GPCRs steer G and G selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors.

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G, G or G proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT, 5-HT, and 5-HT with G, and 5-HT with G.

Biophysical mechanism underlying compensatory preservation of neural synchrony over the adult lifespan.

We propose that the preservation of functional integration, estimated from measures of neural synchrony, is a key objective of neurocompensatory mechanisms associated with healthy human ageing. To support this proposal, we demonstrate how phase-locking at the peak alpha frequency in Magnetoencephalography recordings remains invariant over the lifespan in a large cohort of human participants, aged 18-88 years. Using empirically derived connection topologies from diffusion tensor imaging data, we create an in-silico model of whole-brain alpha dynamics.

Imaging the Deep Spinal Cord Microvascular Structure and Function with High-Speed NIR-II Fluorescence Microscopy.

The spinal cord (SC) is crucial for a myriad of somatosensory, autonomic signal processing, and transductions. Understanding the SC vascular structure and function thus plays an integral part in neuroscience and clinical research. However, the dense layers of myelinated ascending axons on the dorsal side inconveniently grant the SC tissue with high optical scattering property, which significantly hinders the imaging depth of the SC vasculature in vivo.

Lighting Up Neural Circuits by Viral Tracing.

Neurons are highly interwoven to form intricate neural circuits that underlie the diverse functions of the brain. Dissecting the anatomical organization of neural circuits is key to deciphering how the brain processes information, produces thoughts, and instructs behaviors. Over the past decades, recombinant viral vectors have become the most commonly used tracing tools to define circuit architecture.

Molecular insights into ligand recognition and activation of chemokine receptors CCR2 and CCR3.

Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes: CCR2 bound to its endogenous ligand CCL2, and CCR3 in the apo state. The structure of the CCL2-CCR2-G-protein complex reveals that CCL2 inserts deeply into the extracellular half of the transmembrane domain, and forms substantial interactions with the receptor through the most N-terminal glutamine.

Recurrent circadian circuitry regulates central brain activity to maintain sleep.

Animal brains have discrete circadian neurons, but little is known about how they are coordinated to influence and maintain sleep. Here, through a systematic optogenetic screening, we identified a subtype of uncharacterized circadian DN3 neurons that is strongly sleep promoting in Drosophila. These anterior-projecting DN3s (APDN3s) receive signals from DN1 circadian neurons and then output to newly identified noncircadian "claw" neurons (CLs).

Serum Neurofilament Light Chain in Wilson's Disease: A Promising Indicator but Unparallel to Real-Time Treatment Response.

Background: Wilson's disease (WD) currently lacks a promising indicator that could reflect neurological impairment and monitor treatment outcome. We aimed to investigate whether serum neurofilament light chain (sNfL) functions as a candidate for disease assessment and treatment monitoring of WD.

Methods: We assessed preclinical and manifested WD patients' sNfL levels compared to controls and analyzed the differences between patients with various clinical symptoms.

Optimized simplified pediatric diabetes severity warning system for the early identification of diabetic ketoacidosis in children.

Objective: Diabetic ketoacidosis (DKA) is the leading cause of mortality in children with type 1 diabetes. Diagnosis of DKA is difficult in resource-limited areas owing to the unavailability of blood gas test, the gold standard for DKA diagnosis. The Simplified Pediatric Diabetes Severity Warning System (SPDSWS) has been developed to identify high-risk DKA patients with limited resources in China.

Rational designing of oscillatory rhythmicity for memory rescue in plasticity-impaired learning networks.

In the brain, oscillatory strength embedded in network rhythmicity is important for processing experiences, and this process is disrupted in certain psychiatric disorders. The use of rhythmic network stimuli can change these oscillations and has shown promise in terms of improving cognitive function, although the underlying mechanisms are poorly understood. Here, we combine a two-layer learning model, with experiments involving genetically modified mice, that provides precise control of experience-driven oscillations by manipulating long-term potentiation of excitatory synapses onto inhibitory interneurons (LTP).

ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation.

Ischemic stroke is an acute and serious cerebral vascular disease, which greatly affects people's health and brings huge economic burden to society. Microglia, as important innate immune components in central nervous system (CNS), are double-edged swords in the battle of nerve injury, considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes. High mobility group box 1 (HMGB1) is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia.

A conductive supramolecular hydrogel creates ideal endogenous niches to promote spinal cord injury repair.

The current effective method for treatment of spinal cord injury (SCI) is to reconstruct the biological microenvironment by filling the injured cavity area and increasing neuronal differentiation of neural stem cells (NSCs) to repair SCI. However, the method is characterized by several challenges including irregular wounds, and mechanical and electrical mismatch of the material-tissue interface. In the current study, a unique and facile agarose/gelatin/polypyrrole (Aga/Gel/PPy, AGP3) hydrogel with similar conductivity and modulus as the spinal cord was developed by altering the concentration of Aga and PPy.

GPR177 in A-fiber sensory neurons drives diabetic neuropathic pain via WNT-mediated TRPV1 activation.

Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear.

Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinal-hippocampal circuit contributes to early-life stress-induced memory deficits.

The cell adhesion molecule nectin3 and its presynaptic partner nectin1 have been linked to early-life stress-related cognitive disorders, but how the nectin1-nectin3 system contributes to stress-induced neuronal, circuit, and cognitive abnormalities remains to be studied. Here we show that in neonatally stressed male mice, temporal order and spatial working memories, which require the medial entorhinal cortex (MEC)-CA1 pathway, as well as the structural integrity of CA1 pyramidal neurons were markedly impaired in adulthood. These cognitive and structural abnormalities in stressed mice were associated with decreased nectin levels in entorhinal and hippocampal subregions, especially reduced nectin1 level in the MEC and nectin3 level in the CA1.

Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors.

Peptide hormones and neuropeptides are complex signaling molecules that predominately function through G protein-coupled receptors (GPCRs). Two unanswered questions remaining in the field of peptide-GPCR signaling systems pertain to the basis for the diverse binding modes of peptide ligands and the specificity of G protein coupling. Here, we report the structures of a neuropeptide, galanin, bound to its receptors, GAL1R and GAL2R, in complex with their primary G protein subtypes G and G, respectively.

A Critical Role for γCaMKII in Decoding NMDA Signaling to Regulate AMPA Receptors in Putative Inhibitory Interneurons.

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP). However, the molecular mechanism underlying how γCaMKII mediates LTP remains unclear.

Alpha and theta peak frequency track on- and off-thoughts.

Our thoughts are highly dynamic in their contents. At some points, our thoughts are related to external stimuli or tasks focusing on single content (on-single thoughts), While in other moments, they are drifting away with multiple simultaneous items as contents (off-multiple thoughts). Can such thought dynamics be tracked by corresponding neurodynamics? To address this question, here we track thought dynamics during post-stimulus periods by electroencephalogram (EEG) neurodynamics of alpha and theta peak frequency which, as based on the phase angle, must be distinguished from non-phase-based alpha and theta power.

Cholinergic neurons in the pedunculopontine nucleus guide reversal learning by signaling the changing reward contingency.

Cognitive flexibility enables effective switching between mental processes to generate appropriate responses. Cholinergic neurons (CNs) within the pedunculopontine nucleus (PPN) are associated with many functions, but their contribution to cognitive flexibility remains poorly understood. Here we measure PPN cholinergic activities using calcium indicators during the attentional set-shifting task.

Pathological Networks Involving Dysmorphic Neurons in Type II Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. Dysmorphic neurons are the major histopathological feature of type II FCD, but their role in seizure genesis in FCD is unclear. Here we performed whole-cell patch-clamp recording and morphological reconstruction of cortical principal neurons in postsurgical brain tissue from drug-resistant epilepsy patients.

Protocol for glial Ca imaging in following chemical, mechanical, or optogenetic stimulation.

is an exceptionally transparent model to analyze calcium (Ca) signals, but available protocols for neuronal Ca2 imaging may not be suitable for studying glial cells. Here, we present a detailed protocol for glial Ca imaging in following three different approaches including chemical, mechanical, and optogenetic stimulation. We also provide the details for imaging analysis using Image-J.

In vivo development and single-cell transcriptome profiling of human brain organoids.

Objectives: Human brain organoids can provide not only promising models for physiological and pathological neurogenesis but also potential therapies in neurological diseases. However, technical issues such as surgical lesions due to transplantation still limit their applications.

Materials And Methods: Instead of applying mature organoids, we innovatively developed human brain organoids in vivo by injecting small premature organoids into corpus striatum of adult SCID mice.

KIF2C regulates synaptic plasticity and cognition in mice through dynamic microtubule depolymerization.

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules are the major route for cargo protein trafficking and they specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed depolymerization mechanism that regulates dynamic microtubules in synapses and dendrites is still unclear.

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset.

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information.

A Deep Mesencephalic Nucleus Circuit Regulates Licking Behavior.

Licking behavior is important for water intake. The deep mesencephalic nucleus (DpMe) has been implicated in instinctive behaviors. However, whether the DpMe is involved in licking behavior and the precise neural circuit behind this behavior remains unknown.