Next Directions in the Neuroscience of Cancers Arising outside the CNS.

SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

Electrical stimulation of the dorsal motor nucleus of the vagus in male mice can regulate inflammation without affecting the heart rate.

BACKGROUND: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis. METHODS: Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 µA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 µA or 50 µA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days. RESULTS: Either left or right eDMNS at 500 µA and 250 µA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 µA. Left side eDMNS at 50 µA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice. CONCLUSIONS: For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.

Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial.

BACKGROUND: Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. METHODS: The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. FINDINGS: From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. INTERPRETATION: Cabozantinib shows promising activity in patients with MPPGs. FUNDING: Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.

The fatigue-inducing effects of cancer and its therapy are characterized by decreased physical activity in the absence of any motivational deficit.

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected for this purpose, a model of human papilloma virus-related head and neck cancer and a model of lung cancer. In both models, tumor-bearing mice were submitted to chemoradiotherapy to limit tumor progression. Two dimensions of fatigue were assessed, the physical dimension by changes in physical activity in mice trained to run in wheels and the motivational dimension by changes in the performance of mice trained to nose poke to obtain a food reward in a progressive ratio schedule of food reinforcement. Chemoradiotherapy reliably decreased wheel running activity but had no effect on performance in the progressive ratio in both murine models of cancer. These effects were the same for the two murine models of cancer and did not differ according to sex. Livers and brains were collected at the end of the experiments for qRT-PCR analysis of expression of genes coding for inflammation, mitochondria dynamics, and metabolism. The observed changes were mainly apparent in the liver and typical of activation of type I interferon and NF-κB-dependent signaling, with alterations in mitochondrial dynamics and a shift toward glycolysis. Although the importance of these alterations for the pathophysiology of cancer-related fatigue remains to be explored, the present findings indicate that fatigue brought on by cancer therapy in tumor-bearing mice is more physical than motivational.

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer.

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a male mouse model for head and neck cancer, we utilized neuronal tracing techniques and show that tumor-infiltrating nerves indeed connect to distinct brain areas via the ipsilateral trigeminal ganglion. The activation of this neuronal circuitry led to behavioral alterations represented by decreased nest-building, increased latency to eat a cookie, and reduced wheel running. Tumor-infiltrating nociceptor neurons exhibited heightened activity, as indicated by increased calcium mobilization. Correspondingly, the specific brain regions receiving these neural projections showed elevated cFos and delta FosB expression in tumor-bearing mice, alongside markedly intensified calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons in tumor-bearing mice led to decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running. This discrepancy points towards an intricate relationship, where pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer. Significance Statement: Head and neck cancers are infiltrated by sensory nerves which connect to a pre-existing circuit that includes areas in the brain. Neurons within this circuit are altered and mediate modifications in behavior.

Endothelial activation and fibrotic changes are impeded by laminar flow-induced CHK1-SENP2 activity through mechanisms distinct from endothelial-to-mesenchymal cell transition.

Background: The deSUMOylase sentrin-specific isopeptidase 2 (SENP2) plays a crucial role in atheroprotection. However, the phosphorylation of SENP2 at T368 under disturbed flow (D-flow) conditions hinders its nuclear function and promotes endothelial cell (EC) activation. SUMOylation has been implicated in D-flow-induced endothelial-to-mesenchymal transition (endoMT), but the precise role of SENP2 in counteracting this process remains unclear. Method: We developed a phospho-specific SENP2 S344 antibody and generated knock-in (KI) mice with a phospho-site mutation of SENP2 S344A using CRISPR/Cas9 technology. We then investigated the effects of SENP2 S344 phosphorylation under two distinct flow patterns and during hypercholesteremia (HC)-mediated EC activation. Result: Our findings demonstrate that laminar flow (L-flow) induces phosphorylation of SENP2 at S344 through the activation of checkpoint kinase 1 (CHK1), leading to the inhibition of ERK5 and p53 SUMOylation and subsequent suppression of EC activation. We observed a significant increase in lipid-laden lesions in both the aortic arch (under D-flow) and descending aorta (under L-flow) of female hypercholesterolemic SENP2 S344A KI mice. In male hypercholesterolemic SENP2 S344A KI mice, larger lipid-laden lesions were only observed in the aortic arch area, suggesting a weaker HC-mediated atherogenesis in male mice compared to females. Ionizing radiation (IR) reduced CHK1 expression and SENP2 S344 phosphorylation, attenuating the pro-atherosclerotic effects observed in female SENP2 S344A KI mice after bone marrow transplantation (BMT), particularly in L-flow areas. The phospho-site mutation SENP2 S344A upregulates processes associated with EC activation, including inflammation, migration, and proliferation. Additionally, fibrotic changes and up-regulated expression of EC marker genes were observed. Apoptosis was augmented in ECs derived from the lungs of SENP2 S344A KI mice, primarily through the inhibition of ERK5-mediated expression of DNA damage-induced apoptosis suppressor (DDIAS). Summary: In this study, we have revealed a novel mechanism underlying the suppressive effects of L-flow on EC inflammation, migration, proliferation, apoptosis, and fibrotic changes through promoting CHK1-induced SENP2 S344 phosphorylation. The phospho-site mutation SENP2 S344A responds to L-flow through a distinct mechanism, which involves the upregulation of both mesenchymal and EC marker genes.

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors.

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFßR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.

Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain.

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or δOR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naïve state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.

Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice.

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less energy but also procures energy in the form of food. For this purpose, mice were either trained to run in a wheel or to work for food in various schedules of food reinforcement before being treated with cisplatin. The experiments were carried out only in male mice as we had already reported that sex differences in cisplatin-induced neurotoxicities are minimal. Cisplatin was administered daily for one cycle of five days, or two cycles separated by a five-day rest. As observed in previous experiments, cisplatin drastically reduced voluntary wheel running. In contrast, when cisplatin was administered to food-restricted mice trained to work for a food reward in a progressive ratio schedule or in a fixed-interval schedule, it tended to increase the number of responses emitted to obtain the food rewards. This increase was not associated with any change in the temporal distribution of responses during the interval between two reinforcements in mice submitted to the fixed interval schedule of food reinforcement. When cisplatin was administered to food-restricted mice trained in an effort-based decision-making task in which they had to choose between working for a grain pellet with little effort and working for a preferred chocolate pellet with more effort, it decreased the total number of responses emitted to obtain food rewards. However, this effect was much less marked than the decrease in wheel running induced by cisplatin. The decrease in the effort invested in the procurement of food rewards was not associated with any change in the relative distribution of effort between low reward and high reward during the time course of the test session. These findings show that cisplatin decreases energy-consuming activities but not energy-procuring activities unless they require a choice between options differing in their cost-benefit ratio. Furthermore, they indicate that the physical dimension of fatigue is more likely to develop in cisplatin-treated individuals than the motivational dimension of fatigue.

Resolution of cisplatin-induced fatigue does not require endogenous interleukin-10 in male mice.

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 µg/day for three days) five days later. In the second experiment, they were treated with cisplatin (2.3 mg/kg/day for 5 days twice at a five-day interval) and IL10na (12 µg/day for three days) immediately after the last injection of cisplatin. In both experiments, cisplatin decreased body weight and reduced voluntary wheel running. However, IL-10na did not impair recovery from these effects. These results show that the recovery from the cisplatin-induced decrease in wheel running does not require endogenous IL-10 in contrast to the recovery from cisplatin-induced peripheral neuropathy.

The GDF15-GFRAL axis mediates chemotherapy-induced fatigue in mice.

Cancer-related fatigue is defined as a distressing persistent subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and that interferes with usual functioning. This form of fatigue is highly prevalent during cancer treatment and in some patients, it can persist for years after treatment has ended. An understanding of the mechanisms that drive cancer-related fatigue is still lacking, which hampers the identification of effective treatment options. Various chemotherapeutic agents including cisplatin are known to induce mitochondrial dysfunction and this effect is known to mediate chemotherapy-induced peripheral neuropathy and cognitive dysfunction. Mitochondrial dysfunction results in the release of mitokines that act locally and at distance to promote metabolic and behavioral adjustments to this form of cellular stress. One of these mitokines, growth differentiation factor 15 (GDF15) and its receptor, glial cell line-derived neurotrophic factor family receptor α-like (GFRAL), have received special attention in oncology as activation of GFRAL mediates the anorexic response that is responsible for cancer anorexia. The present study was initiated to determine whether GDF15 and GFRAL are involved in cisplatin-induced fatigue. We first tested the ability of cisplatin to increase circulating GDF15 in mice before assessing whether GDF15 can induce behavioral fatigue measured by decreased wheel running in healthy mice and increase behavioral fatigue induced by cisplatin. Mice administered a long acting form of GDF15, mGDF15-fc, decreased their voluntary wheel running activity. When the same treatment was administered to mice receiving cisplatin, it increased the amplitude and duration of cisplatin-induced decrease in wheel running. To determine whether endogenous GDF15 mediates the behavioral fatigue induced by cisplatin, we then administered a neutralizing monoclonal antibody to GFRAL to mice injected with cisplatin. The GFRAL neutralizing antibody mostly prevented cisplatin-induced decrease in wheel running and accelerated recovery. Taken together these findings demonstrate for the first time the role of the GDF15/GFRAL axis in cisplatin-induced behaviors and indicate that this axis could be a promising therapeutic target for the treatment of cancer-related fatigue.

Associative learning contributes to the persistence of fatigue-like behavior in male mice in a model of cancer survivorship.

Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary wheel running using a longitudinal design. Treatment robustly decreased voluntary wheel running, and this effect persisted for more than a month posttreatment. However, when wheels were removed during treatment, to minimize treatment-related fatigue, mice showed a more rapid return to baseline running levels. We confirmed that the delayed recovery observed in mice with continual wheel access was not due to increased treatment-related toxicity, in fact running attenuated cisplatin-induced kidney toxicity. Finally, we demonstrated that re-exposure to a treatment-related olfactory cue acutely re-instated fatigue. These data provide the first demonstration that associative processes can modulate the persistence of cancer-related fatigue-like behavior.

Chronic restraint stress impairs voluntary wheel running but has no effect on food-motivated behavior in mice.

Chronic restraint stress is known to cause significant alterations of mitochondrial biology. However, its effects on effort-based behavior and the sensitivity of these effects to treatments that restore mitochondrial function have not been assessed. Based on the hypothesis that the behavioral consequences of this stressor should be more severe for an energy demanding activity than for an energy procuring activity, we compared the effects of chronic restraint stress on the performance of male mice trained to use a running wheel or to nose poke for a food reward in an operant conditioning cage. In accordance with our hypothesis, we observed that exposure of mice to 2-hour daily restraint sessions for 14 to 16 days during the light phase of the cycle reliably decreased voluntary wheel running but had no effect on working for food in a fixed ratio 10 schedule of food reinforcement or in a progressive ratio schedule of food reinforcement. This dissociation between the two types of behavioral activities could reflect an adaptive response to the constraint imposed by chronic restraint stress on mitochondria function and its negative consequences on energy metabolism. To determine whether it is the case, we administered mesenchymal stem cells intranasally to chronically restrained mice to repair the putative mitochondrial dysfunction induced by chronic restraint stress. This intervention had no effect on wheel running deficits. Assessment of mitochondrial gene expression in the brain of mice submitted to chronic restraint stress revealed an increase in the expression of genes involved in mitochondrial biology that showed habituation with repetition of daily sessions of restraint stress. These original findings can be interpreted to indicate that chronic restraint stress induces behavioral and mitochondrial adjustments that contribute to metabolic adaptation to this stressor and maintain metabolic flexibility.

Evolutionary Aspects of Infections: Inflammation and Sickness Behaviors.

Sickness behavior was conceptualized initially as the behavioral counterpart of the fever response to infectious pathogens. It helps to raise body temperature to its higher setpoint and to maintain it at this new level and it has the additional benefit of enabling a weakened organism to protect itself from other dangers. The discovery of the behavioral effects of proinflammatory cytokines produced by activated immune cells provided a cellular and molecular basis to this phenomenon. The administration of cytokines or cytokine inducers like lipopolysaccharide to healthy rodents allowed to reveal the similarities and differences between inflammation-induced sickness behavior and the fever response. It also led to the understanding of how the inflammatory response that is triggered at the periphery can propagate into the brain and induce the behavioral manifestations of sickness. At the behavioral level, the demonstration that sickness behavior is the expression of a motivational state that reorganizes perception and action in face of a microbial pathogen just like fear in face of a predator appeared at first glance to strengthen the adaptive value of this behavior. However, all aspects of sickness behavior are not always favorable for the organism. This is the case for anorexia that is beneficial in the context of bacterial infection but detrimental in the context of viral infection. In addition, studies of sickness behavior in natural conditions revealed that like any other defensive behavior, sickness behavior requires trade-offs between its survival benefits for the sick individual and the costs incurred especially in the context of gregarious groups. Thanks to these studies, evidence is emerging that sickness behavior is much more variable in its expression than initially thought, and that part of this variability depends not only on the pathogen and the social context in which the infection develops but also on individual factors including species, sex, age, nutrition, and physiological status.

Love and fear: A special issue.

Love and fear were forged by the same fundamental evolutionary processes that permitted life on Earth. Both love and fear are deeply interwoven with the adaptive management of stress and disease. Love and fear share common roots and both can play a role in reproduction, survival, perceived safety and wellbeing. This special issue of Comprehensive Psychoneuroendocrinology focuses specifically on the causes and consequences of love from the interactive perspectives of evolution, neurobiology and culture.