Foraging, defined as the search for food to sustain one's energetic needs, is a fundamental behavior performed by almost all animals to survive in their environment. Foraging involves a variety of physiological processes, including metabolic and cognitive computations. In this review, we provide a brief historical overview of foraging and foraging theory, highlight recent insights into the neural mechanisms of foraging, and contextualize them within the broader neuroscience literature. We present an integrative approach to foraging that combines neural mechanisms of foraging with ecological, behavioral, and physiological mechanisms.

Calcium imaging with miniature endoscopes has become an essential tool in neuroscience, but conventional miniscopes typically record signals from only a single calcium indicator. Here, we present a dual-color miniature endoscope (miniscope) that enables simultaneous calcium imaging from two neuronal populations using spectrally distinct genetically encoded indicators. In freely moving mice, we used this system to record activity from striatal neurons of the direct (dSPN) and indirect (iSPN) pathways. We showed that dSPNs were activated earlier than iSPNs during contraversive movements, with dSPNs preferentially active during acceleration and iSPNs during deceleration. During ipsiversive turns, however, this temporal relationship was reversed. These findings indicate that dSPNs and iSPNs are not concurrently active, but instead exhibit complementary, direction-dependent dynamics that govern movement velocity. Our dual-color miniscope provides a compact, cost-effective platform for simultaneous two-population imaging, offering new opportunities to dissect coordinated activity across neural circuits in freely behaving animals.

Many insects manipulate plants by injecting effector proteins. In one extreme example of this molecular “hijacking”, Hormaphis cornu aphids inject bicycle proteins into Hamamelis virginiana (Witch Hazel), contributing to the development of novel organs called galls. Bicycle proteins share no amino acid sequence similarity with proteins of known function. Here, we report the crystal structures of two divergent bicycle proteins. Both proteins contain saposin-like folds: one with multiple disulfide bonds exhibits a helix swap; the other has no disulfide bonds and possesses two tandem domains. To explore the structural evolution of bicycle proteins, we predicted bicycle protein structures with Alphafold2 (AF2). While AF2 did not recover the two experimental structures using existing databases, it succeeded after we provided multiple sequence alignments (MSAs) containing protein sequences encoded in new genome sequences from closely related aphid species. Using this customized approach at scale, we generated 2400 high-confidence predictions for bicycle proteins from seven aphid species. This dataset revealed that bicycle proteins without cysteines are outliers in fold space and appear to have evolved from ancestral proteins with disulfide-bonded saposin-like folds. While all bicycle proteins contain predicted saposin-like folds, they display a vast diversity of structural and physicochemical properties. While this diversity thwarts prediction of conserved functions encoded in structure, it suggests that bicycle proteins have evolved to target diverse plant processes and/or to evade plant immune surveillance.Significance statement Parasites introduce specialized “effector” proteins into hosts, both to suppress host immunity and to release nutrients. The molecular functions and structures of most effector proteins are unknown. Effector proteins often evolve rapidly and share no similarity with proteins of known function. Here, we demonstrate that machine learning algorithms can accurately predict the structures of aphid “bicycle” effector proteins when supplemented with data from closely related species. We exploit this finding to generate predictions of 2400 bicycle protein structures. These proteins exploit a common motif, yet exhibit diverse structures that form distinct structural clusters. Despite the clustering of these proteins in structure space, they occupy a nearly uniformly physicochemical space, suggesting that they encode a large diversity of molecular functions.

NPAS4 is an activity-dependent transcription factor that, in CA1 of the hippocampus, regulates inhibitory synapses made onto the active pyramidal neuron. In principle, NPAS4 thereby allows the past activity of a neuron to influence how it encodes information, although this has not yet been demonstrated. Here, we generated a sparse, CA1-specific knockout (KO) of NPAS4 in the mouse hippocampus and used optogenetic tagging to identify KO neurons in vivo. Recordings from intermingled wild-type (WT) and KO neurons in awake behaving animals revealed that NPAS4 deletion degrades spatial representations and temporal precision of spiking: KO neurons exhibited larger place fields with reduced in-field firing and increased out-of-field firing, less stable place fields, reduced coupling to local field potential theta oscillations, and diminished phase precession. These findings demonstrate that NPAS4 plays a crucial role in refining the spatial and temporal properties of CA1 pyramidal neuron spikes, which themselves are thought to be fundamental building blocks of more complex processes such as learning and memory.

Male same-sex sexual behavior (SSB) is widespread among animal species, but its proximate (mechanistic) and ultimate (evolutionary) explanations remain unclear. A prevailing view is that SSB reflects impaired sex recognition, especially in insects. By unbiased behavioral screening, we identified a Drosophila species, D. santomea, in which males seldom attack and spontaneously court males vigorously, in addition to females. Behavioral, chemical, and optogenetic neuronal manipulations indicate that D. santomea males can distinguish conspecific sex and retain functional aggression circuitry. Instead, male SSB reflects three evolved pheromonal changes affecting two separate signaling systems, resulting in both reduced pheromone production and behavioral valence reversal. One of these occurs unexpectedly in females and may have evolved to prevent hybridization with an interfertile, geographically overlapping sibling species. Remarkably, male SSB and similar pheromonal changes also selectively co-occur in D. persimilis, a geographically and phylogenetically distant species and member of another sympatric sibling pair, implying evolutionary convergence in the two young taxa. The results identify a pheromonal mechanism for rapid social evolution in Drosophila and suggest a plausible evolutionary origin for male SSB as arising in concert with female adaptations that ensure reproductive isolation during speciation.

A study establishes a correlative light and electron microscopy workflow that reveals how individual lipid species distribute across nanoscale membrane domains, uncovering sphingomyelin sorting within the early endosome.

Endocytosis actively remodels the neuronal surface proteome to drive diverse cellular processes, yet its global extent and effects on neural circuit development have defied comprehensive interrogation. Here, we introduce endocytome profiling: a systematic, cell-type-specific approach for mapping cell-surface protein (CSP) dynamics in situ. Quantitative proteomic analysis of developing Drosophila olfactory receptor neuron (ORN) axons generated an endocytic atlas comprising over 1,000 proteins and revealed the extent to which the cell-surface proteome is remodeled to meet developmental demands. Targeted interrogation of a junctional CSP showed that its endosome-to-surface ratio is precisely balanced to enable developmental axon pruning while preserving mature axon integrity. Multi-omic integration uncovered widespread transcellular signaling and identified a growth factor secreted by neighboring neurons to direct ORN axon targeting via endocytic regulation of its receptor. Endocytome profiling provides unprecedented access to cell-surface proteome dynamics and offers a platform to dissect proteome-scale remodeling across diverse cell types and contexts.

How intrinsically disordered regions (IDRs) influence chromatin binding and nuclear organization of transcription factors (TFs) remains unclear. We employed proximity-assisted photoactivation (PAPA), a single-molecule protein-protein interaction sensor, to investigate how IDRs might influence TF interactions with each other and with chromatin in live cells. We found that the Sp1 DNA binding domain (DBD) interacted poorly with chromatin and did not colocalize with Sp1. Weak interaction of the isolated IDR with full-length Sp1 was enhanced by fusion to various unrelated DBDs. Live imaging of polytene chromosomes confirmed that an IDR could confer sharp locus specificity on an otherwise nonspecific DBD. These findings suggest that TF specificity emerges on chromatin when ensembles of diverse, unstructured interactions are scaffolded by transient DNA contacts.

Purine nucleotides are essential for mammalian development1,2. Purine monophosphates support cell signaling and proliferation and are synthesized by cells through either de novo synthesis or a salvage pathway3. We previously identified a midgestational metabolic transition in mice (gestational days gd10.5–11.5) characterized by changes in purine metabolism4. Midgestation is a period of rapid growth for placenta and embryo, yet it remains unclear how the placental tissues expand without directly competing with the embryo for biosynthetic resources. Here, we show that this midgestational metabolic transition is associated with a marked reduction in embryonic expression of purine salvage enzymes, which constrains embryonic metabolism and leads to different strategies for purine synthesis between the placenta and embryo. Midgestation embryos are unable to engage the purine salvage pathway even when de novo purine synthesis is blocked either in vivo or in ex utero embryo culture, whereas placental tissue and trophoblasts retain the capacity to use either pathway. Disruption of de novo purine synthesis in mice causes reduced embryonic growth, impaired axial elongation, and abnormal brain and placental development, which are only partially rescued by supplementation with purine salvage precursors. In human placenta, trophoblast stem cells readily switch between the de novo and salvage pathways based on nutrient availability, and syncytiotrophoblasts (STB) preferentially rely on the salvage pathway. We identified guanosine monophosphate (GMP) as a metabolic checkpoint regulating STB differentiation, with insufficient GMP levels causing degradation of the small GTPase Rheb and failure of mTOR activation. Supplementation of purine salvage substrates restored GMP synthesis and STB differentiation in humans, but not mice. Further, in vivo measurements in humans revealed that maternal circulating hypoxanthine decreases during pregnancy and is further reduced in women with clinically small placentas, highlighting the role of hypoxanthine in supporting placental growth. These results uncover compartmentalized purine salvage between the embryo and placenta as a mechanism that limits competition for biosynthetic resources and enables coordinated growth during mammalian development.

After finding food, a foraging animal must decide whether to continue feeding or to explore the environment for potentially better options. One strategy to negotiate this tradeoff is to perform local searches around the food while repeatedly returning to feed. We studied this behavior in flies and used genetic tools to uncover the underlying behavioral strategies. Over time, flies gradually expand their search, shifting from primarily exploiting food sources to exploring the environment, a change likely driven by increased satiety. We found that flies' search patterns preserve these dynamics even as the overall range of the search is modulated by starvation. In contrast, search induced by optogenetic activation of sugar-sensing neurons does not show these dynamics. We asked what navigational strategies underlie local search. Using a generative model, we found that a change in locomotor pattern after food consumption could account for repeated returns to the food, but not the relatively direct return trajectories that flies make even from far away. Such trajectories likely rely on alternative strategies, such as path integration or sensory taxis. We tested this by individually silencing their likely neural components, the compass system, olfaction, and hygrosensation. The only substantial effect was from perturbing hygrosensation, which reduced the number of long exploratory trips with subsequent return to the food. Our study illustrates that local search comprises multiple behavioral features that evolve over time based on both internal and external factors, providing a path toward uncovering the underlying neural mechanisms.