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.
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.
Gaze shifts are fundamental to visual exploration and processing, yet empirical knowledge is largely confined to a small number of model species, limiting our understanding of general principles of visual acquisition across animals. Here, we introduce a versatile, low-cost, and open-source framework design for eye-tracking in small, freely moving animals. Leveraging photogrammetry, 3D modeling, and 3D-printing, we produce headmounts adaptable to diverse head-eye geometries, as we demonstrate for lizards, turtles, and mice. Detailed recordings in Pogona vitticeps, a laterally eyed ectotherm with a high-acuity retina, reveal a rich oculomotor repertoire with kinematics closely resembling the saccadic main sequence in primates. We found both movement-coupled large binocular saccades, which exhibited a strong axial bias as well as small, isotropic, and monocular saccades suggesting a capacity for visual exploration of local details. Visual acquisition strategies were strongly tied to behavioral states with periods of active sampling (3-5 Hz saccades) separated by periods of ocular stillness lasting many seconds and suggesting a visual acquisition strategy distinct from those commonly described in endothermic model species. Furthermore, active states were correlated with pupil constriction in contrast to mammals and similarly to birds. Our results demonstrate the utility of our experimental approach for understanding visual acquisition across terrestrial vertebrates. Such a multi-perspective view on natural visual acquisition across species will be essential for developing a generalized understanding of vision, its ecological functions, and its evolutionary trajectory.
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).
Saccadic suppression, a reduction in visual sensitivity around the time of rapid eye movements, is well-documented in primate psychophysics, but its mechanisms and functions remain debated. Here, we use zebrafish to trace the origins of saccadic suppression, and we demonstrate how saccadic suppression selectively enhances the visual salience of ecologically relevant stimuli. Saccadic suppression thus contributes to more than just compensation for rapid saccade-induced image shifts. We first established a behavioral correlate of saccadic suppression in larval zebrafish escape behavior. Then, using electrophysiology, we show that retinal ganglion cells jumpstart saccadic suppression in a spatial frequency-dependent manner. Calcium imaging, combined with 360° visual stimulation and behavioral tracking, revealed that motor signals enhance peri-saccadic suppression strength in the optic tectum, where suppression lasts for more than 3,000 ms. Notably, saccadic suppression is much weaker and more short-lived for stimuli related to hunting or escape behavior than for behaviorally less relevant global flashes. This unequal attenuation effectively increases the salience of the ecologically relevant stimuli in the optic tectum after saccades. Our results demonstrate that saccadic suppression integrates visual and motor signals to optimize sensory processing within neural constraints, and they provide insights into evolutionarily conserved visual strategies.
