Neural circuits underlying a psychotherapeutic regimen for fear disorders.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Spatial and temporal diversity of glycome expression in mammalian brain.

Mammalian brain glycome remains a relatively poorly understood area compared to other large-scale "omics" studies, such as genomics and transcriptomics due to the inherent complexity and heterogeneity of glycan structure and properties. Here, we first performed spatial and temporal analysis of glycome expression patterns in the mammalian brain using a cutting-edge experimental tool based on liquid chromatography-mass spectrometry, with the ultimate aim to yield valuable implications on molecular events regarding brain functions and development. We observed an apparent diversity in the glycome expression patterns, which is spatially well-preserved among nine different brain regions in mouse. Next, we explored whether the glycome expression pattern changes temporally during postnatal brain development by examining the prefrontal cortex (PFC) at different time point across six postnatal stages in mouse. We found that glycan expression profiles were dynamically regulated during postnatal developments. A similar result was obtained in PFC samples from humans ranging in age from 39 d to 49 y. Novel glycans unique to the brain were also identified. Interestingly, changes primarily attributed to sialylated and fucosylated glycans were extensively observed during PFC development. Finally, based on the vast heterogeneity of glycans, we constructed a core glyco-synthesis map to delineate the glycosylation pathway responsible for the glycan diversity during the PFC development. Our findings reveal high levels of diversity in a glycosylation program underlying brain region specificity and age dependency, and may lead to new studies exploring the role of glycans in spatiotemporally diverse brain functions.

Hexaazatriphenylene-Based Two-Dimensional Conductive Covalent Organic Framework with Anisotropic Charge Transfer.

The development of covalent organic frameworks (COFs) with efficient charge transport is of immense interest for applications in optoelectronic devices. To enhance COF charge transport properties, electroactive building blocks and dopants can be used to induce extended conduction channels. However, understanding their intricate interplay remains challenging. We designed and synthesized a tailor-made COF structure with electroactive hexaazatriphenylene (HAT) core units and planar dioxin (D) linkages, denoted as HD-COF. With the support of theoretical calculations, we found that the HAT units in the HD-COF induce strong, eclipsed π-π stacking. The unique stacking of HAT units and the weak in-plane conjugation of dioxin linkages leads to efficient anisotropic charge transport. We fabricated HD-COF films to minimize the grain boundary effect of bulk COFs, which resulted in enhanced conductivity. As a result, the HD-COF films showed an electrical conductivity as high as 1.25 S cm-1 after doping with tris(4-bromophenyl)ammoniumyl hexachloroantimonate.

Extreme Enhancement of Carbon Hydrogasification via Mechanochemistry.

Carbon hydrogasification is the slowest reaction among all carbon-involved small-molecule transformations. Here, we demonstrate a mechanochemical method that results in both a faster reaction rate and a new synthesis route. The reaction rate was dramatically enhanced by up to 4 orders of magnitude compared to the traditional thermal method. Simultaneously, the reaction exhibited very high selectivity (99.8 % CH4 , versus 80 % under thermal conditions) with a cobalt catalyst. Our study demonstrated that this extreme increase in reaction rate originates from the continuous activation of reactive carbon species via mechanochemistry. The high selectivity is intimately related to the activation at low temperature, at which higher hydrocarbons are difficult to form. This work is expected to advance studies of carbon hydrogasification, and other solid-gas reactions.

LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory.

Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.

Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm.

Exploratory drive is one of the most fundamental emotions, of all organisms, that are evoked by novelty stimulation. Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. Diverse exploratory behaviors have been described, although their heterogeneity is not certain because of the lack of solid experimental evidence for their distinction. Here we present results demonstrating that different neural mechanisms underlie different exploratory behaviors. Localized Cav3.1 knockdown in the medial septum (MS) selectively enhanced object exploration, whereas the null mutant (KO) mice showed enhanced-object exploration as well as open-field exploration. In MS knockdown mice, only type 2 hippocampal theta rhythm was enhanced, whereas both type 1 and type 2 theta rhythm were enhanced in KO mice. This selective effect was accompanied by markedly increased excitability of septo-hippocampal GABAergic projection neurons in the MS lacking T-type Ca(2+) channels. Furthermore, optogenetic activation of the septo-hippocampal GABAergic pathway in WT mice also selectively enhanced object exploration behavior and type 2 theta rhythm, whereas inhibition of the same pathway decreased the behavior and the rhythm. These findings define object exploration distinguished from open-field exploration and reveal a critical role of T-type Ca(2+) channels in the medial septal GABAergic projection neurons in this behavior.

Defect-Free Encapsulation of Fe0 in 2D Fused Organic Networks as a Durable Oxygen Reduction Electrocatalyst.

Because they provide lower cost but comparable activity to precious platinum (Pt)-based catalysts, nonprecious iron (Fe)-based materials, such as Fe/Fe3C and Fe-N-C, have gained considerable attention as electrocatalysts for the oxygen reduction reaction (ORR). However, their practical application is hindered by their poor stability, which is attributed to the defective protection of extremely unstable Fe nanoparticles. Here, we introduce a synthesis strategy for a stable Fe-based electrocatalyst, which was realized by defect-free encapsulation of Fe nanoparticles using a two-dimensional (2D) phenazine-based fused aromatic porous organic network (Aza-PON). The resulting Fe@Aza-PON catalyst showed electrocatalytic activity (half-wave potential, 0.839 V; Tafel slope, 60 mV decade-1) comparable to commercial Pt on activated carbon (Pt/C, 0.826 V and 90 mV decade-1). More importantly, the Fe@Aza-PON displayed outstanding stability (zero current loss even after 100 000 cycles) and tolerance against contamination (methanol and CO poisoning). In a hybrid Li-air battery test, the Fe@Aza-PON demonstrated performance superior to Pt/C.

Knockdown of phospholipase C-ß1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes.

BACKGROUND: Decreased expression of phospholipase C-ß1 (PLC-ß1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-ß1 expression and the pathogenesis of schizophrenia. Although PLC-ß1-null (PLC-ß1(-/-)) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-ß1 expression in the brain contribute to specific behavioural defects. METHODS: We selectively knocked down PLC-ß1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice. RESULTS: Silencing PLC-ß1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophrenia-related behaviours observed in PLC-ß1-/- mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-ß1 knockdown mice. LIMITATIONS: Phenotypes of PLC-ß1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia. CONCLUSION: These results indicate that PLC-ß1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-ß1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.

Adaptive traits of Nitrosocosmicus clade ammonia-oxidizing archaea.

Nitrification is a core process in the global nitrogen (N) cycle mediated by ammonia-oxidizing microorganisms, including ammonia-oxidizing archaea (AOA) as a key player. Although much is known about AOA abundance and diversity across environments, the genetic drivers of the ecophysiological adaptations of the AOA are often less clearly defined. This is especially true for AOA within the genus Nitrosocosmicus, which have several unique physiological traits (e.g., high substrate tolerance, low substrate affinity, and large cell size). To better understand what separates the physiology of Nitrosocosmicus AOA, we performed comparative genomics with genomes from 39 cultured AOA, including five Nitrosocosmicus AOA. The absence of a canonical high-affinity type ammonium transporter and typical S-layer structural genes was found to be conserved across all Nitrosocosmicus AOA. In agreement, cryo-electron tomography confirmed the absence of a visible outermost S-layer structure, which has been observed in other AOA. In contrast to other AOA, the cryo-electron tomography highlighted the possibility that Nitrosocosmicus AOA may possess a glycoprotein or glycolipid-based glycocalyx cell covering outer layer. Together, the genomic, physiological, and metabolic properties revealed in this study provide insight into niche adaptation mechanisms and the overall ecophysiology of members of the Nitrosocosmicus clade in various terrestrial ecosystems. IMPORTANCE: Nitrification is a vital process within the global biogeochemical nitrogen cycle but plays a significant role in the eutrophication of aquatic ecosystems and the production of the greenhouse gas nitrous oxide (N2O) from industrial agriculture ecosystems. While various types of ammonia-oxidizing microorganisms play a critical role in the N cycle, ammonia-oxidizing archaea (AOA) are often the most abundant nitrifiers in natural environments. Members of the genus Nitrosocosmicus are one of the prevalent AOA groups detected in undisturbed terrestrial ecosystems and have previously been reported to possess a range of physiological characteristics that set their physiology apart from other AOA species. This study provides significant progress in understanding these unique physiological traits and their genetic drivers. Our results highlight how physiological studies based on comparative genomics-driven hypotheses can contribute to understanding the unique niche of Nitrosocosmicus AOA.

Deciphering mouse brain spatial diversity via glyco-lipidomic mapping.

Gangliosides in the brain play a crucial role in modulating the integrity of vertebrate central nervous system in a region-specific manner. However, to date, a comprehensive structural elucidation of complex intact ganglioside isomers has not been achieved, resulting in the elusiveness into related molecular mechanism. Here, we present a glycolipidomic approach for isomer-specific and brain region-specific profiling of the mouse brain. Considerable region-specificity and commonality in specific group of regions are highlighted. Notably, we observe a similarity in the abundance of major isomers, GD1a and GD1b, within certain regions, which provides significant biological implications with interpretation through the lens of a theoretical retrosynthetic state-transition network. Furthermore, A glycocentric-omics approaches using gangliosides and N-glycans reveal a remarkable convergence in spatial dynamics, providing valuable insight into molecular interaction network. Collectively, this study uncovers the spatial dynamics of intact glyco-conjugates in the brain, which are relevant to regional function and accelerates the discovery of potential therapeutic targets for brain diseases.

Febrile Seizure Causes Deficit in Social Novelty, Gliosis, and Proinflammatory Cytokine Response in the Hippocampal CA2 Region in Rats.

Febrile seizure (FS), which occurs as a response to fever, is the most common seizure that occurs in infants and young children. FS is usually accompanied by diverse neuropsychiatric symptoms, including impaired social behaviors; however, research on neuropsychiatric disorders and hippocampal inflammatory changes following febrile seizure occurrences is very limited. Here, we provide evidence linking FS occurrence with ASD pathogenesis in rats. We developed an FS juvenile rats model and found ASD-like abnormal behaviors including deficits in social novelty, repetitive behaviors, and hyperlocomotion. In addition, FS model juvenile rats showed enhanced levels of gliosis and inflammation in the hippocampal CA2 region and cerebellum. Furthermore, abnormal levels of social and repetitive behaviors persisted in adults FS model rats. These findings suggest that the inflammatory response triggered by febrile seizures in young children could potentially serve as a mediator of social cognitive impairments.

Hemispherically lateralized rhythmic oscillations in the cingulate-amygdala circuit drive affective empathy in mice.

Observational fear, a form of emotional contagion, is thought to be a basic form of affective empathy. However, the neural process engaged at the specific moment when socially acquired information provokes an emotional response remains elusive. Here, we show that reciprocal projections between the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) in the right hemisphere are essential for observational fear, and 5-7 Hz neural oscillations were selectively increased in those areas at the onset of observational freezing. A closed-loop disruption demonstrated the causal relationship between 5-7 Hz oscillations in the cingulo-amygdala circuit and observational fear responses. The increase/decrease in theta power induced by optogenetic manipulation of the hippocampal theta rhythm bi-directionally modulated observational fear. Together, these results indicate that hippocampus-dependent 5-7 Hz oscillations in the cingulo-amygdala circuit in the right hemisphere are the essential component of the cognitive process that drives empathic fear, but not freezing, in general.

Deletion of phospholipase C beta4 in thalamocortical relay nucleus leads to absence seizures.

Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca(2+) currents. We recently demonstrated that the phospholipase C beta4 (PLCbeta4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T- and L-type Ca(2+) currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLCbeta4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLCbeta4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLCbeta4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca(2+) channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLCbeta4-deficient mice as a potential animal model for absence seizures.

Emotional and cognitive changes in chronic kidney disease.

Chronic kidney disease (CKD) leads to cognitive impairment and emotional changes. However, the precise mechanism underlying the crosstalk between the kidneys and the nervous system is not fully understood. Inflammation and cerebrovascular disease can influence the development of depression in CKD. CKD is one of the strongest risk factors for cognitive impairment. Moreover, cognitive impairment occurs in CKD as patients experience the dysregulation of several brain functional domains due to damage caused to multiple cortical regions and to subcortical modulatory neurons. The differences in structural brain changes between CKD and non-CKD dementia may be attributable to the different mechanisms that occur in CKD. The kidney and brain have similar anatomical vascular systems, which may be susceptible to traditional risk factors. Vascular factors are assumed to be involved in the development of cognitive impairment in patients with CKD. Vascular injury induces white matter lesions, silent infarction, and microbleeds. Uremic toxins may also be directly related to cognitive impairment in CKD. Many uremic toxins, such as indoxyl sulfate, are likely to have an impact on the central nervous system. Further studies are required to identify therapeutic targets to prevent changes in the brain in patients with CKD.

Febrile Seizures Cause Depression and Anxiogenic Behaviors in Rats.

Febrile seizure (FS) is a common type of seizure occurring in human during infancy and childhood. Although an epileptic seizure is associated with psychiatric disorders and comorbid diseases such as depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment, and migraine, the causal relationship between FS and psychiatric disorders is poorly understood. The objective of the current study was to investigate the relationship of FS occurrence in childhood with the pathogenesis of anxiety disorder and depression using an FS rat model. We induced febrile seizures in infantile rats (11 days postnatal) using a mercury vapor lamp. At 3 weeks and 12 weeks after FS induction, we examined behaviors and recorded local field potentials (LFPs) to assess anxiety and depression disorder. Interestingly, after FS induction in infantile rats, anxiogenic behaviors and depression-like phenotypes were found in both adult and juvenile FS rats. The analysis of LFPs revealed that 4-7 Hz hippocampal theta rhythm, a neural oscillatory marker for anxiety disorder, was significantly increased in FS rats compared with their wild-type littermates. Taken together, our findings suggest that FS occurrence in infants is causally related to increased levels of anxiety-related behaviors and depression-like symptoms in juvenile and adult rodents.

Solution-Processable Semiconducting Conjugated Planar Network.

After the emergence of graphene in the material science field, top-down and bottom-up studies to develop semiconducting organic materials with layered structures became highly active. However, most of them have suffered from poor processability, which hampers device fabrication and frustrates practical applications. Here, we suggest an unconventional approach to fabricating semiconducting devices, which avoids the processability issue. We designed a soluble amorphous network using a solution process to form a thin film on a substrate. We then employed heat treatment to develop a flattened organic structure in the thin film, as an active layer for organic thin-film transistors (TFTs). The fabricated TFTs showed good performance in both horizontal and vertical charge transport, suggesting a versatile and useful approach for the development of organic semiconductors.

Phosphodiesterase-5 Inhibitor Attenuates Anxious Phenotypes and Movement Disorder Induced by Mild Ischemic Stroke in Rats.

OBJECTIVE: Patients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. METHODS: We divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. RESULTS: Sildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. CONCLUSION: PDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders.

Cognitive Sequelae and Hippocampal Dysfunction in Chronic Kidney Disease following 5/6 Nephrectomy.

Neurological disorders are prevalent in patients with chronic kidney disease (CKD). Vascular factors and uremic toxins are involved with cognitive impairment in CKD. In addition, vascular dementia-induced alterations in the structure and function of the hippocampus can lead to deficits in hippocampal synaptic plasticity and cognitive function. However, regardless of this clinical evidence, the pathophysiology of cognitive impairment in patients with CKD is not fully understood. We used male Sprague Dawley rats and performed 5/6 nephrectomy to observe the changes in behavior, field excitatory postsynaptic potential, and immunostaining of the hippocampus following CKD progression. We measured the hippocampus volume on magnetic resonance imaging scans in the controls (n = 34) and end-stage renal disease (ESRD) hemodialysis patients (n = 42). In four cognition-related behavior assays, including novel object recognition, Y-maze, Barnes maze, and classical contextual fear conditioning, we identified deficits in spatial working memory, learning and memory, and contextual memory, as well as the ability to distinguish familiar and new objects, in the rats with CKD. Immunohistochemical staining of Na+/H+ exchanger1 was increased in the hippocampus of the CKD rat models. We performed double immunofluorescent staining for aquaporin-4 and glial fibrillary acidic protein and then verified the high coexpression in the hippocampus of the CKD rat model. Furthermore, results from recoding of the field excitatory postsynaptic potential (fEPSP) in the hippocampus showed the reduced amplitude and slope of fEPSP in the CKD rats. ESRD patients with cognitive impairment showed a significant decrease in the hippocampus volume compared with ESRD patients without cognitive impairment or the controls. Our findings suggest that uremia resulting from decreased kidney function may cause the destruction of the blood-brain barrier and hippocampus-related cognitive impairment in CKD.

Affective empathy and prosocial behavior in rodents.

Empathy is an essential function for humans as social animals. Emotional contagion, the basic form of afffective empathy, comprises the cognitive process of perceiving and sharing the affective state of others. The observational fear assay, an animal model of emotional contagion, has enabled researchers to undertake molecular, cellular, and circuit mechanism of this behavior. Such studies have revealed that observational fear is mediated through neural circuits involved in processing the affective dimension of direct pain experiences. A mouse can also respond to milder social stimuli induced by either positive or negative emotional changes in another mouse, which seems not dependent on the affective pain circuits. Further studies should explore how different neural circuits contribute to integrating different dimensions of affective empathy.