Molecular mechanisms of proteoglycan-mediated semaphorin signaling in axon guidance.

The precise assembly of a functional nervous system relies on axon guidance cues. Beyond engaging their cognate receptors and initiating signaling cascades that modulate cytoskeletal dynamics, guidance cues also bind components of the extracellular matrix, notably proteoglycans, yet the role and mechanisms of these interactions remain poorly understood. We found that Drosophila secreted semaphorins bind specifically to glycosaminoglycan (GAG) chains of proteoglycans, showing a preference based on the degree of sulfation. Structural analysis of Sema2b unveiled multiple GAG-binding sites positioned outside canonical plexin-binding site, with the highest affinity binding site located at the C-terminal tail, characterized by a lysine-rich helical arrangement that appears to be conserved across secreted semaphorins. In vivo studies revealed a crucial role of the Sema2b C-terminal tail in specifying the trajectory of olfactory receptor neurons. We propose that secreted semaphorins tether to the cell surface through interactions with GAG chains of proteoglycans, facilitating their presentation to cognate receptors on passing axons.

Embryonically active piriform cortex neurons promote intracortical recurrent connectivity during development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching.

In developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionarily conserved teneurins are transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurins' functions is unclear. Here, we use in situ proximity labeling to obtain the intracellular interactome of a teneurin (Ten-m) in the Drosophila brain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced our understanding of both cellular and molecular mechanisms of synaptic partner matching.

A cerebellar granule cell-climbing fiber computation to learn to track long time intervals.

In classical cerebellar learning, Purkinje cells (PkCs) associate climbing fiber (CF) error signals with predictive granule cells (GrCs) that were active just prior (∼150 ms). The cerebellum also contributes to behaviors characterized by longer timescales. To investigate how GrC-CF-PkC circuits might learn seconds-long predictions, we imaged simultaneous GrC-CF activity over days of forelimb operant conditioning for delayed water reward. As mice learned reward timing, numerous GrCs developed anticipatory activity ramping at different rates until reward delivery, followed by widespread time-locked CF spiking. Relearning longer delays further lengthened GrC activations. We computed CF-dependent GrC→PkC plasticity rules, demonstrating that reward-evoked CF spikes sufficed to grade many GrC synapses by anticipatory timing. We predicted and confirmed that PkCs could thereby continuously ramp across seconds-long intervals from movement to reward. Learning thus leads to new GrC temporal bases linking predictors to remote CF reward signals-a strategy well suited for learning to track the long intervals common in cognitive domains.

Analysis of the Current Status of Nurses' Knowledge of Pressure Injuries and Factors Influencing It in Shaanxi Province, China: A Cross-Sectional Study.

Background: Pressure injuries are present in all healthcare environments and not only pose a significant health risk to individuals but also impose a heavy economic burden on society and families. Nurses, as the primary caregivers responsible for the prevention and management of pressure injuries, have knowledge that directly determines the incidence of pressure injuries. Aim: To understand the current status of nurses' knowledge of pressure injuries in Shaanxi Province and the factors influencing it. Design: A cross-sectional survey. Methods: In April - May 2022, 16,599 nurses from hospitals at all levels in Shaanxi Province were selected as survey subjects by convenience sampling method. They were surveyed using the general information questionnaire and the Pieper-Zulkowski pressure injury Knowledge Questionnaire through the Questionnaire Star platform. Results: 16,599 nurses had a pressure injury knowledge score of (44.32±10.11). Wound description and pressure ulcer staging dimensions were less than 60% correct. Comparison of pressure injury knowledge scores of nursing staff with different genders, hospital levels, titles, education, whether they were specialized nurses in wound stoma when they last attended a lecture on pressure ulcers, when they last read literature or books on pressure ulcers, and whether they ever looked for information about pressure ulcers on the Internet showed that the differences were statistically significant (P < 0.05), which were the influencing factors of the knowledge scores of the nursing staff in Shaanxi Province. Conclusion: Clinical nurses' awareness of stress-related injuries still needs to be improved, and nursing administrators can improve the quality of pressure-related injury care by increasing nursing staff's awareness through continuing education, tiered training, and other measures.

Embryonically Active Piriform Cortex Neurons Promote Intracortical Recurrent Connectivity during Development.

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used Targeted Recombination in Active Populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing of these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Discriminative Grandparental Investment in China : Evidence from an Undergraduate Questionnaire Study.

Many studies in Western societies show a pattern of discriminative grandparental investment as follows: maternal grandmothers (MGMs) > maternal grandfathers (MGFs) > paternal grandmothers (PGMs) > paternal grandfathers (PGFs). This pattern is in line with the expectation from evolutionary reasoning. Yet whether or not this pattern applies in China is in question. The present study was based on a questionnaire survey at a university in Central China (N = 1,195). Results show that (1) when grandparent-grandchild residential distance during grandchildren's childhood is controlled, in the case of grandsons and granddaughters as a whole and granddaughters only, both grandparental caregiving and grandchildren's emotional closeness to grandparents display a rank order of MGM > MGF > PGM > PGF, but in the case of grandsons only, this order is not statistically significant. (2) There are stable relationships between grandparental caregiving/grandchildren's emotional closeness and residential distance/similarity in appearance. (3) The effects of residential distance on either PGFs' or PGMs' caregiving exceed those on either MGFs' or MGMs'. (4) The PGF and PGM prefer grandsons to granddaughters in their caregiving, whereas the MGF and MGM do not have a sex preference, and (5) the fact that the PGF and PGM invest more in grandsons than in granddaughters does not depend on grandsons' duration of living in a rural area. Our results suggest that (1) in general, the Chinese display a pattern of differential grandparental investment predicted by an evolutionary perspective, (2) the evolutionary perspective that combines the two factors of paternal uncertainty and sex-specific reproductive strategies is applicable to grandparental investment in China, and (3) the traditional son-preference culture also plays some role in affecting grandparental investment in China, though the roles of culture and urban-rural cultural difference should not be exaggerated.

Neural landscape diffusion resolves conflicts between needs across time.

Animals perform flexible goal-directed behaviours to satisfy their basic physiological needs1-12. However, little is known about how unitary behaviours are chosen under conflicting needs. Here we reveal principles by which the brain resolves such conflicts between needs across time. We developed an experimental paradigm in which a hungry and thirsty mouse is given free choices between equidistant food and water. We found that mice collect need-appropriate rewards by structuring their choices into persistent bouts with stochastic transitions. High-density electrophysiological recordings during this behaviour revealed distributed single neuron and neuronal population correlates of a persistent internal goal state guiding future choices of the mouse. We captured these phenomena with a mathematical model describing a global need state that noisily diffuses across a shifting energy landscape. Model simulations successfully predicted behavioural and neural data, including population neural dynamics before choice transitions and in response to optogenetic thirst stimulation. These results provide a general framework for resolving conflicts between needs across time, rooted in the emergent properties of need-dependent state persistence and noise-driven shifts between behavioural goals.

[Research on the Progress of Applying Virtual Reality Technology in Preventing Falls in the Elderly].

The primary cause of injury and death in the elderly has been reflected in fall the elderly, so the application of reasonable and effective prevention strategies has great significance in reducing the risk of fall in the elderly. The research progress of virtual reality technology applied in preventing fall in the elderly at home and abroad over the years was systematically reviewed in this study. The mechanism of the technology in preventing fall in the elderly was mainly elaborated from five aspects of improving balance ability, gait disturbance, cognitive impairment, muscle strength and the fear psychology of falling. The purpose of this thesis is to broaden the research ideas of medical personnel on the prevention of fall of the elderly, provide more effective clinical practice plans, reduce the occurrence of fall, and guarantee the safety of the elderly.

A neural circuit for male sexual behavior and reward.

Male sexual behavior is innate and rewarding. Despite its centrality to reproduction, a molecularly specified neural circuit governing innate male sexual behavior and reward remains to be characterized. We have discovered a developmentally wired neural circuit necessary and sufficient for male mating. This circuit connects chemosensory input to BNSTprTac1 neurons, which innervate POATacr1 neurons that project to centers regulating motor output and reward. Epistasis studies demonstrate that BNSTprTac1 neurons are upstream of POATacr1 neurons, and BNSTprTac1-released substance P following mate recognition potentiates activation of POATacr1 neurons through Tacr1 to initiate mating. Experimental activation of POATacr1 neurons triggers mating, even in sexually satiated males, and it is rewarding, eliciting dopamine release and self-stimulation of these cells. Together, we have uncovered a neural circuit that governs the key aspects of innate male sexual behavior: motor displays, drive, and reward.

Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution.

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterized 163 distinct cell types and performed an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further developed aging clock models to predict fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find distinctive cell type-specific aging patterns. This atlas provides a valuable resource for studying fundamental principles of aging in complex organisms.

Expansion spatial transcriptomics.

Capture array-based spatial transcriptomics methods have been widely used to resolve gene expression in tissues; however, their spatial resolution is limited by the density of the array. Here we present expansion spatial transcriptomics to overcome this limitation by clearing and expanding tissue prior to capturing the entire polyadenylated transcriptome with an enhanced protocol. This approach enables us to achieve higher spatial resolution while retaining high library quality, which we demonstrate using mouse brain samples.

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons.

The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a repulsive receptor in distal CA1 neurons to direct their axons to the proximal subiculum, and as a repulsive ligand in the proximal subiculum to direct proximal CA1 axons to the distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to Gα12/13 in heterologous cells; this coupling is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2's tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site alone prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to the proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor in axons. By contrast, neither tethered agonist activity nor autoproteolysis were necessary for Lphn2's role as a repulsive ligand in the subiculum target neurons. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

The complex brain circuits that allow animals to sense and interact with their environment start to form early during development. Throughout this period, neurons extend fiber-like projections to establish precise wiring patterns. Various types of proteins at the surface of both incoming fibers and target cells ensure that only the right partners will connect together. Latrophilin-2, for example, is a neuronal surface protein essential for the formation of accurate connections in the hippocampus, a brain region important for memory. Studded through the membrane of certain neurons, it acts as a signal-sending ligand to direct incoming fibers, with neurons that carry Latrophilin-2 repelling projections from cells that display certain protein partners. At the same time, Latrophilin-2 also allows neurons to receive chemical signals by working with intracellular signaling proteins known as G proteins, which help to relay information between cells. It remained unclear how this role as a signalling receptor participates in the wiring of the hippocampus during development. To explore this question, Pederick, Perry-Hauser et al. examined the impact of Latrophilin-2 on the connection patterns of mouse hippocampal neurons that do not normally carry this protein. Introducing Latrophilin-2 into these 'proximal CA1 cells' misdirected them away from their usual partners ­ unless Latrophilin-2 was altered so that it could not interact with G proteins. In contrast, forcing the connecting partners of CA1 cells to display normal or altered versions of Latrophilin-2 did not interfere with the protein acting as a repulsive ligand. Taken together, these results suggest that the ability of Latrophilin-2 to signal through G proteins is important for neurons that are attempting to project their fibers onto other cells, but not important when Latrophilin-2 acts in targets to direct incoming fibers from other neurons. These results show that a single protein can shape neural circuits by acting both as a signal-receiving receptor and a signal-sending ligand depending on the context. In the future, Pederick, Perry-Hauser et al. hope that their findings will shed new light on how the wiring of the brain is disrupted in neurodevelopmental disorders.

Origin of wiring specificity in an olfactory map revealed by neuron type-specific, time-lapse imaging of dendrite targeting.

How does wiring specificity of neural maps emerge during development? Formation of the adult Drosophila olfactory glomerular map begins with the patterning of projection neuron (PN) dendrites at the early pupal stage. To better understand the origin of wiring specificity of this map, we created genetic tools to systematically characterize dendrite patterning across development at PN type-specific resolution. We find that PNs use lineage and birth order combinatorially to build the initial dendritic map. Specifically, birth order directs dendrite targeting in rotating and binary manners for PNs of the anterodorsal and lateral lineages, respectively. Two-photon- and adaptive optical lattice light-sheet microscope-based time-lapse imaging reveals that PN dendrites initiate active targeting with direction-dependent branch stabilization on the timescale of seconds. Moreover, PNs that are used in both the larval and adult olfactory circuits prune their larval-specific dendrites and re-extend new dendrites simultaneously to facilitate timely olfactory map organization. Our work highlights the power and necessity of type-specific neuronal access and time-lapse imaging in identifying wiring mechanisms that underlie complex patterns of functional neural maps.

The brain's ability to sense, act and remember relies on the intricate network of connections between neurons. Organization of these connections into neural maps is critical for processing sensory information. For instance, different odors are represented by specific neurons in a part of the brain known as the olfactory bulb, allowing animals to distinguish between smells. Projection neurons in the olfactory bulb have extensions known as dendrites that receive signals from sensory neurons. Scientists have extensively used the olfactory map in adult fruit flies to study brain wiring because of the specific connections between their sensory and projection neurons. This has led to the discovery of similar wiring strategies in mammals. But how the olfactory map is formed during development is not fully understood. To investigate, Wong et al. built genetic tools to label specific types of olfactory projection neurons during the pupal stage of fruit fly development. This showed that a group of projection neurons directed their dendrites in a clockwise rotation pattern depending on the order in which they were born: the first-born neuron sent dendrites towards the top right of the antennal lobe (the fruit fly equivalent of the olfactory bulb), while the last-born sent dendrites towards the top left. Wong et al. also carried out high-resolution time-lapse imaging of live brains grown in the laboratory to determine how dendrites make wiring decisions. This revealed that projection neurons send dendrites in all directions, but preferentially stabilize those that extend in the direction which the neurons eventually target. Also, live imaging showed neurons could remove old dendrites (used in the larvae) and build new ones (to be used in the adult) simultaneously, allowing them to quickly create new circuits. These experiments demonstrate the value of imaging specific types of neurons to understand the mechanisms that assemble neural maps in the developing brain. Further work could use the genetic tools created by Wong et al. to study how wiring decisions are determined in this and other neural maps by specific genes, potentially yielding insights into neurological disorders associated with wiring defects.