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  • Sperm phospholipase C signaling via PLCζ1 and PLCδ4 is essential for Ca<sup>2+</sup> oscillations and fertility in mice

    by Neha Gupta, Lei Zhang, Hiroki Akizawa, Maria G. Gervasi, Darya A. Tourzani, Pablo E. Visconti, Ana Romarowski, Mariano Buffone, Wei Cui, Rafael A. Fissore

    Fertilization-induced calcium (Ca2+) oscillations are essential for egg activation and embryonic development in mammals. The sperm-specific phospholipase C isoform, PLCζ1, is the primary trigger of these oscillations. Functional and clinical studies have linked mutations or reduced expression of PLCζ1 to male infertility. However, whether PLCζ1 alone accounts for Ca2+ release at fertilization in all mammals remains uncertain. Male mice lacking Plcζ1 exhibit subfertility and reduced litter sizes; their sperm induce delayed, low-frequency Ca2+ oscillations, indicating a compensatory mechanism. Notably, mouse sperm express high levels of PLCδ4, essential for completing the acrosome reaction (AR). In Plcζ1-null sperm, PLCδ4 is upregulated and retained post-AR. These observations suggest a secondary functional role for PLCδ4. Using CRISPR/Cas9 genome editing, we generated Plcδ4 knockout (KO) mice. Plcδ4-null sperm trigger attenuated, delayed Ca2+ oscillations and significantly reduced fertilization rates, indicating that PLCδ4 contributes to but does not independently drive Ca2+ signaling. We therefore generated a Double Knockout (DKO) mouse line lacking both sperm-enriched PLCs. DKO males were sterile, with sperm failing to induce Ca2+ oscillations, and the isolated residual Ca2+ rise was insufficient to activate eggs. These findings reveal that PLCζ1, the primary oscillator, and PLCδ4, a compensatory factor, work cooperatively within a complex, multi-component PLC system that ensures robust fertilization. This work reveals molecular specialization among mammals in initiating the fertilization Ca2+ signals. It has implications for understanding male infertility, improving assisted reproductive technologies, and developing contraceptive strategies.

  • Phylogenetic evidence that migratory behavior increases ungulate extinction rates

    by Joel O. Abraham, Kaedan O’Brien, Nathan S. Upham, Brett R. Jesmer, Faysal Bibi, J. Tyler Faith

    Widespread instances of migratory collapse have been documented within the past several decades, indicating that migration may be a fragile strategy in the Anthropocene. Yet the fragility of migration as a strategy for navigating seasonally variable resource availability may extend deeper into evolutionary time. We used phylogenetic imputation to infer the migratory habits of 51 ungulate species that went extinct during the late Quaternary and evaluated whether migration enhances extinction rates on macroevolutionary timescales. We found that ~80% (41 of 51) of recently extinct species were migratory, whereas only 46% (95 of 207) of extant ungulates are migratory. Furthermore, Hidden State Speciation and Extinction modeling indicated that migratory species likely experienced higher speciation and extinction rates compared to nonmigratory species, resulting in elevated lineage turnover for migratory ungulates, though diversification parameter estimates depended strongly upon whether extinct species were included in analyses. The extinctions of these ungulates led to negligible declines in global ungulate functional richness (0.8%) but more substantial declines (2.7%) across Africa. Altogether, our findings indicate that migration has complex macroevolutionary consequences, enhancing both speciation and extinction rates, which may render migration an evolutionarily fragile strategy, particularly as increasingly widespread and intensive anthropogenic activity cause gradients of resource availability to become severed (e.g., via human infrastructure) and more unpredictable (e.g., via climate change).

  • Two parallel lateral hypothalamic GABAergic projections differentially modulate pain and anxiety in mice

    by Yi-Ling Sun, Yi-Ting Peng, Xue Zhang, Cui Yin, Cheng Xiao, Junping Chen, Chunyi Zhou

    The lateral hypothalamus (LH) is fundamentally involved in motivated behaviors, yet the precise functional segregation of its GABAergic projections in modulating pain and its affective dimensions remains poorly understood. Here, using male and female mice, we revealed that LH GABAergic neurons sent parallel projections to two pivotal pain and affect processing centers: the lateral parabrachial nucleus (LPB) and the paraventricular nucleus of the thalamus (PVT). In vivo fiber photometry revealed that LH GABAergic terminals in both the PVT and LPB are robustly activated by noxious, aversive, and rewarding stimuli, indicating their roles in encoding salient and affective information. Critically, we uncovered a remarkable functional segregation of these LH GABAergic pathways. Optogenetic activation of the LH-PVT projection exerted anxiogenic effects without altering pain sensitivity in both naïve and neuropathic pain mice; whereas optogenetic inhibition of this pathway exerted significant analgesic and anxiolytic effects specifically in neuropathic pain, highlighting a context-dependent modulation of pain and affect. In contrast, optogenetic activation of the LH-LPB projection induced contralateral pronociception without impacting affective behaviors, conversely, inhibition of this pathway significantly elevated contralateral pain thresholds in both physiological and neuropathic pain conditions. We also demonstrated that stimulation of the LH-LPB projection acted via a disinhibitory mechanism involving local LPB GABAergic interneurons to enhance activity of LPB glutamatergic neurons. Collectively, our findings delineate two parallel and functionally segregated LH GABAergic output pathways that differentially control distinct aspects of pain experience, thereby offering novel circuit-specific targets for the treatment of chronic pain and its debilitating emotional comorbidities.

  • Can the exposome help solve the alcohol and cancer mystery?

    by Vasilis Vasiliou, Arthur Stem, David C. Thompson

    Alcohol consumption is a preventable driver of many cancers, yet a central biological question remains unresolved: by what mechanisms does ethanol promote malignancy? We propose that alcohol in the context of the exposome (i.e., the network of chemical, biological, and social determinants that interact with ethanol across the life span) provides a unifying framework for understanding alcohol-related carcinogenesis. Viewed through the lens of the exposome, alcohol is not only as a direct carcinogen but also as a systemic amplifier of environmental risk acting across multiple levels of biological organization, from molecular damage to whole-body physiology. This reframing has important implications for mechanistic research, precision prevention, and public-health policy.

  • Correction: Correction: Correction: Data-driven analyses of motor impairments in animal models of neurological disorders

    by The PLOS Biology Staff