Heterogeneous pdgfrb+ cells regulate coronary vessel development and revascularization during heart regeneration.

Endothelial cells emerge from the atrioventricular canal to form coronary blood vessels in juvenile zebrafish hearts. We find that pdgfrb is first expressed in the epicardium around the atrioventricular canal and later becomes localized mainly in the mural cells. pdgfrb mutant fish show severe defects in mural cell recruitment and coronary vessel development. Single-cell RNA sequencing analyses identified pdgfrb+ cells as epicardium-derived cells (EPDCs) and mural cells. Mural cells associated with coronary arteries also express cxcl12b and smooth muscle cell markers. Interestingly, these mural cells remain associated with coronary arteries even in the absence of Pdgfrß, although smooth muscle gene expression is downregulated. We find that pdgfrb expression dynamically changes in EPDCs of regenerating hearts. Differential gene expression analyses of pdgfrb+ EPDCs and mural cells suggest that they express genes that are important for regeneration after heart injuries. mdka was identified as a highly upregulated gene in pdgfrb+ cells during heart regeneration. However, pdgfrb but not mdka mutants show defects in heart regeneration after amputation. Our results demonstrate that heterogeneous pdgfrb+ cells are essential for coronary development and heart regeneration.

Self-judgment dissected: A computational modeling analysis of self-referential processing and its relationship to trait mindfulness facets and depression symptoms.

Cognitive theories of depression, and mindfulness theories of well-being, converge on the notion that self-judgment plays a critical role in mental health. However, these theories have rarely been tested via tasks and computational modeling analyses that can disentangle the information processes operative in self-judgments. We applied a drift-diffusion computational model to the self-referential encoding task (SRET) collected before and after an 8-week mindfulness intervention (n = 96). A drift-rate regression parameter representing positive-relative to negative-self-referential judgment strength positively related to mindful awareness and inversely related to depression, both at baseline and over time; however, this parameter did not significantly relate to the interaction between mindful awareness and nonjudgmentalness. At the level of individual depression symptoms, at baseline, a spectrum of symptoms (inversely) correlated with the drift-rate regression parameter, suggesting that many distinct depression symptoms relate to valenced self-judgment between subjects. By contrast, over the intervention, changes in only a smaller subset of anhedonia-related depression symptoms showed substantial relationships with this parameter. Both behavioral and model-derived measures showed modest split-half and test-retest correlations. Results support cognitive theories that implicate self-judgment in depression and mindfulness theories, which imply that mindful awareness should lead to more positive self-views.

Computational Psychiatry Needs Time and Context.

Why has computational psychiatry yet to influence routine clinical practice? One reason may be that it has neglected context and temporal dynamics in the models of certain mental health problems. We develop three heuristics for estimating whether time and context are important to a mental health problem: Is it characterized by a core neurobiological mechanism? Does it follow a straightforward natural trajectory? And is intentional mental content peripheral to the problem? For many problems the answers are no, suggesting that modeling time and context is critical. We review computational psychiatry advances toward this end, including modeling state variation, using domain-specific stimuli, and interpreting differences in context. We discuss complementary network and complex systems approaches. Novel methods and unification with adjacent fields may inspire a new generation of computational psychiatry.

Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina.

In the retina of zebrafish, Müller glia have the ability to reprogram into stem cells capable of regenerating all classes of retinal neurons and restoring visual function. Understanding the cellular and molecular mechanisms controlling the stem cell properties of Müller glia in zebrafish may provide cues to unlock the regenerative potential in the mammalian nervous system. Midkine is a cytokine/growth factor with multiple roles in neural development, tissue repair, and disease. In midkine-a loss-of-function mutants of both sexes, Müller glia initiate the appropriate reprogramming response to photoreceptor death by increasing expression of stem cell-associated genes, and entering the G1 phase of the cell cycle. However, transition from G1 to S phase is blocked in the absence of Midkine-a, resulting in significantly reduced proliferation and selective failure to regenerate cone photoreceptors. Failing to progress through the cell cycle, Müller glia undergo reactive gliosis, a pathological hallmark in the injured CNS of mammals. Finally, we determined that the Midkine-a receptor, anaplastic lymphoma kinase, is upstream of the HLH regulatory protein, Id2a, and of the retinoblastoma gene, p130, which regulates progression through the cell cycle. These results demonstrate that Midkine-a functions as a core component of the mechanisms that regulate proliferation of stem cells in the injured CNS.SIGNIFICANCE STATEMENT The death of retinal neurons and photoreceptors is a leading cause of vision loss. Regenerating retinal neurons is a therapeutic goal. Zebrafish can regenerate retinal neurons from intrinsic stem cells, Müller glia, and are a powerful model to understand how stem cells might be used therapeutically. Midkine-a, an injury-induced growth factor/cytokine that is expressed by Müller glia following neuronal death, is required for Müller glia to progress through the cell cycle. The absence of Midkine-a suspends proliferation and neuronal regeneration. With cell cycle progression stalled, Müller glia undergo reactive gliosis, a pathological hallmark of the mammalian retina. This work provides a unique insight into mechanisms that control the cell cycle during neuronal regeneration.

Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in adult zebrafish.

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas. Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.

The challenge of learning adaptive mental behavior.

Many psychotherapies aim to help people replace maladaptive mental behaviors (such as those leading to unproductive worry) with more adaptive ones (such as those leading to active problem solving). Yet, little is known empirically about how challenging it is to learn adaptive mental behaviors. Mental behaviors entail taking mental operations and thus may be more challenging to perform than motor actions; this challenge may enhance or impair learning. In particular, challenge when learning is often desirable because it improves retention. Yet, it is also plausible that the necessity of carrying out mental operations interferes with learning the expected values of mental actions by impeding credit assignment: the process of updating an action's value after reinforcement. Then, it may be more challenging not only to perform-but also to learn the consequences of-mental (vs. motor) behaviors. We designed a task to assess learning to take adaptive mental versus motor actions via matched probabilistic feedback. In two experiments (N = 300), most participants found it more difficult to learn to select optimal mental (vs. motor) actions, as evident in worse accuracy not only in a learning but also test (retention) phase. Computational modeling traced this impairment to an indicator of worse credit assignment (impaired construction and maintenance of expected values) when learning mental actions, accounting for worse accuracy in the learning and retention phases. The results suggest that people have particular difficulty learning adaptive mental behavior and pave the way for novel interventions to scaffold credit assignment and promote adaptive thinking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina.

Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes. This regeneration requires Müller glia (MG) to reprogram and divide asymmetrically to produce a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, does loss of different retinal cell subtypes induce unique MG regeneration responses? Second, do MG reprogram to a developmental retinal progenitor cell state? And finally, to what extent does regeneration recapitulate retinal development? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. While MG reprogram to a state similar to late-stage retinal progenitors in developing retinas, there are transcriptional differences between reprogrammed MG/MGPCs and late progenitors, as well as reprogrammed MG in outer and inner retinal damage models. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes. This work identifies major differences between gene regulatory networks activated following the selective loss of different subtypes of retina neurons, as well as between retinal regeneration and development.

Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina.

Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes. This regeneration requires Müller glia (MG) to reprogram and divide asymmetrically to produce a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, does loss of different retinal cell subtypes induce unique MG regeneration responses? Second, do MG reprogram to a developmental retinal progenitor cell state? And finally, to what extent does regeneration recapitulate retinal development? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. While MG reprogram to a state similar to late-stage retinal progenitors in developing retinas, there are transcriptional differences between reprogrammed MG/MGPCs and late progenitors, as well as reprogrammed MG in outer and inner retinal damage models. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes. This work identifies major differences between gene regulatory networks activated following the selective loss of different subtypes of retina neurons, as well as between retinal regeneration and development.

Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina.

Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes through Müller glia (MG) reprogramming and asymmetric cell division that produces a multipotent Müller glia-derived neuronal progenitor cell (MGPC). This raises three key questions. First, do MG reprogram to a developmental retinal progenitor cell (RPC) state? Second, to what extent does regeneration recapitulate retinal development? And finally, does loss of different retinal cell subtypes induce unique MG regeneration responses? We examined these questions by performing single-nuclear and single-cell RNA-Seq and ATAC-Seq in both developing and regenerating retinas. Here we show that injury induces MG to reprogram to a state similar to late-stage RPCs. However, there are major transcriptional differences between MGPCs and RPCs, as well as major transcriptional differences between activated MG and MGPCs when different retinal cell subtypes are damaged. Validation of candidate genes confirmed that loss of different subtypes induces differences in transcription factor gene expression and regeneration outcomes.

Human retinopathy-associated ciliary protein retinitis pigmentosa GTPase regulator mediates cilia-dependent vertebrate development.

Dysfunction of primary cilia is associated with tissue-specific or syndromic disorders. RPGR is a ciliary protein, mutations in which can lead to retinitis pigmentosa (RP), cone-rod degeneration, respiratory infections and hearing disorders. Though RPGR is implicated in ciliary transport, the pathogenicity of RPGR mutations and the mechanism of underlying phenotypic heterogeneity are still unclear. Here we have utilized genetic rescue studies in zebrafish to elucidate the effect of human disease-associated mutations on its function. We show that rpgr is expressed predominantly in the retina, brain and gut of zebrafish. In the retina, RPGR primarily localizes to the sensory cilium of photoreceptors. Antisense morpholino (MO)-mediated knockdown of rpgr function in zebrafish results in reduced length of Kupffer's vesicle (KV) cilia and is associated with ciliary anomalies including shortened body-axis, kinked tail, hydrocephaly and edema but does not affect retinal development. These phenotypes can be rescued by wild-type (WT) human RPGR. Several of the RPGR mutants can also reverse the MO-induced phenotype, suggesting their potential hypomorphic function. Notably, selected RPGR mutations observed in XLRP (T99N, E589X) or syndromic RP (T124fs, K190fs and L280fs) do not completely rescue the rpgr-MO phenotype, indicating a more deleterious effect of the mutation on the function of RPGR. We propose that RPGR is involved in cilia-dependent cascades during development in zebrafish. Our studies provide evidence for a heterogenic effect of the disease-causing mutations on the function of RPGR.

The role of microglia in the neurogenesis of zebrafish retina.

Microglia are cells from non-neuronal lineages that reside in the central nervous system. In zebrafish, early macrophages migrate from the yolk sac to the brain and retina at 26-30 hour post fertilization (hpf) and transform into microglia at 55-60 hpf. The migration of macrophages into the central nervous system requires signaling by macrophage colony stimulating factor-1 receptor (csf-1r), which is encoded by the gene fms. In this study, we show that the targeted knockdown of csf-1r with morpholino oligonucleotides delays migration of macrophages from the yolk sac to the retina, and this delay in macrophage migration results in microphthalmia, delay in cell cycle withdrawal among retinal progenitors and the absence of neuronal differentiation. When embryos were allowed to survive beyond the time when morpholino-dependent translation inhibition is lost, microglia re-occupy the retina and neuronal differentiation partially recovers. Our data demonstrate that microglia are required for normal retinal growth and neurogenesis. This study provides new insight into the neurogenic role of microglia during retinal development in zebrafish.

Reactivity of divalent germanium alkoxide complexes is in sharp contrast to the heavier tin and lead analogues.

The chemistry of ß-diketiminate germanium alkoxide complexes has been examined and shown to be in sharp contrast to its heavier congeners. For instance, (BDI)GeOR (BDI = [{N(2,6-(i)Pr(2)C(6)H(3))C(Me)}(2)CH], R = (i)Pr, (s)Bu, (t)Bu) does not react with carbon dioxide to form a metal carbonate complex. Addition of aliphatic electrophiles, such as methyl iodide or methyl triflate, results in the net oxidative addition to the germanium, giving cationic tetravalent germanium complexes, [(BDI)Ge(Me)OR][X] (X = I, OTf). An examination of the contrasting reactivities of the alkoxide ligand and the germanium loan pair with Lewis acids yielded the unusual germanium(II)-copper(I) adduct, {µ(2)-Cu(2)I(2)}[(BDI)GeO(t)Bu](2). This complex not only displays a rare example of a divalent Ge-Cu bond, but is the first example in which a planar Cu(2)I(2) diamond core possesses a three-coordinate copper bound to another metal center.

Disruption of miR-18a Alters Proliferation, Photoreceptor Replacement Kinetics, Inflammatory Signaling, and Microglia/Macrophage Numbers During Retinal Regeneration in Zebrafish.

In mammals, photoreceptor loss causes permanent blindness, but in zebrafish (Danio rerio), photoreceptor loss reprograms Müller glia to function as stem cells, producing progenitors that regenerate photoreceptors. MicroRNAs (miRNAs) regulate CNS neurogenesis, but the roles of miRNAs in injury-induced neuronal regeneration are largely unknown. In the embryonic zebrafish retina, miR-18a regulates photoreceptor differentiation. The purpose of the current study was to determine, in zebrafish, the function of miR-18a during injury-induced photoreceptor regeneration. RT-qPCR, in situ hybridization, and immunohistochemistry showed that miR-18a expression increases throughout the retina between 1 and 5 days post-injury (dpi). To test miR-18a function during photoreceptor regeneration, we used homozygous miR-18a mutants (miR-18ami5012), and knocked down miR-18a with morpholino oligonucleotides. During photoreceptor regeneration, miR-18ami5012 retinas have fewer mature photoreceptors than WT at 7 and 10 dpi, but there is no difference at 14 dpi, indicating that photoreceptor regeneration is delayed. Labeling dividing cells with 5-bromo-2'-deoxyuridine (BrdU) showed that at 7 and 10 dpi, there are excess dividing progenitors in both mutants and morphants, indicating that miR-18a negatively regulates injury-induced proliferation. Tracing 5-ethynyl-2'-deoxyuridine (EdU) and BrdU-labeled cells showed that in miR-18ami5012 retinas excess progenitors migrate to other retinal layers in addition to the photoreceptor layer. Inflammation is critical for photoreceptor regeneration, and RT-qPCR showed that in miR-18ami5012 retinas, inflammatory gene expression and microglia activation are prolonged. Suppressing inflammation with dexamethasone rescues the miR-18ami5012 phenotype. Together, these data show that in the injured zebrafish retina, disruption of miR-18a alters proliferation, inflammation, the microglia/macrophage response, and the timing of photoreceptor regeneration.

Rumination Derails Reinforcement Learning with Possible Implications for Ineffective Behavior.

How does rumination affect reinforcement learning-the ubiquitous process by which we adjust behavior after error in order to behave more effectively in the future? In a within-subject design (n=49), we tested whether experimentally manipulated rumination disrupts reinforcement learning in a multidimensional learning task previously shown to rely on selective attention. Rumination impaired performance, yet unexpectedly this impairment could not be attributed to decreased attentional breadth (quantified using a "decay" parameter in a computational model). Instead, trait rumination (between subjects) was associated with higher decay rates (implying narrower attention), yet not with impaired performance. Our task-performance results accord with the possibility that state rumination promotes stress-generating behavior in part by disrupting reinforcement learning. The trait-rumination finding accords with the predictions of a prominent model of trait rumination (the attentional-scope model). More work is needed to understand the specific mechanisms by which state rumination disrupts reinforcement learning.

Stratospheric impacts on dust transport and air pollution in West Africa and the Eastern Mediterranean.

Saharan dust intrusions strongly impact Atlantic and Mediterranean coastal regions. Today, most operational dust forecasts extend only 2-5 days. Here we show that on timescales of weeks to months, North African dust emission and transport are impacted by sudden stratospheric warmings (SSWs), which establish a negative North Atlantic Oscillation-like surface signal. Chemical transport models show a large-scale dipolar dust response to SSWs, with the burden in the Eastern Mediterranean enhanced up to 30% and a corresponding reduction in West Africa. Observations of inhalable particulate (PM10) concentrations and aerosol optical depth confirm this dipole. On average, a single SSW causes 680-2460 additional premature deaths in the Eastern Mediterranean and prevents 1180-2040 premature deaths in West Africa from exposure to dust-source fine particulate (PM2.5). Currently, SSWs are predictable 1-2 weeks in advance. Altogether, the stratosphere represents an important source of subseasonal predictability for air quality over West Africa and the Eastern Mediterranean.

Activation of carbon dioxide by divalent tin alkoxides complexes.

A series of terminal tin(II) alkoxides have been synthesized utilizing the bulky ß-diketiminate ligand [{N(2,6-(i)Pr(2)C(6)H(3))-C(Me)}(2)CH] (BDI). The nucleophilicities of these alkoxides have been examined, and unexpected trends were observed. For instance, (BDI)SnOR only reacts with highly activated aliphatic electrophiles such as methyl triflate, but reacts reversibly with carbon dioxide. Both the rate of reaction and the degree of reversibility is dependent upon minor changes in the alkoxide ligand, with the bulkier tert-butoxide ligand displaying slower reactivity than the corresponding isopropyl ligand, although the latter system is a more exergonic reaction. Density Function Theory (DFT) calculations show that the differences in the reversibility of carbon dioxide insertion can be attributed to the ground-state energy differences of tin alkoxides while the rate of reaction is attributed to relative bond strengths of the Sn-O bonds. The mechanism of carbon dioxide insertion is discussed.

Inflammation Regulates the Multi-Step Process of Retinal Regeneration in Zebrafish.

The ability to regenerate tissues varies between species and between tissues within a species. Mammals have a limited ability to regenerate tissues, whereas zebrafish possess the ability to regenerate almost all tissues and organs, including fin, heart, kidney, brain, and retina. In the zebrafish brain, injury and cell death activate complex signaling networks that stimulate radial glia to reprogram into neural stem-like cells that repair the injury. In the retina, a popular model for investigating neuronal regeneration, Müller glia, radial glia unique to the retina, reprogram into stem-like cells and undergo a single asymmetric division to generate multi-potent retinal progenitors. Müller glia-derived progenitors then divide rapidly, numerically matching the magnitude of the cell death, and differentiate into the ablated neurons. Emerging evidence reveals that inflammation plays an essential role in this multi-step process of retinal regeneration. This review summarizes the current knowledge of the inflammatory events during retinal regeneration and highlights the mechanisms whereby inflammatory molecules regulate the quiescence and division of Müller glia, the proliferation of Müller glia-derived progenitors and the survival of regenerated neurons.

Computational methods for integrative evaluation of confidence, accuracy, and reaction time in facial affect recognition in schizophrenia.

People with schizophrenia (SZ) process emotions less accurately than do healthy comparators (HC), and emotion recognition have expanded beyond accuracy to performance variables like reaction time (RT) and confidence. These domains are typically evaluated independently, but complex inter-relationships can be evaluated through machine learning at an item-by-item level. Using a mix of ranking and machine learning tools, we investigated item-by-item discrimination of facial affect with two emotion recognition tests (BLERT and ER-40) between SZ and HC. The best performing multi-domain model for ER40 had a large effect size in differentiating SZ and HC (d = 1.24) compared to a standard comparison of accuracy alone (d = 0.48); smaller increments in effect sizes were evident for the BLERT (d = 0.87 vs. d = 0.58). Almost half of the selected items were confidence ratings. Within SZ, machine learning models with ER40 (generally accuracy and reaction time) items predicted severity of depression and overconfidence in social cognitive ability, but not psychotic symptoms. Pending independent replication, the results support machine learning, and the inclusion of confidence ratings, in characterizing the social cognitive deficits in SZ. This moderate-sized study (n = 372) included subjects with schizophrenia (SZ, n = 218) and healthy controls (HC, n = 154).

Whole-mount Immunohistochemistry of Adult Zebrafish Retina for Advanced Imaging.

Immunohistochemistry is a widely used technique to examine the expression and subcellular localization of proteins. This technique relies on the specificity of antibodies and requires adequate penetration of antibodies into tissues. The latter is especially challenging for thick specimens, such as embryos and other whole-mount preparations. Here we describe an improved method of immunohistochemistry for retinal whole-mount preparations. We report that a cocktail of three reagents, Triton X-100, Tween-20, and DMSO, in blocking and antibody dilution buffers strongly enhances immunolabeling in whole-mount retinas from adult zebrafish. In addition, we establish that in whole retinal tissues, a classic epitope retrieval method, based on citrate buffer, is effective for immunolabeling membrane-associated proteins. Overall, this simple modification allows precise and reproducible immunolabeling of proteins in retinal whole-mounts.

Reprogramming Müller Glia to Regenerate Retinal Neurons.

In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.