Empathic control through coordinated interaction of amygdala, theory of mind and extended pain matrix brain regions.

Brain regions in the "pain matrix", can be activated by observing or reading about others in physical pain. In previous research, we found that reading stories about others' emotional suffering, by contrast, recruits a different group of brain regions mostly associated with thinking about others' minds. In the current study, we examined the neural circuits responsible for deliberately regulating empathic responses to others' pain and suffering. In Study 1, a sample of college-aged participants (n=18) read stories about physically painful and emotionally distressing events during functional magnetic resonance imaging (fMRI), while either actively empathizing with the main character or trying to remain objective. In Study 2, the same experiment was performed with professional social workers, who are chronically exposed to human suffering (n=21). Across both studies activity in the amygdala was associated with empathic regulation towards others' emotional pain, but not their physical pain. In addition, psychophysiological interaction (PPI) analysis and Granger causal modeling (GCM) showed that amygdala activity while reading about others' emotional pain was preceded by and positively coupled with activity in the theory of mind brain regions, and followed by and negatively coupled with activity in regions associated with physical pain and bodily sensations. Previous work has shown that the amygdala is critically involved in the deliberate control of self-focused distress - the current results extend the central importance of amygdala activity to the control of other-focused empathy, but only when considering others' emotional pain.

Dynamics of the rapsyn scaffolding protein at the neuromuscular junction of live mice.

The efficacy of synaptic transmission depends on the maintenance of a high density of neurotransmitter receptors and their associated scaffold proteins in the postsynaptic membrane. While the dynamics of receptors has been extensively studied, the dynamics of the intracellular scaffold proteins that make up the postsynaptic density are largely unknown in vivo. Here, we focused on the dynamics of rapsyn, a protein required for the clustering and maintenance of acetylcholine receptor (AChR) density at postsynaptic sites. Using time-lapse imaging, we demonstrated that rapsyn is remarkably dynamic compared to AChRs at functional synapses, turning over 4-6 times more rapidly than AChRs. In addition we found that the rapid turnover of rapsyn is insensitive to alterations in synaptic activity, whereas AChR turnover is profoundly affected, illustrating that rapsyn and receptor dynamics are controlled by distinct mechanisms. These data indicate that individual postsynaptic components are in permanent exchange despite the overall stability of synaptic structure, which may play a role in synaptic plasticity.

Acetylcholine receptor clustering is required for the accumulation and maintenance of scaffolding proteins.

The maintenance of a high density of postsynaptic receptors is essential for proper synaptic function. At the neuromuscular junction, acetylcholine receptor (AChR) aggregation is induced by nerve-clustering factors and mediated by scaffolding proteins. Although the mechanisms underlying AChR clustering have been extensively studied, the role that the receptors themselves play in the clustering process and how they are organized with scaffolding proteins is not well understood. Here, we report that the exposure of AChRs labeled with Alexa 594 conjugates to relatively low-powered laser light caused an effect similar to chromaphore-assisted light inactivation (CALI) , which resulted in the unexpected dissipation of the illuminated AChRs from clusters on cultured myotubes. This technique enabled us to demonstrate that AChR removal from illuminated regions induced the removal of scaffolding proteins and prevented the accumulation of new AChRs and associated scaffolding proteins. Further, the dissipation of clustered AChRs and scaffold was spatially restricted to the illuminated region and had no effect on neighboring nonilluminated AChRs. These results provide direct evidence that AChRs are essential for the local maintenance and accumulation of intracellular scaffolding proteins and suggest that the scaffold is organized into distinct modular units at AChR clusters.

Attitudes towards the outgroup are predicted by activity in the precuneus in Arabs and Israelis.

The modern socio-political climate is defined by conflict between ethnic, religious and political groups: Bosnians and Serbs, Tamils and Singhalese, Irish Catholics and Protestants, Israelis and Arabs. One impediment to the resolution of these conflicts is the psychological bias that members of each group harbor towards each other. These biases, and their neural bases, are likely different from the commonly studied biases towards racial outgroups. We presented Arab, Israeli and control individuals with statements about the Middle East from the perspective of the ingroup or the outgroup. Subjects rated how 'reasonable' each statement was, during fMRI imaging. Increased activation in the precuneus (PC) while reading pro-outgroup vs. pro-ingroup statements correlated strongly with both explicit and implicit measures of negative attitudes towards the outgroup; other brain regions that were involved in reasoning about emotionally-laden information did not show this pattern.

Receptor-associated proteins and synaptic plasticity.

Changes in synaptic strength are important for synaptic development and synaptic plasticity. Most directly responsible for these synaptic changes are alterations in synaptic receptor number and density. Although alterations in receptor density mediated by the insertion, lateral mobility, removal, and recycling of receptors have been extensively studied, the dynamics and regulators of intracellular scaffolding proteins have only recently begun to be illuminated. In particular, a closer look at the receptor-associated proteins, which bind to receptors and are necessary for their synaptic localization and clustering, has revealed broader functions than previously thought and some rather unexpected thematic similarities. More than just "placeholders" or members of a passive protein "scaffold," receptor-associated proteins in every synapse studied have been shown to provide a number of signaling roles. In addition, the most recent state-of-the-art imaging has revealed that receptor-associated proteins are highly dynamic and are involved in regulating synaptic receptor density. Together, these results challenge the view that receptor-associated proteins are members of a static and stable scaffold and argue that their dynamic mobility may be essential for regulating activity-dependent changes in synaptic strength.

A collective blame hypocrisy intervention enduringly reduces hostility towards Muslims.

Hostility towards outgroups contributes to costly intergroup conflict. Here we test an intervention to reduce hostility towards Muslims, a frequently targeted outgroup. Our 'collective blame hypocrisy' intervention highlights the hypocrisy involved in the tendency for people to collectively blame outgroup but not ingroup members for blameworthy actions of individual group members. Using both within-subject and between-subject comparisons in a preregistered longitudinal study in Spain, we find that our intervention reduces collective blame of Muslims and downstream anti-Muslim sentiments relative to a matched control condition and that the effects of the intervention persist one month and also one year later. We replicate the benefits of the intervention in a second study. The effects are mediated by reductions in collective blame and moderated by individual differences in preference for consistency. Together, these data illustrate that the collective blame hypocrisy intervention enduringly reduces harmful intergroup attitudes associated with conflict escalation, particularly among those who value consistency in themselves and others.

Parochial Empathy Predicts Reduced Altruism and the Endorsement of Passive Harm.

Empathic failures are common in hostile intergroup contexts; repairing empathy is therefore a major focus of peacebuilding efforts. However, it is unclear which aspect of empathy is most relevant to intergroup conflict. Although trait empathic concern predicts prosociality in interpersonal settings, we hypothesized that the best predictor of meaningful intergroup attitudes and behaviors might not be the general capacity for empathy (i.e., trait empathy), but the difference in empathy felt for the in-group versus the out-group, or "parochial empathy." Specifically, we predicted that out-group empathy would inhibit intergroup harm and promote intergroup helping, whereas in-group empathy would have the opposite effect. In three intergroup contexts-Americans regarding Arabs, Hungarians regarding refugees, Greeks regarding Germans-we found support for this hypothesis. In all samples, in-group and out-group empathy had independent, significant, and opposite effects on intergroup outcomes, controlling for trait empathic concern.

Running to stand still: ionotropic receptor dynamics at central and peripheral synapses.

For synapses to form and function, neurotransmitter receptors must be recruited to a location on the postsynaptic cell in direct apposition to presynaptic neurotransmitter release. However, once receptors are inserted into the postsynaptic membrane, they are not fixed in place but are continually exchanged between synaptic and extrasynaptic regions, and they cycle between the surface and intracellular compartments. This article highlights and compares the current knowledge about the dynamics of acetylcholine receptors at the vertebrate peripheral neuromuscular junction and AMPA, N-methyl-D-aspartate, and gamma-aminobutyric acid receptors in central synapses.

Increased expression of glutaminase and glutamine synthetase mRNA in the thalamus in schizophrenia.

Numerous molecules enable the handling of glutamate that is destined for neurotransmitter release, including transporters, receptors and glutamatergic enzymes. Previous work in our lab has shown altered levels of transcript expression of excitatory amino acid transporters and a vesicular glutamate transporter in the thalamus in schizophrenia. These changes suggest that molecules that facilitate the release and reuptake of glutamate may be abnormal in schizophrenia. In this study we determined the levels of expression of phosphate activated glutaminase (PAG), which converts glutamine to glutamate, and glutamine synthetase (GS), which converts glutamate to glutamine, with the hypothesis that thalamic PAG and GS transcript expression is altered in schizophrenia. We investigated expression of PAG and GS mRNA using in situ hybridization in six different thalamic nuclei (anterior, dorsomedial, centromedial, ventral anterior, ventral and reticular) from 13 persons with schizophrenia and 8 comparison subjects and found that transcripts for PAG and GS were significantly increased in schizophrenia. Increased PAG and GS transcripts suggest enhanced glutamatergic neurotransmission in the thalamus and its efferent targets in schizophrenia.

Minding the Gap: Narrative Descriptions about Mental States Attenuate Parochial Empathy.

In three experiments, we examine parochial empathy (feeling more empathy for in-group than out-group members) across novel group boundaries, and test whether we can mitigate parochial empathy with brief narrative descriptions. In the absence of individuating information, participants consistently report more empathy for members of their own assigned group than a competitive out-group. However, individualized descriptions of in-group and out-group targets significantly reduce parochial empathy by interfering with encoding of targets' group membership. Finally, the descriptions that most effectively decrease parochial empathy are those that describe targets' mental states. These results support the role of individuating information in ameliorating parochial empathy, suggest a mechanism for their action, and show that descriptions emphasizing targets' mental states are particularly effective.

Social cognition in members of conflict groups: behavioural and neural responses in Arabs, Israelis and South Americans to each other's misfortunes.

In contexts of cultural conflict, people delegitimize the other group's perspective and lose compassion for the other group's suffering. These psychological biases have been empirically characterized in intergroup settings, but rarely in groups involved in active conflict. Similarly, the basic brain networks involved in recognizing others' narratives and misfortunes have been identified, but how these brain networks are modulated by intergroup conflict is largely untested. In the present study, we examined behavioural and neural responses in Arab, Israeli and South American participants while they considered the pain and suffering of individuals from each group. Arabs and Israelis reported feeling significantly less compassion for each other's pain and suffering (the 'conflict outgroup'), but did not show an ingroup bias relative to South Americans (the 'distant outgroup'). In contrast, the brain regions that respond to others' tragedies showed an ingroup bias relative to the distant outgroup but not the conflict outgroup, particularly for descriptions of emotional suffering. Over all, neural responses to conflict group members were qualitatively different from neural responses to distant group members. This is the first neuroimaging study to examine brain responses to others' suffering across both distant and conflict groups, and provides a first step towards building a foundation for the biological basis of conflict.

Distinct roles of the 'shared pain' and 'theory of mind' networks in processing others' emotional suffering.

The brain mechanisms involved in processing another's physical pain have been extensively studied in recent years. The link between understanding others' physical pain and emotional suffering is less well understood. Using whole brain analysis and two separate functional localizers, we characterized the neural response profiles of narrative scenarios involving physical pain (PP), and scenarios involving emotional pain (EP) with functional magnetic resonance imaging (fMRI). Whole brain analyses revealed that PP narratives activated the Shared Pain network, and that the brain regions responsible for processing EP overlapped substantially with brain regions involved in Theory of Mind. Region of interest (ROI) analysis provided a finer-grained view. Some regions responded to stories involving physical states, regardless of painful content (secondary sensory regions), some selectively responded to both emotionally and physically painful events (bilateral anterior thalamus and anterior middle cingulate cortex), one brain region responded selectively to physical pain (left insula), and one brain region responded selectively to emotional pain (dorsomedial prefrontal cortex). These results replicated in two groups of participants given different explicit tasks. Together, these results clarify the distinct roles of multiple brain regions in responding to others who are in physical or emotional pain.

The dynamics of recycled acetylcholine receptors at the neuromuscular junction in vivo.

At the peripheral neuromuscular junction (NMJ), a significant number of nicotinic acetylcholine receptors (AChRs) recycle back into the postsynaptic membrane after internalization to intermingle with not-yet-internalized ;pre-existing' AChRs. However, the way in which these receptor pools are maintained and regulated at the NMJ in living animals remains unknown. Here, we demonstrate that recycled receptors in functional synapses are removed approximately four times faster than pre-existing receptors, and that most removed recycled receptors are replaced by new recycled ones. In denervated NMJs, the recycling of AChRs is significantly depressed and their removal rate increased, whereas direct muscle stimulation prevents their loss. Furthermore, we show that protein tyrosine phosphatase inhibitors cause the selective accumulation of recycled AChRs in the peri-synaptic membrane without affecting the pre-existing AChR pool. The inhibition of serine/threonine phosphatases, however, has no effect on AChR recycling. These data show that recycled receptors are remarkably dynamic, and suggest a potential role for tyrosine dephosphorylation in the insertion and maintenance of recycled AChRs at the postsynaptic membrane. These findings may provide insights into long-term recycling processes at less accessible synapses in the central nervous system in vivo.

The effect of agrin and laminin on acetylcholine receptor dynamics in vitro.

Using optical imaging assays, we investigated the dynamics of acetylcholine receptors (AChRs) at laminin-associated clusters on cultured myotubes in the absence or presence of the nerve-derived clustering factor, agrin. Using fluorescence recovery after photobleaching (FRAP) on fluorescent bungarotoxin-labeled receptors, we found that approximately 9% of original fluorescence was recovered after 8 h as surface AChRs were recruited into clusters. By quantifying the loss of labeled receptors and the recovery of fluorescence after photobleaching, we estimated that the half-life of clustered receptors was approximately 4.5 h. Despite the rapid removal of receptors, the accumulation of new receptors at clusters was robust enough to maintain receptor density over time. We also found that the AChR half-life was not affected by agrin despite its role in inducing the aggregation of AChRs. Interestingly, when agrin was added to myotubes grown on laminin-coated substrates, most new receptors were not directed into preexisting laminin-induced clusters but instead formed numerous small aggregates on the entire muscle surface. Time-lapse imaging revealed that the agrin-induced clusters could be seen as early as 1 h, and agrin treatment resulted in the complete dissipation of laminin-associated clusters by 24 h. These results reveal that while laminin and agrin are involved in the clustering of receptors they are not critical to the regulation of receptor metabolic stability at these clusters, and further argue that agrin is able to rapidly and fully negate the laminin substrate clustering effect while inducing the rapid formation of new clusters.