Microglia are the primary immune cells in the brain. Under physiological conditions, they typically stay in a “resting” state, with ramified processes continuously extending to and retracting from ...surrounding neural tissues. Whether and how such highly dynamic resting microglia functionally interact with surrounding neurons are still unclear. Using in vivo time-lapse imaging of both microglial morphology and neuronal activity in the optic tectum of larval zebrafish, we found that neuronal activity steers resting microglial processes and facilitates their contact with highly active neurons. This process requires the activation of pannexin-1 hemichannels on neurons. Reciprocally, such resting microglia-neuron contact reduces both spontaneous and visually evoked activities of contacted neurons. Our findings reveal an instructive role for neuronal activity in resting microglial motility and suggest the function for microglia in homeostatic regulation of neuronal activity in the healthy brain.
► Resting microglial processes dynamically contact neuronal soma via bulbous endings ► Neuronal activity instructs resting microglial processes to contact active neurons ► Pannexin-1 hemichannel in neurons and Rac in microglia are required for this effect ► Resting microglia-neuron contact downregulates the activity of contacted neurons
Little is known about the role of resting microglia in the healthy brain. Looking in vivo in zebrafish, Li et al. uncover reciprocal regulation between neurons and resting microglia in which neuronal activity provokes the formation of microglial contacts that, in turn, downregulate the activity of contacted neurons.
The China Brain Project covers both basic research on neural mechanisms underlying cognition and translational research for the diagnosis and intervention of brain diseases as well as for ...brain-inspired intelligence technology. We discuss some emerging themes, with emphasis on unique aspects.
The China Brain Project covers both basic research on neural mechanisms underlying cognition and translational research for the diagnosis and intervention of brain diseases as well as for brain-inspired intelligence technology.
Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can ...regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.
Habenula (Hb) plays critical roles in emotion-related behaviors through integrating inputs mainly from the limbic system and basal ganglia. However, Hb also receives inputs from multiple sensory ...modalities. The function and underlying neural circuit of Hb sensory inputs remain unknown. Using larval zebrafish, we found that left dorsal Hb (dHb, a homolog of mammalian medial Hb) mediates light-preference behavior by receiving visual inputs from a specific subset of retinal ganglion cells (RGCs) through eminentia thalami (EmT). Loss- and gain-of-function manipulations showed that left, but not right, dHb activities, which encode environmental illuminance, are necessary and sufficient for light-preference behavior. At circuit level, left dHb neurons receive excitatory monosynaptic inputs from bilateral EmT, and EmT neurons are contacted mainly by sustained ON-type RGCs at the arborization field 4 of retinorecipient brain areas. Our findings discover a previously unidentified asymmetrical visual pathway to left Hb and its function in mediating light-preference behavior.
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•Left dorsal habenula (L-dHb) mediates light-preference behavior in zebrafish•Activities of L-dHb neurons encode the presence and intensity of ambient light•L-dHb receives inputs from a subset of retinal ganglion cells via eminentia thalami•Bilateral eminentia thalami preferentially innervate the L-dHb
The habenula plays critical roles in emotion-related behaviors. Zhang et al. discover a novel function for the left dorsal habenula: it can mediate zebrafish light-preference behavior via receiving visual inputs from a dedicated asymmetrical retina-thalamus-left dorsal habenula pathway.
The circadian clock orchestrates a wide variety of physiological and behavioral processes, enabling animals to adapt to daily environmental changes, particularly the day-night cycle. However, the ...circadian clock's role in the developmental processes remains unclear. Here, we employ the in vivo long-term time-lapse imaging of retinotectal synapses in the optic tectum of larval zebrafish and reveal that synaptogenesis, a fundamental developmental process for neural circuit formation, exhibits circadian rhythm. This rhythmicity arises primarily from the synapse formation rather than elimination and requires the hypocretinergic neural system. Disruption of this synaptogenic rhythm, by impairing either the circadian clock or the hypocretinergic system, affects the arrangement of the retinotectal synapses on axon arbors and the refinement of the postsynaptic tectal neuron's receptive field. Thus, our findings demonstrate that the developmental synaptogenesis is under hypocretin-dependent circadian regulation, suggesting an important role of the circadian clock in neural development.
Visual cues often modulate auditory signal processing, leading to improved sound detection. However, the synaptic and circuit mechanism underlying this cross-modal modulation remains poorly ...understood. Using larval zebrafish, we first established a cross-modal behavioral paradigm in which a preceding flash enhances sound-evoked escape behavior, which is known to be executed through auditory afferents (VIIIth nerves) and command-like neurons (Mauthner cells). In vivo recording revealed that the visual enhancement of auditory escape is achieved by increasing sound-evoked Mauthner cell responses. This increase in Mauthner cell responses is accounted for by the increase in the signal-to-noise ratio of sound-evoked VIIIth nerve spiking and efficacy of VIIIth nerve-Mauthner cell synapses. Furthermore, the visual enhancement of Mauthner cell response and escape behavior requires light-responsive dopaminergic neurons in the caudal hypothalamus and D1 dopamine receptor activation. Our findings illustrate a cooperative neural mechanism for visual modulation of audiomotor processing that involves dopaminergic neuromodulation.
► Visual input improves audiomotor behavior via enhancing command neuron responses ► The modulation is achieved by decreasing neural noise and increasing synaptic gain ► Hypothalamic dopaminergic neurons mediate this cross-modal modulation ► D1 dopamine receptor activation is required for this cross-modal modulation
Mu et al. provide a mechanism for visual cross-modal modulation of zebrafish audiomotor behavior, finding that hypothalamic dopaminergic neurons modulate both the signal-to-noise ratio of auditory nerves and transmission efficacy of downstream synapses.
Dear Editor, Animals carrying exogenous genes integrated at specific genomic loci are versatile tools for biological research 1. Zebrafish （Danio rerio）, an emerging vertebrate animal model, is ...widely used in studies on genetics, developmental biology and neurobiology. Although loss-of-function genomic editing for zebrafish has been well developed 2-5, lack of feasible methods for inserting a large exogenous DNA sequence into the zebrafish genome is becoming a bottleneck for zebrafish-relevant research.
PRKAG2 cardiac syndrome is an autosomal dominant inherited disease resulted from mutations in the PRK- AG2 gene that encodes γ2 regulatory subunit of AMP-activated protein kinase. Affected patients ...usually develop ventricular tachyarrhythmia and experience progressive heart failure that is refractory to medical treatment and requires cardiac transplantation. In this study, we identify a H530R mutation in PRKAG2 from patients with familial Wolff-Parkinson-White syndrome. By generating H530R PRKAG2 transgenic and knock-in mice, we show that both models recapitulate human symptoms including cardiac hypertrophy and glycogen storage, confirming that the H530R mutation is causally related to PRKAG2 cardiac syndrome. We further combine adeno-associated virus-9 （AAV9） and the CRISPR/Cas9 gene-editing system to disrupt the mutant PRKAG2 allele encoding H530R while leav- ing the wild-type allele intact. A single systemic injection of AAV9-Cas9/sgRNA at postnatal day 4 or day 42 substantially restores the morphology and function of the heart in H530R PRKAG2 transgenic and knock-in mice. Together, our work suggests that in vivo CRISPR/Cas9 genome editing is an effective tool in the treatment of PRKAG2 cardiac syndrome and other dominant inherited cardiac diseases by selectively disrupting disease-causing mutations.
Retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. Although it is ...known that the wave is initiated successively by amacrine cells and bipolar cells, the behavior and function of glia in retinal waves remain unclear. Using multiple in vivo methods in larval zebrafish, we found that Müller glial cells (MGCs) display wave-like spontaneous activities, which start at MGC processes within the inner plexiform layer, vertically spread to their somata and endfeet, and horizontally propagate into neighboring MGCs. MGC waves depend on glutamatergic signaling derived from bipolar cells. Moreover, MGCs express both glia-specific glutamate transporters and the AMPA subtype of glutamate receptors. The AMPA receptors mediate MGC calcium activities during retinal waves, whereas the glutamate transporters modulate the occurrence of retinal waves. Thus, MGCs can sense and regulate retinal waves via AMPA receptors and glutamate transporters, respectively.
As noted by Darwin, chickens have the greatest phenotypic diversity of all birds, but an interesting evolutionary difference between domestic chickens and their wild ancestor, the Red Junglefowl, is ...their comparatively weaker vi- sion. Existing theories suggest that diminished visual prowess among domestic chickens reflect changes driven by the relaxation of functional constraints on vision, but the evidence identifying the underlying genetic mechanisms respon- sible for this change has not been definitively characterized. Here, a genome-wide analysis of the domestic chicken and Red Junglefowl genomes showed significant enrichment for positively selected genes involved in the development of vision. There were significant differences between domestic chickens and their wild ancestors regarding the level of mRNA expression for these genes in the retina. Numerous additional genes involved in the development of vision also showed significant differences in mRNA expression between domestic chickens and their wild ancestors, particularly for genes associated with phototransduction and photoreceptor development, such as RHO （rhodopsin）, GUCAIA, PDE6B and NR2E3. Finally, we characterized the potential role of the VIT gene in vision, which experienced positive selection and downregulated expression in the retina of the village chicken. Overall, our results suggest that positive selection, rather than relaxation of purifying selection, contributed to the evolution of vision in domestic chickens. The progenitors of domestic chickens harboring weaker vision may have showed a reduced fear response and vigi- lance, making them easier to be unconsciously selected and/or domesticated.
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