Dynamic diversity is the answer to proxy failure.

We argue that a diverse and dynamic pool of agents mitigates proxy failure. Proxy modularity plays a key role in the ongoing production of diversity. We review examples from a range of scales.

Excitatory and Inhibitory Neurons of the Spinal Cord Superficial Dorsal Horn Diverge in Their Somatosensory Responses and Plasticity in Vivo.

The superficial dorsal horn (SDH) of the spinal cord represents the first site of integration between innocuous and noxious somatosensory stimuli. According to gate control theory, diverse populations of excitatory and inhibitory interneurons within the SDH are activated by distinct sensory afferents, and their interplay determines the net nociceptive output projecting to higher pain centers. Although specific SDH cell types are ill defined, numerous classifications schemes find that excitatory and inhibitory neurons fundamentally differ in their morphology, electrophysiology, neuropeptides, and pain-associated plasticity; yet little is known about how these neurons respond over a range of natural innocuous and noxious stimuli. To address this question, we applied an in vivo imaging approach in male mice where the genetically encoded calcium indicator GCaMP6s was expressed either in vGluT2-positive excitatory or vIAAT-positive inhibitory neurons. We found that inhibitory neurons were markedly more sensitive to innocuous touch than excitatory neurons but still responded dynamically over a wide range of noxious mechanical stimuli. Inhibitory neurons were also less sensitive to thermal stimuli than their excitatory counterparts. In a capsaicin model of acute pain sensitization, the responses of excitatory neurons were significantly potentiated to innocuous and noxious mechanical stimuli, whereas inhibitory neural responses were only depressed to noxious stimuli. These in vivo findings show that excitatory and inhibitory SDH neurons diverge considerably in their somatosensory responses and plasticity, as postulated by gate control theory.SIGNIFICANCE STATEMENT Gate control theory posits that opposing spinal excitatory and inhibitory neurons, differently tuned across somatosensory modalities, determine the net nociceptive output to higher pain centers. Little is known about how natural stimuli activate these two neural populations. This study applied an in vivo calcium imaging approach to genetically target these neurons and contrast their responses over a range of innocuous and noxious mechanical and thermal stimuli. Compared with excitatory neurons, we found that inhibitory neurons are more sensitive to innocuous touch and far less sensitive to thermal stimuli. An acute model of pain also revealed that these subtypes undergo divergent mechanosensory plasticity. Our data provide important and novel insights for gate-control inspired models of pain processing.

Dorsal column and root stimulation at Aß-fiber intensity activate superficial dorsal horn glutamatergic and GABAergic populations.

Neurostimulation therapies are frequently used in patients with chronic pain conditions. They emerged from Gate Control Theory (GCT), which posits that Aß-fiber activation recruits superficial dorsal horn (SDH) inhibitory networks to "close the gate" on nociceptive transmission, resulting in pain relief. However, the efficacy of current therapies is limited, and the underlying circuits remain poorly understood. For example, it remains unknown whether ongoing stimulation of Aß-fibers is sufficient to drive activity in SDH neurons. We used multiphoton microscopy in spinal cords extracted from mice expressing the genetically encoded calcium indicator GCaMP6s in glutamatergic and GABAergic populations; activity levels were inferred from deconvolved calcium signals using CaImAn software. Sustained Aß-fiber stimulation at the dorsal columns or dorsal roots drove robust yet transient activation of both SDH populations. Following the initial increase, activity levels decreased below baseline in glutamatergic neurons and were depressed after stimulation ceased in both populations. Surprisingly, only about half of GABAergic neurons responded to Aß-fiber stimulation. This subset showed elevated activity for the entire duration of stimulation, while non-responders decreased with time. Our findings suggest that Aß-fiber stimulation initially recruits both excitatory and inhibitory populations but has divergent effects on their activity, providing a foundation for understanding the analgesic effects of neurostimulation devices.Perspective: This article used microscopy to characterize the responses of mouse spinal cord cells to stimulation of non-painful nerve fibers. These findings deepen our understanding of how the spinal cord processes information and provide a foundation for improving pain-relieving therapies.

Mental Health Clinician Community Clergy Collaboration to Address Moral Injury Symptoms: A Feasibility Study.

Moral injury (MI) symptoms (guilt, shame, isolation) can be associated with military experiences. While a degree of overlap is recognized between MI and posttraumatic stress disorder (PTSD) symptoms, MI symptoms do not always respond to evidence-based treatments for PTSD. Mental Health Clinician Community Chaplain Collaboration (MC4) was delivered by community clergy to address MI symptoms through facilitation of forgiveness and community reintegration. Thirteen veterans participated and the results suggested that MC4 was generally feasible and acceptable. However, it is unlikely community clergy time could keep up with demand. Shifting intervention delivery to Department of Veterans Affairs (VA) chaplains will alleviate many barriers experienced in this feasibility study.

Mental Health Clinician and Community Clergy Collaboration to Address Moral Injury in Veterans and the Role of the Veterans Affairs Chaplain.

Moral injury in veterans with posttraumatic stress disorder includes symptoms of guilt and shame, and these symptoms are often not responsive to evidence-based mental health treatments. Clergy provide a pathway for relieving the guilt and shame. However, there is a long history of mistrust between clergy and mental health clinicians and not enough Veterans Health Administration chaplains to meet this need. The goal of this study was to gather qualitative interview data from relevant stakeholders regarding whether and how Veterans Affairs (VA) mental health clinicians and community clergy could collaborate to address moral injury issues such as guilt and shame in veterans being treated for posttraumatic stress disorder. The stakeholders for this study were veterans, mental health clinicians, and clergy. Qualitative data were organized into three domains: barriers, facilitators, and intervention suggestions. These data were used to develop a new intervention for moral injury that includes a central role for the Veterans Affairs chaplain.

The Morality of Disordered Eating and Recovery in Southern Italy.

Scholars have traced the processes through which moral subjectivities are constituted in culturally meaningful ways through eating disorders and recovery practices, demonstrating how subjective meanings of eating disorders and recovery from them are imbued with moral undertones and become meaningful ways of existing within specific historical and cultural contexts. Drawing on ethnographic insights and interviews with young women with disordered eating histories in southern Italy, we show how suffering from eating disorders and recovery from them enables women to retool their identities and craft moral selves. We draw attention to the value of medical anthropology in the care and comprehension of well-being of girls and women suffering from disordered eating.

TARP γ-2 Is Required for Inflammation-Associated AMPA Receptor Plasticity within Lamina II of the Spinal Cord Dorsal Horn.

In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking stargazer (stg/stg) mice. Examination of EPSCs revealed the targeting of γ-2 to be synapse-specific; the amplitude of spontaneously occurring miniature EPSCs (mEPSCs) was reduced in neurons from stg/stg mice, but the amplitude of capsaicin-induced mEPSCs from C-fiber synapses was unaltered. This suggests that γ-2 is associated with AMPARs at synapses in lamina II but excluded from those at C-fiber inputs, a view supported by our immunohistochemical colabeling data. Following induction of peripheral inflammation, a model of hyperalgesia, there was a switch in the current-voltage relationships of capsaicin-induced mEPSCs, from linear to inwardly rectifying, indicating an increased prevalence of calcium-permeable (CP) AMPARs. This effect was abolished in stg/stg mice. Our results establish that, although γ-2 is not typically associated with calcium-impermeable AMPARs at C-fiber synapses, it is required for the translocation of CP-AMPARs to these synapses following peripheral inflammation.SIGNIFICANCE STATEMENT In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically determine the functional properties of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. An increase in the excitability of neurons within the superficial dorsal horn (SDH) of the spinal cord is thought to underlie heighted pain sensitivity. One mechanism considered to contribute to such long-lived changes is the remodeling of the ionotropic AMPA-type glutamate receptors that underlie fast excitatory synaptic transmission in the SDH. Here we show that the TARP γ-2 (stargazin) is present in SDH neurons and is necessary in a form of inflammatory pain-induced plasticity, which involves an increase in the prevalence of synaptic calcium-permeable AMPARs.

Using Community Advisory Boards to Build Partnerships and Develop Peer-Led Services for Rural Student Veterans.

BACKGROUND: The Department of Veterans' Affairs (VA)/Student Partnership for Rural Veterans (VSP) built partnerships between institutional (health services researchers, VA chaplains) and community groups to develop veteran-to-veteran services on college campuses. OBJECTIVES: Describe challenges and lessons learned in year 1 of the VSP project at six campuses in rural Arkansas. METHODS: Researchers leveraged established community advisory boards (CABs) to develop veteran-to-veteran services. Ethnographic and qualitative methods were used to assess partnership building and evaluate peer-led services. RESULTS: Local established CABs and buy-in from student services and veteran organizations was instrumental to building partnerships and developing services. Challenges included developing rapport with campus leaders and creating sustainable role/expectations for student veteran leaders. CONCLUSIONS: Peer-led services are an ideal way to connect student veterans and link them to resources and health care services. Partnerships can facilitate grassroots efforts to develop local services that meet the needs of diverse student veteran populations.

The Religious and Spiritual Dimensions of Cutting Down and Stopping Cocaine Use: A Qualitative Exploration Among African Americans in the South.

This study qualitatively examines the religious and spiritual dimensions of cutting down and stopping cocaine use among African Americans in rural and urban areas of Arkansas. The analyses compare and contrast the narrative data of 28 current cocaine users living in communities where the Black church plays a fundamental role in the social and cultural lives of many African Americans, highlighting the ways that participants used religious symbols, idiomatic expression, and Biblical scriptures to interpret and make sense of their substance-use experiences. Participants drew on diverse religious and spiritual beliefs and practices, including participation in organized religion, reliance on a personal relationship with God, and God's will to cut down and stop cocaine use. Our findings suggest that culturally sensitive interventions addressing the influence of religion and spirituality in substance use are needed to reduce cocaine use and promote recovery in this at-risk, minority population.

Building partnerships with rural Arkansas faith communities to promote veterans' mental health: lessons learned.

BACKGROUND: The Mental Health-Clergy Partnership Program established partnerships between institutional (Department of Veterans' Affairs [VA] chaplains, mental health providers) and community (local clergy, parishioners) groups to develop programs to assist rural veterans with mental health needs. OBJECTIVES: Describe the development, challenges, and lessons learned from the Mental Health-Clergy Partnership Program in three Arkansas towns between 2009 and 2012. METHODS: Researchers identified three rural Arkansas sites, established local advisory boards, and obtained quantitative ratings of the extent to which partnerships were participatory. RESULTS: Partnerships seemed to become more participatory over time. Each site developed distinctive programs with variation in fidelity to original program goals. Challenges included developing trust and maintaining racial diversity in local program leadership. CONCLUSIONS: Academics can partner with local faith communities to create unique programs that benefit the mental health of returning veterans. Research is needed to determine the effectiveness of community based programs, especially relative to typical "top-down" outreach approaches.

The pew versus the couch: relationship between mental health and faith communities and lessons learned from a VA/clergy partnership project.

The history of the relationship between religion and mental health is one of commonality, conflict, controversy, and distrust. An awareness of this complex relationship is essential to clinicians and clergy seeking to holistically meet the needs of people in our clinics, our churches, and our communities. Understanding this relationship may be particularly important in rural communities. This paper briefly discusses the history of this relationship and important areas of disagreement and contention. The paper moves beyond theory to present some current practical tensions identified in a brief case study of VA/Clergy partnerships in rural Arkansas. The paper concludes with a framework of three models for understanding how most faith communities perceive mental health and suggests opportunities to overcome the tensions between "the pew" and "the couch."

AMPA receptor-dependent, light-evoked D-serine release acts on retinal ganglion cell NMDA receptors.

NMDA receptor (NMDAR) activation requires coincident binding of the excitatory neurotransmitter glutamate and a coagonist, either glycine or D-serine. Changes in NMDAR currents during neural transmission are typically attributed to glutamate release against a steady background of coagonist, excluding the possibility of coagonist release. AMPA receptor (AMPAR) stimulation evokes D-serine release, but it is unknown whether this is a physiological phenomenon capable of influencing synaptic responses. In this study, we utilized the intact retina to determine whether light-evoked synaptic activity in retinal ganglion cells (RGCs) is shaped by a dynamic pool of coagonist. The application of AMPAR antagonist abolished light-evoked NMDAR currents, which were rescued by adding coagonist to the bath. When NMDA was globally applied to RGCs via bath or picospritzing, the coagonist occupancy was also dependent on AMPARs but to a lesser extent than that observed during light responses, suggesting a difference in extrasynaptic coagonist regulation. By saturating the glutamate binding site of NMDARs, we were able to detect released coagonist reaching RGCs during light-evoked responses. Mutant mice lacking the d-serine-synthesizing enzyme serine racemase were deficient in coagonist release. Coagonist release in wild-type retinas was notably greater in ON than in OFF responses and depended on AMPARs. These findings suggest activity-dependent modulation of coagonist availability, particularly D-serine, and may add an extra dimension to NMDAR coincidence detection in the retina.

Serine racemase deletion abolishes light-evoked NMDA receptor currents in retinal ganglion cells.

Glycine and/or D-serine are obligatory coagonists of the N-methyl-D-aspartate receptor (NMDAR). Serine racemase, the D-serine-synthesizing enzyme, is expressed by astrocytes and Müller cells of the retina, but little is known about its role in retinal signalling. In this study, we utilize a serine racemase knockout (SRKO) mouse to explore the contribution of D-serine to inner-retinal function. Retinal tissue levels of D-serine in SRKO mice are reduced by 85%. Whole-cell recordings from SRKO retinal ganglion cells showed markedly reduced coagonist occupancy of NMDARs and consequently a dramatic reduction in the NMDAR component of light-evoked responses. NMDAR currents in SRKOs could be rescued by applying exogenous coagonist, but SRKO ganglion cells still displayed lower NMDA/AMPA receptor ratios than wild-type (WT) controls when the coagonist site was saturated. Despite having abnormalities in synaptic glutamatergic transmission, SRKO mice displayed no obvious signs of visual impairment in behavioural testing. These findings raise interesting questions about the role of D-serine in inner-retinal function and development.

AMPA receptor mediated D-serine release from retinal glial cells.

The N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine is important in a number of different processes in the CNS, ranging from synaptic plasticity to disease states, including schizophrenia. D-serine appears to be the major co-agonist acting on retinal ganglion cell NMDA receptors, but the cell type from which it originates and whether its release can be modulated by activity are unknown. In this study, we utilized a mutant mouse line with elevated d-serine to investigate this question. Direct measurements of extracellular D-serine using capillary electrophoresis demonstrate that D-serine can be released from the intact mouse retina through an α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) dependent mechanism. α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-evoked D-serine release persisted in the presence of a cocktail of neural inhibitors but was abolished after administration of a glial toxin. These findings provide the first evidence that extracellular D-serine levels in the retina can be modulated, and that such modulation is contingent upon glial cell activity.

Bird pollination of Canary Island endemic plants.

The Canary Islands are home to a guild of endemic, threatened bird-pollinated plants. Previous work has suggested that these plants evolved floral traits as adaptations to pollination by flower specialist sunbirds, but subsequently, they appear to have co-opted generalist passerine birds as sub-optimal pollinators. To test this idea, we carried out a quantitative study of the pollination biology of three of the bird-pollinated plants, Canarina canariensis (Campanulaceae), Isoplexis canariensis (Veronicaceae) and Lotus berthelotii (Fabaceae), on the island of Tenerife. Using colour vision models, we predicted the detectability of flowers to bird and bee pollinators. We measured pollinator visitation rates, nectar standing crops as well as seed-set and pollen removal and deposition. These data showed that the plants are effectively pollinated by non-flower specialist passerine birds that only occasionally visit flowers. The large nectar standing crops and extended flower longevities (>10 days) of Canarina and Isoplexis suggests that they have evolved a bird pollination system that effectively exploits these low frequency non-specialist pollen vectors and is in no way sub-optimal. Seed set in two of the three species was high and was significantly reduced or zero in flowers where pollinator access was restricted. In L. berthelotii, however, no fruit set was observed, probably because the plants were self-incompatible horticultural clones of a single genet. We also show that, while all three species are easily detectable for birds, the orange Canarina and the red Lotus (but less so the yellow-orange Isoplexis) should be difficult to detect for insect pollinators without specialised red receptors, such as bumblebees. Contrary to expectations if we accept that the flowers are primarily adapted to sunbird pollination, the chiffchaff (Phylloscopus canariensis) was an effective pollinator of these species.