Hematological and histopathological effects of silver nanoparticles in rainbow trout ( Oncorhynchus mykiss )—how about increase of salinity?

Abstract

Hematological and histopathological toxicities of silver nanoparticles (Ag-NPs) to rainbow trout were assessed in three water salinities: 0.4 ppt (low salinity), 6 ± 0.3 ppt (moderate salinity), and 12 ± 0.2 ppt (high salinity). The concentrations of Ag-NPs in the low salinity were 0.032, 0.1, 0.32, and 1 ppm, and in the moderate and high salinities were 3.2, 10, 32, and 100 ppm. The results indicated a concentration-dependently increased (thrombocyte, monocyte, and large lymphocyte) and decreased (neutrophil and small lymphocyte) white blood cell count in the Ag-NP treatments in the low salinity than the other ones in the moderate and high salinities. Red blood cell volume significantly increased in all of the experimental groups exposed to higher Ag-NP concentrations, especially those in the low salinity. In the moderate and high salinities, blood plasma total protein decreased in 10 and 32 ppm Ag-NP treatments, but albumin increased in the groups in the low salinity. Blood plasma ions (Cl⁻, Na⁺, K⁺, Ca²⁺, and Mg²⁺) showed high changes in the higher Ag-NP treatments. In all treatments, gill histological analysis demonstrated a time- and Ag-NP concentration-dependent extent of abnormalities, with the highest epithelial lifting in 1 ppm Ag-NPs in the low salinity and also the highest necrosis and aneurism in the 32 ppm treatments in other salinities. Lower Ag-NP concentrations in the low salinity led to fibrosis, villus fusion, inflammation, vacuolization, and microvillus hyperplasia in the gut, yet villi lifting and necrosis in 0.32 and 1 ppm of Ag-NPs were the main anomalies. In addition to the mentioned alterations, villi abolitions predominantly occurred in 32 ppm Ag-NP concentrations in the moderate and high salinities. Overall, despite exposing to lower Ag-NP concentrations, the fish kept in the low salinity demonstrated more vulnerability to Ag-NPs than those in the other salinities.

Alterations of antioxidant indexes and inflammatory cytokine expression aggravated hepatocellular apoptosis through mitochondrial and death receptor-dependent pathways in Gallus gallus exposed to arsenic and copper

Abstract

In this study, we sought to investigate the effects of sub-chronic exposure of arsenic (As) and copper (Cu) on oxidative stress, inflammatory response, and mitochondria and death receptor apoptosis pathways in chicken liver. Seventy-two 1-day-old male Hy-line chickens were treated with basal diet, 30 mg/kg arsenic trioxide (As₂O₃), or/and 300 mg/kg copper sulfate (CuSO₄) for 4, 8, and 12 weeks. Study revealed that exposure to As or/and Cu undermined the antioxidant function and increased lipid peroxidation. Worse yet, liver cell swollen, vacuolar degeneration, and inflammatory cell infiltration were accompanied by an increase of the nuclear factor-κB (NF-κB) and its downstream inflammation-related genes after exposure to As or/and Cu. Furthermore, mitochondria swollen and chromatin condensation were found in As and Cu groups, and hepatocyte nuclear membrane rupture and markedly increased (P < 0.01) apoptosis index were observed in As combined with Cu group. Meanwhile, the transcription and protein expression levels of Bcl-2-associated X protein (Bax), p53, cytochrome c (Cyt c), and caspase-3, 8, 9 were upregulated and B cell lymphoma-2 (Bcl-2) was downregulated in As, Cu, and As + Cu groups in the liver tissues (P < 0.05, P < 0.01). Our results indicated that exposure to As or/and Cu could lead to oxidative stress, inflammatory response, and tissue damage and aggravate hepatocellular apoptosis through mitochondrial and death receptor-dependent pathways in chicken liver. And As and Cu showed a possible synergistic relationship in liver damage.

Detection of 2-aminoethylphosphonic acid in suspended particles in an ultraoligotrophic lake: a two-dimensional nuclear magnetic resonance (2D-NMR) study

Abstract

Particulate organic phosphorus (P) compounds were examined in ultraoligotrophic Lake Saiko, Japan. A cartridge filter was used to collect sufficient amount of suspended particles for analysis by a two-dimensional NMR (¹H-³¹P heteronuclear multiple bond correlation). 2-Aminoethylphosphonic acid (2-AEP), a phosphonate, was detected in suspended particles in Lake Saiko. The identity of the phosphonate was confirmed by comparison with a commercially available compound. Because 2-AEP is bioavailable, microorganisms can store and use this compound under extremely P-limited conditions. This is the first study to detect 2-AEP in an ultra-oligotrophic environment.

Correction to: Subcutaneous lipomas: A minimally invasive method for resection of subcutaneous lipomas preserving retaining ligaments

Abstract

The article Subcutaneous lipomas: A minimally invasivemethod for resection of subcutaneous lipomas preserving retaining ligaments, written by Akio Sakamoto, Takeshi Okamoto, Shuichi Matsuda, was originally published electronically on the publisher's internet portal (currently SpringerLink).

Implementation of GPU accelerated SPECT reconstruction with Monte Carlo-based scatter correction

Abstract

Objective

Statistical SPECT reconstruction can be very time-consuming especially when compensations for collimator and detector response, attenuation, and scatter are included in the reconstruction. This work proposes an accelerated SPECT reconstruction algorithm based on graphics processing unit (GPU) processing.

Methods

Ordered subset expectation maximization (OSEM) algorithm with CT-based attenuation modelling, depth-dependent Gaussian convolution-based collimator-detector response modelling, and Monte Carlo-based scatter compensation was implemented using OpenCL. The OpenCL implementation was compared against the existing multi-threaded OSEM implementation running on a central processing unit (CPU) in terms of scatter-to-primary ratios, standardized uptake values (SUVs), and processing speed using mathematical phantoms and clinical multi-bed bone SPECT/CT studies.

Results

The difference in scatter-to-primary ratios, visual appearance, and SUVs between GPU and CPU implementations was minor. On the other hand, at its best, the GPU implementation was noticed to be 24 times faster than the multi-threaded CPU version on a normal 128 × 128 matrix size 3 bed bone SPECT/CT data set when compensations for collimator and detector response, attenuation, and scatter were included.

Conclusions

GPU SPECT reconstructions show great promise as an every day clinical reconstruction tool.

Innovative Clinical Investigations: featured papers in IJCARS

Oral exposure of deltamethrin and/or lipopolysaccharide (LPS) induced activation of the pulmonary immune system in Swiss albino mice

Abstract

The deltamethrin, a synthetic pyrethroid, is used worldwide and has been linked with several type of acute toxicity. However, effect of low level of deltamethrin alone or in combination with the microbial antigen on pulmonary system is not understood. Lipopolysaccharide (LPS) was used as antigen which is a key inflammatory component of gram-negative bacteria, which induces a distinctive pattern of cytokine release that regulates inflammation. The aim was to determine whether chronic exposure to a low level of deltamethrin alone or in combination with LPS impair the lung response in adult male Swiss albino mice. The mice were orally exposed to different doses of deltamethrin (0.1, 0.05, 0.005, 0.001 mg/kg bwt) and then immunized with LPS at the 60th day. None of the treatment groups contained residues of deltamethrin above the limits of quantification. Deltamethrin combined with LPS challenge caused significant lymphocytosis and neutropenia in group 1 (0.1 mg/kg) mice (P < 0.05). The highest dose of deltamethrin exposure (0.1 mg/kg bwt) alone altered the total cell count significantly in blood and total leukocyte count (TLC) and macrophage count in bronchoalveolar lavage fluid. Microscopic pulmonary damage was evaluated by H&E staining and EM which indicated that two higher doses of deltamethrin, i.e., 0.1 and 0.05 mg/kg bwt, distinctly increased inflammatory cell infiltration and caused alveolar septa thickening and leukocyte infiltration into the alveolar septum (septal cell infiltration) in the lungs. Deltamethrin exposure alone and/or with endotoxin revealed different degrees of immunopositive reaction for Toll-like receptor 4 (TLR4) and pro-inflammatory cytokine-like tumor necrosis factor-alpha (TNFα) in different parts of the lungs. The expression of TLR4 and TNFα in the lung tissue was more pronounced in two higher dose groups. Thus, chronic low-level deltamethrin exposure may impair the main pro-inflammatory response in the lungs which is more pronounced in combination with LPS. Further research is required in direction of the mechanism of action of deltamethrin on the immune cell lineage and their differentiation.

Synthesis of NiO nanoparticles via a green route using Monsonia burkeana: The physical and biological properties

Publication date: Available online 21 March 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): P. Kganyago, L.M. Mahlaule-Glory, M.M. Mathipa, B. Ntsendwana, N. Mketo, Z. Mbita, N.C. Hintsho-Mbita
NiO nanoparticles have emerged as ideal candidates in various fields due to their magnetic, electrical and optical properties. The coupling of plant extracts that have anticancer and antibacterial properties with NiO nanoparticles has increased their usage in the biomedical field. In this work, we report on the novel synthesis of NiO nanoparticles using a local medicinal plant, Monsonia burkenea. The nickel nanoparticles were characterized using Fourier transform infrared spectroscopy (FTIR), Energy dispersive X-ray analysis (EDX), Scanning electron microscope (SEM), High-resolution transmission electron microscope (HRTEM) and X-ray diffraction (XRD). FTIR showed that the extraction of the plant phytochemicals was successful and the green synthesized nanoparticles from plants contained the phytochemical groups that are found in the Monsonia burkeana plant. XRD and HRTEM confirmed the successful formation of NiO nanoparticles with an average particle size range of 20 nm. These results were also corroborated by elemental mapping and EDX, where the dominant groups were identified.The Monsonia burkeana NiO particles exhibited selective bactericidal activity against Gram-negative strains, such as E. coli and P. aeruginosa. Additionally, cytotoxicity studies showed the materials did not have any anti proliferative effect against A549 lung cancer cells but could be used as potential drug delivery vehicles against human cancers.

Graphical abstract

Authentication of an Italian PDO hazelnut (“Nocciola Romana”) by NIR spectroscopy

Abstract

Common hazelnuts are widely present in human diet all over the world, and their beneficial effects on the health have been extensively investigated and demonstrated. Different in-depth researches have highlighted that the harvesting area can define small variations in the chemical composition of the fruits, affecting their quality. As a consequence, it has become relevant to develop methodologies which would allow authenticating and tracing hazelnuts. In the light of this, the present work aims to develop a non-destructive method for the authentication of a specific high-quality Italian hazelnut, "Nocciola Romana," registered with a protected designation of origin (PDO). Thus, different samples of this fruit have been analyzed by near-infrared (NIR) spectroscopy and then classification models have been built, in order to distinguish between the PDO fruits and the hazelnuts not coming from the designated region. In particular, two different classification approaches have been tested, a discriminant one, partial least squares-discriminant analysis, and a class-modeling one, soft independent modeling of class analogies. Both methods led to very high prediction capability in external validation on a test set (classification accuracy in one case, and sensitivity and specificity in the other, all higher than 92%), suggesting that the proposed methodologies are suitable for a rapid and non-destructive authentication of the product.

Biopsia selectiva del ganglio centinela de la región inguinal: técnica quirúrgica

Publication date: Available online 21 March 2018
Source:Actas Dermo-Sifiliográficas
Author(s): D. Moreno-Ramírez, J. Pérez-Anker, A. Perissinotti, R. Pigem, S. Podlipnik, I. Fragakis, T. Toledo Pastrana

Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function

Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.

SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.

Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models

Sleep–wake abnormalities are common in patients with Alzheimer's disease, and can be a major reason for institutionalization. However, an emerging concept is that these sleep–wake disturbances are part of the causal pathway accelerating the neurodegenerative process. Recently, new findings have provided intriguing evidence for a positive feedback loop between sleep–wake dysfunction and β-amyloid (Aβ) aggregation. Studies in both humans and animal models have shown that extended periods of wakefulness increase Aβ levels and aggregation, and accumulation of Aβ causes fragmentation of sleep. This perspective is aimed at presenting evidence supporting causal links between sleep–wake dysfunction and aggregation of Aβ peptide in Alzheimer's disease, and explores the role of astrocytes, a specialized type of glial cell, in this context underlying Alzheimer's disease pathology. The utility of current animal models and the unexplored potential of alternative animal models for testing mechanisms involved in the reciprocal relationship between sleep disruption and Aβ are also discussed.

Dual Perspectives Companion Paper: Microglia-Mediated Synapse Loss in Alzheimer's Disease by Lawrence Rajendran and Rosa Paolicelli

This Week in The Journal

Microglia-Mediated Synapse Loss in Alzheimer's Disease

Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention.

Dual Perspectives Companion Paper: Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner

Visual Working Memory Is Independent of the Cortical Spacing Between Memoranda

The sensory recruitment hypothesis states that visual short-term memory is maintained in the same visual cortical areas that initially encode a stimulus' features. Although it is well established that the distance between features in visual cortex determines their visibility, a limitation known as crowding, it is unknown whether short-term memory is similarly constrained by the cortical spacing of memory items. Here, we investigated whether the cortical spacing between sequentially presented memoranda affects the fidelity of memory in humans (of both sexes). In a first experiment, we varied cortical spacing by taking advantage of the log-scaling of visual cortex with eccentricity, presenting memoranda in peripheral vision sequentially along either the radial or tangential visual axis with respect to the fovea. In a second experiment, we presented memoranda sequentially either within or beyond the critical spacing of visual crowding, a distance within which visual features cannot be perceptually distinguished due to their nearby cortical representations. In both experiments and across multiple measures, we found strong evidence that the ability to maintain visual features in memory is unaffected by cortical spacing. These results indicate that the neural architecture underpinning working memory has properties inconsistent with the known behavior of sensory neurons in visual cortex. Instead, the dissociation between perceptual and memory representations supports a role of higher cortical areas such as posterior parietal or prefrontal regions or may involve an as yet unspecified mechanism in visual cortex in which stimulus features are bound to their temporal order.

SIGNIFICANCE STATEMENT Although much is known about the resolution with which we can remember visual objects, the cortical representation of items held in short-term memory remains contentious. A popular hypothesis suggests that memory of visual features is maintained via the recruitment of the same neural architecture in sensory cortex that encodes stimuli. We investigated this claim by manipulating the spacing in visual cortex between sequentially presented memoranda such that some items shared cortical representations more than others while preventing perceptual interference between stimuli. We found clear evidence that short-term memory is independent of the intracortical spacing of memoranda, revealing a dissociation between perceptual and memory representations. Our data indicate that working memory relies on different neural mechanisms from sensory perception.

Expression of Bona Fide Epithelial Stem Cell Marker in Postmitotic Olfactory Bulb Neurons Suggest Novel Roles for Wnt Signaling in the Brain

Dendritic A-Current in Rhythmically Active PreBötzinger Complex Neurons in Organotypic Cultures from Newborn Mice

The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K⁺ current, I_A. Inspiratory rhythm generation can be studied ex vivo because the preBötC remains rhythmically active in vitro, both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how I_A impacts Ca²⁺ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons. The amplitude of dendritic Ca²⁺ transients evoked via voltage increases originating from the soma significantly increased after an I_A antagonist, 4-aminopyridine (4-AP), was applied to the perfusion bath or to local dendritic regions. Similarly, glutamate-evoked postsynaptic depolarizations recorded at the soma increased in amplitude when 4-AP was coapplied with glutamate at distal dendritic locations. We conclude that I_A is expressed on type-1 preBötC neuron dendrites. We propose that I_A filters synaptic input, shunting sparse excitation, while enabling temporally summated events to pass more readily as a result of I_A inactivation. Dendritic I_A in rhythmically active preBötC neurons could thus ensure that inspiratory motor activity does not occur until excitatory synaptic drive is synchronized and well coordinated among cellular constituents of the preBötC during inspiratory rhythmogenesis. The biophysical properties of dendritic I_A might thus promote robustness and regularity of breathing rhythms.

SIGNIFICANCE STATEMENT Brainstem neurons in the preBötC generate the oscillatory activity that underlies breathing. PreBötC neurons express voltage-dependent currents that can influence inspiratory activity, among which is a transient potassium current (I_A) previously identified in a rhythmogenic excitatory subset of type-1 preBötC neurons. We sought to determine whether I_A is expressed in the dendrites of preBötC. We found that dendrites of type-1 preBötC neurons indeed express I_A, which may aid in shunting sparse non-summating synaptic inputs, while enabling strong summating excitatory inputs to readily pass and thus influence somatic membrane potential trajectory. The subcellular distribution of I_A in rhythmically active neurons of the preBötC may thus be critical for producing well coordinated ensemble activity during inspiratory burst formation.

Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity

Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss of function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina. Therefore, we investigated the progression of synapse and photoreceptor loss and whether hUTC treatment preserves photoreceptors and synaptic connectivity in the RCS rats of both sexes. We found that RCS retinas display significant deficits in synaptic development already by postnatal day 21 (P21), before the onset of photoreceptor degeneration. Subretinal transplantation of hUTC at P21 is necessary to rescue visual function in RCS rats, and the therapeutic effect is enhanced with repeated injections. Synaptic development defects occurred concurrently with morphological changes in Müller glia, the major perisynaptic glia in the retina. hUTC transplantation strongly diminished Müller glia reactivity and specifically protected the α2-1-containing retinal synapses, which are responsive to thrombospondin family synaptogenic proteins secreted by Müller glia. Müller glial reactivity and reduced synaptogenesis observed in RCS retinas could be recapitulated by CRISPR/Cas9-mediated loss-of-Mertk in Müller glia in wild-type rats. Together, our results show that hUTC transplantation supports the health of retina at least in part by preserving the functions of Müller glial cells, revealing a previously unknown aspect of hUTC transplantation-based therapy.

SIGNIFICANCE STATEMENT Despite the promising effects observed in clinical trials and preclinical studies, how subretinal human umbilical tissue-derived cell (hUTC) transplantation mediates vision improvements is not fully known. Using a rat model of retinal degeneration, the RCS rat (lacking Mertk), here we provide evidence that hUTC transplantation protects visual function and health by protecting photoreceptors and preserving retinal synaptic connectivity. Furthermore, we find that loss of Mertk function only in Müller glia is sufficient to impair synaptic development and cause activation of Müller glia. hUTC transplantation strongly attenuates the reactivity of Müller glia in RCS rats. These findings highlight novel cellular and molecular mechanisms within the neural retina, which underlie disease mechanisms and pinpoint Müller glia as a novel cellular target for hUTC transplantation.

Detecting Unattended Stimuli Depends on the Phase of Prestimulus Neural Oscillations

Neural oscillations appear important for perception and attention processes because stimulus detection is dependent upon the phase of 7–11 Hz oscillations before stimulus onset. Previous work has examined stimulus detection at attended locations, but it is unknown whether unattended locations are also subject to phasic modulation by ongoing oscillatory activity, as would be predicted by theories proposing a role for neural oscillations in organizing general neural processing. Here, we recorded brain activity with EEG while human participants of both sexes detected brief visual targets preceded by a spatial cue and determined whether performance for cued (attended) and uncued (unattended) targets was influenced by oscillatory phase across a range of frequencies. Detection of both attended and unattended targets depended upon an ~5 Hz theta rhythm and an ~11–15 Hz alpha rhythm. Critically, detection of unattended stimuli was more strongly modulated by the phase of theta oscillations than was detection of attended stimuli, suggesting that attentional allocation involves a disengagement from ongoing theta sampling. There was no attention-related difference in the strength of alpha phase dependence, consistent with a perceptual rather than attentional role of oscillatory phase in this frequency range. These results demonstrate the importance of neural oscillations in modulating visual processing at both attended and unattended locations and clarify one way in which attention may produce its effects: through disengagement from low-frequency sampling at attended locations.

SIGNIFICANCE STATEMENT Past work on the interaction between oscillatory phase and neural processing has shown the involvement of posterior ~7–11 Hz oscillations in visual processing. Most studies, however, have presented stimuli at attended locations, making it difficult to disentangle frequencies related to attention from those related to perception. Here, we compared the oscillatory frequencies involved in the detection of attended and unattended stimuli and found that ~11–15 Hz oscillations were related to perception independently of attention, whereas ~5 Hz oscillations were more prominent for the detection of unattended stimuli. This work demonstrates the importance of neural oscillations for mediating stimulus processing at both attended and unattended locations and clarifies the different oscillatory frequencies involved in attention and perception.

Neurobiological Mechanisms of Responding to Injustice

People are particularly sensitive to injustice. Accordingly, deeper knowledge regarding the processes that underlie the perception of injustice, and the subsequent decisions to either punish transgressors or compensate victims, is of important social value. By combining a novel decision-making paradigm with functional neuroimaging, we identified specific brain networks that are involved with both the perception of, and response to, social injustice, with reward-related regions preferentially involved in punishment compared with compensation. Developing a computational model of punishment allowed for disentangling the neural mechanisms and psychological motives underlying decisions of whether to punish and, subsequently, of how severely to punish. Results show that the neural mechanisms underlying punishment differ depending on whether one is directly affected by the injustice, or whether one is a third-party observer of a violation occurring to another. Specifically, the anterior insula was involved in decisions to punish following harm, whereas, in third-party scenarios, we found amygdala activity associated with punishment severity. Additionally, we used a pharmacological intervention using oxytocin, and found that oxytocin influenced participants' fairness expectations, and in particular enhanced the frequency of low punishments. Together, these results not only provide more insight into the fundamental brain mechanisms underlying punishment and compensation, but also illustrate the importance of taking an explorative, multimethod approach when unraveling the complex components of everyday decision-making.

SIGNIFICANCE STATEMENT The perception of injustice is a fundamental precursor to many disagreements, from small struggles at the dinner table to wasteful conflict between cultures and countries. Despite its clear importance, relatively little is known about how the brain processes these violations. Taking an interdisciplinary approach, we combine methods from neuroscience, psychology, and economics to explore the neurobiological mechanisms involved in both the perception of injustice as well as the punishment and compensation decisions that follow. Using a novel behavioral paradigm, we identified specific brain networks, developed a computational model of punishment, and found that administrating the neuropeptide oxytocin increases the administration of low punishments of norm violations in particular. Results provide valuable insights into the fundamental neurobiological mechanisms underlying social injustice.