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To view more press releases, please visit http://www.snl.com/irweblinkx/news.aspx?iid=1024452.

Some of the troubling reports of corporate responses to COVID-19 include forced work in unsafe areas, not enough -- or any -- protection gear, massive layoffs and furloughs, and the sense that a critical mass of well-paid CEOs and politicians don't get that many people live paycheck to paycheck. There are exceptions though, and HP stands out, thanks to HR VP Tracy Keogh and CEO Enrique Lores.

Far-right groups and individuals in the United States are exploiting the COVID-19 pandemic to promote disinformation, hate, extremism and authoritarianism. "COVID-19 has been seized by far-right groups as an opportunity to call for extreme violence," states a report from ISD, based on a combination of natural language processing, network analysis and ethnographic online research.

Merchants soon will be able to sell products on Google Shopping at no charge. Previously, they had to pay per click, but the cost was not fixed. There was no minimum, but they had to set a maximum for ad spend and Google would stop displaying their ads once the maximum was reached. Starting next week, search results on the Google Shopping tab will consist primarily of free product listings.

The enterprise IT environment is complex. Many systems, technologies and practices developed at various times coexist in the same world. With expectations for technological advancements at their peak, we're tasked with enabling these systems to work together harmoniously to support the continuous sharing of information. Systems and data must connect as if all information were native to each.

Customer service doesn't have to suffer while your company goes through a difficult transition. In fact, 78 percent of consumers said they stopped doing business with a company because of poor customer service. Now is the time to show your most valuable buyers how you'll keep them informed, updated and respected throughout this crisis by adapting your practices to the moment.

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02020-02-03: Pink Lakes in Tunisia

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Speech by Mr Agustín Carstens, General Manager of the BIS, to the Basler Bankenforum, Basel, 5 September 2019.

Welcoming remarks by Mr Fernando Restoy, Chairman, Financial Stability Institute, Bank for International Settlements, at the FSI-IADI conference on crisis management, resolution and deposit insurance: what's next and how to prepare, Basel, 4 September 2019.

On-the-record remarks of the September 2019 Quarterly Review media briefing by Mr Claudio Borio, Head of the Monetary and Economic Department, and Mr Hyun Song Shin, Economic Adviser and Head of Research, 20 September 2019.

Speech by Mr Agustín Carstens, General Manager of the BIS, at the Fourteenth ASBA-BCBS-FSI High-level Meeting on Global and Regional Supervisory Priorities, Lima, 1 October 2019.

Speech by Mr Fernando Restoy, Chairman, Financial Stability Institute, Bank for International Settlements, at the ASBA-BID-FELABAN XVI Banking public-private sector regional policy dialogue "Challenges and opportunities in the new financial ecosystem", Washington DC, 16 October 2019.

Op-ed by Mr Claudio Borio, Head of the Monetary and Economic Department of the BIS, published in Il Sole 24 Ore, 8 November 2019.

On-the-record remarks of the December 2019 Quarterly Review media briefing by Mr Claudio Borio, Head of the Monetary and Economic Department, and Mr Hyun Song Shin, Economic Adviser and Head of Research, 6 December 2019.

On-the-record remarks of the March 2020 Quarterly Review media briefing by Mr Claudio Borio, Head of the Monetary and Economic Department, and Mr Hyun Song Shin, Economic Adviser and Head of Research, 28 February 2020.

Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by overstimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterization of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterize a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties of the auditory receptors remain unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialized receptor lymph that bathes the auditory receptors, revealing striking parallels with the mammalian auditory system.

SIGNIFICANCE STATEMENT Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive sound-induced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to, for the first time in any animal, characterize changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something that we show rings true for invertebrate ears too.

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bβ2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bβ2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bβ2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca²⁺ homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bβ2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bβ2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bβ2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.

SIGNIFICANCE STATEMENT With recent advances in clinical practice including mechanical thrombectomy up to 24 h after the ischemic event, there is resurgent interest in neuroprotective stroke therapies. In this study, we demonstrate reduced stroke damage in the brain of mice lacking the Bβ2 regulatory subunit of protein phosphatase 2A, which we have shown previously acts as a positive regulator of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Importantly, we provide evidence that deletion of Bβ2 can rescue excessive ischemic damage in mice lacking the mitochondrial PKA scaffold AKAP1, apparently via opposing effects on Drp1 S637 phosphorylation. These results highlight reversible phosphorylation in bidirectional regulation of Drp1 activity and identify Bβ2 as a potential pharmacological target to protect the brain from stroke injury.

Krabbe's disease is an infantile neurodegenerative disease, which is affected by mutations in the lysosomal enzyme galactocerebrosidase, leading to the accumulation of its metabolite psychosine. We have shown previously that the S1P receptor agonist fingolimod (FTY720) attenuates psychosine-induced glial cell death and demyelination both in vitro and ex vivo models. These data, together with a lack of therapies for Krabbe's disease, prompted the current preclinical study examining the effects of fingolimod in twitcher mice, a murine model of Krabbe's disease. Twitcher mice, both male and female, carrying a natural mutation in the galc gene were given fingolimod via drinking water (1 mg/kg/d). The direct impact of fingolimod administration was assessed via histochemical and biochemical analysis using markers of myelin, astrocytes, microglia, neurons, globoid cells, and immune cells. The effects of fingolimod on twitching behavior and life span were also demonstrated. Our results show that treatment of twitcher mice with fingolimod significantly rescued myelin levels compared with vehicle-treated animals and also regulated astrocyte and microglial reactivity. Furthermore, nonphosphorylated neurofilament levels were decreased, indicating neuroprotective and neurorestorative processes. These protective effects of fingolimod on twitcher mice brain pathology was reflected by an increased life span of fingolimod-treated twitcher mice. These in vivo findings corroborate initial in vitro studies and highlight the potential use of S1P receptors as drug targets for treatment of Krabbe's disease.

SIGNIFICANCE STATEMENT This study demonstrates that the administration of the therapy known as fingolimod in a mouse model of Krabbe's disease (namely, the twitcher mouse model) significantly rescues myelin levels. Further, the drug fingolimod also regulates the reactivity of glial cells, astrocytes and microglia, in this mouse model. These protective effects of fingolimod result in an increased life span of twitcher mice.

A prominent theory claims that the right temporoparietal junction (rTPJ) is especially associated with embodied processes relevant to perspective-taking. In the present study, we use high-definition transcranial direct current stimulation to provide evidence that the rTPJ is causally associated with the embodied processes underpinning perspective-taking. Eighty-eight young human adults were stratified to receive either rTPJ or dorsomedial PFC anodal high-definition transcranial direct current stimulation in a sham-controlled, double-blind, repeated-measures design. Perspective-tracking (line-of-sight) and perspective-taking (embodied rotation) were assessed using a visuo-spatial perspective-taking task that required understanding what another person could see or how they see it, respectively. Embodied processing was manipulated by positioning the participant in a manner congruent or incongruent with the orientation of an avatar on the screen. As perspective-taking, but not perspective-tracking, is influenced by bodily position, this allows the investigation of the specific causal role for the rTPJ in embodied processing. Crucially, anodal stimulation to the rTPJ increased the effect of bodily position during perspective-taking, whereas no such effects were identified during perspective-tracking, thereby providing evidence for a causal role for the rTPJ in the embodied component of perspective-taking. Stimulation to the dorsomedial PFC had no effect on perspective-tracking or taking. Therefore, the present study provides support for theories postulating that the rTPJ is causally involved in embodied cognitive processing relevant to social functioning.

SIGNIFICANCE STATEMENT The ability to understand another's perspective is a fundamental component of social functioning. Adopting another perspective is thought to involve both embodied and nonembodied processes. The present study used high-definition transcranial direct current stimulation (HD-tDCS) and provided causal evidence that the right temporoparietal junction is involved specifically in the embodied component of perspective-taking. Specifically, HD-tDCS to the right temporoparietal junction, but not another hub of the social brain (dorsomedial PFC), increased the effect of body position during perspective-taking, but not tracking. This is the first causal evidence that HD-tDCS can modulate social embodied processing in a site-specific and task-specific manner.

The cerebellum influences motor control through Purkinje target neurons, which transmit cerebellar output. Such output is required, for instance, for larval zebrafish to learn conditioned fictive swimming. The output cells, called eurydendroid neurons (ENs) in teleost fish, are inhibited by Purkinje cells and excited by parallel fibers. Here, we investigated the electrophysiological properties of glutamatergic ENs labeled by the transcription factor olig2. Action potential firing and synaptic responses were recorded in current clamp and voltage clamp from olig2⁺ neurons in immobilized larval zebrafish (before sexual differentiation) and were correlated with motor behavior by simultaneous recording of fictive swimming. In the absence of swimming, olig2⁺ ENs had basal firing rates near 8 spikes/s, and EPSCs and IPSCs were evident. Comparing Purkinje firing rates and eurydendroid IPSC rates indicated that 1-3 Purkinje cells converge onto each EN. Optogenetically suppressing Purkinje simple spikes, while preserving complex spikes, suggested that eurydendroid IPSC size depended on presynaptic spike duration rather than amplitude. During swimming, EPSC and IPSC rates increased. Total excitatory and inhibitory currents during sensory-evoked swimming were both more than double those during spontaneous swimming. During both spontaneous and sensory-evoked swimming, the total inhibitory current was more than threefold larger than the excitatory current. Firing rates of ENs nevertheless increased, suggesting that the relative timing of IPSCs and EPSCs may permit excitation to drive additional eurydendroid spikes. The data indicate that olig2⁺ cells are ENs whose activity is modulated with locomotion, suiting them to participate in sensorimotor integration associated with cerebellum-dependent learning.

SIGNIFICANCE STATEMENT The cerebellum contributes to movements through signals generated by cerebellar output neurons, called eurydendroid neurons (ENs) in fish (cerebellar nuclei in mammals). ENs receive sensory and motor signals from excitatory parallel fibers and inhibitory Purkinje cells. Here, we report electrophysiological recordings from ENs of larval zebrafish that directly illustrate how synaptic inhibition and excitation are integrated by cerebellar output neurons in association with motor behavior. The results demonstrate that inhibitory and excitatory drive both increase during fictive swimming, but inhibition greatly exceeds excitation. Firing rates nevertheless increase, providing evidence that synaptic integration promotes cerebellar output during locomotion. The data offer a basis for comparing aspects of cerebellar coding that are conserved and that diverge across vertebrates.

During differentiation, oligodendrocyte precursor cells (OPCs) extend a network of processes that make contact with axons and initiate myelination. Recent studies revealed that actin polymerization is required for initiation of myelination whereas actin depolymerization promotes myelin wrapping. Here, we used primary OPCs in culture isolated from neonatal rat cortices of both sexes and young male and female mice with oligodendrocyte-specific deletion of mechanistic target of rapamycin (mTOR) to demonstrate that mTOR regulates expression of specific cytoskeletal targets and actin reorganization in oligodendrocytes during developmental myelination. Loss or inhibition of mTOR reduced expression of profilin2 and ARPC3, actin polymerizing factors, and elevated levels of active cofilin, which mediates actin depolymerization. The deficits in actin polymerization were revealed in reduced phalloidin and deficits in oligodendrocyte cellular branching complexity at the peak of morphologic differentiation and a delay in initiation of myelination. We further show a critical role for mTOR in expression and localization of myelin basic protein (Mbp) mRNA and MBP protein to the cellular processes where it is necessary at the myelin membrane for axon wrapping. Mbp mRNA transport deficits were confirmed by single molecule RNA FISH. Moreover, expression of the kinesin family member 1B, an Mbp mRNA transport protein, was reduced in CC1+ cells in the mTOR cKO and in mTOR inhibited oligodendrocytes undergoing differentiation in vitro. These data support the conclusion that mTOR regulates both initiation of myelination and axon wrapping by targeting cytoskeletal reorganization and MBP localization to oligodendrocyte processes.

SIGNIFICANCE STATEMENT Myelination is essential for normal CNS development and adult axon preservation and function. The mechanistic target of rapamycin (mTOR) signaling pathway has been implicated in promoting CNS myelination; however, there is a gap in our understanding of the mechanisms by which mTOR promotes developmental myelination through regulating specific downstream targets. Here, we present evidence that mTOR promotes the initiation of myelination through regulating specific cytoskeletal targets and cellular process expansion by oligodendrocyte precursor cells as well as expression and cellular localization of myelin basic protein.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

It has been proposed that people can generate probabilistic predictions at multiple levels of representation during language comprehension. We used magnetoencephalography (MEG) and electroencephalography (EEG), in combination with representational similarity analysis, to seek neural evidence for the prediction of animacy features. In two studies, MEG and EEG activity was measured as human participants (both sexes) read three-sentence scenarios. Verbs in the final sentences constrained for either animate or inanimate semantic features of upcoming nouns, and the broader discourse context constrained for either a specific noun or for multiple nouns belonging to the same animacy category. We quantified the similarity between spatial patterns of brain activity following the verbs until just before the presentation of the nouns. The MEG and EEG datasets revealed converging evidence that the similarity between spatial patterns of neural activity following animate-constraining verbs was greater than following inanimate-constraining verbs. This effect could not be explained by lexical-semantic processing of the verbs themselves. We therefore suggest that it reflected the inherent difference in the semantic similarity structure of the predicted animate and inanimate nouns. Moreover, the effect was present regardless of whether a specific word could be predicted, providing strong evidence for the prediction of coarse-grained semantic features that goes beyond the prediction of individual words.

SIGNIFICANCE STATEMENT Language inputs unfold very quickly during real-time communication. By predicting ahead, we can give our brains a "head start," so that language comprehension is faster and more efficient. Although most contexts do not constrain strongly for a specific word, they do allow us to predict some upcoming information. For example, following the context of "they cautioned the...," we can predict that the next word will be animate rather than inanimate (we can caution a person, but not an object). Here, we used EEG and MEG techniques to show that the brain is able to use these contextual constraints to predict the animacy of upcoming words during sentence comprehension, and that these predictions are associated with specific spatial patterns of neural activity.

The PFC, through its high degree of interconnectivity with cortical and subcortical brain areas, mediates cognitive and emotional processes in support of adaptive behaviors. This includes the formation of fear memories when the anticipation of threat demands learning about temporal or contextual cues, as in trace fear conditioning. In this variant of fear learning, the association of a cue and shock across an empty trace interval of several seconds requires sustained cue-elicited firing in the prelimbic cortex (PL). However, it is unknown how and when distinct PL afferents contribute to different associative components of memory. Among the prominent inputs to PL, the hippocampus shares with PL a role in both working memory and contextual processing. Here we tested the necessity of direct hippocampal input to the PL for the acquisition of trace-cued fear memory and the simultaneously acquired contextual fear association. Optogenetic silencing of ventral hippocampal (VH) terminals in the PL of adult male Long-Evans rats selectively during paired trials revealed that direct communication between the VH and PL during training is necessary for contextual fear memory, but not for trace-cued fear acquisition. The pattern of the contextual memory deficit and the disruption of local PL firing during optogenetic silencing of VH-PL suggest that the VH continuously updates the PL with the current contextual state of the animal, which, when disrupted during memory acquisition, is detrimental to the subsequent rapid retrieval of aversive contextual associations.

SIGNIFICANCE STATEMENT Learning to anticipate threat from available contextual and discrete cues is crucial for survival. The prelimbic cortex is required for forming fear memories when temporal or contextual complexity is involved, as in trace fear conditioning. However, the respective contribution of distinct prelimbic afferents to the temporal and contextual components of memory is not known. We report that direct input from the ventral hippocampus enables the formation of the contextual, but not trace-cued, fear memory necessary for the subsequent rapid expression of a fear response. This finding dissociates the contextual and working-memory contributions of prelimbic cortex to the formation of a fear memory and demonstrates the crucial role for hippocampal input in contextual fear learning.

Prohibitin (PHB) is a critical protein involved in many cellular activities. In brain, PHB resides in mitochondria, where it forms a large protein complex with PHB2 in the inner TFmembrane, which serves as a scaffolding platform for proteins involved in mitochondrial structural and functional integrity. PHB overexpression at moderate levels provides neuroprotection in experimental brain injury models. In addition, PHB expression is involved in ischemic preconditioning, as its expression is enhanced in preconditioning paradigms. However, the mechanisms of PHB functional regulation are still unknown. Observations that nitric oxide (NO) plays a key role in ischemia preconditioning compelled us to postulate that the neuroprotective effect of PHB could be regulated by NO. Here, we test this hypothesis in a neuronal model of ischemia–reperfusion injury and show that NO and PHB are mutually required for neuronal resilience against oxygen and glucose deprivation stress. Further, we demonstrate that NO post-translationally modifies PHB through protein S-nitrosylation and regulates PHB neuroprotective function, in a nitric oxide synthase-dependent manner. These results uncover the mechanisms of a previously unrecognized form of molecular regulation of PHB that underlies its neuroprotective function.

SIGNIFICANCE STATEMENT Prohibitin (PHB) is a critical mitochondrial protein that exerts a potent neuroprotective effect when mildly upregulated in mice. However, how the neuroprotective function of PHB is regulated is still unknown. Here, we demonstrate a novel regulatory mechanism for PHB that involves nitric oxide (NO) and shows that PHB and NO interact directly, resulting in protein S-nitrosylation on residue Cys⁶⁹ of PHB. We further show that nitrosylation of PHB may be essential for its ability to preserve neuronal viability under hypoxic stress. Thus, our study reveals a previously unknown mechanism of functional regulation of PHB that has potential therapeutic implications for neurologic disorders.

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

Microglial cells are considered as sensors of brain pathology by detecting any sign of brain lesions, infections, or dysfunction and can influence the onset and progression of neurological diseases. They are capable of sensing their neuronal environment via many different signaling molecules, such as neurotransmitters, neurohormones and neuropeptides. The neuropeptide VGF has been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide and has been shown to signal via C3aR1 and C1qBP receptors. The effect of TLQP21 on microglial functions in health or disease is not known. Studying microglial cells in acute brain slices, we found that TLQP21 impaired metabotropic purinergic signaling. Specifically, it attenuated the ATP-induced activation of a K⁺ conductance, the UDP-stimulated phagocytic activity, and the ATP-dependent laser lesion-induced process outgrowth. These impairments were reversed by blocking C1qBP, but not C3aR1 receptors. While microglia in brain slices from male mice lack C3aR1 receptors, both receptors are expressed in primary cultured microglia. In addition to the negative impact on purinergic signaling, we found stimulating effects of TLQP21 in cultured microglia, which were mediated by C3aR1 receptors: it directly evoked membrane currents, stimulated basal phagocytic activity, evoked intracellular Ca²⁺ transient elevations, and served as a chemotactic signal. We conclude that TLQP21 has differential effects on microglia depending on C3aR1 activation or C1qBP-dependent attenuation of purinergic signaling. Thus, TLQP21 can modulate the functional phenotype of microglia, which may have an impact on their function in health and disease.

SIGNIFICANCE STATEMENT The neuropeptide VGF and its peptides have been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide that activates C1qBP receptors, which are expressed by microglia. We show here, for the first time, that TLQP21 impairs P2Y-mediated purinergic signaling and related functions. These include modulation of phagocytic activity and responses to injury. As purinergic signaling is central for microglial actions in the brain, this TLQP21-mediated mechanism might regulate microglial activity in health and disease. We furthermore show that, in addition to C1qBP, functional C3aR1 responses contribute to TLQP21 action on microglia. However, C3aR1 responses were only present in primary cultures but not in situ, suggesting that the expression of these receptors might vary between different microglial activation states.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

Priming refers to the influence that a previously encountered object exerts on future responses to similar objects. For many years, visual priming has been known as a facilitation and sometimes an inhibition effect that lasts for an extended period of time. It contrasts with the recent finding of an oscillated priming effect where facilitation and inhibition alternate over time periodically. Here we developed a computational model of visual priming that combines rhythmic sampling of the environment (attentional oscillation) with active preparation for future events (temporal expectation). Counterintuitively, it shows that both the sustained and oscillated priming effects can emerge from an interaction between attentional oscillation and temporal expectation. The interaction also leads to novel predictions, such as the change of visual priming effects with temporal expectation and attentional oscillation. Reanalysis of two published datasets and the results of two new experiments of visual priming tasks with male and female human participants provide support for the model's relevance to human behavior. More generally, our model offers a new perspective that may unify the increasing findings of behavioral and neural oscillations with the classic findings in visual perception and attention.

SIGNIFICANCE STATEMENT There is increasing behavioral and neural evidence that visual attention is a periodic process that sequentially samples different alternatives in the theta frequency range. It contrasts with the classic findings of sustained facilitatory or inhibitory attention effects. How can an oscillatory perceptual process give rise to sustained attention effects? Here we make this connection by proposing a computational model for a "fruit fly" visual priming task and showing both the sustained and oscillated priming effects can have the same origin: an interaction between rhythmic sampling of the environment and active preparation for future events. One unique contribution of our model is to predict how temporal contexts affects priming. It also opens up the possibility of reinterpreting other attention-related classic phenomena.