BRCA1–BARD1 Regulates Axon Regeneration in Concert with the Gqα–DAG Signaling Network

The breast cancer susceptibility protein BRCA1 and its partner BRCA1-associated RING domain protein 1 (BARD1) form an E3-ubiquitin (Ub) ligase complex that acts as a tumor suppressor in mitotic cells. However, the roles of BRCA1–BARD1 in postmitotic cells, such as neurons, remain poorly defined. Here, we report that BRC-1 and BRD-1, the Caenorhabditis elegans orthologs of BRCA1 and BARD1, are required for adult-specific axon regeneration, which is positively regulated by the EGL-30 Gqα–diacylglycerol (DAG) signaling pathway. This pathway is downregulated by DAG kinase (DGK), which converts DAG to phosphatidic acid (PA). We demonstrate that inactivation of DGK-3 suppresses the brc-1 brd-1 defect in axon regeneration, suggesting that BRC-1–BRD-1 inhibits DGK-3 function. Indeed, we show that BRC-1–BRD-1 poly-ubiquitylates DGK-3 in a manner dependent on its E3 ligase activity, causing DGK-3 degradation. Furthermore, we find that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. These results suggest that the BRC-1–BRD-1 complex regulates axon regeneration in concert with the Gqα–DAG signaling network. Thus, this study describes a new role for breast cancer proteins in fully differentiated neurons and the molecular mechanism underlying the regulation of axon regeneration in response to nerve injury.SIGNIFICANCE STATEMENT BRCA1–BRCA1-associated RING domain protein 1 (BARD1) is an E3-ubiquitin (Ub) ligase complex acting as a tumor suppressor in mitotic cells. The roles of BRCA1–BARD1 in postmitotic cells, such as neurons, remain poorly defined. We show here that Caenorhabditis elegans BRC-1/BRCA1 and BRD-1/BARD1 are required for adult-specific axon regeneration, a process that requires high diacylglycerol (DAG) levels in injured neurons. The DAG kinase (DGK)-3 inhibits axon regeneration by reducing DAG levels. We find that BRC-1–BRD-1 poly-ubiquitylates and degrades DGK-3, thereby keeping DAG levels elevated and promoting axon regeneration. Furthermore, we demonstrate that axon injury causes the translocation of BRC-1 from the nucleus to the cytoplasm, where DGK-3 is localized. Thus, this study describes a new role for BRCA1–BARD1 in fully-differentiated neurons.     

Absence of ephrin-A2/A3 increases retinal regenerative potential for Müller cells in Rhodopsin knockout mice

Müller cells (MC) are considered dormant retinal progenitor cells in mammals. Previous studies demonstrated ephrin-As act as negative regulators of neural progenitor cells in the retina and brain. It remains unclear whether the lack of ephrin-A2/A3 is sufficient to promote the neurogenic potential of MC. Here we investigated whether the MC is the primary retinal cell type expressing ephrin-A2/A3 and their role on the neurogenic potential of Müller cells. In this study, we showed that ephrin-A2/A3 and their receptor EphA4 were expressed in retina and especially enriched in MC. The level of ephrinAs/EphA4 expression increased as the retina matured that is correlated with the reduced proliferative and progenitor cell potential of MC. Next, we investigated the proliferation in primary MC cultures isolated from wild-type and A2^–/–A3^–/– mice by 5-ethynyl-2′-deoxyuridine (EdU) incorporation. We detected a significant increase of EdU⁺ cells in MC derived from A2^–/–A3^–/– mice. Next, we investigated the role of ephrin-A2/A3 in mice undergoing photoreceptor degeneration such as Rhodopsin knockout (Rho^–/–) mice. To further evaluate the role of ephrin-A2/A3 in MC proliferation in vivo, EdU was injected intraperitoneally to adult wild-type, A2^–/–A3^–/– , Rho^–/– and Rho^–/–A2^–/–A3^–/– mice and the numbers of EdU⁺ cells distributed among different layers of the retina. EphrinAs/EphA4 expression was upregulated in the retina of Rho^–/– mice compared to the wild-type mice. In addition, cultured MC derived from ephrin-A2^–/–A3^–/– mice also expressed higher levels of progenitor cell markers and exhibited higher proliferation potential than those from wild-type mice. Interestingly, we detected a significant increase of EdU⁺ cells in the retinas of adult ephrin-A2^–/–A3^–/– mice mainly in the inner nuclear layer; and these EdU⁺ cells were co-localized with MC marker, cellular retinaldehyde-binding protein, suggesting some proliferating cells are from MC. In Rhodopsin knockout mice (Rho^–/–A2^–/–A3^–/– mice), a significantly greater amount of EdU⁺ cells were located in the ciliary body, retina and RPE than that of Rho^–/– mice. Comparing between 6 and 12 weeks old Rho^–/–A2^–/–A3^–/– mice, we recorded more EdU⁺ cells in the outer nuclear layer in the 12-week-old mice undergoing severe retinal degeneration. Taken together, Ephrin-A2/A3 are negative regulators of the proliferative and neurogenic potentials of MC. Absence of ephrin-A2/A3 promotes the migration of proliferating cells into the outer nuclear layer and may lead to retinal cell regeneration. All experimental procedures were approved by the Animal Care and Use Committee at Schepens Eye Research Institute, USA (approval No. S-353-0715) on October 24, 2012.

Chinese Library Classification No. R459.9; R364; R774     

Bexarotene Blocks Calcium-Permeable Ion Channels Formed by Neurotoxic Alzheimer’s β-Amyloid Peptides

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Psychopathy as a Risk Factor for Violence

As a result of Kansas v Hendricks, many sex offenders in the U.S. are likely to be civilly committed to mental institutions for indefinite periods, and many others with histories of violent offenses may also be so committed. It therefore becomes critical for mental health professionals to understand the risk factors for re-offending that put the public in jeopardy. The most reliable of these factors is psychopathy, which will here be defined, along with its differentiation from the more commonly diagnosed antisocial personality disorder. The assessment of psychopathy, its relationship to crime—especially, to violent crime, its (non-) responsiveness to the usual treatment, and an outline of a potentially more effective one, are presented. Finally, and particularly in view of its widely accepted validity, the potential for abuse of the PCL-R and :SV are noted.     

The anxiety‐specific hippocampus–prefrontal cortex pathways links to procrastination through self‐control

Procrastination, which is defined as delaying an intended course of action despite negative outcomes, is demonstrated to have a deal with negative emotion including trait anxiety. Although highly anxious individuals showed impoverished control ability, no studies have indicated the role of self‐control in the relationship between trait anxiety and procrastination, and its neural correlates. To this end, we used the sliding window method to calculate the temporal deviation of dynamic functional connectivity (FC) in 312 healthy participants who underwent the resting‐state functional magnetic resonance imaging (fMRI) scanning. In line with our hypothesis, higher trait anxiety is linked to more procrastination via poorer self‐control. Besides, the dynamic FC analyses showed that trait anxiety was positively correlated with dynamic FC variability in hippocampus–prefrontal cortex (HPC–PFC) pathways, including left rostral hippocampus–left superior frontal gyrus (left rHPC–left SFG), and left rHPC–right middle frontal gyrus (left rHPC–‐MFG). Furthermore, the structural equation modeling (SEM) uncovered a mediated role of self‐control in the association between the anxiety‐specific brain connectivity and procrastination. These findings suggest that the HPC–PFC pathways may reflect impoverished regulatory ability over the negative thoughts for anxious individuals, and thereby incurs more procrastination, which enhances our understanding of how trait anxiety links to procrastination.     

Hippocampal Theta Oscillations Support Successful Associative Memory Formation

Models of memory formation posit that episodic memory formation depends critically on the hippocampus, which binds features of an event to its context. For this reason, the contrast between study items that are later recollected with their associative pair versus those for which no association is made fails should reveal electrophysiological patterns in the hippocampus selectively involved in associative memory encoding. Extensive data from studies in rodents support a model in which theta oscillations fulfill this role, but results in humans have not been as clear. Here, we used an associative recognition memory procedure to identify hippocampal correlates of successful associative memory encoding and retrieval in patients (10 females and 9 males) undergoing intracranial EEG monitoring. We identified a dissociation between 2–5 Hz and 5–9 Hz theta oscillations, by which power increases in 2–5 Hz oscillations were uniquely linked with successful associative memory in both the anterior and posterior hippocampus. These oscillations exhibited a significant phase reset that also predicted successful associative encoding and distinguished recollected from nonrecollected items at retrieval, as well as contributing to relatively greater reinstatement of encoding-related patterns for recollected versus nonrecollected items. Our results provide direct electrophysiological evidence that 2–5 Hz hippocampal theta oscillations preferentially support the formation of associative memories, although we also observed memory-related effects in the 5–9 Hz frequency range using measures such as phase reset and reinstatement of oscillatory activity.SIGNIFICANCE STATEMENT Models of episodic memory encoding predict that theta oscillations support the formation of interitem associations. We used an associative recognition task designed to elicit strong hippocampal activation to test this prediction in human neurosurgical patients implanted with intracranial electrodes. The findings suggest that 2–5 Hz theta oscillatory power and phase reset in the hippocampus are selectively associated with associative memory judgments. Furthermore, reinstatement of oscillatory patterns in the hippocampus was stronger for successful recollection. Collectively, the findings support a role for hippocampal theta oscillations in human associative memory.     

Economic decision-making in psychopathy: A comparison with ventromedial prefrontal lesion patients

Psychopathy, which is characterized by a constellation of antisocial behavioral traits, may be subdivided on the basis of etiology: “primary” (low-anxious) psychopathy is viewed as a direct consequence of some core intrinsic deficit, whereas “secondary” (high-anxious) psychopathy is viewed as an indirect consequence of environmental factors or other psychopathology. Theories on the neurobiology of psychopathy have targeted dysfunction within ventromedial prefrontal cortex (vmPFC) as a putative mechanism, yet the relationship between vmPFC function and psychopathy subtype has not been fully explored. In this study, we administered two laboratory decision-making tasks (the Ultimatum Game and the Dictator Game) to a group of prisoners (n = 47) to determine whether the different subtypes of psychopathy (primary vs. secondary) are associated with characteristic patterns of economic decision-making, and furthermore, whether either subtype exhibits similar performance to patients with vmPFC lesions. Comparing primary psychopaths (n = 6) to secondary psychopaths (n = 6) and non-psychopaths (n = 22), we found that primary psychopathy was associated with significantly lower acceptance rates of unfair Ultimatum offers and lower offer amounts in the Dictator Game. Moreover, primary psychopaths were quantitatively similar to vmPFC lesion patients in their response patterns. These results support the purported connection between psychopathy and vmPFC dysfunction, bolster the distinction between primary and secondary psychopathy, and demonstrate the utility of laboratory economic decision-making tests in differentiating clinical subgroups.     

Angiotensin-(1–7) reduces α-synuclein aggregation by enhancing autophagic activity in Parkinson's disease

Abnormal accumulation of α-synuclein contributes to the formation of Lewy bodies in the substantia nigra, which is considered the typical pathological hallmark of Parkinson''s disease. Recent research indicates that angiotensin-(1–7) plays a crucial role in several neurodegenerative disorders, including Parkinson''s disease, but the underlying mechanisms remain elusive. In this study, we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson''s disease model. We investigated whether angiotensin-(1–7) is neuroprotective in this model by continuous administration of angiotensin-(1–7) into the right substantia nigra for 4 weeks. We found that angiotensin-(1–7) infusion relieved characteristic parkinsonian behaviors and reduced α-synuclein aggregation in the substantia nigra. Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone, angiotensin-(1–7), and/or the Mas receptor blocker A-779 for 24 hours. After binding to the Mas receptor, angiotensin-(1–7) attenuated apoptosis and α-synuclein aggregation in rotenone-treated cells. Primary dopaminergic neurons were also treated with angiotensin-(1–7) and/or the autophagy inhibitor 3-methyladenine for 24 hours. Angiotensin-(1–7) increased α-synuclein removal and increased the autophagy of rotenone-treated cells. We conclude that angiotensin-(1–7) reduces α-synuclein aggregation by alleviating autophagy dysfunction in Parkinson''s disease. Therefore, the angiotensin-(1–7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson''s disease and angiotensin-(1–7) has potential therapeutic value for Parkinson''s disease. All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital (approval No. DWSY-2000932) in January 2020.

Chinese Library Classification No. R459.9; R363; R364     

Altered task-induced cerebral blood flow and oxygen metabolism underlies motor impairment in multiple sclerosis

The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO₂), and flow–metabolism coupling (ΔCBF/ΔCMRO₂), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO₂ increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO₂) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO₂ in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO₂ responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling.     

Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach

Intranasal administration of the neuropeptide oxytocin has been shown to influence a range of complex social cognitions and social behaviors, and it holds therapeutic potential for the treatment of mental disorders characterized by social functioning deficits such as autism, social phobia and borderline personality disorder. However, considerable variability exists in individual responses to oxytocin administration. Here, we undertook a study to investigate the role of genetic variation in sensitivity to exogenous oxytocin using a socioemotional task. In a randomized, double-blind, placebo-controlled experiment with a repeated-measures (crossover) design, we assessed the performance of 203 men on an emotion recognition task under oxytocin and placebo. We took a haplotype-based approach to investigate the association between oxytocin receptor gene variation and oxytocin sensitivity. We identified a six-marker haplotype block spanning the promoter region and intron 3 that was significantly associated with our measure of oxytocin sensitivity. Specifically, the TTCGGG haplotype comprising single-nucleotide polymorphisms rs237917–rs2268498–rs4564970–rs237897–rs2268495–rs53576 is associated with increased emotion recognition performance under oxytocin versus placebo, and the CCGAGA haplotype with the opposite pattern. These results on the genetic modulation of sensitivity to oxytocin document a significant source of individual differences with implications for personalized treatment approaches using oxytocin administration.     

BDNF–TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms

Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF–TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg⁻¹ per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg⁻¹ per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10 mg kg⁻¹ per day for 14 days). In vivo microdialysis showed that METH (1 mg kg⁻¹)-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF–TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers.     

A multidimensional examination of psychopathy traits and gray matter volume in adults

Uncovering the neurobiological abnormalities that may contribute to the manifestation of psychopathic traits is an important step toward understanding the etiology of this disorder. Although many studies have examined gray matter volume (GMV) in relation to psychopathy, few have examined how dimensions of psychopathic traits interactively relate to GMV, an approach that holds promise for parsing heterogeneity in neurobiological risk factors for this disorder. The aim of this study was to investigate the affective-interpersonal (Factor 1) and impulsive-antisocial (Factor 2) dimensions of psychopathy in relation to cortical surface and subcortical GMV in a mixed-gender, high-risk community sample with significant justice-system involvement (N = 156, 50.0% men). Cortex-wide analysis indicated that (i) the Factor 1 traits correlated negatively with GMV in two cortical clusters, one in the right rostral middle frontal region and one in the occipital lobe, and (ii) the interaction of the affective-interpersonal and impulsive-antisocial traits was negatively associated with GMV bilaterally in the parietal lobe, such that individuals high on both trait dimensions evidenced reduced GMV relative to individuals high on only one psychopathy factor. An interactive effect also emerged for bilateral amygdalar and hippocampal GMV, such that Factor 1 psychopathic traits were significantly negatively associated with GMV only at high (but not low) levels of Factor 2 traits. Results extend prior research by demonstrating the neurobiological correlates of psychopathy differ based on the presentation of Factor 1 and 2 traits.     

Biochemical Identification of a Linear Cholesterol-Binding Domain within Alzheimer’s β Amyloid Peptide

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Memory Load Alters Perception-Related Neural Oscillations during Multisensory Integration

Integrating information across different senses is a central feature of human perception. Previous research suggests that multisensory integration is shaped by a context-dependent and largely adaptive interplay between stimulus-driven bottom-up and top-down endogenous influences. One critical question concerns the extent to which this interplay is sensitive to the amount of available cognitive resources. In the present study, we investigated the influence of limited cognitive resources on audiovisual integration by measuring high-density electroencephalography (EEG) in healthy participants performing the sound-induced flash illusion (SIFI) and a verbal n-back task (0-back, low load and 2-back, high load) in a dual-task design. In the SIFI, the integration of a flash with two rapid beeps can induce the illusory perception of two flashes. We found that high compared with low load increased illusion susceptibility and modulated neural oscillations underlying illusion-related crossmodal interactions. Illusion perception under high load was associated with reduced early β power (18–26 Hz, ∼70 ms) in auditory and motor areas, presumably reflecting an early mismatch signal and subsequent top-down influences including increased frontal θ power (7–9 Hz, ∼120 ms) in mid-anterior cingulate cortex (ACC) and a later β power suppression (13–22 Hz, ∼350 ms) in prefrontal and auditory cortex. Our study demonstrates that integrative crossmodal interactions underlying the SIFI are sensitive to the amount of available cognitive resources and that multisensory integration engages top-down θ and β oscillations when cognitive resources are scarce.SIGNIFICANCE STATEMENT The integration of information across multiple senses, a remarkable ability of our perceptual system, is influenced by multiple context-related factors, the role of which is highly debated. It is, for instance, poorly understood how available cognitive resources influence crossmodal interactions during multisensory integration. We addressed this question using the sound-induced flash illusion (SIFI), a phenomenon in which the integration of two rapid beeps together with a flash induces the illusion of a second flash. Replicating our previous work, we demonstrate that depletion of cognitive resources through a working memory (WM) task increases the perception of the illusion. With respect to the underlying neural processes, we show that when available resources are limited, multisensory integration engages top-down θ and β oscillations.     

Psychopathy and Human Evil: An Overview

The term “psychopath” usually conjures images of serial killers or acts of genocide. Less frequently considered are those who are intelligent enough to avoid detection by the criminal justice system while hiding in the boardrooms of corporations or lurking in the halls of government institutions. This article provides an overview of psychopathy and human evil by exploring the personality characteristics, organization, and cognitive style of the psychopath, the role of superego pathology, contributions from the field of attachment, and ways in which dissociation plays a role in psychopathy and the potential for confusing this with the dissociative structuring of the mind. The article closes with a brief discussion about “corporate” or “successful psychopaths” and how they have a negative impact on culture and society.     

Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.     

Structural models of psychopathy

Psychopathy traditionally is defined by a cluster of inferred personality traits and socially deviant behaviors. The accepted standard for the reliable and valid assessment of psychopathy is the Psychopathy Checklist-Revised (PCL-R). Because of its importance in basic and applied research, and in the mental health and criminal justice systems, the PCL-R has been subjected to intense scrutiny by researchers and clinicians. In this article we discuss issues surrounding its structural properties and those of its derivatives. Using factor analysis, item response theory, and multidimensional scaling, we propose that the PCL-R and its derivatives are underpinned by at least four correlated factors: Interpersonal, Affective, Lifestyle, and Antisocial. We argue that attempts to characterize antisocial behaviors as merely “downstream” manifestations of more central traits are inconsistent with the structural properties of the PCL-R and with evidence that the development of traits and actions are interactive and reciprocal. We also report new evidence that psychopathy and its factors are dimensional in nature, perhaps extreme variants of normal personality traits and behaviors.     

The Integrin Signaling Network Promotes Axon Regeneration via the Src–Ephexin–RhoA GTPase Signaling Axis

Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In Caenorhabditis elegans hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase–ROCK (Rho-associated coiled-coil kinase)–regulatory nonmuscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP–Epac (exchange protein directly activated by cAMP)–Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA–ROCK signaling pathway. We found that the nonreceptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src–RhoGEF–RhoA axis.SIGNIFICANCE STATEMENT The ability of axons to regenerate after injury is governed by cell-intrinsic regeneration pathways. We have previously demonstrated that the Caenorhabditis elegans RhoA GTPase–ROCK (Rho-associated coiled-coil kinase) pathway promotes axon regeneration by inducing MLC-4 phosphorylation. In this study, we found that axon injury activates TLN-1/talin through the cAMP–Epac (exchange protein directly activated by cAMP)–Rap GTPase cascade, leading to integrin inside-out activation, which promotes axonal regeneration by activating the RhoA signaling pathway. In this pathway, SRC-1/Src acts downstream of integrin activation and subsequently activates EPHX-1/ephexin RhoGEF by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src–RhoGEF–RhoA axis.     

Amyloid β-Peptide 25–35 Self-Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer’s Disease Process and Treatment

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Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories

Background

Growing evidence suggests that small ubiquitin-like modifier (SUMO) conjugation plays a key role in brain plasticity by modulating activity-dependent synaptic transmission. However, these observations are based largely on cell culture experiments. We hypothesized that episodic and fear memories would be affected by silencing SUMO1–3 expression.

Methods

To investigate the role of SUMO conjugation in neuronal functioning in vivo, we generated a novel Sumo transgenic mouse model in which a Thy1 promoter drives expression of 3 distinct microRNAs to silence Sumo1–3 expression, specifically in neurons. Wild-type and Sumo1–3 knockdown mice were subjected to a battery of behavioural tests to elucidate whether Sumoylation is involved in episodic and emotional memory.

Results

Expression of Sumo1–3 microRNAs and the corresponding silencing of Sumo expression were particularly pronounced in hippocampal, amygdala and layer V cerebral cortex neurons. The Sumo knockdown mice displayed anxiety-like responses and were impaired in episodic memory processes, contextual and cued fear conditioning and fear-potentiated startle.

Limitations

Since expression of Sumo1–3 was silenced in this mouse model, we need to verify in future studies which of the SUMO paralogues play the pivotal role in episodic and emotional memory.

Conclusion

Our results indicate that a functional SUMO conjugation pathway is essential for emotionality and cognition. This novel Sumo knockdown mouse model and the technology used in generating this mutant may help to reveal novel mechanisms that underlie a variety of neuropsychiatric conditions associated with anxiety and impairment of episodic and emotional memory.