The effect of a prosocial environment on health and well-being during the first COVID-19 lockdown and a year later.

The outset of the COVID-19 pandemic was characterized by prolonged periods of chronic stress and social isolation. While studies have investigated the changes to well-being (WB) during this period, the impact of the social environment on long-term physical and mental health requires further study. This study aimed to assess the factors influencing WB and health outcomes, with the hypothesis that a positive social environment would play a significant immediate and long-term role in improving WB and preventing the effects of anxiety associated with the pandemic. At time point 1 (April 2020), an Israeli sample of 206 participants (84% female, mean age 31.5) responded to traditional questionnaires assessing mental health and social support. Factors affecting WB were assessed within subjects during the first COVID-19 lockdown for 6 weeks using a daily survey (Beiwe phone application). A year later, in May 2021, at time point 2, the initial questionnaires were readministered to a subset of the same participants (N = 94). We found that anxiety during the first lockdown adversely affected WB and predicted health and WB deterioration a year later. In contrast, a high quality of social relationships was associated with better short- and long-term WB, and mitigated the adverse effects of anxiety. Daily activities, including physical activity, meditation, and romantic relations, were also positively associated with WB during the first lockdown but did not have long-term effects. In summary, our study underscores the enduring health advantages of a positive social environment, particularly during stressful periods. These results have implications for health policymakers: programs which support individuals with high anxiety and low support, by integrating them into community-based interventions, promise to enhance well-being (WB) and health, as well as to fortify the community as a whole.

Negative energy balance hinders prosocial helping behavior.

The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum-fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.

Neural activation associated with outgroup helping in adolescent rats.

Prosocial behavior, helping others in need in particular, occurs preferentially in response to the perceived distress of one's own group members or ingroup. To investigate the development of ingroup bias, neural activity during a helping test was analyzed in adolescent and adult rats. Although adults selectively released trapped ingroup members, adolescent rats helped both ingroup and outgroup members, suggesting that ingroup bias emerges in adulthood. Analysis of brain-wide neural activity, indexed by expression of the early-immediate gene c-Fos, revealed increased activity for ingroup members across a broad set of regions previously associated with empathy. Adolescents showed reduced hippocampal and insular activity and increased orbitofrontal cortex activity compared to adults. Non-helper adolescents demonstrated increased amygdala connectivity. These findings demonstrate that biases for group-dependent prosocial behavior develop with age in rats and suggest that specific brain regions contribute to prosocial selectivity, pointing to possible targets for the functional modulation of ingroup bias.

What's familiarity got to do with it? Neural mechanisms of observational fear in siblings and strangers.

Social modulation of pain sensitivity is considered part of the empathic response. In this issue of Neuron, Zhang at al. (2022) uncover the neurobiological basis of observational pain in mice. They report increased synaptic transmission from the insular cortex to the basolateral amygdala and explore genes mediating this effect.

Neural correlates of ingroup bias for prosociality in rats.

Prosocial behavior, in particular helping others in need, occurs preferentially in response to distress of one's own group members. In order to explore the neural mechanisms promoting mammalian helping behavior, a discovery-based approach was used here to identify brain-wide activity correlated with helping behavior in rats. Demonstrating social selectivity, rats helped others of their strain ('ingroup'), but not rats of an unfamiliar strain ('outgroup'), by releasing them from a restrainer. Analysis of brain-wide neural activity via quantification of the early-immediate gene c-Fos identified a shared network, including frontal and insular cortices, that was active in the helping test irrespective of group membership. In contrast, the striatum was selectively active for ingroup members, and activity in the nucleus accumbens, a central network hub, correlated with helping. In vivo calcium imaging showed accumbens activity when rats approached a trapped ingroup member, and retrograde tracing identified a subpopulation of accumbens-projecting cells that was correlated with helping. These findings demonstrate that motivation and reward networks are associated with helping an ingroup member and provide the first description of neural correlates of ingroup bias in rodents.

Anxiolytic Treatment Impairs Helping Behavior in Rats.

Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats' subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat's behavior on one session influenced his behavior on the next session. Results suggest that helping a trapped rat has a greater motivational value than does chocolate. In sum, this series of experiments clearly demonstrates the fundamental role of affect in motivating pro-social behavior in rodents and the need for a helper to resonate with the affect of a victim.

Empathy as a driver of prosocial behaviour: highly conserved neurobehavioural mechanisms across species.

Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well-being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions.

Pro-social behavior in rats is modulated by social experience.

In mammals, helping is preferentially provided to members of one's own group. Yet, it remains unclear how social experience shapes pro-social motivation. We found that rats helped trapped strangers by releasing them from a restrainer, just as they did cagemates. However, rats did not help strangers of a different strain, unless previously housed with the trapped rat. Moreover, pair-housing with one rat of a different strain prompted rats to help strangers of that strain, evidence that rats expand pro-social motivation from one individual to phenotypically similar others. To test if genetic relatedness alone can motivate helping, rats were fostered from birth with another strain and were not exposed to their own strain. As adults, fostered rats helped strangers of the fostering strain but not rats of their own strain. Thus, strain familiarity, even to one's own strain, is required for the expression of pro-social behavior. DOI: http://dx.doi.org/10.7554/eLife.01385.001.

Empathy and pro-social behavior in rats.

Whereas human pro-social behavior is often driven by empathic concern for another, it is unclear whether nonprimate mammals experience a similar motivational state. To test for empathically motivated pro-social behavior in rodents, we placed a free rat in an arena with a cagemate trapped in a restrainer. After several sessions, the free rat learned to intentionally and quickly open the restrainer and free the cagemate. Rats did not open empty or object-containing restrainers. They freed cagemates even when social contact was prevented. When liberating a cagemate was pitted against chocolate contained within a second restrainer, rats opened both restrainers and typically shared the chocolate. Thus, rats behave pro-socially in response to a conspecific's distress, providing strong evidence for biological roots of empathically motivated helping behavior.

"Feeling" the pain of those who are different from us: Modulation of EEG in the mu/alpha range.

We explored how apparently painful stimuli and the ability to identify with the person on whom the pain is inflicted modulate EEG suppression in the mu/alpha range (8-12 Hz). In a 2 × 2 design, we presented pictures of hands either experiencing needle pricks or being touched by a Q-tip. In the dissimilar-other condition, the hand was assigned to a patient suffering from a neurological disease in which Q-tips inflicted pain, whereas needle pricks did not. In the similar-other condition, the hand was assigned to a patient who responded to stimulation in the same way as the healthy participant. Participants were instructed to imagine the feeling of the person whose hand was shown and to evaluate his or her affective state. Pain conditions elicited greater EEG suppression than did nonpain conditions, particularly over frontocentral regions. Moreover, an interaction between pain and similarity revealed that for similar others, the pain effect was significant, whereas in the dissimilar-other group, suppression was equally large in the pain and no-pain conditions. We conclude that mu/alpha suppression is elicited both automatically, by observing a situation that is potentially painful for the observer, and by empathy for pain, even if the other person is different from oneself.

Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression.

BACKGROUND: A unique opportunity to eradicate cancer is presented immediately after the excision of the primary tumor, but surgical procedures often induce the release of immunosuppressing factors that render cell mediated immunity ineffective. Here we tested the hypothesis that integration of peri-operative immunostimulation and blockade of immunosuppression could synergistically improve post-operative anti-metastatic immunity and long-term survival. METHODS: Two syngeneic tumor models in F344 rats were employed, studying post-operative tumor progression. In the first model, survival following laparotomy and CRNK-16 leukemia was studied. Rats were peri-operatively treated with the immuno-stimulant poly I-C (5x0.2 mg/kg/inj), with catecholamine- and prostaglandin-blockers (shown to prevent post-operative immunosuppression: 4.5 mg/kg nadolol, 4 mg/kg indomethacin), with both interventions, or with neither. Long-term survival was assessed thereafter. The second model used the MADB106 mammary adenocarcinoma, assessing its lung tumor retention (LTR) following i.v. inoculation, as well as host marginating-pulmonary NK numbers and activity against this tumor. IL-12 was employed for immunostimulation (4x1.5 microg/kg/inj), with and without the above blockers. RESULTS: Post-operative CRNK-16 survival rates were significantly improved only by the integrated approach of immune stimulation and endocrine blockers. Post-operative MADB106 LTR was additively reduced by the two interventions. Importantly, while IL-12 increased pulmonary NK cytotoxicity against MADB106, surgery markedly suppressed this cytotoxicity in both IL-12 and vehicle treated animals. The blockers prevented this suppression per lung and per single NK cell. CONCLUSIONS: Immunostimulation could be rendered ineffective post-operatively due to immunosuppression; therefore integrating endocrine-blocker therapies into the realm of peri-operative immunotherapy could optimize immune control over residual disease, potentially improving clinical outcomes.

Immune perturbations in patients along the perioperative period: alterations in cell surface markers and leukocyte subtypes before and after surgery.

BACKGROUND: Surgery renders patients susceptible to life-threatening complications, including infections, multiple organ failure, and presumably cancer metastases. Surgery-induced immune perturbations were suggested to contribute to such deleterious effects, but also to facilitate post-injury healing. Preoperative psychological and physiological stress responses may contribute to these immune perturbations, and could thus jeopardize patients even before surgery. The current study assessed the effects of various operations on an array of immune indices during the perioperative period. To qualify immune changes before surgery, patients' immune status was also compared to that of healthy controls. METHODS: A total of 81 subjects (operated patients and healthy controls) provided up to five daily blood samples during the perioperative period, for assessment of leukocyte subtypes (granulocytes, monocytes, Tc, Th, NK, NKT, CD4+CD25+, CD8(bright)CD4(dim), and B cells) and their surface markers (HLA-DR and LFA-1). RESULTS: Even before surgery patients displayed immune perturbations, including reduced lymphocyte HLA-DR expression and increased monocyte LFA-1 expression. Following surgery, we recorded a reduction in lymphocyte numbers that was subtype specific, increased granulocyte numbers, and reduced expression of HLA-DR by lymphocytes and monocytes. Finally, no significant associations were found between alteration in leukocyte numbers and cell surface markers (although these indices showed high correlations with other variables), implying differential mediating mechanisms. CONCLUSION: Several immune alterations are manifested prior to surgery, and contribute to the marked postoperative changes, which are commonly interpreted as immune suppression. We discuss the possible adaptive and maladaptive nature of these perturbations in the context of natural injury, stress, and surgery.

Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis.

BACKGROUND: COX inhibitors and beta-blockers were recently suggested to reduce cancer progression through inhibition of tumor proliferation and growth factor secretion, induction of tumor apoptosis, and prevention of cellular immune suppression during the critical perioperative period. Here we evaluated the perioperative impact of clinically applicable drugs from these categories in the context of surgery, studying natural killer (NK) cell activity and resistance to experimental metastases. METHODS: F344 rats were treated with COX-1 inhibitors (SC560), COX-2 inhibitors (indomethacin, etodolac, or celecoxib), a beta-blocker (propranolol), or a combination of a COX-2 inhibitor and a beta-blocker (etodolac and propranolol). Rats underwent laparotomy, and were inoculated intravenously with syngeneic MADB106 tumor cells for the assessment of lung tumor retention (LTR). Additionally, the impact of these drug regimens on postoperative levels of NK cytotoxicity was studied in peripheral blood and marginating-pulmonary leukocytes. RESULTS: Surgery increased MADB106 LTR. COX-2 inhibition, but not COX-1 inhibition, reduced postoperative LTR. Etodolac and propranolol both attenuated the deleterious impact of surgery, and their combined use abolished it. Surgery decreased NK cytotoxicity per NK cell in both immune compartments, and only the combination of etodolac and propranolol significantly attenuated these effects. Lastly, the initiation of drug treatment three days prior to surgery yielded the same beneficial effects as a single pre-operative administration, but, as discussed, prolonged treatment may be more advantageous clinically. CONCLUSIONS: Excess prostaglandin and catecholamine release contributes to postoperative immune-suppression. Treatment combining perioperative COX-2 inhibition and beta-blockade is practical in operated cancer patients, and our study suggests potential immunological and clinical benefits.