Neurocognitive profile associated with borderline personality disorder: building specific indices of executive function.

The objective of this work is the creation of specific indices of the different executive functions (EF).

Correction: Sensory Neuron-Derived Eph Regulates Glomerular Arbors and Modulatory Function of a Central Serotonergic Neuron.

[This corrects the article DOI: 10.1371/journal.pgen.1003452.].

Sensory neuron-derived eph regulates glomerular arbors and modulatory function of a central serotonergic neuron.

Olfactory sensory neurons connect to the antennal lobe of the fly to create the primary units for processing odor cues, the glomeruli. Unique amongst antennal-lobe neurons is an identified wide-field serotonergic neuron, the contralaterally-projecting, serotonin-immunoreactive deutocerebral neuron (CSDn). The CSDn spreads its termini all over the contralateral antennal lobe, suggesting a diffuse neuromodulatory role. A closer examination, however, reveals a restricted pattern of the CSDn arborization in some glomeruli. We show that sensory neuron-derived Eph interacts with Ephrin in the CSDn, to regulate these arborizations. Behavioural analysis of animals with altered Eph-ephrin signaling and with consequent arborization defects suggests that neuromodulation requires local glomerular-specific patterning of the CSDn termini. Our results show the importance of developmental regulation of terminal arborization of even the diffuse modulatory neurons to allow them to route sensory-inputs according to the behavioural contexts.

Synapsin function in GABA-ergic interneurons is required for short-term olfactory habituation.

In Drosophila, short-term (STH) and long-term habituation (LTH) of olfactory avoidance behavior are believed to arise from the selective potentiation of GABAergic synapses between multiglomerular local circuit interneurons (LNs) and projection neurons in the antennal lobe. However, the underlying mechanisms remain poorly understood. Here, we show that synapsin (syn) function is necessary for STH and that syn(97)-null mutant defects in STH can be rescued by syn(+) cDNA expression solely in the LN1 subset of GABAergic local interneurons. As synapsin is a synaptic vesicle-clustering phosphoprotein, these observations identify a presynaptic mechanism for STH as well as the inhibitory interneurons in which this mechanism is deployed. Serine residues 6 and/or 533, potential kinase target sites of synapsin, are necessary for synapsin function suggesting that synapsin phosphorylation is essential for STH. Consistently, biochemical analyses using a phospho-synapsin-specific antiserum show that synapsin is a target of Ca(2+) calmodulin-dependent kinase II (CaMKII) phosphorylation in vivo. Additional behavioral and genetic observations demonstrate that CaMKII function is necessary in LNs for STH. Together, these data support a model in which CaMKII-mediated synapsin phosphorylation in LNs induces synaptic vesicle mobilization and thereby presynaptic facilitation of GABA release that underlies olfactory STH. Finally, the striking observation that LTH occurs normally in syn(97) mutants indicates that signaling pathways for STH and LTH diverge upstream of synapsin function in GABAergic interneurons.

The zinc finger transcription factor Jing is required for dendrite/axonal targeting in Drosophila antennal lobe development.

An important role in olfactory system development is played by transcription factors which act in sensory neurons or in their interneuron targets as cell autonomous regulators of downstream effectors such as cell surface molecules and signalling systems that control neuronal identity and process guidance. Some of these transcriptional regulators have been characterized in detail in the development of the neural elements that innervate the antennal lobe in the olfactory system of Drosophila. Here we identify the zinc finger transcription factor Jing as a cell autonomously acting transcriptional regulator that is required both for dendrite targeting of projection neurons and local interneurons as well as for axonal targeting of olfactory sensory neurons in Drosophila olfactory system development. Immunocytochemical analysis shows that Jing is widely expressed in the neural cells during postembryonic development. MARCM-based clonal analysis of projection neuron and local interneuron lineages reveals a requirement for Jing in dendrite targeting; Jing loss-of-function results in loss of innervation in specific glomeruli, ectopic innervation of inappropriate glomeruli, aberrant profuse dendrite arborisation throughout the antennal lobe, as well as mistargeting to other parts of the CNS. ey-FLP-based MARCM analysis of olfactory sensory neurons reveals an additional requirement for Jing in axonal targeting; mutational inactivation of Jing causes specific mistargeting of some olfactory sensory neuron axons to the DA1 glomerulus, reduction of targeting to other glomeruli, as well as aberrant stalling of axons in the antennal lobe. Taken together, these findings indicate that Jing acts as a key transcriptional control element in wiring of the circuitry in the developing olfactory sensory system in Drosophila.

The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation.

Local control of mRNA translation has been proposed as a mechanism for regulating synapse-specific plasticity associated with long-term memory. We show here that glomerulus-selective plasticity of Drosophila multiglomerular local interneurons observed during long-term olfactory habituation (LTH) requires the Ataxin-2 protein (Atx2) to function in uniglomerular projection neurons (PNs) postsynaptic to local interneurons (LNs). PN-selective knockdown of Atx2 selectively blocks LTH to odorants to which the PN responds and in addition selectively blocks LTH-associated structural and functional plasticity in odorant-responsive glomeruli. Atx2 has been shown previously to bind DEAD box helicases of the Me31B family, proteins associated with Argonaute (Ago) and microRNA (miRNA) function. Robust transdominant interactions of atx2 with me31B and ago1 indicate that Atx2 functions with miRNA-pathway components for LTH and associated synaptic plasticity. Further direct experiments show that Atx2 is required for miRNA-mediated repression of several translational reporters in vivo. Together, these observations (i) show that Atx2 and miRNA components regulate synapse-specific long-term plasticity in vivo; (ii) identify Atx2 as a component of the miRNA pathway; and (iii) provide insight into the biological function of Atx2 that is of potential relevance to spinocerebellar ataxia and neurodegenerative disease.

Plasticity of local GABAergic interneurons drives olfactory habituation.

Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA(A) receptors in odorant-selective, glomerulus-specific projection neurons(PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant-evoked calcium fluxes in PNs as well as growth of the respective odorant-responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems.

Inflammatory profiles in women with eating disorder: Linking inflammatory biomarkers to clinical phenotypes.

INTRODUCTION: Eating disorders (ED) represent a group of very complex and serious diagnoses characterized by emotional dysregulation and impulsivity. New approaches are necessary to achieve effective diagnosis and treatments. Shifting biomarker research away from the constraints of diagnostic categories may effectively contribute to a dimensional differentiation across disorders according to neurobiology (e.g., inflammatory biomarkers). Thus, the aim of our study was to identify inflammatory profiles in patients with ED. METHODS: A sample of 100 women with an ED (23.4 ± 8.55 years) and 59 healthy controls (HC) (20.22 ± 4.18 years) was used. K-means cluster analysis was followed to identify inflammatory clusters considering seven blood biomarkers (iNOS, TNFα, COX2, p38, ERK, TBARS and PPARγ). Moreover, a wide assessment of clinical features was conducted. RESULTS: Two distinct clusters were identified. Cluster 1 patients were characterized by higher inflammatory levels of TNF-α, COX2, p38, and ERK, and had more restrictive anorexia diagnosis than cluster 2. Cluster 2 participants showed higher inflammatory levels of iNOS and were older than cluster 1 and controls and had lower BMI than HC. In addition, they had higher levels of bulimic symptoms than those from the cluster 1 and HC, and higher impulsivity than HC. All ED patients (regardless of cluster) showed higher ED symptoms and more trauma than HC. CONCLUSIONS: Our study revealed that inflammatory dysfunction may be linked with clinical endophenotypes in ED, one more restrictive (cluster 1) with an inflammation/oxidative endophenotype more cytokine and MAPK/ERK mediated, and the other more impulsive, with more bulimic symptoms (cluster 2) with NO free radical high output source iNOS. Trauma seems to be a vulnerability factor for both endophenotypes.

Psychiatric profiles in suicidal attempters: Relationships with suicide behaviour features.

BACKGROUND: Suicide constitutes a major health concern worldwide, being a significant contributor of death, globally. The diagnosis of a mental disorder has been extensively linked to the varying forms of suicidal ideation and behaviour. The aim of our study was to identify the varying diagnostic profiles in a sample of suicide attempters. METHODS: A sample of 683 adults (71.3% females, 40.10±15.74 years) admitted at a hospital emergency department due to a suicide attempt was recruited. Latent class analysis was used to identify diagnostic profiles and logistic regression to study the relationship between comorbidity profile membership and sociodemographic and clinical variables. RESULTS: Two comorbidity profiles were identified (Class I: low comorbidity class, 71.3% of attempters; Class II: high comorbidity class, 28.7% of attempters). Class I members were featured by the diagnosis of depression and general anxiety disorder, and low comorbidity; by contrast, the high comorbidity profile was characterized by a higher probability of presenting two or more coexisting psychiatric disorders. Class II included more females, younger, with more depressive symptoms and with higher impulsivity levels. Moreover, Class II members showed more severe suicidal ideation, higher number of suicide behaviours and a greater number of previous suicide attempts (p<.01, for all the outcomes), compared to Class I members. CONCLUSIONS: Psychiatric profiles may be considered for treatment provision and personalized psychiatric treatment in suicidal attempters as well as tackle suicide risk.

Anxious and depressive symptoms and health-related quality of life in a cohort of people who recently attempted suicide: A network analysis.

BACKGROUND: Suicide is an international health concern with immeasurable impact from the perspective of human and social suffering. Prior suicide attempts, anxious and depressive symptoms, and relatively lower health-related quality of life (HRQoL) are among the most replicated risk factors for suicide. Our goal was to visualize the distribution of these features and their interconnections with use of a network analysis approach in individuals who recently attempted suicide. METHODS: Individuals with a recent suicide attempt were recruited from nine University Hospitals across Spain as part of the SURVIVE cohort study. Anxious and depressive symptoms, and perceived HRQoL were included in the network analysis. Network structures were estimated with the EBICglasso model. Centrality measures and bridge symptoms connecting communities were explored. Subnetworks comparing younger and older individuals, and women and men were analyzed. RESULTS: A total of 1106 individuals with a recent suicide attempt were included. Depressed mood was the symptom with the greatest influence in the overall network, followed by anxiety symptoms such as feeling nervous, worrying, restless, and having difficulties to relax. Perceived general health was associated with increased suicidal ideation in the whole sample. Older people showed a specific connection between perceived general health and depressed mood. LIMITATIONS: The cross-sectional design does not allow determination of established causality. CONCLUSIONS: Depressed mood was the core network's symptom and, therefore, an important target in the management and prevention of suicide. HRQoL had more influence on the network of older populations, in which it should be a primary focus.

Plasticity of recurrent inhibition in the Drosophila antennal lobe.

Recurrent inhibition, wherein excitatory principal neurons stimulate inhibitory interneurons that feedback on the same principal cells, occurs ubiquitously in the brain. However, the regulation and function of recurrent inhibition are poorly understood in terms of the contributing interneuron subtypes as well as their effect on neural and cognitive outputs. In the Drosophila olfactory system, odorants activate olfactory sensory neurons (OSNs), which stimulate projection neurons (PNs) in the antennal lobe. Both OSNs and PNs activate local inhibitory neurons (LNs) that provide either feedforward or recurrent/feedback inhibition in the lobe. During olfactory habituation, prior exposure to an odorant selectively decreases the animal's subsequent response to the odorant. We show here that habituation occurs in response to feedback from PNs. Output from PNs is necessary for olfactory habituation and, in the absence of odorant, direct PN activation is sufficient to induce the odorant-selective behavioral attenuation characteristic of olfactory habituation. PN-induced habituation occludes further odor-induced habituation and similarly requires GABA(A)Rs and NMDARs in PNs, as well as VGLUT and cAMP signaling in the multiglomerular inhibitory local interneurons (LN1) type of LN. Thus, PN output is monitored by an LN subtype whose resultant plasticity underlies behavioral habituation. We propose that recurrent inhibitory motifs common in neural circuits may similarly underlie habituation to other complex stimuli.

Expression and function of the empty spiracles gene in olfactory sense organ development of Drosophila melanogaster.

In Drosophila, the cephalic gap gene empty spiracles plays key roles in embryonic patterning of the peripheral and central nervous system. During postembryonic development, it is involved in the development of central olfactory circuitry in the antennal lobe of the adult. However, its possible role in the postembryonic development of peripheral olfactory sense organs has not been investigated. Here, we show that empty spiracles acts in a subset of precursors that generate the olfactory sense organs of the adult antenna. All empty spiracles-expressing precursor cells co-express the proneural gene amos and the early patterning gene lozenge. Moreover, the expression of empty spiracles in these precursor cells is dependent on both amos and lozenge. Functional analysis reveals two distinct roles of empty spiracles in the development of olfactory sense organs. Genetic interaction studies in a lozenge-sensitized background uncover a requirement of empty spiracles in the formation of trichoid and basiconic olfactory sensilla. MARCM-based clonal mutant analysis reveals an additional role during axonal targeting of olfactory sensory neurons to glomeruli within the antennal lobe. Our findings on empty spiracles action in olfactory sense organ development complement previous studies that demonstrate its requirement in olfactory interneurons and, taken together with studies on the murine homologs of empty spiracles, suggest that conserved molecular genetic programs might be responsible for the formation of both peripheral and central olfactory circuitry in insects and mammals.

Dendritic refinement of an identified neuron in the Drosophila CNS is regulated by neuronal activity and Wnt signaling.

The dendrites of neurons undergo dramatic reorganization in response to developmental and other cues, such as stress and hormones. Although their morphogenesis is an active area of research, there are few neuron preparations that allow the mechanistic study of how dendritic fields are established in central neurons. Dendritic refinement is a key final step of neuronal circuit formation and is closely linked to emergence of function. Here, we study a central serotonergic neuron in the Drosophila brain, the dendrites of which undergo a dramatic morphological change during metamorphosis. Using tools to manipulate gene expression in this neuron, we examine the refinement of dendrites during pupal life. We show that the final pattern emerges after an initial growth phase, in which the dendrites function as 'detectors', sensing inputs received by the cell. Consistent with this, reducing excitability of the cell through hyperpolarization by expression of K(ir)2.1 results in increased dendritic length. We show that sensory input, possibly acting through NMDA receptors, is necessary for dendritic refinement. Our results indicate that activity triggers Wnt signaling, which plays a 'pro-retraction' role in sculpting the dendritic field: in the absence of sensory input, dendritic arbors do not retract, a phenotype that can be rescued by activating Wnt signaling. Our findings integrate sensory activity, NMDA receptors and Wingless/Wnt5 signaling pathways to advance our understanding of how dendritic refinement is established. We show how the maturation of sensory function interacts with broadly distributed signaling molecules, resulting in their localized action in the refinement of dendritic arbors.

Gustatory habituation in Drosophila relies on rutabaga (adenylate cyclase)-dependent plasticity of GABAergic inhibitory neurons.

In some situations, animals seem to ignore stimuli which in other contexts elicit a robust response. This attenuation in behavior, which enables animals to ignore a familiar, unreinforced stimulus, is called habituation. Despite the ubiquity of this phenomenon, it is generally poorly understood in terms of the underlying neural circuitry. Hungry fruit flies show a proboscis extension reflex (PER) when sensory receptors are stimulated by sugars. The PER is usually followed by feeding. However, if feeding is disallowed following sugar stimulation, PER is no longer robust, and the animal is considered to be habituated to this stimulus. Our results suggest that PER habituation requires an adenylate cyclase-dependent enhancement of inhibitory output of GABAergic neurons in the subesophageal ganglion (SOG), which mediates PER. GABA synthesis in and release from glutamic acid decarboxylase (GAD1) expressing neurons is necessary, and GABA(A) receptors on cholinergic neurons are required for PER habituation. The proposed inhibitory potentiation requires glutamate/NMDA-receptor signaling, possibly playing a role in stimulus selectivity. We explain why these data provide significant and independent support for a general model in which inhibitory potentiation underlies habituation in multiple neural systems and species.

Clinical predictors and psychosocial risk factors of suicide attempt severity.

BACKGROUND: Suicide attempts are an important predictor of completed suicide and may differ in terms of severity of medical consequences or medical lethality. There is little evidence on serious suicide attempt (SSA) and very few studies have compared SSA with non-SSA. OBJECTIVE: The aim of this multisite, coordinated, cohort study was to analyze the role of clinical variables and the sociodemographic and psychological risk factors of SSA. METHOD: In this multisite, coordinated, cohort study, 684 participants (222 for the mild suicide attempt group, 371 for the moderate suicide attempt group and 91 for the SSA group) were included in the study. Ordinal regression models were performed to analyze the predictor variables of SSA. RESULTS: Early physical abuse (OR=1.231) and impulsivity (OR=1.036) were predictors of SSA, while depressive symptoms were associated with a lower risk of SSA. CONCLUSION: Environmental and psychological factors as physical abuse and impulsivity are related with severe suicide severity. These findings will help to develop strategies to prevent suicide and may be considered for the treatment and management of suicide.

Sedation with intranasal midazolam of Angolan children undergoing invasive procedures.

AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier.

Risk factors for suicidal behaviour in late-life depression: A systematic review.

BACKGROUND: Suicide is a leading cause of preventable death worldwide, with its peak of maximum incidence in later life. Depression often puts an individual at higher risk for suicidal behaviour. In turn, depression deserves particular interest in old age due to its high prevalence and dramatic impact on health and wellbeing. AIM: To gather integrated evidence on the potential risk factors for suicide behaviour development in depressive older adults, and to examine the effects of depression treatment to tackle suicide behaviour in this population. METHODS: A systematic review of empirical studies, published from 2000 onwards, was conducted. Suicidal behaviour was addressed considering its varying forms (i.e., wish to die, ideation, attempt, and completed suicide). RESULTS: Thirty-five papers were selected for review, comprising both clinical and epidemiological studies. Most of studies focused on suicidal ideation (60%). The studies consistently pointed out that the risk was related to depressive episode severity, psychiatric comorbidity (anxiety or substance use disorders), poorer health status, and loss of functionality. Reduced social support and loneliness were also associated with suicide behaviour in depressive older adults. Finally, the intervention studies showed that suicidal behaviour was a robust predictor of depression treatment response. Reductions in suicidal ideation were moderated by reductions in risk factors for suicide symptoms. CONCLUSION: To sum up, common and age-specific risk factors seem to be involved in suicide development in depressive older adults. A major effort should be made to tackle this serious public health concern so as to promote older people to age healthily and well.

Brain development in the yellow fever mosquito Aedes aegypti: a comparative immunocytochemical analysis using cross-reacting antibodies from Drosophila melanogaster.

Considerable effort has been directed towards understanding the organization and function of peripheral and central nervous system of disease vector mosquitoes such as Aedes aegypti. To date, all of these investigations have been carried out on adults but none of the studies addressed the development of the nervous system during the larval and pupal stages in mosquitoes. Here, we first screen a set of 30 antibodies, which have been used to study brain development in Drosophila, and identify 13 of them cross-reacting and labeling epitopes in the developing brain of Aedes. We then use the identified antibodies in immunolabeling studies to characterize general neuroanatomical features of the developing brain and compare them with the well-studied model system, Drosophila melanogaster, in larval, pupal, and adult stages. Furthermore, we use immunolabeling to document the development of specific components of the Aedes brain, namely the optic lobes, the subesophageal neuropil, and serotonergic system of the subesophageal neuropil in more detail. Our study reveals prominent differences in the developing brain in the larval stage as compared to the pupal (and adult) stage of Aedes. The results also uncover interesting similarities and marked differences in brain development of Aedes as compared to Drosophila. Taken together, this investigation forms the basis for future cellular and molecular investigations of brain development in this important disease vector.

Central synaptic mechanisms underlie short-term olfactory habituation in Drosophila larvae.

Naive Drosophila larvae show vigorous chemotaxis toward many odorants including ethyl acetate (EA). Chemotaxis toward EA is substantially reduced after a 5-min pre-exposure to the odorant and recovers with a half-time of ∼20 min. An analogous behavioral decrement can be induced without odorant-receptor activation through channelrhodopsin-based, direct photoexcitation of odorant sensory neurons (OSNs). The neural mechanism of short-term habituation (STH) requires the (1) rutabaga adenylate cyclase; (2) transmitter release from predominantly GABAergic local interneurons (LNs); (3) GABA-A receptor function in projection neurons (PNs) that receive excitatory inputs from OSNs; and (4) NMDA-receptor function in PNs. These features of STH cannot be explained by simple sensory adaptation and, instead, point to plasticity of olfactory synapses in the antennal lobe as the underlying mechanism. Our observations suggest a model in which NMDAR-dependent depression of the OSN-PN synapse and/or NMDAR-dependent facilitation of inhibitory transmission from LNs to PNs contributes substantially to short-term habituation.

Notch regulates the generation of diverse cell types from the lateral lineage of Drosophila antennal lobe.

Diverse neuronal cell types arise from the lateral neuroblast in the antennal lobe of Drosophila. The authors show that loss of Notch function from the entire lineage during development leads to an absence of local interneurons (LNs) with a concomitant increase in the number of projection neurons (PNs). The presence of the intracellular domain of Notch was observed within the nucleus of newly born neurons within the neuroblast lineage. This leads to the suggestion that Notch acts in a binary fate decision to determine formation of LNs and PNs, resulting in two distinct hemilineages from the single neuroblast. The observation of nuclear Notch in several neuroblast lineages leads us to speculate that this mechanism is widespread during the developing Drosophila brain.