselegans

Landschaft-Berliner D., Goldstein K., Teichman G., Anava S., Gingold H., Salzberg Y., Rieger I., Levy N., Pechuk V., Setty H., Agarwal P., Sagi D., Cohen D., Nikelshparg E., Ben-Zvi A., Miranda-Vizuete A., Zaidel-Bar R., Oren-Suissa M. & Rechavi O. (2026) Nature Neuroscience. 29, 2, p. 387-398

The persistence of memory reflects not only how it is formed but also how forgetting is delayed. The mechanisms controlling forgetting remain obscure, and in particular it is unclear to what degree this process is actively regulated. We discovered that cold exposure delays forgetting of specific olfactory memories by more than eight-fold and that adaptation to cold abolishes this effect. To study the underlying mechanism, we performed RNA sequencing, mutant analyses and pharmacological assays. Here we show that regulation of membrane properties underlies the presence and absence of cold-induced delayed forgetting. Furthermore, lithium can also delay forgetting in cold-sensitive worms but not in cold-tolerant worms; this effect involves downregulation of the diacylglycerol pathway in AWC neurons and long-term suppression of activity in the downstream AIY interneurons. Thus, the genetic tractability of worms might be harnessed to study the mechanism of action of lithium and cold exposure and, more fundamentally, how memory is stored and lost.

Modulation by NPY/NPF-like receptor underlies experience-dependent, sexually dimorphic learning

Peedikayil-Kurien S., Haque R., Gat A. & Oren-Suissa M. (2025) Nature Communications. 16, 1, 662.

The evolutionary paths taken by each sex within a given species sometimes diverge, resulting in behavioral differences. Given their distinct needs, the mechanism by which each sex learns from a shared experience is still an open question. Here, we reveal sexual dimorphism in learning: C. elegans males do not learn to avoid the pathogenic bacteria PA14 as efficiently and rapidly as hermaphrodites. Notably, neuronal activity following pathogen exposure was dimorphic: hermaphrodites generate robust representations, while males, in line with their behavior, exhibit contrasting representations. Transcriptomic and behavioral analysis revealed that the neuropeptide receptor npr-5, an ortholog of the mammalian NPY/NPF-like receptor, regulates male learning by modulating neuronal activity. Furthermore, we show the dependency of the males decision-making on their sexual status and demonstrate the role of npr-5 as a modulator of incoming sensory cues. Taken together, these findings illustrate how neuromodulators drive sex-specific behavioral plasticity in response to a shared experience.

Evolution of nervous systems: Molecular divergence in a conserved body plan

Oren-Suissa M. (2025) Current Biology. 35, 15, p. R748-R750

Neural Circuits Underlying Sexually Dimorphic Innate Behaviors

Oren-Suissa M. & Shirangi T. R. (2025) Annual Review of Neuroscience. 48, p. 191-210

Sexually dimorphic instinctual behaviors that set females and males apart are found across animal clades. Recent studies in a variety of animal systems have provided deep insights into the neural circuits that guide sexually dimorphic behaviors, such as mating practices and social responses, and how sex differences in these circuits develop. Here, we discuss the neural circuits of several sexually dimorphic instinctual behaviors in rodents, flies, and worms - from mate attraction and aggression to pain perception and empathy. We highlight several salient similarities and differences between these circuits and reveal general principles that underlie the function and development of neural circuits for dimorphic behaviors.

All Publications