Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to the bed nucleus of stria terminalis (BNST), which expresses OT receptors (OTRs) and vasopressin receptors, and governs fear responses. However, understanding the integrated role of AVP and OT is complicated by their cross-reactivity and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by cell-type-specific receptor selectivity and input specificity. We show that OTR-expressing BNST neurons, excited by hypothalamic AVP and OT inputs via OTR, play a major role in regulating BNST excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNST neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs.

Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to dorsolateral bed nucleus of stria terminalis (BNSTDL), which expresses oxytocin receptors (OTR) and vasopressin receptors and mediates fear responses. However, understanding the integrated role of neurohypophysial hormones is complicated by the cross-reactivity of AVP and OT and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNST excitability are driven by input specificity and cell type-specific receptor selectivity. We show that OTR-expressing BNSTDL neurons, excited by hypothalamic OT and AVP inputs via OTR, play a major role in regulating BNSTDL excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNSTDL neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs.

The autonomous navigation of vehicles, aircraft, spacecraft, and other very complex systems critically depends on gyroscopes and their performance. Applications that require high performance, typically identified as navigation grade, are currently mainly covered by extremely accurate bulk photonic and electromechanical sensors, which, however, are partially incompatible with some emerging application domains, such as those deriving from the New Space Economy. Consequently, interest in miniaturized chip-scale gyroscopes is progressively growing, with specific attention to compatibility with harsh environments. The miniaturization of photonic gyroscopes up to their at least partial integration on chip is an interesting technological challenge in this context.The paper critically analyzes the emerging approaches potentially capable of enabling the demonstration of a navigation grade photonic chip-scale gyroscope. The results of our analysis show that the enabling technologies available today make a navigation grade photonic gyroscope technically feasible with dimensional features comparable to those of microelectromechanical gyroscopes, but at the same time, it highlights that various technological challenges must be faced to achieve experimental demonstration.

Considerable work has been done investigating the role of corticotropin-releasing factor (CRF) in defensive behaviors, but the role of CRF-producing neurons in the dorsolateral bed nucleus of the stria terminalis (BNSTdl) in driving these behaviors remain elusive.

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) contains GABA-ergic neurons classified based on intrinsic membrane properties into three types (Type I-III neurons). BNSTDL is innervated by fibers expressing vasopressin (AVP), but the cellular effects of AVP in the BNST are unknown.

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear. However, the role of OTR in the modulation of BNSTDL activity remains elusive. BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties into three types. Using in vitro patch-clamp recordings in male rats, we demonstrate that OT selectively excites and increases spontaneous firing rate of Type I BNSTDL neurons. As a consequence, OT increases the frequency, but not amplitude, of spontaneous inhibitory post-synaptic currents (sIPSCs) selectively in Type II neurons, an effect abolished by OTR antagonist or tetrodotoxin, and reduces spontaneous firing rate in these neurons. These results suggest an indirect effect of OT in Type II neurons, which is mediated via OT-induced increase in firing of Type I interneurons. As Type II BNSTDL neurons were shown projecting to the central amygdala (CeA), we also recorded from retrogradely labeled BNST→CeA neurons and we show that OT increases the frequency of sIPSC in these Type II BNST→CeA output neurons. In contrast, in Type III neurons, OT reduces the amplitude, but not frequency, of both sIPSCs and evoked IPSCs via a postsynaptic mechanism without changing their intrinsic excitability. We present a model of fine-tuned modulation of BNSTDL activity by OT, which selectively excites BNSTDL interneurons and inhibits Type II BNST→CeA output neurons. These results suggest that OTR in the BNST might facilitate cued fear by inhibiting the BNST→CeA neurons.

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin (OT) receptors (OTR), which were shown to facilitate cued fear measured in the fear-potentiated startle. However, the mechanisms of these OT effects in the BNSTDL remain elusive.

The dorsolateral bed nucleus of the stria terminalis (BNSTDL) has high expression of oxytocin receptors, but their role in the modulation of BNSTDL activity remains elusive. BNSTDL contains GABA-ergic neurons classified based on intrinsic membrane properties into three types. Using in vitro patch-clamp and cell-attached recordings in male rats, we demonstrate that oxytocin excites and increases spontaneous firing of Type I, putative BNSTDL interneurons. As a consequence, oxytocin increases the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) (tetrodotoxin-sensitive) and reduces spontaneous firing of Type II neurons. In contrast, in Type III neurons, oxytocin reduces the amplitude of both sIPSCs and evoked IPSCs, suggesting a direct postsynaptic inhibitory effect. As Type II and Type III are the BNSTDL projection neurons, we present a model of fine-tuned modulation by oxytocin, which selectively excites Type I BNSTDL interneurons and inhibits Type II and Type III output neurons, via an indirect and direct mechanism, respectively.

Abstract Introduction Obesity has been considered a risk factor for cardiovascular death and for poor outcomes from a variety of surgical procedures, recent studies suggest that overweight (OW) and obese (OB) patients may paradoxically have a better prognosis in cardiac surgery (CS) compared with patients with normal body mass index (BMI). We aimed to investigate the obesity paradox and assess the effect of BMI on early and late clinical outcomes after CS Methods A retrospective cohort study of consecutive patients undergoing CS from January 2007 to January 2019 was carried out. Patients were divided into 4 groups defined by BMI:underweight (UW) (≤18,5 kg/m2):0.5%, n=27; normal weight (NW) (18,5–25 kg/m2): 25.7%, n=1393; OW (25–30 kg/m2): 44.7%, n=2423; OB (≥30 kg/m2): 29.1%, n=1576. Multivariable analyses was used to compare the outcomes among the different BMI groups. Overall 1-year survival of BMI categories were determined by the Kaplan-Meier method. Results We included 5419 patients (72% male, mean age 65,8±12.1). The BMI groups were significantly different regarding pre-surgical variables, UW patients were statistically more comorbid and severe clinical presentation. Categorical mortality was 7% in UW, 5,2% in NW, 3,2% in OW, 4,3% in the OB group, P=0,016. The risk of death according to BMI exhibited a reverse J-shaped curve. Low cardiac output syndrome, medical and surgical bleeding and longer hospital stay was more frequent in the UW group (P<0,05), and mediastinitis, hyperglycemia and prolonged mechanical ventilation in OB group (P<0,05). Univariable regression detected the following significant predictors of in-hospital mortality: Age, female, non-elective surgery, non isolated coronary surgery, vascular peripheral disease, chronic obstructive pulmonary disease, severe left ventricular fraction ejection, chronic renal disease, anemia, stroke, myocardial infarction, heart failure and BMI categories (P<0.05): NW (odds ratio (OR), 1,49; 95% CI: 1,09–1,9, P=0,01), in contrast, OW had a significantly lower risk of death (OR 0,66; 95% CI: 0,5–0,88, P=0,005), with no statistical significance in the UW and OB categories. After adjusting for other risk factors at the multivariate analysis, BMI as a continuous variable was not an independent predictor of in-hospital mortality. One-year follow-up was completed in 95%, during this period 223 (4,12%) died. The analysis of unadjusted long-term mortality did not show a significant difference between BMI categories (P log rank = 0,16). Conclusion In our population OW patients had lower mortality and better outcomes after cardiac surgery. However, when other preoperative variables are taken into account, BMI did not have independent effect on in-hospital and one-year mortality, questioning the existence of an “obesity paradox”. Its effect on mortality could be indirect, being mediated through other comorbidities.

Protein palmitoylation and depalmitoylation alter protein function. This post-translational modification is critical for synaptic transmission and plasticity. Mutation of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) causes infantile neuronal ceroid lipofuscinosis (CLN1), a pediatric neurodegenerative disease. However, the role of protein depalmitoylation in synaptic maturation is unknown. Therefore, we studied synapse development in Ppt1-/- mouse visual cortex. We demonstrate that the developmental N-methyl-D-aspartate receptor (NMDAR) subunit switch from GluN2B to GluN2A is stagnated in Ppt1-/- mice. Correspondingly, Ppt1-/- neurons exhibit immature evoked NMDAR currents and dendritic spine morphology in vivo. Further, dissociated Ppt1-/- cultured neurons show extrasynaptic, diffuse calcium influxes and enhanced vulnerability to NMDA-induced excitotoxicity, reflecting the predominance of GluN2B-containing receptors. Remarkably, Ppt1-/- neurons demonstrate hyperpalmitoylation of GluN2B as well as Fyn kinase, which regulates surface retention of GluN2B. Thus, PPT1 plays a critical role in postsynapse maturation by facilitating the GluN2 subunit switch and proteostasis of palmitoylated proteins.

Real-world stressors are complex and multimodal, involving physical, psychological, and social dimensions. However, the brain networks that mediate stress responses to these stimuli need to be further studied. We used c-Fos mapping in mice to characterize brain circuits activated by exposure to a single episode of multimodal stress (MMS), and compared these to circuits activated by electric foot shocks (EFS). We focused on characterizing c-Fos activity in stress-relevant brain regions including the paraventricular nucleus (PVN) of the hypothalamus and the bed nucleus of the stria terminalis (BNST). We also assessed stress-induced activation of CRH-positive neurons in each of these structures. MMS and EFS activated an overlapping network of brain regions with a similar time course. c-Fos expression within the PVN and the BNST peaked 30-60 min after exposure to both MMS and EFS, and returned to baseline levels within 24 h. Quantification of c-Fos expression within BNST subregions revealed that while c-Fos expression peaked in all subregions 30-60 min after MMS and EFS exposure, the neuronal density of c-Fos expression was significantly higher in the dorsomedial and ventral BNST relative to the dorsolateral BNST. Our preliminary assessment indicated that a great majority of MMS or EFS-activated neurons in the PVN were CRH-positive (>87%); in contrast, about 6-35% of activated neurons in the BNST were CRH-positive. Our findings indicate that both MMS and EFS are effective at activating stress-relevant brain areas and support the use of MMS as an effective approach for studying multidimensional stress in animal models. The results also reveal that the PVN and BNST are part of a common neural circuit substrate involved in neural processing related to stress.

In HIV+ individuals, the virus enters the central nervous system and invades innate immune cells, producing important changes that result in neurological deficits. We aimed to determine whether HIV plays a direct role in neuronal excitability. Of the HIV peptides, Tat is secreted and acts in other cells. In order to examine whether the HIV Tat can modify neuronal excitability, we exposed primary murine hippocampal neurons to that peptide, and tested its effects on the intrinsic membrane properties, 4 and 24 h after exposure.

Background: PSM is uncommon but one of the most feared complication of cardiac surgery, with high mortality and cost of treatment. Our objective is to describe the clinical characteristics, microbiology, medical and surgical management and the results of PSM in a single cardiovascular reference center. Methods & Materials: Retrospective analysis of consecutive episodes of PSM registered in the institutional database. Categorical variables were compared using Chi-square or Fischer exact tests; continuous variables with Student's t was used as applicable. IBM® SPSS Statistics program version 21 was used. Results: From November/1998 to December/2016, 182 (1.78%) PSM episodes in 10.233 cardiothoracic surgeries performed (57% CABG, 18% valve replacement and 22% CABG + valve replacement; 72% programmed) were included. Mean age: 65 yo (SD + 11,96). Male: 131 (72%). BMI: 28.83 (SD + 4.91). Comorbidities: DBT 43%, previous MI 33%, smokers 50%, CHF 19%, previous cardiac surgery 8.8%, bilateral internal thoracic artery grafting 29%. Clinical picture: fever 70%, pain 46.7%, erythema 33.5%, sternal click 13%, purulent discharge 69.2%, wound dehiscence 16%, sepsis 30%. Most frequent combined clinical signs/symptoms were: fever + purulent discharge (11%). Most PSM turned up during the 2nd week after surgery (median time: 11 d). Diagnostic methods: subxiphoid aspiration was positive in 121/134 (90.3%); blood cultures 107/161 (66.45%). Microbiology: GPC 122 (60.7%; S. aureus 41.7%, CNS 13.9%, Enterococcus spp 3.8%, SVG 1.3%), GNB 78 (42.9%; K. pneumonia 23%, P. aeruginosa 21%, E. coli 18%), polimicrobial 33 (18.1%), Candida spp 7 (1.3%), negative cultures 1.1%. Surgical treatment: 159/180 (88%) pts underwent open debridement; in 157 surgical treatment was completed with primary sternal closure in the early 72 hs from the diagnosis of PSM. Complications: infective endocarditis 1.6%, sternal osteomyelitis 23%, in-hospital mortality: 17%. Outcome: cure and improvement 145 (80.6%); relapse 2/180 (1.1%) requiring second debridement. Conclusion: PSM is an unusual but very complex and frequently subtle disease that requires a high index of suspicion to be identified. It demands combined medical and surgical approach in order to decrease the mortality. Wound (subxiphoid) aspiration is an extremely easy way to perform rapid diagnosis, yielding high microbiology performance. Immediate debridement, drainage and primary sternal closure could be an interesting approach.

Rationale Drugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. Results A history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na + current ( I NaP ). Conclusion These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.

The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra−/−), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons.SIGNIFICANCE STATEMENTLoss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.

The bed nucleus of the stria terminalis (BNST) is a key component of the extended amygdala and has been implicated in anxiety and addiction. As individual neurons function within neural circuits, it is important to understand local microcircuits and larger network connections of identified neuronal types and understand how maladaptive changes in the BNST neural networks are induced by stress and drug abuse. However, due to limitations of classic anatomical and physiological methods, the local circuit organization of synaptic inputs to specific BNST neuron types is not well understood. In this study, we report on the application of high-resolution and cell-type-specific photostimulation methodology developed in our laboratory to local circuit mapping in the BNST. Under calibrated experimental conditions, laser photostimulation via glutamate uncaging or channelrhodopsin-2 photoactivation evokes spiking of BNST neurons perisomatically, without activating spikes from axons of passage or distal dendrites. Whole cell recordings, combined with spatially restricted photostimulation of presynaptic neurons at many different locations over a large region, allow high-resolution mapping of presynaptic input sources to single recorded neurons in the BNST. We constructed maps of synaptic inputs impinging onto corticotrophin-releasing hormone-expressing (CRH+) BNST neurons in the dorsolateral BNST and found that the CRH+ neurons receive predominant local inhibitory synaptic connections with very weak excitatory connections. Through cell-type-specific optogenetic stimulation mapping, we generated maps of somatostatin-expressing neuron-specific inhibitory inputs to BNST neurons. Taken together, the photostimulation-based techniques offer us powerful tools for determining the functional organization of local circuits of specific BNST neuron types.

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the proteins whose expression levels are altered, directly or indirectly, by loss of FMRP during brain development. Here we systematically measured protein expression in neocortical synaptic fractions from Fmr1 knockout (KO) and wild-type (WT) mice at both adolescent and adult stages. Although hundreds of proteins are up-regulated in the absence of FMRP in young mice, this up-regulation is largely diminished in adulthood. Up-regulated proteins included previously unidentified as well as known targets involved in synapse formation and function and brain development and others linked to intellectual disability and autism. Comparison with putative FMRP target mRNAs and autism susceptibility genes revealed substantial overlap, consistent with the idea that the autism endophenotype of FXS is due to a "multiple hit" effect of FMRP loss, particularly within the PSD95 interactome. Through studies of de novo protein synthesis in primary cortical neurons from KO and WT mice, we found that neurons lacking FMRP produce nascent proteins at higher rates, many of which are synaptic proteins and encoded by FMRP target mRNAs. Our results provide a greatly expanded view of protein changes in FXS and identify age-dependent effects of FMRP in shaping the neuronal proteome.

An attractive, but as yet generally unrealized, approach to cancer therapy concerns discovering agents that change the state of differentiation of the cancer cells. Recently, we discovered a phenomenon that we call "receptor pleiotropism" in which agonist antibodies against known receptors induce cell fates that are very different from those induced by the natural agonist to the same receptor. Here, we show that one can take advantage of this phenomenon to convert acute myeloblastic leukemic cells into natural killer cells. Upon induction with the antibody, these leukemic cells enter into a differentiation cascade in which as many as 80% of the starting leukemic cells can be differentiated. The antibody-induced killer cells make large amounts of perforin, IFN-γ, and granzyme B and attack and kill other members of the leukemic cell population. Importantly, induction of killer cells is confined to transformed cells, in that normal bone marrow cells are not induced to form killer cells. Thus, it seems possible to use agonist antibodies to change the differentiation state of cancer cells into those that attack and kill other members of the malignant clone from which they originate.