Cross-Frequency Phase-Amplitude Coupling between Hippocampal Theta and Gamma Oscillations during Recall Destabilizes Memory and Renders It Susceptible to Reconsolidation Disruption.

Avoidance memory reactivation at recall triggers theta-gamma hippocampal phase amplitude coupling (hPAC) only when it elicits hippocampus-dependent reconsolidation. However, it is not known whether there is a causal relationship between these phenomena. We found that in adult male Wistar rats, silencing the medial septum during recall did not affect avoidance memory expression or maintenance but abolished hPAC and the amnesia caused by the intrahippocampal administration of reconsolidation blockers, both of which were restored by concomitant theta burst stimulation of the fimbria-fornix pathway. Remarkably, artificial hPAC generated by fimbria-fornix stimulation during recall of a learned avoidance response naturally resistant to hippocampus-dependent reconsolidation made it susceptible to reactivation-dependent amnesia. Our results indicate that hPAC mediates the destabilization required for avoidance memory reconsolidation and suggest that the generation of artificial hPAC at recall overcomes the boundary conditions of this process.SIGNIFICANCE STATEMENT Theta-gamma hippocampal phase-amplitude coupling (hPAC) increases during the induction of hippocampus-dependent avoidance memory reconsolidation. However, whether hPAC plays a causal role in this process remains unknown. Using behavioral, electrophysiological, optogenetic, and biochemical tools in adult male Wistar rats, we demonstrate that reactivation-induced hPAC is necessary for avoidance memory destabilization, and that artificial induction of this patterned activity during recall of reconsolidation-resistant aversive memories renders them liable to the amnesic effect of reconsolidation inhibitors.

Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. METHODS: We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. RESULTS: We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in ß-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6). CONCLUSIONS: No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

Prior Learning of Relevant Nonaversive Information Is a Boundary Condition for Avoidance Memory Reconsolidation in the Rat Hippocampus.

Reactivated memories can be modified during reconsolidation, making this process a potential therapeutic target for posttraumatic stress disorder (PTSD), a mental illness characterized by the recurring avoidance of situations that evoke trauma-related fears. However, avoidance memory reconsolidation depends on a set of still loosely defined boundary conditions, limiting the translational value of basic research. In particular, the involvement of the hippocampus in fear-motivated avoidance memory reconsolidation remains controversial. Combining behavioral and electrophysiological analyses in male Wistar rats, we found that previous learning of relevant nonaversive information is essential to elicit the participation of the hippocampus in avoidance memory reconsolidation, which is associated with an increase in theta- and gamma-oscillation power and cross-frequency coupling in dorsal CA1 during reactivation of the avoidance response. Our results indicate that the hippocampus is involved in memory reconsolidation only when reactivation results in contradictory representations regarding the consequences of avoidance and suggest that robust nesting of hippocampal theta-gamma rhythms at the time of retrieval is a specific reconsolidation marker.SIGNIFICANCE STATEMENT Posttraumatic stress disorder (PTSD) is characterized by maladaptive avoidance responses to stimuli or behaviors that represent or bear resemblance to some aspect of a traumatic experience. Disruption of reconsolidation, the process by which reactivated memories become susceptible to modifications, is a promising approach for treating PTSD patients. However, much of what is known about fear-motivated avoidance memory reconsolidation derives from studies based on fear conditioning instead of avoidance-learning paradigms. Using a step-down inhibitory avoidance task in rats, we found that the hippocampus is involved in memory reconsolidation only when the animals acquired the avoidance response in an environment that they had previously learned as safe and showed that increased theta- and gamma-oscillation coupling during reactivation is an electrophysiological signature of this process.

Environmental risk factors and nonpharmacological and nonsurgical interventions for obesity: An umbrella review of meta-analyses of cohort studies and randomized controlled trials.

BACKGROUND: Multiple environmental factors have been implicated in obesity, and multiple interventions, besides drugs and surgery, have been assessed in obese patients. Results are scattered across many studies and meta-analyses, and they often mix obese and overweight individuals. MATERIALS AND METHODS: PubMed and Cochrane Database of Systematic Reviews were searched through 21 January 2017 for meta-analyses of cohort studies assessing environmental risk factors for obesity, and randomized controlled trials investigating nonpharmacological and nonsurgical therapeutic interventions for obesity. We excluded data on overweight participants. Evidence from observational studies was graded according to criteria that included the statistical significance of the random-effects summary estimate and of the largest study in a meta-analysis, the number of obesity cases, heterogeneity between studies, 95% prediction intervals, small-study effects and excess significance. The evidence of intervention studies for obesity was assessed with the GRADE framework. RESULTS: Fifty-four articles met eligibility criteria, including 26 meta-analyses of environmental risk factors (166 studies) and 46 meta-analyses of nondrug, nonsurgical interventions (206 trials). In adults, the only risk factor with convincing evidence was depression, and childhood obesity, adolescent obesity, childhood abuse and short sleep duration had highly suggestive evidence. Infancy weight gain during the first year of life, depression and low maternal education had convincing evidence for association with paediatric obesity. All interventions had low or very-low-quality evidence with one exception of moderate-quality evidence for one comparison (no differences in efficacy between brief lifestyle primary care interventions and other interventions for paediatric obesity). Summary effect sizes were mostly small across compared interventions (maximum 5.1 kg in adults and 1.78 kg in children) and even these estimates may be inflated. CONCLUSIONS: Depression, obesity in earlier age groups, short sleep duration, childhood abuse and low maternal education have the strongest support among proposed risk factors for obesity. Furthermore, there is no high-quality evidence to recommend treating obesity with a specific nonpharmacological and nonsurgical intervention among many available, and whatever benefits in terms of magnitude of weight loss appear small.

Skin picking disorder: prevalence, correlates, and associations with quality of life in a large sample.

OBJECTIVE: Evidence suggests that skin picking disorder (SPD) could be a prevalent condition associated with comorbidity and psychosocial dysfunction. However, just a few studies have assessed the prevalence and correlates of SPD in samples from low- and middle-income countries. In addition, the impact of SPD on quality of life (QoL) dimension after multivariable adjustment to potential confounders remains unclear. METHODS: Data were obtained from a Brazilian anonymous Web-based research platform. Participants provided sociodemographic data and completed the modified Skin Picking-Stanford questionnaire, the Hypomania Checklist (HCL-32), the Patient Health Questionnaire-9 (PHQ-9), the Fagerström Test for Nicotine Dependence, Alcohol Use Disorder Identification Test (AUDIT), Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report-short form, and the World Health Organization quality of life abbreviated scale (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models. RESULTS: For our survey, 7639 participants took part (71.3% females; age: 27.2±7.9 years). The prevalence of SPD was 3.4% (95% CI: 3.0-3.8%), with a female preponderance (P<0.001). In addition, SPD was associated with a positive screen for a major depressive episode, nicotine dependence, and alcohol dependence, as well as suicidal ideation. Physical and psychological QoL was significantly more impaired in participants with SPD compared to those without SPD, even after adjustment for comorbidity. CONCLUSIONS: In this large sample, SPD was a prevalent condition associated with co-occurring depression, nicotine, and alcohol dependence. In addition, SPD was independently associated with impaired physical and psychological QoL. Public health efforts toward the early recognition and treatment of SPD are warranted.

BDNF controls object recognition memory reconsolidation.

Reconsolidation restabilizes memory after reactivation. Previously, we reported that the hippocampus is engaged in object recognition memory reconsolidation to allow incorporation of new information into the original engram. Here we show that BDNF is sufficient for this process, and that blockade of BDNF function in dorsal CA1 impairs updating of the reactivated recognition memory trace.

Peripheral inflammatory markers in Alzheimer's disease: a systematic review and meta-analysis of 175 studies.

OBJECTIVES: Increasing evidence suggests that inflammation is involved in Alzheimer's disease (AD) pathology. This study quantitatively summarised the data on peripheral inflammatory markers in patients with AD compared with healthy controls (HC). METHODS: Original reports containing measurements of peripheral inflammatory markers in AD patients and HC were included for meta-analysis. Standardised mean differences were calculated using a random effects model. Meta-regression and exploration of heterogeneity was performed using publication year, age, gender, Mini-Mental State Examination (MMSE) scores, plasma versus serum measurements and immunoassay type. RESULTS: A total of 175 studies were combined to review 51 analytes in 13 344 AD and 12 912 HC patients. Elevated peripheral interleukin (IL)-1ß, IL-2, IL-6, IL-18, interferon-γ, homocysteine, high-sensitivity C reactive protein, C-X-C motif chemokine-10, epidermal growth factor, vascular cell adhesion molecule-1, tumour necrosis factor (TNF)-α converting enzyme, soluble TNF receptors 1 and 2, α1-antichymotrypsin and decreased IL-1 receptor antagonist and leptin were found in patients with AD compared with HC. IL-6 levels were inversely correlated with mean MMSE scores. CONCLUSIONS: These findings suggest that AD is accompanied by a peripheral inflammatory response and that IL-6 may be a useful biological marker to correlate with the severity of cognitive impairment. Further studies are needed to determine the clinical utility of these markers.

Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVES: The pathophysiology of bipolar disorder is likely to involve both genetic and environmental risk factors. In our study, we aimed to perform a systematic search of environmental risk factors for BD. In addition, we assessed possible hints of bias in this literature, and identified risk factors supported by high epidemiological credibility. METHODS: We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases up to 7 October 2016 to identify systematic reviews and meta-analyses of observational studies that assessed associations between putative environmental risk factors and BD. For each meta-analysis, we estimated its summary effect size by means of both random- and fixed-effects models, 95% confidence intervals (CIs), the 95% prediction interval, and heterogeneity. Evidence of small-study effects and excess of significance bias was also assessed. RESULTS: Sixteen publications met the inclusion criteria (seven meta-analyses and nine qualitative systematic reviews). Fifty-one unique environmental risk factors for BD were evaluated. Six meta-analyses investigated associations with a risk factor for BD. Only irritable bowel syndrome (IBS) emerged as a risk factor for BD supported by convincing evidence (k=6; odds ratio [OR]=2.48; 95% CI=2.35-2.61; P<.001), and childhood adversity was supported by highly suggestive evidence. Asthma and obesity were risk factors for BD supported by suggestive evidence, and seropositivity to Toxoplasma gondii and a history of head injury were supported by weak evidence. CONCLUSIONS: Notwithstanding that several environmental risk factors for BD were identified, few meta-analyses of observational studies were available. Therefore, further well-designed and adequately powered studies are necessary to map the environmental risk factors for BD.

Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities.

BACKGROUND: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). METHODS: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. RESULTS: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. CONCLUSIONS: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.

Requirement for BDNF in the reconsolidation of fear extinction.

Therapies based on the impairment of reconsolidation or the enhancement of extinction offer the possibility of decreasing the persistent recollection of distressing memories. However, the direct interplay between reconsolidation and extinction has rarely been considered. Previously, we reported that reactivation induces reconsolidation of fear extinction memory. Here, using a step-down inhibitory avoidance learning paradigm in rats, we show that intrahippocampus infusion of function-blocking anti-BDNF antibody immediately or 6 h after extinction memory reactivation impairs the reconsolidation of extinction. Extinction memory reactivation increases proBDNF, BDNF, and tropomyosin receptor kinase B (TrkB) phosphorylation levels in dorsal CA1, while blocking BDNF maturation in the hippocampus with plasminogen activator inhibitor 1 hinders the persistence of extinction and induces the recurrence of fear. Moreover, coinfusion of recombinant BDNF (0.25 µg/side) after extinction memory reactivation impedes the recovery of the avoidance response induced by inhibiting gene expression and protein synthesis in the dorsal hippocampus. Our findings unravel a new role for BDNF, suggesting that this neurotrophin is necessary and sufficient to maintain the reactivated fear extinction engram.

Cognitive remission: a novel objective for the treatment of major depression?

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

Bias in Peripheral Depression Biomarkers.

BACKGROUND: To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted. METHODS: Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015. RESULTS: From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (I2 ≥ 50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects. CONCLUSIONS: Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of 'positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature.

Affective temperaments and emotional traits are associated with a positive screening for premenstrual dysphoric disorder.

OBJECTIVES: Preliminary evidence indicates that premenstrual dysphoric disorder (PMDD) may be frequently co-morbid with bipolar spectrum disorders. In addition, the manifestations of PMDD seem similar to a subthreshold depressive mixed state. Nevertheless, the associations between PMDD and affective temperaments and emotional traits have not been previously investigated. METHODS: A consecutive sample of 514 drug-free Brazilian women (mean age: 22.8; SD=5.4years) took part in this cross-sectional study. Screening for PMDD was obtained with the validated Brazilian Portuguese version of the Premenstrual Symptoms Screening Tool (PSST). Affective temperaments and emotional dimensions were evaluated with the Affective and Emotional Composite Temperament Scale (AFECTS). In addition, socio-demographic and data on menstrual cycle were collected. RESULTS: According to the PSST, 83 (16.1%) women screened positive for PMDD, while 216 (42.0%) women had no/mild premenstrual symptoms. The cyclothymic temperament was independently associated with PMDD (OR=4.57; 95% CI: 2.11-9.90), while the euthymic temperament had an independent association with a lower likelihood of a positive screening for PMDD (OR=0.28; 95% CI: 0.12-0.64). In addition, anger and sensitivity emerged as emotional dimensions significantly associated with PMDD. CONCLUSIONS: A positive screening for PMDD was associated with a predominant cyclothymic temperament, while an euthymic temperament was associated with a lower likelihood for a positive screening for PMDD. These data deserve replication in prospective studies.

Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies.

BACKGROUND: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. METHODS: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. RESULTS: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. CONCLUSIONS: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.

Inactivation of the dorsal hippocampus or the medial prefrontal cortex impairs retrieval but has differential effect on spatial memory reconsolidation.

Active memories can incorporate new information through reconsolidation. However, the notion that memory retrieval is necessary for reconsolidation has been recently challenged. Non-reinforced retrieval induces hippocampus and medial prefrontal cortex (mPFC)-dependent reconsolidation of spatial memory in the Morris water maze (MWM). We found that the effect of protein synthesis inhibition on this process is abolished when retrieval of the learned spatial preference is hindered through mPFC inactivation but not when it is blocked by deactivation of dorsal CA1. Our results do not fully agree with the hypothesis that retrieval is unneeded for reconsolidation. Instead, they support the idea that a hierarchic interaction between the hippocampus and the mPFC controls spatial memory in the MWM, and indicate that this cortex is sufficient to retrieve the information essential to reconsolidate the spatial memory trace, even when the hippocampus is inactivated.

Autobiographical Memory Disturbances in Depression: A Novel Therapeutic Target?

Major depressive disorder (MDD) is characterized by a dysfunctional processing of autobiographical memories. We review the following core domains of deficit: systematic biases favoring materials of negative emotional valence; diminished access and response to positive memories; a recollection of overgeneral memories in detriment of specific autobiographical memories; and the role of ruminative processes and avoidance when dealing with autobiographical memories. Furthermore, we review evidence from functional neuroimaging studies of neural circuits activated by the recollection of autobiographical memories in both healthy and depressive individuals. Disruptions in autobiographical memories predispose and portend onset and maintenance of depression. Thus, we discuss emerging therapeutics that target memory difficulties in those with depression. We review strategies for this clinical domain, including memory specificity training, method-of-loci, memory rescripting, and real-time fMRI neurofeedback training of amygdala activity in depression. We propose that the manipulation of the reconsolidation of autobiographical memories in depression might represent a novel yet largely unexplored, domain-specific, therapeutic opportunity for depression treatment.

Nicotine modulates the long-lasting storage of fear memory.

Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that α7-nAChR-mediated cholinergic interactions between the pedunculopontine tegmental nucleus and the medial prefrontal cortex modulate the duration of fear-motivated memories, maybe by regulating the activation state of VTA-hippocampus dopamine connections.

Facilitating the Sharing of Electrophysiology Data Analysis Results Through In-Depth Provenance Capture.

Scientific research demands reproducibility and transparency, particularly in data-intensive fields like electrophysiology. Electrophysiology data are typically analyzed using scripts that generate output files, including figures. Handling these results poses several challenges due to the complexity and iterative nature of the analysis process. These stem from the difficulty to discern the analysis steps, parameters, and data flow from the results, making knowledge transfer and findability challenging in collaborative settings. Provenance information tracks data lineage and processes applied to it, and provenance capture during the execution of an analysis script can address those challenges. We present Alpaca (Automated Lightweight Provenance Capture), a tool that captures fine-grained provenance information with minimal user intervention when running data analysis pipelines implemented in Python scripts. Alpaca records inputs, outputs, and function parameters and structures information according to the W3C PROV standard. We demonstrate the tool using a realistic use case involving multichannel local field potential recordings of a neurophysiological experiment, highlighting how the tool makes result details known in a standardized manner in order to address the challenges of the analysis process. Ultimately, using Alpaca will help to represent results according to the FAIR principles, which will improve research reproducibility and facilitate sharing the results of data analyses.

Consolidation of object recognition memory requires simultaneous activation of dopamine D1/D5 receptors in the amygdala and medial prefrontal cortex but not in the hippocampus.

The mesocorticolimbic dopaminergic system includes the ventral tegmental area (VTA) and its projections to the amygdala (AMY), the hippocampus (HIP) and the medial prefrontal cortex (mPFC), among others. Object recognition (OR) long-term memory (LTM) processing requires dopaminergic activity but, although some of the brain regions mentioned above are necessary for OR LTM consolidation, their possible dopamine-mediated interplay remains to be analyzed. Using adult male Wistar rats, we found that posttraining microinjection of the dopamine D1/D5 receptor antagonist SCH23390 in mPFC or AMY, but not in HIP, impaired OR LTM. The dopamine D2 receptor agonist quinpirole had no effect on retention. VTA inactivation also hindered OR LTM, and even though this effect was unaffected by co-infusion of the dopamine D1/D5 receptor agonist SKF38393 in HIP, mPFC or AMY alone, it was reversed by simultaneous activation of D1/D5 receptors in the last two regions. Our results demonstrate that the mesocorticolimbic dopaminergic system is indeed essential for OR LTM consolidation and suggest that the role played by some of its components during this process is much more complex than previously thought.

Zika Virus as an Emerging Neuropathogen: Mechanisms of Neurovirulence and Neuro-Immune Interactions.

Zika virus (ZIKV) is an emerging arbovirus of the genus Flaviviridae, which causes a febrile illness and has spread from across the Pacific to the Americas in a short timeframe. Convincing evidence has implicated the ZIKV to incident cases of neonatal microcephaly and a set of neurodevelopmental abnormalities referred to as the congenital Zika virus syndrome. In addition, emerging data points to an association with the ZIKV and the development of the so-called Guillain-Barre syndrome, an acute autoimmune polyneuropathy. Accumulating knowledge suggests that neurovirulent strains of the ZIKV have evolved from less pathogenic lineages of the virus. Nevertheless, mechanisms of neurovirulence and host-pathogen neuro-immune interactions remain incompletely elucidated. This review provides a critical discussion of genetic and structural alterations in the ZIKV which could have contributed to the emergence of neurovirulent strains. In addition, a mechanistic framework of neuro-immune mechanisms related to the emergence of neuropathology after ZIKV infection is discussed. Recent advances in knowledge point to avenues for the development of a putative vaccine as well as novel therapeutic strategies. Nevertheless, there are unique unmet challenges that need to be addressed in this regard. Finally, a research agenda is proposed.