Oxidized glutathione reverts carbapenem resistance in blaNDM-1-carrying Escherichia coli.

The emergence of drug-resistant Enterobacteriaceae carrying plasmid-mediated ß-lactamase genes has become a significant threat to public health. Organisms in the Enterobacteriaceae family containing New Delhi metallo-ß-lactamase­1 (NDM-1) and its variants, which are capable of hydrolyzing nearly all ß-lactam antibacterial agents, including carbapenems, are referred to as superbugs and distributed worldwide. Despite efforts over the past decade, the discovery of an NDM-1 inhibitor that can reach the clinic remains a challenge. Here, we identified oxidized glutathione (GSSG) as a metabolic biomarker for blaNDM-1 using a non-targeted metabolomics approach and demonstrated that GSSG supplementation could restore carbapenem susceptibility in Escherichia coli carrying blaNDM-1 in vitro and in vivo. We showed that exogenous GSSG promotes the bactericidal effects of carbapenems by interfering with intracellular redox homeostasis and inhibiting the expression of NDM-1 in drug-resistant E. coli. This study establishes a metabolomics-based strategy to potentiate metabolism-dependent antibiotic efficacy for the treatment of antibiotic-resistant bacteria.

Impact of the addition of dexmedetomidine to patient-controlled intravenous analgesia on postoperative pain-sleep interaction cycle and delirium: A systematic review and meta-analysis of randomized controlled trials.

Background: The reciprocal nexus between sleep and pain is well-documented, with the deleterious impact of operative trauma potentially playing a pivotal role in the dysregulation of this interplay, which could significantly contribute to the manifestation of postoperative delirium (POD). Studies have investigated the effect of adding dexmedetomidine (DEX) to patient-controlled intravenous analgesia (PCIA) pumps on postoperative pain-sleep interaction cycle and POD, but conclusions remained uncertain. The objective of this investigation is to perform a meta-analysis that thoroughly assesses the impact of integrating DEX into PCIA, focusing on analgesic effectiveness, sleep quality, and the incidence of delirium in postoperative patients. Methods: PubMed, Embase, Cochrane Library, SinoMed, and Wanfang Data Knowledge Service Platform were searched, for publications in any language, from database inception to September 2023. Our analysis encompassed randomized controlled trials (RCTs) that examine the therapeutic efficacy and risk profile of adding DEX to the PCIA on the postoperative pain-sleep interaction cycle, by focusing on changes in postoperative analgesia (Visual analog scale (VAS) score), sleep efficiency, sleep structure, subjective sleep score (Assen insomnia scale and numerical rating scale) and adverse event rate. Results: 34 RCTs (4324 patients) were analyzed. This study shows DEX improved analgesia and reduced VAS scores at 6, 12, and 24 h after surgery. Sleep efficiency was enhanced on the 1st and 2nd postoperative night. DEX improved sleep structure at the 1st postoperative night by reducing non-rapid eye movement stage 1 (N1) sleep and increasing non-rapid eye movement stage 2 (N2) and non-rapid eye movement stage 3 (N3) sleep. At the 2nd night, DEX reduced N1 sleep and increased N2 sleep, but not N3 sleep. Data from AIS and NRS showed improvement in subjective sleep scores on the 1st postoperative night and 2nd night. Additionally, DEX decreased the occurrence of POD on the 24 h and first-three days. Conclusion: This study shows that the typical DEX doses added to PCIA with sufentanil were 2-5 µg/kg or approximately 200-250 µg, and the addition of DEX to PCIA can improve pain-sleep interaction cycle from multiple perspectives, and further decrease the occurrence of POD.

Deep-learning-augmented microscopy for super-resolution imaging of nanoparticles.

Conventional optical microscopes generally provide blurry and indistinguishable images for subwavelength nanostructures. However, a wealth of intensity and phase information is hidden in the corresponding diffraction-limited optical patterns and can be used for the recognition of structural features, such as size, shape, and spatial arrangement. Here, we apply a deep-learning framework to improve the spatial resolution of optical imaging for metal nanostructures with regular shapes yet varied arrangement. A convolutional neural network (CNN) is constructed and pre-trained by the optical images of randomly distributed gold nanoparticles as input and the corresponding scanning-electron microscopy images as ground truth. The CNN is then learned to recover reversely the non-diffracted super-resolution images of both regularly arranged nanoparticle dimers and randomly clustered nanoparticle multimers from their blurry optical images. The profiles and orientations of these structures can also be reconstructed accurately. Moreover, the same network is extended to deblur the optical images of randomly cross-linked silver nanowires. Most sections of these intricate nanowire nets are recovered well with a slight discrepancy near their intersections. This deep-learning augmented framework opens new opportunities for computational super-resolution optical microscopy with many potential applications in the fields of bioimaging and nanoscale fabrication and characterization. It could also be applied to significantly enhance the resolving capability of low-magnification scanning-electron microscopy.

Melatonin regulates the circadian rhythm to ameliorate postoperative sleep disorder and neurobehavioral abnormalities in aged mice.

BACKGROUND: Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging evidence indicates that circadian rhythm contributes to various neuropathological diseases, including Alzheimer's disease. Thus, we analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice and determined whether exogenous melatonin could facilitate entrainment of the circadian rhythm after laparotomy under sevoflurane anesthesia. METHODS: We selected old C57BL/6J mice which receiving laparotomy/sevoflurane anesthesia as model animals. We employed buried food, open field, and Y maze test to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) were used to investigate sleep changes. We analyzed the transcription rhythm of clock genes in superchiasmatic nucleus (SCN) to explore the effects of surgery and melatonin pretreatment on the circadian rhythm. Then, we measured melatonin receptor levels in SCN and ERK/CREB pathway-related proteins in hippocampus and prefrontal cortex to assess their role in PSDs and delirium-like behavior. RESULTS: Laparotomy under sevoflurane anesthesia had a greater influence than sevoflurane alone, leading to sleep disorder, a shift in sleep-wake rhythm, and delirium-like behavior. Bmal1, Clock, and Cry1 mRNA expression showed a peak shift, MT1 melatonin receptor expression level was increased in the SCN, and p-ERK/ERK and p-CREB/CREB were decreased in hippocampus and prefrontal cortex of aged mice 1 day after laparotomy. Melatonin showed significant efficacy in ameliorating PSD and delirium-like behavior and restoring the circadian rhythm, reversing melatonin receptor and ERK/CREB pathway expression abnormalities. In addition, most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist. CONCLUSIONS: Melatonin receptors in SCN, circadian rhythm, and ERK/CREB signaling pathway participate in the pathophysiological processes of PSD and delirium-like behavior. Melatonin intervention could be a potential preventative approach for PSD and delirium.

Weight Decay With Tailored Adam on Scale-Invariant Weights for Better Generalization.

Weight decay (WD) is a fundamental and practical regularization technique in improving generalization of current deep learning models. However, it is observed that the WD does not work effectively for an adaptive optimization algorithm (such as Adam), as it works for SGD. Specifically, the solution found by Adam with the WD often generalizes unsatisfactorily. Though efforts have been made to mitigate this issue, the reason for such deficiency is still vague. In this article, we first show that when using the Adam optimizer, the weight norm increases very fast along with the training procedure, which is in contrast to SGD where the weight norm increases relatively slower and tends to converge. The fast increase of weight norm is adverse to WD; in consequence, the Adam optimizer will lose efficacy in finding solution that generalizes well. To resolve this problem, we propose to tailor Adam by introducing a regularization term on the adaptive learning rate, such that it is friendly to WD. Meanwhile, we introduce first moment on the WD to further enhance the regularization effect. We show that the proposed method is able to find solution with small norm and generalizes better than SGD. We test the proposed method on general image classification and fine-grained image classification tasks with different networks. Experimental results on all these cases substantiate the effectiveness of the proposed method in help improving the generalization. Specifically, the proposed method improves the test accuracy of Adam by a large margin and even improves the performance of SGD by 0.84% on CIFAR 10 and 1.03 % on CIFAR 100 with ResNet-50. The code of this article is public available at xxx.

Nobiletin Attenuates Anesthesia/Surgery-Induced Neurocognitive Decline by Preserving the Expression of Clock Genes in Mice.

Postoperative cognitive dysfunction (POCD) is commonly observed during the postoperative period and significantly affects the prognosis of patients. Neuroinflammation plays a vital role in the pathogenesis of POCD. Despite laboratory and clinical research over the past decades, practical pharmacological strategies for the treatment and prevention of POCD are not yet available currently. Nobiletin (NOB) is a natural polymethoxylated flavone. As an enhancer of the clock protein retinoic acid receptor-related orphan receptors (RORs), NOB has been shown to attenuate inflammation and improve cognitive decline. We speculate that NOB is a candidate for the treatment and prevention of POCD. In this study, we investigated whether and how NOB affected surgery-induced neuroinflammation and POCD in adult CD1 mice. NOB pretreatment suppressed exploratory laparotomy-induced systemic inflammation and neuroinflammation in a dose-dependent manner (< 50 mg/kg), and attenuated POCD. Moreover, NOB dose-dependently reversed the decrease of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1, also known as Arntl) and Rors expression induced by exploratory laparotomy. The expression of Bmal was negatively correlated with tumor necrosis factor-α (TNF-α). Our results suggest that NOB attenuated POCD, possibly via preserving the expression of Bmal and Rors and inhibiting inflammation.

Deep RED Unfolding Network for Image Restoration.

The deep unfolding network (DUN) provides an efficient framework for image restoration. It consists of a regularization module and a data fitting module. In existing DUN models, it is common to directly use a deep convolution neural network (DCNN) as the regularization module, and perform data fitting before regularization in each iteration/stage. In this work, we present a DUN by incorporating a new regularization module, and putting the regularization module before the data fitting module. The proposed regularization model is deducted by using the regularization by denoing (RED) and plugging in it a newly designed DCNN. For the data fitting module, we use the closed-form solution with Faster Fourier Transform (FFT). The resulted DRED-DUN model has some major advantages. First, the regularization model inherits the flexibility of learned image-adaptive and interpretability of RED. Second, the DRED-DUN model is an end-to-end trainable DUN, which learns the regularization network and other parameters jointly, thus leads to better restoration performance than the plug-and-play framework. Third, extensive experiments show that, our proposed model significantly outperforms the-state-of-the-art model-based methods and learning based methods in terms of PSNR indexes as well as the visual effects. In particular, our method has much better capability in recovering salient image components such as edges and small scale textures.

Effects of general versus subarachnoid anaesthesia on circadian melatonin rhythm and postoperative delirium in elderly patients undergoing hip fracture surgery: A prospective cohort clinical trial.

BACKGROUND: Circadian rhythm disturbance is common postoperatively in older patients with hip fractures, which may contribute to the development of postoperative delirium (POD). As a reliable biomarker of endogenous circadian rhythms, melatonin regulates the sleep-wake cycle and environmental adaptation, and its secretory rhythm may be modified by anaesthesia and surgery. This study compared the impact of subarachnoid anaesthesia (SA) and general anaesthesia (GA), on the peak of melatonin secretion (primary outcome), the circadian rhythm of melatonin, cortisol and sleep, and the POD incidence (secondary outcome). METHODS: In this prospective cohort observational study, hip fracture surgery patients were enrolled and assigned to receive either SA or GA. Postoperative plasma melatonin and cortisol levels were dynamically measured every six hours on seven time-points, and the circadian rhythm parameters including mesor, amplitude, and acrophase were calculated. Subjective and objective sleep assessments were performed by sleep diaries and sleep trackers, respectively. The Confusion Assessment Method was used twice daily by a specific geriatrician to screen for POD occurrence. FINDINGS: In a cohort of 138 patients who underwent hip fracture surgery, the circadian rhythm disruption of the patients in the GA group (n=69) was greater than the SA group (n=69). Compared with SA, GA provided the lower peak concentration, mesor, and amplitude of melatonin secretion on postoperative day 1 (p < 0.05). Patients in the GA group experienced higher awakenings, more sleep deprivation, and poor sleep quality on surgery day (p < 0.05). A proportion of 12 patients in the SA group (17.4%) and 24 patients in the GA group (34.8%) experienced POD (p = 0.020). INTERPRETATION: These results suggest that SA may be superior to GA in elderly patients undergoing hip fracture surgery as SA is associated with less impairment of the melatonin rhythm and sleep patterns, and fewer POD occurrences. FUNDING: The study was supported by the National Natural Science Foundation of China (81971012, 81873726, 81901095, 81701052, and 81801070), Key Clinical Projects of Peking University Third Hospital (BYSYZD2019027), and Peking University "Clinical Medicine plus X" Youth Project (PKU2020LCXQ016).

Effects of general versus regional anaesthesia on circadian melatonin rhythm and its association with postoperative delirium in elderly patients undergoing hip fracture surgery: study protocol for a prospective cohort clinical trial.

INTRODUCTION: Postoperative delirium (POD) is a common neurological complication after hip fracture surgery and is associated with high morbidity and mortality in elderly patients. Although the specific mechanism of POD remains unclear, circadian rhythm disruptions have recently drawn increased attention. To date, only limited postoperative time points of plasma melatonin level measurements were recorded in previous studies, and such data cannot represent a comprehensive melatonin rhythm. The process of anaesthesia (either general anaesthesia (GA) or regional anaesthesia (RA)) is known to influence the melatonin rhythm. However, how these two anaesthesia methods differently affect the postoperative melatonin rhythm is still unknown. Therefore, we hypothesise that RA may attenuate the disruption of the melatonin rhythm, which might decrease the incidence of POD in elderly patients undergoing hip surgery. METHODS AND ANALYSIS: In this prospective cohort clinical trial, 138 patients scheduled for hip fracture surgery will be divided into two groups to receive either GA or RA. The primary aim is to compare the circadian rhythm of melatonin secretion between the two groups and explore its association with the incidence of POD. ETHICS AND DISSEMINATION: The study has been approved by the Medical Science Research Ethics Committees of Beijing Jishuitan Hospital (JLKS201901-04). The results of the study will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: ChiCTR1900027393.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

Generalized Unitarily Invariant Gauge Regularization for Fast Low-Rank Matrix Recovery.

Spectral regularization is a widely used approach for low-rank matrix recovery (LRMR) by regularizing matrix singular values. Most of the existing LRMR solvers iteratively compute the singular values via applying singular value decomposition (SVD) on a dense matrix, which is computationally expensive and severely limits their applications to large-scale problems. To address this issue, we present a generalized unitarily invariant gauge (GUIG) function for LRMR. The proposed GUIG function does not act on the singular values; however, we show that it generalizes the well-known spectral functions, including the rank function, the Schatten- p quasi-norm, and logsum of singular values. The proposed GUIG regularization model can be formulated as a bilinear variational problem, which can be efficiently solved without computing SVD. Such a property makes it well suited for large-scale LRMR problems. We apply the proposed GUIG model to matrix completion and robust principal component analysis and prove the convergence of the algorithms. Experimental results demonstrate that the proposed GUIG method is not only more accurate but also much faster than the state-of-the-art algorithms, especially on large-scale problems.

The ventromedial hypothalamic circuitry and male alloparental behaviour in a socially monogamous rodent species.

As prairie voles (Microtus ochrogaster) display spontaneous biparental care, and the ventromedial hypothalamus (VMH) has been implicated in reproductive behaviour, we conducted experiments to test the hypothesis that the VMH neurochemical circuitry is involved in alloparental behaviours in male prairie voles. We compared alloparental behaviours of adult, sexually naïve male and female voles-both displayed licking/grooming, huddling and retrieving behaviours towards conspecific pups. We also stained for the immediate-early gene encoded early growth protein Egr-1 in the vole brain. The pup-exposed animals showed levels of Egr-1 staining that was higher in the VMH but lower in the amygdala compared to animals exposed to a pup-sized piece of plastic (control). A retrograde tracer, Fluoro-Gold (FG), was injected into the VMH of male voles that were subsequently tested in the pup exposure or control condition. More FG/Egr-1 cells were detected for glutamatergic (GLU) staining in the ventral bed nucleus of the stria terminalis (BNSTv) and medial amygdala (MeA), whereas less FG/Egr-1 cells were stained for gamma-aminobutyric acid (GABA) in the MeA of the pup-exposed group compared to the control group. Further, the ratio of GLU:GABA expression in FG/Egr-1 projection neurons from both the BNSTv and MeA to the VMH was increased following pup exposure. Finally, pharmacological blockade of either dopamine D1 receptor or oxytocin receptor in the VMH impaired the onset of male alloparental behaviour. Together, these data suggest that the VMH may be involved in the onset of alloparental care and play a role in regulating social approach in male prairie voles.

A Benchmark for Edge-Preserving Image Smoothing.

Edge-preserving image smoothing is an important step for many low-level vision problems. Though many algorithms have been proposed, there are several difficulties hindering its further development. First, most existing algorithms cannot perform well on a wide range of image contents using a single parameter setting. Second, the performance evaluation of edge-preserving image smoothing remains subjective, and there lacks a widely accepted datasets to objectively compare the different algorithms. To address these issues and further advance the state of the art, in this work we propose a benchmark for edge-preserving image smoothing. This benchmark includes an image dataset with groundtruth image smoothing results as well as baseline algorithms that can generate competitive edge-preserving smoothing results for a wide range of image contents. The established dataset contains 500 training and testing images with a number of representative visual object categories, while the baseline methods in our benchmark are built upon representative deep convolutional network architectures, on top of which we design novel loss functions well suited for edge-preserving image smoothing. The trained deep networks run faster than most state-of-the-art smoothing algorithms with leading smoothing results both qualitatively and quantitatively. The benchmark will be made publicly accessible.

Perioperative management of paraganglioma and catecholamine-induced cardiomyopathy in child- a case report and review of the literature.

BACKGROUND: Paragangliomas are catecholamine-secreting tumors of the paraganglia. Perioperative mortality of children with paraganglioma is high, but preoperative therapy and anesthetic management of paraganglioma resection are controversial in children. The literatures on catecholamine-induced cardiomyopathy are limited to several case reports,with few reports of studies on children. CASE PRESENTATION: Here we report the anesthetic management of a child with paraganglioma and catecholamine-induced cardiomyopathy, and the possible perioperative anesthesia problems of the paraganglioma resection are discussed. CONCLUSION: Preoperative and intraoperative anesthetic management of Pheochromocytomas children should follow the same principles as for adults, The most important aspects are the control of blood pressure liability and maintenance of adequate blood volume. Pheochromocytomas patient may have cardiomoyopathy due to myocardial toxicity of excessive circulating catecholamines level. The perioperative management of catecholamine-induced cardiomyopathy should include lowering sympathetic activation by means of α-and ß-adrenergic receptor blocker and diuretics administration in case of volume overload.

Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding.

BACKGROUND: The neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood. METHODS: Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical experiments examined neuronal activation using Fos and neurochemical/neuroreceptor profiles on brain areas involved in these social behaviors. Finally, a series of behavioral pharmacologic and real-time in vivo brain microdialysis experiments were performed on male prairie voles displaying affiliation or aggression. RESULTS: We localized a subpopulation of excitatory vasopressin neurons in the anterior hypothalamus that may gate corticotropin-releasing factor output from the amygdala to the anterior hypothalamus and then the lateral septum to modulate aggression associated with mate guarding. Conversely, we identified a subset of inhibitory serotonergic projection neurons in the dorsal raphe that project to the anterior hypothalamus and may mediate the spatiotemporal release of neuropeptides and their interactions in modulating aggression and affiliation. CONCLUSIONS: Together, this study establishes the medial extended amygdala as a major neural substrate regulating the switch between positive and negative affective states, wherein several neurochemicals converge and interact to coordinate divergent social behaviors.

Fatherhood reduces the survival of adult-generated cells and affects various types of behavior in the prairie vole (Microtus ochrogaster ).

Motherhood has profound effects on physiology, neuronal plasticity, and behavior. We conducted a series of experiments to test the hypothesis that fatherhood, similarly to motherhood, affects brain plasticity (such as cell proliferation and survival) and various behaviors in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult males were housed with their same-sex cage mate (control), single-housed (isolation), or housed with a receptive female to mate and produce offspring (father) for 6 weeks. Fatherhood significantly reduced cell survival (assessed by bromodeoxyuridine labeling), but not cell proliferation (assessed by Ki67-labeling), in the amygdala, dentate gyrus of the hippocampus, and ventromedial hypothalamus, suggesting that fatherhood affects brain plasticity. In Experiment 2, neither acute (20 min) nor chronic (20 min daily for 10 consecutive days) pup exposure altered cell proliferation or survival in the brain, but chronic pup exposure increased circulating corticosterone levels. These data suggest that reduced cell survival in the brain of prairie vole fathers was unlikely to be due to the level of pup exposure and display of paternal behavior, and may not be mediated by circulating corticosterone. The effects of fatherhood on various behaviors (including anxiety-like, depression-like, and social behaviors) were examined in Experiment 3. The data indicated that fatherhood increased anxiety- and depression-like behaviors as well as altered aggression and social recognition memory in male prairie voles. These results warrant further investigation of a possible link between brain plasticity and behavioral changes observed due to fatherhood.

Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles.

Disruptions in the social environment, such as social isolation, are distressing and can induce various behavioral and neural changes in the distressed animal. We conducted a series of experiments to test the hypothesis that long-term social isolation affects brain plasticity and alters behavior in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult female prairie voles were injected with a cell division marker, 5-bromo-2'-deoxyuridine (BrdU), and then same-sex pair-housed (control) or single-housed (isolation) for 6 weeks. Social isolation reduced cell proliferation, survival, and neuronal differentiation and altered cell death in the dentate gyrus of the hippocampus and the amygdala. In addition, social isolation reduced cell proliferation in the medial preoptic area and cell survival in the ventromedial hypothalamus. These data suggest that long-term social isolation affects distinct stages of adult neurogenesis in specific limbic brain regions. In Experiment 2, isolated females displayed higher levels of anxiety-like behaviors in both the open field and elevated plus maze tests and higher levels of depression-like behavior in the forced swim test than controls. Further, isolated females showed a higher level of affiliative behavior than controls, but the two groups did not differ in social recognition memory. Together, our data suggest that social isolation not only impairs cell proliferation, survival, and neuronal differentiation in limbic brain areas, but also alters anxiety-like, depression-like, and affiliative behaviors in adult female prairie voles. These data warrant further investigation of a possible link between altered neurogenesis within the limbic system and behavioral changes.

Anterior hypothalamic neural activation and neurochemical associations with aggression in pair-bonded male prairie voles.

Male prairie voles (Microtus ochrogaster) display mating-induced pair bonding indicated by social affiliation with their female partners and aggression toward unfamiliar conspecifics. In the present study, we characterized their aggression associated with pair bonding and examined the related neuronal activation and neurochemical architecture. Males that were pair-bonded for 2 weeks displayed intense levels of aggression toward a female or male conspecific stranger but maintained a high level of social affiliation with their familiar female partners. These social interactions induced increases in neural activation, indicated by increased density of Fos-immunoreactive staining (Fos-ir) in several brain regions including the bed nucleus of the stria terminalis (BNST), medial preoptic area (MPOA), paraventricular nucleus (PVN), anterior cortical (AcA), and medial nuclei (MeA) of the amygdala. In the anterior hypothalamus (AH), increased density of Fos-ir staining was found specifically to be associated with aggression toward unfamiliar female or male strangers. In addition, higher densities of AH cells that were stained for tyrosine hydroxylase (TH) or vasopressin (AVP) were also labeled with Fos-ir in these males displaying aggression toward a conspecific stranger compared with males displaying social affiliation toward their female partner. Together, our results indicate that dopamine and vasopressin in the AH may be involved in the regulation of enduring aggression associated with pair bonding in male prairie voles.