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 Agustín Carstens, General Manager of the BIS, at the Founding Ceremony, Swiss Centre BIS Innovation Hub, Zurich, 8 October 2019.

Original quotes from interview by Mr Agustin Carstens, General Manager of the BIS, with Exame, conducted by Mr Felipe Serrano on 9 October 2019 and published on 24 October 2019.

Speech by Mr Claudio Borio, Head of the Monetary and Economic Department of the BIS, at the OECD-G20 High Level Policy Seminar, Paris, 11 September 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.

Speech by Mr Claudio Borio, Head of the Monetary and Economic Department of the BIS, at the SUERF Annual Lecture Conference on "Populism, Economic Policies and Central Banking", SUERF/BAFFI CAREFIN Centre Conference, Milan, 8 November 2019.

Lecture by Claudio Borio, Head of the Monetary and Economic Department, at the University of Zürich, Zürich, 19 November 2019.

Original quotes from interview with Mr Claudio Borio, Head of the Monetary and Economic Department of the BIS, in Germany's Boerzen-Zeitung, conducted by Mr Mark Schroers and published on 21 November 2019.

Speech by Dr Agustín Carstens at the celebration of 25 years of Bank of Mexico independence, Mexico City, 22 November 2019.

Lecture by Mr Agustín Carstens, General Manager of the BIS, at the Princeton University, Princeton, New Jersey, 5 December 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.

Exiting low inflation traps by "consensus": nominal wages and price stability - Speech by Luiz A Pereira da Silva and Benoît Mojon, based on the keynote speech at the Eighth High-level Policy Dialogue between the Eurosystem and Latin American Central Banks, Cartagena de Indias, Colombia, 28-29 November 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.

Op-ed by Agustín Carstens published in the Financial Times on 29 March 2020.

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Once the search has begun, something will be found

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.

Knowledge about objects encompasses not only their prototypical features but also complex, atypical, semantic knowledge (e.g., "Pizza was invented in Naples"). This fMRI study of male and female human participants combines univariate and multivariate analyses to consider the cortical representation of this more complex semantic knowledge. Using the categories of food, people, and places, this study investigates whether access to spatially related geographic semantic knowledge (1) involves the same domain-selective neural representations involved in access to prototypical taste knowledge about food; and (2) elicits activation of neural representations classically linked to places when this geographic knowledge is accessed about food and people. In three experiments using word stimuli, domain-relevant and atypical conceptual access for the categories food, people, and places were assessed. Results uncover two principles of semantic representation: food-selective representations in the left insula continue to be recruited when prototypical taste knowledge is task-irrelevant and under conditions of high cognitive demand; access to geographic knowledge for food and people categories involves the additional recruitment of classically place-selective parahippocampal gyrus, retrosplenial complex, and transverse occipital sulcus. These findings underscore the importance of object category in the representation of a broad range of knowledge, while showing how the cross recruitment of specialized representations may endow the considerable flexibility of our complex semantic knowledge.

SIGNIFICANCE STATEMENT We know not only stereotypical things about objects (an apple is round, graspable, edible) but can also flexibly combine typical and atypical features to form complex concepts (the metaphorical role an apple plays in Judeo-Christian belief). In this fMRI study, we observe that, when atypical geographic knowledge is accessed about food dishes, domain-selective sensorimotor-related cortical representations continue to be recruited, but that regions classically associated with place perception are additionally engaged. This interplay between categorically driven representations, linked to the object being accessed, and the flexible recruitment of semantic stores linked to the content being accessed, provides a potential mechanism for the broad representational repertoire of our semantic system.

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.

Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In the experiments conducted in male laboratory rats we show that astrocytes of the nucleus of the solitary tract (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca²⁺]_i elevations. Astroglial [Ca²⁺]_i responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT_2A receptors. In conscious freely behaving animals blockade of Ca²⁺-dependent vesicular release mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% (p < 0.001). This effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP is considered the principle gliotransmitter and is released by vesicular mechanisms blocked by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, pharmacological activation of P2Y₁ purinoceptors in the NTS decreased baroreflex gain by 40% (p = 0.031), whereas blockade of P2Y₁ receptors increased baroreflex gain by 57% (p = 0.018). These results suggest that glutamate and 5-HT, released by NTS afferent terminals, trigger Ca²⁺-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y₁ receptors. These data add to the growing body of evidence supporting an active role of astrocytes in brain information processing.

SIGNIFICANCE STATEMENT Cardiorespiratory reflexes maintain autonomic balance and ensure cardiovascular health. Impaired baroreflex may contribute to the development of cardiovascular disease and serves as a robust predictor of cardiovascular and all-cause mortality. The data obtained in this study suggest that astrocytes are integral components of the brainstem mechanisms that process afferent information and modulate baroreflex sensitivity via the release of ATP. Any condition associated with higher levels of "ambient" ATP in the NTS would be expected to decrease baroreflex gain by the mechanism described here. As ATP is the primary signaling molecule of glial cells (astrocytes, microglia), responding to metabolic stress and inflammatory stimuli, our study suggests a plausible mechanism of how the central component of the baroreflex is affected in pathological conditions.

We can adapt flexibly to environment changes and search for the most appropriate rule to a context. The orbital prefrontal cortex (PFo) has been associated with decision making, rule generation and maintenance, and more generally has been considered important for behavioral flexibility. To better understand the neural mechanisms underlying the flexible behavior, we studied the ability to generate a switching signal in monkey PFo when a strategy is changed. In the strategy task, we used a visual cue to instruct two male rhesus monkeys either to repeat their most recent choice (i.e., stay strategy) or to change it (i.e., shift strategy). To identify the strategy switching-related signal, we compared nonswitch and switch trials, which cued the same or a different strategy from the previous trial, respectively. We found that the switching-related signal emerged during the cue presentation and it was combined with the strategy signal in a subpopulation of cells. Moreover, the error analysis showed that the activity of the switch-related cells reflected whether the monkeys erroneously switched or not the strategy, rather than what was required for that trial. The function of the switching signal could be to prompt the use of different strategies when older strategies are no longer appropriate, conferring the ability to adapt flexibly to environmental changes. In our task, the switching signal might contribute to the implementation of the strategy cued, overcoming potential interference effects from the strategy previously cued. Our results support the idea that ascribes to PFo an important role for behavioral flexibility.

SIGNIFICANCE STATEMENT We can flexibly adapt our behavior to a changing environment. One of the prefrontal areas traditionally associated with the ability to adapt to new contingencies is the orbital prefrontal cortex (PFo). We analyzed the switching related activity using a strategy task in which two rhesus monkeys were instructed by a visual cue either to repeat or change their most recent choice, respectively using a stay or a shift strategy. We found that PFo neurons were modulated by the strategy switching signal, pointing to the importance of PFo in behavioral flexibility by generating control over the switching of strategies.

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.

Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.

SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.

Adaptive coding of stimuli is well documented in perception, where it supports efficient encoding over a broad range of possible percepts. Recently, a similar neural mechanism has been reported also in value-based decision, where it allows optimal encoding of vast ranges of values in PFC: neuronal response to value depends on the choice context (relative coding), rather than being invariant across contexts (absolute coding). Additionally, value learning is sensitive to the amount of feedback information: providing complete feedback (both obtained and forgone outcomes) instead of partial feedback (only obtained outcome) improves learning. However, it is unclear whether relative coding occurs in all PFC regions and how it is affected by feedback information. We systematically investigated univariate and multivariate feedback encoding in various mPFC regions and compared three modes of neural coding: absolute, partially-adaptive and fully-adaptive.

Twenty-eight human participants (both sexes) performed a learning task while undergoing fMRI scanning. On each trial, they chose between two symbols associated with a certain outcome. Then, the decision outcome was revealed. Notably, in one-half of the trials participants received partial feedback, whereas in the other half they got complete feedback. We used univariate and multivariate analysis to explore value encoding in different feedback conditions.

We found that both obtained and forgone outcomes were encoded in mPFC, but with opposite sign in its ventral and dorsal subdivisions. Moreover, we showed that increasing feedback information induced a switch from absolute to relative coding. Our results suggest that complete feedback information enhances context-dependent outcome encoding.

SIGNIFICANCE STATEMENT This study offers a systematic investigation of the effect of the amount of feedback information (partial vs complete) on univariate and multivariate outcome value encoding, within multiple regions in mPFC and cingulate cortex that are critical for value-based decisions and behavioral adaptation. Moreover, we provide the first comparison of three possible models of neural coding (i.e., absolute, partially-adaptive, and fully-adaptive coding) of value signal in these regions, by using commensurable measures of prediction accuracy. Taken together, our results help build a more comprehensive picture of how the human brain encodes and processes outcome value. In particular, our results suggest that simultaneous presentation of obtained and foregone outcomes promotes relative value representation.

Revealing the organization and function of neural circuits is greatly facilitated by viral tools that spread transsynaptically. Adeno-associated virus (AAV) exhibits anterograde transneuronal transport, however, the synaptic specificity of this spread and its broad application within a diverse set of circuits remains to be explored. Here, using anatomic, functional, and molecular approaches, we provide evidence for the preferential transport of AAV1 to postsynaptically connected neurons and reveal its spread is strongly dependent on synaptic transmitter release. In addition to glutamatergic pathways, AAV1 also spreads through GABAergic synapses to both excitatory and inhibitory cell types. We observed little or no transport, however, through neuromodulatory projections (e.g., serotonergic, cholinergic, and noradrenergic). In addition, we found that AAV1 can be transported through long-distance descending projections from various brain regions to effectively transduce spinal cord neurons. Combined with newly designed intersectional and sparse labeling strategies, AAV1 can be applied within a wide variety of pathways to categorize neurons according to their input sources, morphology, and molecular identities. These properties make AAV1 a promising anterograde transsynaptic tool for establishing a comprehensive cell-atlas of the brain, although its capacity for retrograde transport currently limits its use to unidirectional circuits.

SIGNIFICANCE STATEMENT The discovery of anterograde transneuronal spread of AAV1 generates great promise for its application as a unique tool for manipulating input-defined cell populations and mapping their outputs. However, several outstanding questions remain for anterograde transsynaptic approaches in the field: (1) whether AAV1 spreads exclusively or specifically to synaptically connected neurons, and (2) how broad its application could be in various types of neural circuits in the brain. This study provides several lines of evidence in terms of anatomy, functional innervation, and underlying mechanisms, to strongly support that AAV1 anterograde transneuronal spread is highly synapse specific. In addition, several potentially important applications of transsynaptic AAV1 in probing neural circuits are described.

Endogenous neuropeptide Y (NPY) and corticotrophin-releasing factor (CRF) modulate the responses of the basolateral amygdala (BLA) to stress and are associated with the development of stress resilience and vulnerability, respectively. We characterized persistent effects of repeated NPY and CRF treatment on the structure and function of BLA principal neurons in a novel organotypic slice culture (OTC) model of male rat BLA, and examined the contributions of specific NPY receptor subtypes to these neural and behavioral effects. In BLA principal neurons within the OTCs, repeated NPY treatment caused persistent attenuation of excitatory input and induced dendritic hypotrophy via Y₅ receptor activation; conversely, CRF increased excitatory input and induced hypertrophy of BLA principal neurons. Repeated treatment of OTCs with NPY followed by an identical treatment with CRF, or vice versa, inhibited or reversed all structural changes in OTCs. These structural responses to NPY or CRF required calcineurin or CaMKII, respectively. Finally, repeated intra-BLA injections of NPY or a Y₅ receptor agonist increased social interaction, a validated behavior for anxiety, and recapitulated structural changes in BLA neurons seen in OTCs, while a Y₅ receptor antagonist prevented NPY's effects both on behavior and on structure. These results implicate the Y₅ receptor in the long-term, anxiolytic-like effects of NPY in the BLA, consistent with an intrinsic role in stress buffering, and highlight a remarkable mechanism by which BLA neurons may adapt to different levels of stress. Moreover, BLA OTCs offer a robust model to study mechanisms associated with resilience and vulnerability to stress in BLA.

SIGNIFICANCE STATEMENT Within the basolateral amygdala (BLA), neuropeptide Y (NPY) is associated with buffering the neural stress response induced by corticotropin releasing factor, and promoting stress resilience. We used a novel organotypic slice culture model of BLA, complemented with in vivo studies, to examine the cellular mechanisms associated with the actions of NPY. In organotypic slice cultures, repeated NPY treatment reduces the complexity of the dendritic extent of anxiogenic BLA principal neurons, making them less excitable. NPY, via activation of Y5 receptors, additionally inhibits and reverses the increases in dendritic extent and excitability induced by the stress hormone, corticotropin releasing factor. This NPY-mediated neuroplasticity indicates that resilience or vulnerability to stress may thus involve neuropeptide-mediated dendritic remodeling in BLA principal neurons.

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.

Giving birth triggers a wide repertoire of physiological and behavioral changes in the mother to enable her to feed and care for her offspring. These changes require coordination and are often orchestrated from the CNS, through as of yet poorly understood mechanisms. A neuronal population with a central role in puerperal changes is the tuberoinfundibular dopamine (TIDA) neurons that control release of the pituitary hormone, prolactin, which triggers key maternal adaptations, including lactation and maternal care. Here, we used Ca²⁺ imaging on mice from both sexes and whole-cell recordings on female mouse TIDA neurons in vitro to examine whether they adapt their cellular and network activity according to reproductive state. In the high-prolactin state of lactation, TIDA neurons shift to faster membrane potential oscillations, a reconfiguration that reverses upon weaning. During the estrous cycle, however, which includes a brief, but pronounced, prolactin peak, oscillation frequency remains stable. An increase in the hyperpolarization-activated mixed cation current, I_h, possibly through unmasking as dopamine release drops during nursing, may partially explain the reconfiguration of TIDA rhythms. These findings identify a reversible plasticity in hypothalamic network activity that can serve to adapt the dam for motherhood.

SIGNIFICANCE STATEMENT Motherhood requires profound behavioral and physiological adaptations to enable caring for offspring, but the underlying CNS changes are poorly understood. Here, we show that, during lactation, neuroendocrine dopamine neurons, the "TIDA" cells that control prolactin secretion, reorganize their trademark oscillations to discharge in faster frequencies. Unlike previous studies, which typically have focused on structural and transcriptional changes during pregnancy and lactation, we demonstrate a functional switch in activity and one that, distinct from previously described puerperal modifications, reverses fully on weaning. We further provide evidence that a specific conductance (I_h) contributes to the altered network rhythm. These findings identify a new facet of maternal brain plasticity at the level of membrane properties and consequent ensemble activity.

Neurons and circuits each with a distinct balance of intrinsic and synaptic conductances can generate similar behavior but sometimes respond very differently to perturbation. Examining a large family of circuit models with non-identical neurons and synapses underlying rhythmic behavior, we analyzed the circuits' response to modifications in single and multiple intrinsic conductances in the individual neurons. To summarize these changes over the entire range of perturbed parameters, we quantified circuit output by defining a global stability measure. Using this measure, we identified specific subsets of conductances that when perturbed generate similar behavior in diverse individuals of the population. Our unbiased clustering analysis enabled us to quantify circuit stability when simultaneously perturbing multiple conductances as a nonlinear combination of single conductance perturbations. This revealed surprising conductance combinations that can predict the response to specific perturbations, even when the remaining intrinsic and synaptic conductances are unknown. Therefore, our approach can expose hidden variability in the balance of intrinsic and synaptic conductances of the same neurons across different versions of the same circuit solely from the circuit response to perturbations. Developed for a specific family of model circuits, our quantitative approach to characterizing high-dimensional degenerate systems provides a conceptual and analytic framework to guide future theoretical and experimental studies on degeneracy and robustness.

SIGNIFICANCE STATEMENT Neural circuits can generate nearly identical behavior despite neuronal and synaptic parameters varying several-fold between individual instantiations. Yet, when these parameters are perturbed through channel deletions and mutations or environmental disturbances, seemingly identical circuits can respond very differently. What distinguishes inconsequential perturbations that barely alter circuit behavior from disruptive perturbations that drastically disturb circuit output remains unclear. Focusing on a family of rhythmic circuits, we propose a computational approach to reveal hidden variability in the intrinsic and synaptic conductances in seemingly identical circuits based solely on circuit output to different perturbations. We uncover specific conductance combinations that work similarly to maintain stability and predict the effect of changing multiple conductances simultaneously, which often results from neuromodulation or injury.

Phototransduction in Drosophila is mediated by phospholipase C (PLC) and Ca²⁺-permeable TRP channels, but the function of endoplasmic reticulum (ER) Ca²⁺ stores in this important model for Ca²⁺ signaling remains obscure. We therefore expressed a low affinity Ca²⁺ indicator (ER-GCaMP6-150) in the ER, and measured its fluorescence both in dissociated ommatidia and in vivo from intact flies of both sexes. Blue excitation light induced a rapid (tau ~0.8 s), PLC-dependent decrease in fluorescence, representing depletion of ER Ca²⁺ stores, followed by a slower decay, typically reaching ~50% of initial dark-adapted levels, with significant depletion occurring under natural levels of illumination. The ER stores refilled in the dark within 100–200 s. Both rapid and slow store depletion were largely unaffected in InsP₃ receptor mutants, but were much reduced in trp mutants. Strikingly, rapid (but not slow) depletion of ER stores was blocked by removing external Na⁺ and in mutants of the Na⁺/Ca²⁺ exchanger, CalX, which we immuno-localized to ER membranes in addition to its established localization in the plasma membrane. Conversely, overexpression of calx greatly enhanced rapid depletion. These results indicate that rapid store depletion is mediated by Na⁺/Ca²⁺ exchange across the ER membrane induced by Na⁺ influx via the light-sensitive channels. Although too slow to be involved in channel activation, this Na⁺/Ca²⁺ exchange-dependent release explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors exposed to Ca²⁺-free solutions.

SIGNIFICANCE STATEMENT Phototransduction in Drosophila is mediated by phospholipase C, which activates TRP cation channels by an unknown mechanism. Despite much speculation, it is unknown whether endoplasmic reticulum (ER) Ca²⁺ stores play any role. We therefore engineered flies expressing a genetically encoded Ca²⁺ indicator in the photoreceptor ER. Although NCX Na⁺/Ca²⁺ exchangers are classically believed to operate only at the plasma membrane, we demonstrate a rapid light-induced depletion of ER Ca²⁺ stores mediated by Na⁺/Ca²⁺ exchange across the ER membrane. This NCX-dependent release was too slow to be involved in channel activation, but explains the decades-old observation of a light-induced rise in cytosolic Ca²⁺ in photoreceptors bathed in Ca²⁺-free solutions.

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.

Gamma-band oscillations (GBOs) elicited by transient nociceptive stimuli are one of the most promising biomarkers of pain across species. Still, whether these GBOs reflect stimulus encoding in the primary somatosensory cortex (S1) or nocifensive behavior in the primary motor cortex (M1) is debated. Here we recorded neural activity simultaneously from the brain surface as well as at different depths of the bilateral S1/M1 in freely-moving male rats receiving nociceptive stimulation. GBOs measured from superficial layers of S1 contralateral to the stimulated paw not only had the largest magnitude, but also showed the strongest temporal and phase coupling with epidural GBOs. Also, spiking of superficial S1 interneurons had the strongest phase coherence with epidural GBOs. These results provide the first direct demonstration that scalp GBOs, one of the most promising pain biomarkers, reflect neural activity strongly coupled with the fast spiking of interneurons in the superficial layers of the S1 contralateral to the stimulated side.

SIGNIFICANCE STATEMENT Nociceptive-induced gamma-band oscillations (GBOs) measured at population level are one of the most promising biomarkers of pain perception. Our results provide the direct demonstration that these GBOs reflect neural activity coupled with the spike firing of interneurons in the superficial layers of the primary somatosensory cortex (S1) contralateral to the side of nociceptive stimulation. These results address the ongoing debate about whether nociceptive-induced GBOs recorded with scalp EEG or epidurally reflect stimulus encoding in the S1 or nocifensive behavior in the primary motor cortex (M1), and will therefore influence how experiments in pain neuroscience will be designed and interpreted.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.

SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.

Biases in sensory perception can arise from both experimental manipulations and personal trait-like features. These idiosyncratic biases and their neural underpinnings are often overlooked in studies on the physiology underlying perception. A potential candidate mechanism reflecting such idiosyncratic biases could be spontaneous alpha band activity, a prominent brain rhythm known to influence perceptual reports in general. Using a temporal order judgment task, we here tested the hypothesis that alpha power reflects the overcoming of an idiosyncratic bias. Importantly, to understand the interplay between idiosyncratic biases and contextual (temporary) biases induced by experimental manipulations, we quantified this relation before and after temporal recalibration. Using EEG recordings in human participants (male and female), we find that prestimulus frontal alpha power correlates with the tendency to respond relative to an own idiosyncratic bias, with stronger α leading to responses matching the bias. In contrast, alpha power does not predict response correctness. These results also hold after temporal recalibration and are specific to the alpha band, suggesting that alpha band activity reflects, directly or indirectly, processes that help to overcome an individual's momentary bias in perception. We propose that combined with established roles of parietal α in the encoding of sensory information frontal α reflects complementary mechanisms influencing perceptual decisions.

SIGNIFICANCE STATEMENT The brain is a biased organ, frequently generating systematically distorted percepts of the world, leading each of us to evolve in our own subjective reality. However, such biases are often overlooked or considered noise when studying the neural mechanisms underlying perception. We show that spontaneous alpha band activity predicts the degree of biasedness of human choices in a time perception task, suggesting that alpha activity indexes processes needed to overcome an individual's idiosyncratic bias. This result provides a window onto the neural underpinnings of subjective perception, and offers the possibility to quantify or manipulate such priors in future studies.

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to lateral parabrachial (LPB) neurons from the CeA in animals of either sex. Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin, and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.

SIGNIFICANCE STATEMENT We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin, and corticotropin-releasing hormone-expressing neurons in the CeA that project to the parabrachial nucleus. We show that this pathway regulates the activity of pain-related neurons in parabrachial nucleus, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

Stress alters brain function by modifying the structure and function of neurons and astrocytes. The fine processes of astrocytes are critical for the clearance of neurotransmitters during synaptic transmission. Thus, experience-dependent remodeling of glial processes is anticipated to alter the output of neural circuits. However, the molecular mechanisms that underlie glial structural plasticity are not known. Here we show that a single exposure of male and female mice to an acute stress produced a long-lasting retraction of the lateral processes of cerebellar Bergmann glial cells. These cells express the GluA1 subunit of AMPA-type glutamate receptors, and GluA1 knockdown is known to shorten the length of glial processes. We found that stress reduced the level of GluA1 protein and AMPA receptor-mediated currents in Bergmann glial cells, and these effects were absent in mice devoid of CPEB3, a protein that binds to GluA1 mRNA and regulates GluA1 protein synthesis. Administration of a β-adrenergic receptor blocker attenuated the reduction in GluA1, and deletion of adenylate cyclase 5 prevented GluA1 suppression. Therefore, stress suppresses GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway, and reduces the length of astrocyte lateral processes. Our results identify a novel mechanism for GluA1 subunit plasticity in non-neuronal cells and suggest a previously unappreciated role for AMPA receptors in stress-induced astrocytic remodeling.

SIGNIFICANCE STATEMENT Astrocytes play important roles in synaptic transmission by extending fine processes around synapses. In this study, we showed that a single exposure to an acute stress triggered a retraction of lateral/fine processes in mouse cerebellar astrocytes. These astrocytes express GluA1, a glutamate receptor subunit known to lengthen astrocyte processes. We showed that astrocytic structural changes are associated with a reduction of GluA1 protein levels. This requires activation of β-adrenergic receptors and is triggered by noradrenaline released during stress. We identified adenylyl cyclase 5, an enzyme that elevates cAMP levels, as a downstream effector and found that lowering GluA1 levels depends on CPEB3 proteins that bind to GluA1 mRNA. Therefore, stress regulates GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway in astrocytes and remodels their fine processes.

The Drosophila nervous system is ensheathed by a layer of outer glial cells, the perineurial glia, and a specialized extracellular matrix, the neural lamella. The function of perineurial glial cells and how they interact with the extracellular matrix are just beginning to be elucidated. Integrin-based focal adhesion complexes link the glial membrane to the extracellular matrix, but little is known about integrin's regulators in the glia. The transmembrane Ig domain protein Basigin/CD147/EMMPRIN is highly expressed in the perineurial glia surrounding the Drosophila larval nervous system. Here we show that Basigin associates with integrin at the focal adhesions to uphold the structure of the glia-extracellular matrix sheath. Knockdown of Basigin in perineurial glia using RNAi results in significant shortening of the ventral nerve cord, compression of the glia and extracellular matrix in the peripheral nerves, and reduction in larval locomotion. We determined that Basigin is expressed in close proximity to integrin at the glial membrane, and that expression of the extracellular integrin-binding domain of Basigin is sufficient to rescue peripheral glial compression. We also found that a reduction in expression of integrin at the membrane rescues the ventral nerve cord shortening, peripheral glial compression, and locomotor phenotypes, and that reduction in the integrin-binding protein Talin can partially rescue glial compression. These results identify Basigin as a potential negative regulator of integrin in the glia, supporting proper glial and extracellular matrix ensheathment of the nervous system.

SIGNIFICANCE STATEMENT The glial cells and extracellular matrix play important roles in supporting and protecting the nervous system, but the interactions between these components have not been well characterized. Our study identified expression of a conserved Ig superfamily protein, Basigin, at the glial membrane of Drosophila where it associates with the integrin-based focal adhesion complexes to ensure proper ensheathment of the CNS and PNS. Loss of Basigin in the glia results in an overall compression of the nervous system due to integrin dysregulation, which causes locomotor defects in the animals. This underlies the importance of glia-matrix communication for structural and functional support of the nervous system.