The roles of inflammation, affect, and interoception in predicting social perception.

"Sickness behavior" is an orchestrated suite of symptoms that commonly occur in the context of inflammation, and is characterized by changes in affect, social experience, and behavior. However, recent evidence suggests that inflammation may not always produce the same set of sickness behavior (e.g., fatigue, anhedonia, and social withdrawal). Rather, inflammation may be linked with different behavior across contexts and/or across individuals, though research in this area is under-developed to-date. In the present study (n = 30), we evaluated the influence of affective context and individual differences in difficulty detecting bodily sensations (i.e., interoceptive difficulty) on social perception following an inflammatory challenge. Inflammation was induced using the influenza vaccine and inflammatory reactivity was operationalized as changes in circulating levels of interleukin-6 (IL-6) before the vaccine and approximately 24 h later. Twenty-four hours after administration of the influenza vaccine, we manipulated affective context using a well-validated affect misattribution task in which participants made trustworthiness judgments of individuals with neutral facial expressions following the rapid presentation of "prime" images that were positive or negative in affective content. Interoceptive difficulty was measured at baseline using a validated self-report measure. Results revealed significant interactions between inflammatory reactivity to the influenza vaccine and affective context on social perception. Specifically, individuals with greater inflammatory reactivity were more biased by affective context when judging the trustworthiness of neutral faces. In addition, interoceptive difficulty and affective context interacted to predict social perception such that individuals with greater interoceptive difficulty were more biased by affective context in these judgments. In sum, we provide some of the first evidence that inflammation may amplify the saliency of affective cues during social decision making. Our findings also replicate prior work linking interoceptive ability to the use of affect-as-information during social perception, but in the novel context of inflammation.

Sleepy Mice Case Study: Implementation and Assessment.

Case studies are a valuable teaching tool to engage students in course content using real-world scenarios. As part of the High-throughput Discovery Science & Inquiry-based Case Studies for Today's Students (HITS) Research Coordination Network (RCN), our team has created the Sleepy Mice Case Study for students to engage with RStudio and the Allen Institute for Brain Science's open access high-throughput sleep dataset on mice. Sleep is important for health, a familiar concern to college students, and was a basis for this case study. In this case, students completed an initial homework assignment, in-class work, and a final take-home application assignment. The case study was implemented in synchronous and asynchronous Introductory Neuroscience courses, a Biopsychology course, and a Human Anatomy and Physiology course, reflecting its versatility. The case can be used to teach course-specific learning objectives such as sleep-related content and/or science data processing skills. The case study was successful as shown by gains in student scores and confidence in achieving learning objectives. Most students reported enjoying learning about sleep deprivation course content using the case study. Best practices based on instructor experiences in implementation are also included to facilitate future use so that the Sleepy Mice Case Study can be used to teach content and/or research-related skills in various courses and modalities.

Inflammatory reactivity to the influenza vaccine is associated with changes in automatic social behavior.

Recent evidence suggests differential patterns of social behavior following an inflammatory challenge, such that increases in inflammation may not uniformly lead to social withdrawal. Indeed, increases in inflammation have been associated with enhanced self-reported motivation to approach a specific close other, and greater neural sensitivity to positive social cues. However, no known studies have examined the association between inflammation in response to an inflammatory challenge and social behavior in humans, nor has past research examined specifically how approach and withdrawal behavior may differ based on whether the target is a close other or stranger. To address this, 31 participants (ages 18-24) received the influenza vaccine to elicit a low-grade inflammatory response. The morning before and approximately 24 h after the vaccine, participants provided a blood sample and completed a computer task assessing automatic (implicit) approach and withdrawal behavior toward a social support figure and strangers. Greater increases in the inflammatory cytokine interleukin-6 (IL-6) in response to the vaccine were associated with an increase in accuracy in avoiding strangers and a decrease in accuracy in approaching them. Increases in IL-6 were also associated with a decrease in reaction time to approach a support figure, but only when controlling for baseline IL-6 levels. There were no associations between change in IL-6 and changes in self-reported motivation to engage in social behavior with either close others, or strangers. Together, these findings reveal that increases in inflammation following the influenza vaccine are associated with automatic social behavior, especially behavior suggesting avoidance of unfamiliar social targets and ease in approaching a support figure. These data add to the growing literature suggesting that the association between inflammation and social behavior includes both social withdrawal and social approach, depending on the specific target.

Effects of plant-based versus marine-based omega-3 fatty acids and sucrose on brain and liver fatty acids in a mouse model of chemotherapy.

Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

A Versatile Psychoneuroimmunology Course-based Undergraduate Research Experience.

The Psychoneuroimmunology Course-based Undergraduate Research Experience (PNI CURE) was designed with the purpose of engaging undergraduate students in research and discovery. As part of this experience, students were assigned to a team based on their personal interests. Each team selected a psychosocial variable of interest (e.g., sleep, belongingness, stress, or happiness) and identified two well-validated questionnaires to assess it. Then, student volunteers donated blood samples and completed student-selected questionnaires via Qualtrics. The blood samples were assayed by the course instructor for proinflammatory cytokines. With the collected data, students 1) evaluated the association between peripheral inflammation and their psychosocial variable of interest and 2) created hypotheses regarding inflammation in the brain. Students' experimental results were reported in the form of a research manuscript and scientific poster, both of which comprised 15 percent of their course grade. Further, to evaluate the effectiveness of the PNI CURE, students were asked to complete assessment surveys before and after project implementation. Assessment results demonstrate that participating in the PNI CURE increased self-efficacy and research identity among students. Besides exposing undergraduates at UNC-CH to a comprehensive research experience, we hope to inspire neuroscience educators to adopt and adapt the PNI CURE as a mechanism to broaden undergraduate research opportunities in neuroscience.

ß-Adrenergic Contributions to Emotion and Physiology During an Acute Psychosocial Stressor.

OBJECTIVE: ß-Adrenergic receptor signaling, a critical mediator of sympathetic nervous system influences on physiology and behavior, has long been proposed as one contributor to subjective stress. However, prior findings are surprisingly mixed about whether ß-blockade (e.g., propranolol) blunts subjective stress, with many studies reporting no effects. We reevaluated this question in the context of an acute psychosocial stressor with more comprehensive measures and a larger-than-typical sample. We also examined the effects of ß-blockade on psychophysiological indicators of sympathetic and parasympathetic nervous system reactivity, given that ß-blockade effects for these measures specifically under acute psychosocial stress are not yet well established. METHODS: In a double-blind, randomized, placebo-controlled study, 90 healthy young adults received 40 mg of the ß-blocker propranolol or placebo. Participants then completed the Trier Social Stress Test, which involved completing an impromptu speech and difficult arithmetic in front of evaluative judges. Self-reported emotions and appraisals as well as psychophysiology were assessed throughout. RESULTS: Propranolol blunted Trier Social Stress Test preejection period reactivity (b = 9.68, p = .003), a marker of sympathetic nervous system activity, as well as salivary α-amylase reactivity (b = -0.50, p = .006). Critically, propranolol also blunted negative, high arousal emotions in response to the stressor (b = -0.22, p = .026), but cognitive appraisals remained intact (b values < -0.17, p values > .10). CONCLUSIONS: These results provide updated experimental evidence that ß-adrenergic blockade attenuates negative, high arousal emotions in response to a psychosocial stressor while also blunting sympathetic nervous system reactivity. Together, these findings shed light on the neurophysiological mechanisms by which stressors transform into the subjective experience we call "stress."Trial Registration: ClinicalTrials.gov Identifier: NCT02972554.

Acute exposure to low-level light at night is sufficient to induce neurological changes and depressive-like behavior.

The advent and wide-spread adoption of electric lighting over the past century has profoundly affected the circadian organization of physiology and behavior for many individuals in industrialized nations; electric lighting in homes, work environments, and public areas have extended daytime activities into the evening, thus, increasing night-time exposure to light. Although initially assumed to be innocuous, chronic exposure to light at night (LAN) is now associated with increased incidence of cancer, metabolic disorders, and affective problems in humans. However, little is known about potential acute effects of LAN. To determine whether acute exposure to low-level LAN alters brain function, adult male, and female mice were housed in either light days and dark nights (LD; 14 h of 150 lux:10 h of 0 lux) or light days and low level light at night (LAN; 14 h of 150 lux:10 h of 5 lux). Mice exposed to LAN on three consecutive nights increased depressive-like responses compared to mice housed in dark nights. In addition, female mice exposed to LAN increased central tendency in the open field. LAN was associated with reduced hippocampal vascular endothelial growth factor-A (VEGF-A) in both male and female mice, as well as increased VEGFR1 and interleukin-1ß mRNA expression in females, and reduced brain derived neurotrophic factor mRNA in males. Further, LAN significantly altered circadian rhythms (activity and temperature) and circadian gene expression in female and male mice, respectively. Altogether, this study demonstrates that acute exposure to LAN alters brain physiology and can be detrimental to well-being in otherwise healthy individuals.

Motivation, Belongingness, and Anxiety in Neuroscience Undergraduates: Emphasizing First-Generation College Students.

The growth of undergraduate neuroscience programs nation-wide demonstrates that interest in this field is escalating. By understanding what motivates neuroscience undergraduates to do well and how they generally feel toward their major and environment, educators will be better able to attend to the needs of their neuroscience students. Thus, the present study aimed to characterize the psychosocial profiles of neuroscience majors in the U.S., with a particular interest in potential differences by generation in college, school type, and gender. For this, U.S. institutions that offer a neuroscience major were identified, and program directors/coordinators were asked to share a study survey with neuroscience majors at their school. The survey, which included demographics and measures of motivation, sense of belongingness, and anxiety, was completed by 756 students from 69 different institutions. Results showed that first-generation college students had lower academic performance (i.e., GPA), which was mediated by differences in motivation, and test- and trait-anxiety. Further, students from Liberal Arts Colleges reported valuing neuroscience courses more than students at National Universities, and the desire to meet others expectations, value of neuroscience course work, and anxiety were higher among female neuroscience students than males. Finally, test-anxiety was the strongest correlate of academic performance. These insights help identify potential targets for developing new teaching and advising strategies that could be employed to facilitate success among all neuroscience undergraduates.

Clearing the fog: a review of the effects of dietary omega-3 fatty acids and added sugars on chemotherapy-induced cognitive deficits.

Cancer treatments such as chemotherapy have been an important part of extending survival in women diagnosed with breast cancer. However, chemotherapy can cause potentially toxic side effects in the brain that impair memory, verbal fluency, and processing speed in up to 30% of women treated. Women report that post-chemotherapy cognitive deficits negatively impact quality of life and may last up to ten years after treatment. Mechanisms underlying these cognitive impairments are not fully understood, but emerging evidence suggests that chemotherapy induces structural changes in the brain, produces neuroinflammation, and reduces adult hippocampal neurogenesis. Dietary approaches that modify inflammation and neurogenesis are promising strategies for reducing chemotherapy-induced cognitive deficits in breast cancer survivors. In this review, we describe the cognitive and neuronal side effects associated with commonly used chemotherapy treatments for breast cancer, and we focus on the often opposing actions of omega-3 fatty acids and added sugars on cognitive function, neuroinflammation, and adult hippocampal neurogenesis. Omega-3 fatty acids administered concurrently with doxorubicin chemotherapy have been shown to prevent depressive-like behaviors and reduce neuroinflammation, oxidative stress, and neural apoptosis in rodent models. In contrast, diets high in added sugars may interact with n-3 FAs to diminish their anti-inflammatory activity or act independently to increase neuroinflammation, reduce adult hippocampal neurogenesis, and promote cognitive deficits. We propose that a diet rich in long-chain, marine-derived omega-3 fatty acids and low in added sugars may be an ideal pattern for preventing or alleviating neuroinflammation and oxidative stress, thereby protecting neurons from the toxic effects of chemotherapy. Research testing this hypothesis could lead to the identification of modifiable dietary choices to reduce the long-term impact of chemotherapy on the cognitive functions that are important to quality of life in breast cancer survivors.

Breast cancer and social environment: getting by with a little help from our friends.

Social environment is a well-recognized determinant in health and wellbeing. Among breast cancer patients, inadequate social support is associated with a substantial increase in cancer-related mortality. A common explanation is that socially isolated individuals fare worse due to reduced instrumental support (i.e., assistance meeting the demands of treatment). However, the ability to replicate the detrimental effects of social isolation on mammary tumor growth in rodents strongly suggests an alternative explanation; i.e., socially isolated individuals have a physiological milieu that promotes tumor growth. This review summarizes the clinical and basic science literature supporting social influences on breast cancer, and provides a conceptual physiological framework for these effects. We propose that social environment contributes to the vast individual differences in prognosis among breast cancer survivors because social environment is capable of altering basic physiological processes, which in turn can modulate tumor growth. Appreciation of the role of social environment in breast cancer progression could promote the identification of patients at increased risk for poor outcomes. In addition, characterization of the underlying physiological mechanisms could lead to targeted disruption of detrimental pathways that promote tumor progression in socially isolated individuals, or exploitation of protective pathways activated through social engagement as novel therapeutic complements to contemporary treatments.

Cytotoxic chemotherapy increases sleep and sleep fragmentation in non-tumor-bearing mice.

Sleep disruption ranks among the most common complaints of breast cancer patients undergoing chemotherapy. Because of the complex interactions among cancer, treatment regimens, and life-history traits, studies to establish a causal link between chemotherapy and sleep disruption are uncommon. To investigate how chemotherapy acutely influences sleep, adult female c57bl/6 mice were ovariectomized and implanted with wireless biotelemetry units. EEG/EMG biopotentials were collected over the course of 3days pre- and post-injection of 13.5mg/kg doxorubicin and 135mg/kg cyclophosphamide or the vehicle. We predicted that cyclophosphamide+doxorubicin would disrupt sleep and increase central proinflammatory cytokine expression in brain areas that govern vigilance states (i.e., hypothalamus and brainstem). The results largely support these predictions; a single chemotherapy injection increased NREM and REM sleep during subsequent active (dark) phases; this induced sleep was fragmented and of low quality. Mice displayed marked increases in low theta (5-7Hz) to high theta (7-10Hz) ratios following chemotherapy treatment, indicating elevated sleep propensity. The effect was strongest during the first dark phase following injection, but mice displayed disrupted sleep for the entire 3-day duration of post-injection sleep recording. Vigilance state timing was not influenced by treatment, suggesting that acute chemotherapy administration alters sleep homeostasis without altering sleep timing. qPCR analysis revealed that disrupted sleep was accompanied by increased IL-6 mRNA expression in the hypothalamus. Together, these data implicate neuroinflammation as a potential contributor to sleep disruption after chemotherapy.

A case study to engage students in the research design and ethics of high-throughput metagenomics.

Case studies present students with an opportunity to learn and apply course content through problem solving and critical thinking. Supported by the High-throughput Discovery Science & Inquiry-based Case Studies for Today's Students (HITS) Research Coordination Network, our interdisciplinary team designed, implemented, and assessed two case study modules entitled "You Are What You Eat." Collectively, the case study modules present students with an opportunity to engage in experimental research design and the ethical considerations regarding microbiome research and society. In this manuscript, we provide instructors with tools for adopting or adapting the research design and/or the ethics modules. To date, the case has been implemented using two modalities (remote and in-person) in three courses (Microbiology, Physiology, and Neuroscience), engaging over 200 undergraduate students. Our assessment data demonstrate gains in content knowledge and students' perception of learning following case study implementation. Furthermore, when reflecting on our experiences and student feedback, we identified ways in which the case study could be modified for different settings. In this way, we hope that the "You Are What You Eat" case study modules can be implemented widely by instructors to promote problem solving and critical thinking in the traditional classroom or laboratory setting when discussing next-generation sequencing and/or metagenomics research.

Investigating social connection as a protective factor against exam stress in college students.

Objective: To examine social connection as a protective factor against exam stress. Participants: 55 undergraduate students at two universities. Methods: Students were evaluated on an exam day for their hardest class and at baseline, a day in a week where they had no exams. Social connection, salivary cortisol, perceived stress, and cognitive control (measured with the Stroop test) were assessed. Exam scores were later reported. Results: Higher social connection was associated with lower perceived stress on exam day. At a small liberal arts school, higher levels of social connection were associated with higher Stroop scores. This correlation with cognitive control was not significant at a large public university. Conclusions: These findings indicate that social connection may be a protective factor in mitigating perceived stress and cognitive control capabilities may help facilitate reduced exam stress in some school environments.

Three Steps to Adapt Case Studies for Synchronous and Asynchronous Online Learning.

Pandemic SARS-CoV-2 has ushered in a renewed interest in science along with rapid changes to educational modalities. While technology provides a variety of ways to convey learning resources, the incorporation of alternate modalities can be intimidating for those designing curricula. We propose strategies to permit rapid adaptation of curricula to achieve learning in synchronous, asynchronous, or hybrid learning environments. Case studies are a way to engage students in realistic scenarios that contextualize concepts and highlight applications in the life sciences. While case studies are commonly available and adaptable to course goals, the practical considerations of how to deliver and assess cases in online and blended environments can instill panic. Here we review existing resources and our collective experiences creating, adapting, and assessing case materials across different modalities. We discuss the benefits of using case studies and provide tips for implementation. Further, we describe functional examples of a three-step process to prepare cases with defined outcomes for individual student preparation, collaborative learning, and individual student synthesis to create an inclusive learning experience, whether in a traditional or remote learning environment.

Beta-adrenergic blockade blunts inflammatory and antiviral/antibody gene expression responses to acute psychosocial stress.

Dysregulation of the immune system is one potential mechanism by which acute stress may contribute to downstream disease etiology and psychopathology. Here, we tested the role of ß-adrenergic signaling as a mediator of acute stress-induced changes in immune cell gene expression. In a randomized, double-blind, and placebo-controlled trial, 90 healthy young adults (44% female) received a single 40 mg dose of the ß-blocker propranolol (n = 43) or a placebo (n = 47) and then completed the Trier Social Stress Test (TSST). Pre- and post-stress blood samples were assayed for prespecified sets of pro-inflammatory and antiviral/antibody gene transcripts. Analyses revealed increased expression of both inflammatory and antiviral/antibody-related genes in response to the TSST, and these effects were blocked by pre-treatment with propranolol. Bioinformatics identified natural killer cells and dendritic cells as the primary cellular context for transcriptional upregulation, and monocytes as the primary cellular carrier of genes downregulated by the TSST. These effects were in part explained by acute changes in circulating cell types. Results suggest that acute psychosocial stress can induce an "acute defense" molecular phenotype via ß-adrenergic signaling that involves mobilization of natural killer cells and dendritic cells at the expense of monocytes. This may represent an adaptive response to the risk of acute injury. These findings offer some of the first evidence in humans that ß-blockade attenuates psychosocial stress-induced increases in inflammatory gene expression, offering new insights into the molecular and immunologic pathways by which stress may confer risks to health and well-being.

Social influences on microglial reactivity and neuronal damage after cardiac arrest/cardiopulmonary resuscitation.

Social isolation presents a risk factor and worsens outcome to cerebrovascular diseases; however, the underlying mechanisms remain underspecified. This study examines the effect of social environment on microglial reactivity after global cerebral ischemia, to test the hypothesis that social isolation leads to greater microglial responses. Adult female and male mice were pair-housed or socially isolated for one week prior to cardiac arrest/cardiopulmonary resuscitation (CA/CPR) or the sham procedure, and following either 2 or 24 h of reperfusion, microglia samples were enriched and analyzed for gene expression. At the 2-hour time point, microglia from both females and males exhibited ischemia-induced inflammation, characterized by the gene expression increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 6 (IL-6), regardless of the housing conditions. However, at 24 h post-ischemia, social housing attenuated microglial pro-inflammatory gene expression in a sex-specific manner. At this time point, the ischemia-induced increased expression of IL-1ß and IL-6 was attenuated by social interaction in microglia from male mice, while among female mice social attenuation of the inflammatory response was observed in the microglial expression of cell surface protein major histocompatibility complex II (MHC II). A second study examined behavioral and physiological measures 96 h after ischemic injury. At this time point, female and male mice displayed increased locomotion and exploratory behavior following CA/CPR relative to controls. Regardless of sex, ischemia also elicited neuroinflammation and neurodegeneration, both of which were modulated by the social environment. Hippocampal nitric oxide (iNOS), cortical TNF-α, and counts of Fluoro-Jade C positive stained cells in the CA1 region of the hippocampus, were increased in the isolated CA/CPR group relative to sham controls and the pair-housed CA/CPR groups. Together, these data indicate that female and male mice exhibit similar outcome measures and social modulation at 96 h post-ischemic injury, nonetheless, that social environment influences microglial reactivity to global cerebral ischemia in a sex-specific manner.

Low Sucrose, Omega-3 Enriched Diet Has Region-Specific Effects on Neuroinflammation and Synaptic Function Markers in a Mouse Model of Doxorubicin-Based Chemotherapy.

Chemotherapeutic agents such as doxorubicin may negatively affect long-term brain functioning in cancer survivors; neuroinflammation may play a causal role. Dietary approaches that reduce inflammation, such as lowering sucrose and increasing eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA), may attenuate chemotherapy-induced neuroinflammation and synaptic damage, thereby improving quality of life. Ovariectomized, C57BL/6 mice were assigned to a chemotherapy (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide) or vehicle two-injection regimen, with injections two and four weeks after starting diets. In Study 1, mice received low sucrose diets with EPA + DHA or No EPA + DHA for four to six weeks; tissues were collected four, seven, or 14 days after the second injection. Compared to vehicle, chemotherapy increased pro-inflammatory cytokine IL-1ß at day seven in the cortex and hippocampus, and reduced gene expression of synaptic marker Shank 3 at all timepoints in cortex, while EPA + DHA increased expression of Shank 3. In Study 2, high or low sucrose/EPA + DHA or No EPA + DHA diets were fed for five weeks; tissues were collected ten days after the second injection. Among chemotherapy-treated mice, brain DHA was higher with low sucrose feeding. Furthermore, low sucrose increased gene expression of Shank 1, while EPA + DHA increased expression of Shank 3 and reduced protein concentrations of pro-inflammatory markers IL-5, IL-6 and KC/GRO in the cortex, but not the hippocampus. Low sucrose, EPA + DHA diets may attenuate neuroinflammation and synaptic damage induced by doxorubicin-based chemotherapy in specific brain regions.

Social interaction modulates the neuroinflammatory response to global cerebral ischemia in male mice.

Social isolation is a risk factor for cardiovascular and cerebrovascular diseases, although the underlying mechanisms remain underspecified. Considering the potential of microglia to become sensitized by stressors and their role in neuroinflammation, we hypothesized that social isolation primes microglia, resulting in an exaggerated neuroimmune response to experimental cerebral ischemia. First, major histocompatibility complex II (MHC II) gene expression, an indicator of microglial priming, was compared between mice that were socially isolated or pair-housed. MHC II increased in the hippocampus and cortex of socially isolated mice, which is suggestive of isolation-induced microglial priming. In experiment 2, isolated and pair-housed mice underwent ∼8min of global cerebral ischemia. Hippocampal mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was significantly increased among both isolated and pair-housed ischemia groups relative to sham controls. Hippocampal expression of interleukin 1 beta (IL-1ß) and cortical TNF-α, IL-1ß and IL-6, were significantly increased 24-h post ischemia in isolated mice, but not pair-housed mice, relative to controls. Ischemia-induced increases in microglial cell body area and percent area fraction of ionized calcium binding adaptor molecule 1 (Iba-1) positive staining were also observed in isolated, but not pair-housed mice, relative to controls. For experiment 3, brain sections from socially isolated and pair-housed mice underwent 15min of oxygen glucose deprivation (OGD), an ex vivo model of cerebral ischemia. IL-6 gene expression was significantly elevated following OGD only in hippocampi from mice that had been socially isolated, indicating that isolation prior to ischemia is sufficient to modulate the neuroinflammatory response. Together, these data suggest microglial priming as a possible mechanism underlying the detrimental effects of social isolation on cerebral ischemia outcome.

Mammary Tumors Induce Central Pro-inflammatory Cytokine Expression, but Not Behavioral Deficits in Balb/C Mice.

Breast cancer survivors are more likely to develop mood disorders and cognitive deficits than women in the general population. Previous studies suggest that peripheral tumors elicit central pro-inflammatory cytokine production, in turn leading to depression and cognitive deficits. In the current study, two cohorts of female Balb/C mice received bilateral orthotopic injections of syngeneic 67NR, 4T07, or 4T1cells (1 × 105 cells per injection) to induce mammary tumors. Approximately three weeks later, learned fear (via fear conditioning) or depressive-like behavior (via tail suspension and forced swim test) was assessed. Proinflammatory cytokine levels were increased in the serum (IL-1ß, TNFα, IFNγ) and livers (IL-1ß, IL-6, TNFα) of mice with 4T07 or 4T1 tumors compared to 67NR tumors and the vehicle control. IL-1ß was increased in both the hippocampus and cortex of mice injected with 4T07 or 4T1 cell lines relative to the other treatment groups. However, mammary tumors had no effect on hippocampal doublecortin + and did not alter depressive-like behavior or learned fear. These data demonstrate that similarly sized tumors can produce differential immune responses and that tumor-induced central pro-inflammatory cytokine production can exist in the absence of depressive-like behavior or cognitive deficits.