Involvement and regulation of the left anterior cingulate cortex in the ultrasonic communication deficits of autistic mice.

Introduction: Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions. Methods: Fragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male-female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity. Results: In wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In FMR1-/-- and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in FMR1-/- or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice. Discussion: The excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in FMR1-/- and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in FMR1-/- and VPA-pretreated mice.

Establishment of a two-hit mouse model of environmental factor induced autism spectrum disorder.

Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations, environmental factors play important roles in the development of ASD. Valproic acid (VPA) is widely used for modeling environmental factor induced ASD in rodents. However, traditional VPA modeling is low-in-efficiency and the phenotypes often vary among different batches of experiments. To optimize this ASD-modeling method, we tested "two-hit" hypothesis by single or double exposure of VPA and poly:IC at the critical time points of embryonic and postnatal stage. The autistic-like behaviors of mice treated with two-hit schemes (embryonic VPA plus postnatal poly:IC, embryonic poly:IC plus postnatal VPA, embryonic VPA plus poly: IC, or postnatal VPA plus poly:IC) were compared with mice treated with traditional VPA protocol. The results showed that all single-hit and two-hit schemes produced core ASD phenotypes as VPA single treatment did. Only one group, namely, mice double-hit by VPA and poly:IC simultaneously at E12.5 showed severe impairment of social preference, social interaction and ultrasonic communication, as well as significant increase of grooming activity and anxiety-like behaviors, in comparation with mice treated with the traditional VPA protocol. These data demonstrated that embryonic two-hit of VPA and poly:IC is more efficient in producing ASD phenotypes in mice than the single-hit of VPA, indicating this two-hit scheme could be utilized for modeling environmental factors induced ASD.

Quiescent Adult Neural Stem Cells: Developmental Origin and Regulatory Mechanisms.

The existence of neural stem cells (NSCs) in the adult mammalian nervous system, although small in number and restricted to the sub-ventricular zone of the lateral ventricles, the dentate gyrus of the hippocampus, and the olfactory epithelium, is a gift of evolution for the adaptive brain function which requires persistent plastic changes of these regions. It is known that most adult NSCs are latent, showing long cell cycles. In the past decade, the concept of quiescent NSCs (qNSCs) has been widely accepted by researchers in the field, and great progress has been made in the biology of qNSCs. Although the spontaneous neuronal regeneration derived from adult NSCs is not significant, understanding how the behaviors of qNSCs are regulated sheds light on stimulating endogenous NSC-based neuronal regeneration. In this review, we mainly focus on the recent progress of the developmental origin and regulatory mechanisms that maintain qNSCs under normal conditions, and that mobilize qNSCs under pathological conditions, hoping to give some insights for future study.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Construction of an immunosensor based on Cys/Au@TiO2 modification for the detection of liver cancer marker PIVKA-II.

An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL-1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml-1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.

The Alterations in the Brain Corresponding to Low Back Pain: Recent Insights and Advances.

Low back pain (LBP) is a leading cause of global disabilities. Numerous molecular, cellular, and anatomical factors are implicated in LBP. Current issues regarding neurologic alterations in LBP have focused on the reorganization of peripheral nerve and spinal cord, but neural mechanisms of exactly what LBP impacts on the brain required further researches. Based on existing clinical studies that chronic pain problems were accompanying alterations in brain structures and functions, researchers proposed logical conjectures that similar alterations occur in LBP patients as well. With recent extensive studies carried out using noninvasive neuroimaging technique, increasing number of abnormalities and alterations has been identified. Here, we reviewed brain alterations including white matters, grey matters, and neural circuits between brain areas, which are involved in chronic LBP. Moreover, brain structural and functional connectivity abnormalities are correlated to the happening and transition of LBP. The negative emotions related to back pain indicate possible alterations in emotional brain regions. Thus, the aim of this review is to summarize current findings on the alterations corresponding to LBP in the brain. It will not only further our understanding of etiology of LBP and understanding of negative emotions accompanying with back pain but also provide ideas and basis for new accesses to the diagnosis, treatment, and rehabilitation afterward based on integral medicine.

High-efficiency recovery of valuable metals from spent lithium-ion batteries: Optimization of SO2 pressure leaching and selective extraction of trace impurities.

The recovery of valuable metals from spent lithium-ion batteries (LIBs) is crucial for environmental protection and resource optimization. In the traditional recovery process of spent LIBs, the leaching of high-valence metals has the problems of high cost and limited reagent utilization, and some valuable metals are lost in the subsequent purification process of the leaching solution. To reduce the cost of reagents, this study proposes the use of low-cost SO2 as a reagent combined with pressure leaching to efficiently recover high-valence metals from delithiated materials of spent LIBs, while selective solvent extraction is used to remove trace impurities in the leaching solution to avoid the loss of valuable metals. Experimental results demonstrated that by optimizing the conditions to 0.25 MPa SO2 partial pressure and 60 min reaction time at 70 °C, the leaching efficiencies for Ni, Co, and Mn reached 99.6%, 99.3%, and 99.6%, respectively. The kinetic study indicated that the leaching process was diffusion-controlled. Furthermore, the delithiated materials were used to completely utilize the residual SO2 in the solution to obtain a high concentration Ni-Co-Mn rich solution. Subsequently, Fe and Al impurities were deeply removed through a synergistic extraction of Di-2-ethylhexyl phosphoric acid (D2EHPA) and tributyl phosphate (TBP) without loss of valuable metals, achieving a high-purity Ni-Co-Mn solution. The process developed based on this work has the characteristics of environmental friendliness, high valuable metal recovery, and high product purity, providing a reference technical method for the synergistic treatment of waste SO2 flue gas with spent LIBs and the deep purification of impurities in spent LIBs.

ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive-Like Behavior in Adolescent Mice.

Ca2+ signaling is essential for oligodendrocyte (OL) development and myelin formation. Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) is an endoplasmic reticulum calcium channel and shows stage-dependent high levels in postmitotic oligodendrocyte precursor cells (OPCs). The role and potential mechanism of ITPR2 in OLs remain unclear. In this study, it is revealed that loss of Itpr2 in OLs disturbs Ca2+ homeostasis and inhibits myelination in adolescent mice. Animals with OL-specific deletion of Itpr2 exhibit anxiety/depressive-like behaviors and manifest with interrupted OPC proliferation, leading to fewer mature OLs in the brain. Detailed transcriptome profiling and signal pathway analysis suggest that MAPK/ERK-CDK6/cyclin D1 axis underlies the interfered cell cycle progression in Itpr2 ablated OPCs. Besides, blocking MAPK/ERK pathway significantly improves the delayed OPC differentiation and myelination in Itpr2 mutant. Notably, the resting [Ca2+]i is increased in Itpr2 ablated OPCs, with the elevation of several plasma calcium channels. Antagonists against these plasma calcium channels can normalize the resting [Ca2+]i level and enhance lineage progression in Itpr2-ablated OPCs. Together, the findings reveal novel insights for calcium homeostasis in manipulating developmental transition from OPCs to pre-OLs; additionally, the involvement of OLs-originated ITPR2 in depressive behaviors provides new therapeutic strategies to alleviate myelin-associated psychiatric disorders.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model.

Impaired extinction of fear memory is one of the most common symptoms in post-traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD-ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle-based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD-related impaired extinction of fear memory and provide therapeutic insights into Kv3.2-targeted RNA therapy for PTSD.

CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex.

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR). Our findings suggest that local bilateral injection of CCR2 antagonist in the ACC inhibits CFA-induced inflammatory pain and anxiety-like behavior. Meanwhile, the expression of CCR2 and CCL2 was significantly increased in ACC after 14 days of intraplantar injection of CFA, and CCR2 was mainly expressed in excitatory neurons. Whole-cell patch-clamp recordings showed that the CCR2 inhibitor RS504393 reduced the frequency of miniature excitatory postsynaptic currents (mEPSC) in ACC, and CCL2 was involved in the regulation of NMDAR-induced current in ACC neurons in the pathological state. In addition, local injection of the NR2B inhibitor of NMDAR subunits, Ro 25-6981, attenuated the effects of CCL2-induced hyperalgesia and anxiety-like behavior in the ACC. In summary, CCL2 acts on CCR2 in ACC excitatory neurons and participates in the regulation of CFA-induced pain and related anxiety-like behaviors through upregulation of NR2B. CCR2 in the ACC neuron may be a potential target for the treatment of chronic inflammatory pain and pain-related anxiety.

Presynaptic glutamate receptors in nociception.

Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain.

Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons.

The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability.

PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons.

Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg2+/Mn2+ dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke.

Evidence for developmental vascular-associated necroptosis and its contribution to venous-lymphatic endothelial differentiation.

During development, apoptosis removes redundant cells and ensures proper organ morphogenesis. Necrosis is long known as an adult-bound inflammatory and pathologic cell death. Whether there exists physiological necrosis during early development has been speculated but yet clearly demonstrated. Here, we report evidence of necroptosis, a type of programmed necrosis, specifically in perivascular cells of cerebral cortex and skin at the early stage of development. Phosphorylated Mixed Lineage Kinase Domain-Like protein (MLKL), a key molecule in executing necroptosis, co-expressed with blood endothelial marker CD31 and venous-lymphatic progenitor marker Sox18. Depletion of Mlkl did not affect the formation of blood vessel network but increased the differentiation of venous-lymphatic lineage cells in postnatal cerebral cortex and skin. Consistently, significant enhancement of cerebrospinal fluid diffusion and lymphatic drainage was found in brain and skin of Mlkl-deficient mice. Under hypobaric hypoxia induced cerebral edema and inflammation induced skin edema, Mlkl mutation significantly attenuated brain-blood-barrier damage and edema formation. Our data, for the first time, demonstrated the presence of physiological vascular-associated necroptosis and its potential involvement in the development of venous-lymphatic vessels.

Alterations in synapses and mitochondria induced by acute or chronic intermittent hypoxia in the pre-Bötzinger complex of rats: an ultrastructural triple-labeling study with immunocytochemistry and histochemistry.

Introduction: The pre-Bötzinger complex (pre-BötC), a kernel of inspiratory rhythmogenesis, is a heterogeneous network with excitatory glutamatergic and inhibitory GABAergic and glycinergic neurons. Inspiratory rhythm generation relies on synchronous activation of glutamatergic neuron, whilst inhibitory neurons play a critical role in shaping the breathing pattern, endowing the rhythm with flexibility in adapting to environmental, metabolic, and behavioral needs. Here we report ultrastructural alterations in excitatory, asymmetric synapses (AS) and inhibitory, symmetric synapses (SS), especially perforated synapses with discontinuous postsynaptic densities (PSDs) in the pre-BötC in rats exposed to daily acute intermittent hypoxia (dAIH) or chronic (C) IH. Methods: We utilized for the first time a combination of somatostatin (SST) and neurokinin 1 receptor (NK1R) double immunocytochemistry with cytochrome oxidase histochemistry, to reveal synaptic characteristics and mitochondrial dynamic in the pre-BötC. Results: We found perforated synapses with synaptic vesicles accumulated in distinct pools in apposition to each discrete PSD segments. dAIH induced significant increases in the PSD size of macular AS, and the proportion of perforated synapses. AS were predominant in the dAIH group, whereas SS were in a high proportion in the CIH group. dAIH significantly increased SST and NK1R expressions, whereas CIH led to a decrease. Desmosome-like contacts (DLC) were characterized for the first time in the pre-BötC. They were distributed alongside of synapses, especially SS. Mitochondria appeared in more proximity to DLC than synapses, suggestive of a higher energy demand of the DLC. Findings of single spines with dual AS and SS innervation provide morphological evidence of excitation-inhibition interplay within a single spine in the pre-BötC. In particular, we characterized spine-shaft microdomains of concentrated synapses coupled with mitochondrial positioning that could serve as a structural basis for synchrony of spine-shaft communication. Mitochondria were found within spines and ultrastructural features of mitochondrial fusion and fission were depicted for the first time in the pre-BötC. Conclusion: We provide ultrastructural evidence of excitation-inhibition synapses in shafts and spines, and DLC in association with synapses that coincide with mitochondrial dynamic in their contribution to respiratory plasticity in the pre-BötC.

Spatial Distribution of Parvalbumin-Positive Fibers in the Mouse Brain and Their Alterations in Mouse Models of Temporal Lobe Epilepsy and Parkinson's Disease.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.