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Background The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. Results Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds. Conclusions These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

Background We previously reported that heat shock protein 27 (HSP27) phosphorylation plays an important role in the activation of glucose-6-phosphate dehydrogenase (G6PD), resulting in the upregulation of the pentose phosphate pathway and antioxidant effects against cerebral ischemia–reperfusion injury. The present study investigated the effect of geranylgeranylacetone, an inducer of HSP27, on ischemia–reperfusion injury in male rats as a preliminary study to see if further research of the effects of geranylgeranylacetone on the ischemic stroke was warranted. Methods In all experiments, male Wistar rats were used. First, we conducted pathway activity profiling based on a gas chromatography–mass spectrometry to identify ischemia–reperfusion-related metabolic pathways. Next, we investigated the effects of geranylgeranylacetone on the pentose phosphate pathway and ischemia–reperfusion injury by real-time polymerase chain reaction (RT-PCR), immunoblotting, and G6PD activity, protein carbonylation and infarct volume analysis. Geranylgeranylacetone or vehicle was injected intracerebroventricularly 3 h prior to middle cerebral artery occlusion or sham operation. Results Pathway activity profiling demonstrated that changes in the metabolic state depended on reperfusion time and that the pentose phosphate pathway and taurine-hypotaurine metabolism pathway were the most strongly related to reperfusion among 137 metabolic pathways. RT-PCR demonstrated that geranylgeranylacetone did not significantly affect the increase in HSP27 transcript levels after ischemia–reperfusion. Immunoblotting showed that geranylgeranylacetone did not significantly affect the elevation of HSP27 protein levels. However, geranylgeranylacetone significantly increase the elevation of phosphorylation of HSP27 after ischemia–reperfusion. In addition, geranylgeranylacetone significantly affected the increase in G6PD activity, and reduced the increase in protein carbonylation after ischemia–reperfusion. Accordingly, geranylgeranylacetone significantly reduced the infarct size (median 31.3% vs 19.9%, p = 0.0013). Conclusions As a preliminary study, these findings suggest that geranylgeranylacetone may be a promising agent for the treatment of ischemic stroke and would be worthy of further study. Further studies are required to clearly delineate the mechanism of geranylgeranylacetone-induced HSP27 phosphorylation in antioxidant effects, which may guide the development of new approaches for minimizing the impact of cerebral ischemia–reperfusion injury.

Background It has been shown that eosinophils are decreased and monocytes are elevated in patients with acute ischemic stroke (AIS), but the impact of eosinophil-to-monocyte ratio (EMR) on clinical outcomes among AIS patients remains unclear. We aimed to determine the relationship between EMR on admission and 3-month poor functional outcome in AIS patients. Methods A total of 521 consecutive patients admitted to our hospital within 24 h after onset of AIS were prospectively enrolled and categorized in terms of quartiles of EMR on admission between August 2016 and September 2018. The endpoint was the poor outcome defined as modified Rankin Scale score of 3 to 6 at month 3 after admission. Results As EMR decreased, the risk of poor outcome increased (p p = 0.0003), which is consistent with the result of EMR (quartile) as a categorical variable (odds ratio, 0.23; 95% CI 0.10–0.52; ptrend p = 0.382; integrated discrimination improvement: 2.41%, p Conclusions EMR on admission was independently correlated with poor outcome in AIS patients, suggesting that EMR may be a potential prognostic biomarker for AIS.

Background Bipolar disorder is a severe psychiatric illness with poor prognosis and problematic and suboptimal treatments. Understanding the pathoetiologic mechanisms may improve treatment and outcomes. Discussion Dysregulation of cationic homeostasis is the most reproducible aspect of bipolar pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Recent discoveries of the role of endogenous sodium pump modulators (which include ‘endogenous ouabain’) in regulation of sodium and potassium distribution, inflammation, and activation of key cellular second messenger systems that are important in cell survival, and the demonstration that these stress-responsive chemicals may be dysregulated in bipolar patients, suggest that these compounds may be candidates for the coupling of environmental stressors and illness onset. Specifically, individuals with bipolar disorder appear to be unable to upregulate endogenous ouabain under conditions that require it, and therefore may experience a relative deficiency of this important regulatory hormone. In the absence of elevated endogenous ouabain, neurons are unable to maintain their normal resting potential, become relatively depolarized, and are then susceptible to inappropriate activation. Furthermore, sodium pump activity appears to be necessary to prevent inflammatory signals within the central nervous system. Nearly all available data currently support this model, but additional studies are required to solidify the role of this system. Conclusion Endogenous ouabain dysregulation appears to be a reasonable candidate for understanding the pathophysiology of bipolar disorder.

Background Attachment theory demonstrates that early attachment experience shapes internal working models with mental representations of self and close relationships, which affects personality traits and interpersonal relationships in adulthood. Although research has focused on brain structural and functional underpinnings to disentangle attachment styles in healthy individuals, little is known about the spontaneous brain activity associated with self-reported attachment anxiety and avoidance during the resting state. Methods One hundred and nineteen individuals participated in the study, completing the Experience in Close Relationship scale immediately after an 8-min fMRI scanning. We used the resting-state functional magnetic resonance imaging (rs-fMRI) signal of the amplitude of low-frequency fluctuation and resting-state functional connectivity to identify attachment-related regions and networks. Results Consequently, attachment anxiety is closely associated with the amplitude of low-frequency fluctuations in the right posterior cingulate cortex, over-estimating emotional intensity and exaggerating outcomes. Moreover, the functional connectivity between the posterior cingulate cortex and fusiform gyrus increases detection ability for potential threat or separation information, facilitating behavior motivation. The attachment avoidance is positively correlated with the amplitude of low-frequency fluctuation in the bilateral lingual gyrus and right postcentral and negatively correlated with the bilateral orbital frontal cortex and inferior temporal gyrus. Functional connection with attachment avoidance contains critical nodes in the medial temporal lobe memory system, frontal-parietal network, social cognition, and default mode network necessary to deactivate the attachment system and inhibit attachment-related behavior. Conclusion and implications These findings clarify the amplitude of low-frequency fluctuation and resting-state functional connectivity neural signature of attachment style, associated with attachment strategies in attachment anxiety and attachment avoidance individuals. These findings may improve our understanding of the pathophysiology of the attachment-related disorder.

Background The Period Circadian Regulator 2 (Per2) gene is important for the modulation of circadian rhythms that influence biological processes. Circadian control of the hypothalamus-pituitary-adrenal (HPA) axis is critical for regulation of hormones involved in the stress response. Dysregulation of the HPA axis is associated with neuropsychiatric disorders. Therefore, it is important to understand how disruption of the circadian rhythm alters the HPA axis. One way to address this question is to delete a gene involved in regulating a central circadian gene such as Per2 in an animal model and to determine how this deletion may affect the HPA axis and behaviors that are altered when the HPA axis is dysregulated. To study this, corticosterone (CORT) levels were measured through the transition from light (inactive phase) to dark (active phase). Additionally, CORT levels as well as pituitary and adrenal mRNA expression were measured following a mild restraint stress. Mice were tested for depressive-like behaviors (forced swim test (FST)), acoustic startle response (ASR), and pre-pulse inhibition (PPI). Results The present results showed that Per2 knockout impacted CORT levels, mRNA expression, depressive-like behaviors, ASR and PPI. Unlike wild-type (WT) mice, Per2 knockout (Per2) mice showed no diurnal rise in CORT levels at the onset of the dark cycle. Per2−/− mice had enhanced CORT levels and adrenal melanocortin receptor 2 (Mc2R) mRNA expression following restraint. There were no changes in expression of any other pituitary or adrenal gene. In the FST, Per2−/− mice spent more time floating (less time struggling) than WT mice, suggesting increased depressive-like behaviors. Per2−/− mice had deficits in ASR and PPI startle responses compared to WT mice. Conclusions In summary, these findings showed that disruption of the circadian system via Per2 gene deletion dysregulated the HPA stress axis and is subsequently correlated with increased depressive-like behaviors and deficits in startle response.

Background This study aimed to investigate the changes in the expression of hippocampal genes upon acute noise exposure. Methods Three-week-old Sprague–Dawley rats were assigned to control (n = 15) and noise (n = 15) groups. White noise (2–20 kHz, 115 dB sound pressure level [SPL]) was delivered for 4 h per day for 3 days to the noise group. All rats were sacrificed on the last day of noise exposure, and gene expression in the hippocampus was analyzed using a microarray. Pathway analyses were conducted for genes that showed differential expression ≥ 1.5-fold and P ≤ 0.05 compared to the control group. The genes included in the putative pathways were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results Thirty-eight upregulated genes and 81 downregulated genes were identified. The pathway analyses revealed that upregulated genes were involved in the cellular responses to external stimuli and immune system pathways. qRT-PCR confirmed the upregulation of the involved genes. The downregulated genes were involved in neuronal systems and synapse-related pathways, and qRT-PCR confirmed the downregulation of the involved genes. Conclusions Acute noise exposure upregulated the expression of immune-related genes and downregulated the expression of neurotransmission-related genes in the hippocampus.

Background As a noninvasive perfusion-weighted MRI technique, arterial spin-labeling (ASL) was becoming increasingly used to evaluate cerebral hemodynamics in many studies. The relation between ASL-MRI and crossed cerebellar diaschisis (CCD) was rarely discussed. In this study, the aim of our study was to assess the performance of ASL-MRI in the detection of crossed cerebellar diaschisis after stroke in compared with single-photon emission CT (SPECT). Results 17 of 51(33.3%) patients revealed CCD phenomenon by the SPECT method. In CCD-positive group, CBFASL of ipsilateral cerebellar were significantly increased compared with contralateral cerebellar (p p = 0.063, > 0.001) in the CCD-negative group. Positive correlation was detected between admission National institute of health stroke scale (NIHSS) and asymmetry index of SPECT (AISPECT) (r = 0.351, p = 0.011), AIASL (r = 0.372, p = 0.007); infract volume and AISPECT (r = 0.443, p = 0.001), AIASL (r = 0.426, p = 0.002). Significant correlation was also found between cerebral blood flow of SPECT (CBFSPECT) and CBFASL, AISPECT and AIASL (r = 0.204, p = 0.04; r = 0.467, p = 0.001, respectively). Furthermore, the area under the receiver operating characteristic (ROC) curve value of AIASL was 0.829. Conclusions CBF derived from ASL-MRI could be valuable for assessment of CCD in supratentorial stroke patients. Additionally, CCD was significantly associated with larger ischemic volume and higher initial NIHSS score.

Background ADHD is one of the most common psychiatric disorders in children and adolescents. Altered functional connectivity has been associated with ADHD symptoms. This study aimed to investigate abnormal changes in the functional connectivity of resting-state brain networks (RSNs) among adolescent patients with different subtypes of ADHD. Methods The data were obtained from the ADHD-200 Global Competition, including fMRI data from 88 ADHD patients (56 patients of ADHD-Combined, ADHD-C and 32 patients of ADHD-Inattentive, ADHD-I) and 67 typically developing controls (TD-C). Group ICA was utilized to research aberrant brain functional connectivity within the different subtypes of ADHD. Results In comparison with the TD-C group, the ADHD-C group showed clusters of decreased functional connectivity in the left inferior occipital gyrus (p = 0.0041) and right superior occipital gyrus (p = 0.0011) of the dorsal attention network (DAN), supplementary motor area (p = 0.0036) of the executive control network (ECN), left supramarginal gyrus (p = 0.0081) of the salience network (SN), middle temporal gyrus (p = 0.0041), and superior medial frontal gyrus (p = 0.0055) of the default mode network (DMN), while the ADHD-I group showed decreased functional connectivity in the right superior parietal gyrus (p = 0.0017) of the DAN and left middle temporal gyrus (p = 0.0105) of the DMN. In comparison with the ADHD-I group, the ADHD-C group showed decreased functional connectivity in the superior temporal gyrus (p = 0.0062) of the AN, inferior temporal gyrus (p = 0.0016) of the DAN, and the dorsolateral superior frontal gyrus (p = 0.0082) of the DMN. All the clusters surviving at p Conclusion The results suggested that decreased functional connectivity within the DMN and DAN was responsible, at least in part, for the symptom of inattention in ADHD-I patients. Similarly, we believed that the impaired functional connectivity within networks may contribute to the manifestations of ADHD-C patients, including inattention, hyperactivity/impulsivity, and unconscious movements.

Background Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding involves genomics, neurochemistry, electrophysiology, and behavior. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders. This paper presents a new deterministic model of serotonin metabolism and a new systems population model that takes into account the large variation in enzyme and transporter expression levels, tryptophan input, and autoreceptor function. Results We discuss the steady state of the model and the steady state distribution of extracellular serotonin under different hypotheses on the autoreceptors and we show the effect of tryptophan input on the steady state and the effect of meals. We use the deterministic model to interpret experimental data on the responses in the hippocampus of male and female mice, and to illustrate the short-time dynamics of the autoreceptors. We show there are likely two reuptake mechanisms for serotonin and that the autoreceptors have long-lasting influence and compare our results to measurements of serotonin dynamics in the substantia nigra pars reticulata. We also show how histamine affects serotonin dynamics. We examine experimental data that show very variable response curves in populations of mice and ask how much variation in parameters in the model is necessary to produce the observed variation in the data. Finally, we show how the systems population model can potentially be used to investigate specific biological and clinical questions. Conclusions We have shown that our new models can be used to investigate the effects of tryptophan input and meals and the behavior of experimental response curves in different brain nuclei. The systems population model incorporates individual variation and can be used to investigate clinical questions and the variation in drug efficacy. The codes for both the deterministic model and the systems population model are available from the authors and can be used by other researchers to investigate the serotonergic system.

Background Bipolar offspring are considered a high-risk group for developing mental disorders. Developmental outcomes result from additive and interactive effects of biological vulnerability and environmental influences. Mother–infant interactions represent important early environmental influences that may modify infants’ risk of mental disorders. The aim of the current prospective study was to investigate the patterns and development of mother–infant interactions in the first year of life in dyads in which the mothers have bipolar disorder (BD). Methods Twenty-six dyads in which the mothers had BD and 28 dyads in which the mothers had no mental disorder were video-taped in a free play interaction. The Parent–Child Early Relational Assessment (PCERA) was used to assess the quality of the interactions on three domains (maternal behaviour, infant behaviour and dyadic coordination) at 3 and 12 months of infant age. First, we compared the mother–infant interaction patterns between the two groups at 12 months. Second, we investigated how the patterns developed within and between the groups from infant ages 3 to 12 months. Results BD dyads demonstrated significantly more challenges in all three interaction domains at infant age 12 months compared to the healthy dyads. This observation was in line with the findings at infant age 3 months. Subdued expression of positive affect and mutual underinvolvement represented core challenges in maternal and infant behaviours in the BD dyads. Continuous difficulties with dyadic coordination and reciprocity were the most concerning interaction behaviours at 3 and 12 months. On the positive side, there was little expression of negative affect or tension in maternal, infant and dyadic behaviour, and some positive changes in infant behaviour from 3 to 12 months. Conclusions The current results suggest that challenges in mother–infant interaction patterns in the first year of life may enhance the developmental risk for bipolar offspring. Clinical interventions should address both the BD mothers’ needs in relation to postpartum mood deviations and mother–infant interactions. We suggest interaction interventions to promote dyadic coordination and reciprocity, such as helping mothers being more sensitive to their infant’s cues and to provide attuned contingent responses.

According to the influential “Two Visual Pathways” hypothesis, the cortical visual system is segregated into two pathways, with the ventral, occipitotemporal pathway subserving object perception, and the dorsal, occipitoparietal pathway subserving the visuomotor control of action. However, growing evidence suggests that the dorsal pathway also plays a functional role in object perception. In the current article, we present evidence that the dorsal pathway contributes uniquely to the perception of a range of visuospatial attributes that are not redundant with representations in ventral cortex. We describe how dorsal cortex is recruited automatically during perception, even when no explicit visuomotor response is required. Importantly, we propose that dorsal cortex may selectively process visual attributes that can inform the perception of potential actions on objects and environments, and we consider plausible developmental and cognitive mechanisms that might give rise to these representations. As such, we consider whether naturalistic stimuli, such as real-world solid objects, might engage dorsal cortex more so than simplified or artificial stimuli such as images that do not afford action, and how the use of suboptimal stimuli might limit our understanding of the functional contribution of dorsal cortex to visual perception.

Background Retinal circuitry provides a fundamental window to neural networks, featuring widely investigated visual phenomena ranging from direction selectivity to fast detection of approaching motion. As the divide between experimental and theoretical visual neuroscience is fading, neuronal modeling has proven to be important for retinal research. In neuronal modeling a delicate balance is maintained between bio-plausibility and model tractability, giving rise to myriad modeling frameworks. One biologically detailed framework for neuro modeling is NeuroConstruct, which facilitates the creation, visualization and analysis of neural networks in 3D. Results Here, we extended NeuroConstruct to support the generation of structured visual stimuli, to feature different synaptic dynamics, to allow for heterogeneous synapse distribution and to enable rule-based synaptic connectivity between cell populations. We utilized this framework to demonstrate a simulation of a dense plexus of biologically realistic and morphologically detailed starburst amacrine cells. The amacrine cells were connected to a ganglion cell and stimulated with expanding and collapsing rings of light. Conclusions This framework provides a powerful toolset for the investigation of the yet elusive underlying mechanisms of retinal computations such as direction selectivity. Particularly, we showcased the way NeuroConstruct can be extended to support advanced field-specific neuro-modeling.

Background Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Stabilization of PNPH with bound carbon monoxide prevents methemoglobin formation during storage and permits it to serve as a carbon monoxide donor. We determined whether small volume transfusion of hyperoncotic PNPH is neuroprotective in a polytrauma model of traumatic brain injury (TBI) plus hemorrhagic shock. Guinea pigs were used because, like humans, they do not synthesize their own ascorbic acid, which is important in reducing methemoglobin. Results TBI was produced by controlled cortical impact and was followed by 20 mL/kg hemorrhage to a mean arterial pressure (MAP) of 40 mmHg. At 90 min, animals were resuscitated with 20 mL/kg lactated Ringer’s solution or 10 mL/kg PNPH. Resuscitation with PNPH significantly augmented the early recovery of MAP after hemorrhagic shock by 10–18 mmHg; whole blood methemoglobin was only 1% higher and carboxyhemoglobin was 2% higher. At 9 days of recovery, unbiased stereology analysis revealed that, compared to animals resuscitated with lactated Ringer’s solution, those treated with PNPH had significantly more viable neurons in the hippocampus CA1 + 2 region (59 ± 10% versus 87 ± 18% of sham and naïve mean value) and in the dentate gyrus (70 ± 21% versus 96 ± 24%; n = 12 per group). Conclusion PNPH may serve as a small-volume resuscitation fluid for polytrauma involving TBI and hemorrhagic shock. The neuroprotection afforded by PNPH seen in other species was sustained in a species without endogenous ascorbic acid synthesis, thereby supporting potential translatability for human use.

Background Diagnostic stability of bipolar disorder (BD) in children and adolescents, beyond the first contact has been investigated sparsely. The aim of this study was to investigate the diagnostic stability of BD in children and adolescents using over two decades of nationwide register-based data, and to examine factors associated with change from BD to schizophrenia (ICD-10: F20.x), schizoaffective disorder (ICD-10: F25.x) or other primary psychotic disorders (ICD-10 F23.x–24.x and F28.x–29.x). Methods Danish register-based data for all incident BD patients diagnosed prior to age 18 years, between January 1st 1995 and December 31st 2014 (N = 519). We graphically illustrated diagnostic change at different follow-up times and studied variables associated with diagnostic change after 3-year follow-up using Poisson regression with robust standard error estimates. Results The diagnosis of incident BD was relatively stable. The diagnosis did not change for 93% of those followed for at least 6 months, and remained unchanged for 86% and 73% of those followed at least 3 years and 10 years, respectively. In patients followed for at least 3 years after index BD (N = 478), the risk of diagnostic change was 61% higher in males versus females. The risk of diagnostic change for patients diagnosed during hospitalization was 74% higher compared to patients diagnosed at outpatient clinics/emergency rooms. The risk of diagnostic change for patients abusing substances other than alcohol and cannabis was 173% higher compared to patients not abusing such substances. The risk of diagnostic change for patients previously diagnosed with schizophrenia or related diagnosis was 257% higher compared to patients not having been diagnosed with such diagnosis previously, while the risk of diagnostic change in offspring of parents with schizophrenia or related diagnosis was 126% higher compared to patients who did not have parents diagnosed with such disorders. Conclusion Overall, the stability of the BD diagnosis in the Danish nationwide healthcare registers was high. Factors associated with risk of diagnostic change within 3 years of the initial diagnosis were being male, diagnosis given during hospitalization, substance abuse other than alcohol and cannabis, and a prior diagnosis of schizophrenia or related diagnosis in the patient or in their parents.

Background Empathy refers to the ability to recognise and share emotions with others. Several research groups have recognised observational fear in mice as a useful behavioural model for assessing their ability to empathise. However, in these observation systems, it remains unclear whether the observer mouse truly recognises the movements of, and empathises with, the demonstrator mouse. We examined changes in the behaviour of an observer mouse when a demonstrator mouse was anaesthetised, when the demonstrator’s activity was increased, and when the interval of electrical stimulation was altered. If mice exhibit an ability to empathise, then the observer should display empathic behaviour when the demonstrator experiences pain or discomfort under any circumstances. Results Relative to low-frequency stimulation, frequent electrical stimulation reduced immobility time among observer mice. Moreover, when demonstrators exhibited excessive activity, the activity of the observers significantly increased. In addition, the proportion of immobility time among observer mice significantly increased when demonstrator mice exhibited fear learning and excessive immobility. Conclusion Although our results indicate that observer mice change their behaviour based on the movements of demonstrator mice, increases in immobility time may reflect conformity-like behaviour rather than emotional empathy. Thus, not only visual but also auditory and odour information additionally influenced the conformity-like behaviour shown by observer mice. Thus, our findings suggest that methods other than the fear observation system should be used to investigate rodent empathy-like behaviour.

Background Evidence from epidemiological, clinical and high-risk studies has established that the peak period of risk for onset of bipolar disorder spans late adolescence and early adulthood. However, the proposal of the existence of a pre-pubertal form of bipolar disorder manifesting in early childhood created substantial debate. In this narrative review, the literature and contributing factors pertaining to the controversy surrounding the proposed pre-pubertal bipolar disorder subtype are discussed. The resolution of the debate and lessons learned are highlighted. Main body In the mid 1990s US researchers proposed that chronic irritability and explosive temper in pre-pubertal children with pre-existing ADHD and/or other learning and developmental disorders might represent a variant of mania. A number of factors contributed to this proposal including severely ill children with no diagnostic home given changes in the ADHD DSM diagnostic criteria and over-reliance on symptoms and structured interviews rather than on a clinical assessment incorporating developmental history, social context and clinical course. Prospective studies of children at high familial risk did not support the proposed pre-pubertal bipolar phenotype; but rather provided convergent evidence that bipolar disorder onset in adolescence and early adulthood not uncommonly preceded by sleep and internalizing symptoms and most often debuting as depression in adolescence (after puberty). Epidemiological studies of population and hospital discharge data provided evidence that the pre-pubertal bipolar phenotype was largely a US driven phenomenon. Conclusions Psychiatric diagnosis is particularly challenging given the current lack of objective biomarkers. However, validity and utility of clinical diagnoses can be strengthened if all available predictive information is used to formulate a diagnosis. As in other areas of medicine, critical information required to make a valid diagnosis includes developmental history, clinical course, family history and treatment response—weighed against the known trajectories of classical disorders. Moreover, given that psychiatric disorders are in evolution over childhood and adolescence and symptoms, in of themselves, are often non-specific, a thorough clinical assessment incorporating collateral history and psychosocial context is paramount. Such an approach might have avoided or at least brought a more timely resolution to the debate on pre-pubertal mania.

Background Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons. Results Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density. Conclusions We show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.

Background The growing abuse of amphetamine-type stimulants leads to new challenges to human health. A possible addiction mechanism has been proposed by altered functional architecture of the nucleus accumbens (NAc) during resting state. NAc contains different subdivisions and they may play different roles in addiction. The aim of the present study was to examine whether there are common or distinct patterns of functional connectivity of the NAc subdivisions in amphetamine-type stimulant abusers (ATSAs). Methods The present study recruited 17 male ATSAs and 22 healthy male controls. All the subjects underwent resting-state functional magnetic resonance imaging (fMRI) with their eyes closed. The NAc was divided into core-like and shell-like subdivisions. We used seed-based resting-state functional connectivity (RSFC) analyses to identify differences in brain functional architecture between ATSAs and healthy controls (HCs). Results ATSAs had lower positive RSFCs with all of the NAc subdivisions over the left orbital part of superior frontal gyrus and higher positive RSFCs with the NAc subdivisions over the left opercular part of inferior frontal gyrus than HCs, which indicates common abnormalities across the NAc subdivisions in ATSAs. In addition, the RSFCs between the NAc subdivisions and the left orbital part of superior frontal gyrus were negatively correlated with the addiction severity in ATSAs. Conclusion These results provide evidence that there are common RSFC patterns of the NAc subdivisions in ATSAs. The abnormality indicated by disrupted functional connectivity between the NAc subdivisions and prefrontal cortex suggests abnormal interaction between the rewarding process and cognitive control in ATSAs. Our results shed insight on the neurobiological mechanisms of ATSA and suggest potential novel therapeutic targets for treatment and intervention of ATSAs.

Background Histone deacetylase-3 (HDAC3) promotes neurodegeneration in various cell culture and in vivo models of neurodegeneration but the mechanism by which HDAC3 exerts neurotoxicity is not known. HDAC3 is known to be a transcriptional co-repressor. The goal of this study was to identify transcriptional targets of HDAC3 in an attempt to understand how it promotes neurodegeneration. Results We used chromatin immunoprecipitation analysis coupled with deep sequencing (ChIP-Seq) to identify potential targets of HDAC3 in cerebellar granule neurons. One of the genes identified was the activity-dependent and neuroprotective transcription factor, Neuronal PAS Domain Protein 4 (Npas4). We confirmed using ChIP that in healthy neurons HDAC3 associates weakly with the Npas4 promoter, however, this association is robustly increased in neurons primed to die. We find that HDAC3 also associates differentially with the brain-derived neurotrophic factor (Bdnf) gene promoter, with higher association in dying neurons. In contrast, association of HDAC3 with the promoters of other neuroprotective genes, including those encoding c-Fos, FoxP1 and Stat3, was barely detectable in both healthy and dying neurons. Overexpression of HDAC3 leads to a suppression of Npas4 and Bdnf expression in cortical neurons and treatment with RGFP966, a chemical inhibitor of HDAC3, resulted in upregulation of their expression. Expression of HDAC3 also repressed Npas4 and Bdnf promoter activity. Conclusion Our results suggest that Bdnf and Npas4 are transcriptional targets of Hdac3-mediated repression. HDAC3 inhibitors have been shown to protect against behavioral deficits and neuronal loss in mouse models of neurodegeneration and it is possible that these inhibitors work by upregulating neuroprotective genes like Bdnf and Npas4.

Background Infection is an important clinical complication facing stroke-patients and triples the risk of death within 30 days post-stroke via mechanisms which are poorly understood. Aims We tried to explore the mechanisms that inflammation caused by infections aggravated the ischemic brain injury after middle cerebral artery occlusion (MCAO). Methods We used lipopolysaccharide (LPS) as systemic inflammatory stimuli to explore the mechanisms of aggravated ischemic brain injury after Sprague-Dawley male rats subjected to MCAO. Brain damage was evaluated by cerebral blood perfusion, Longa-5 scores, infarct volume and edema degree. Systemic cytokine responses and inflammatory changes in the plasma and brain were analyzed by ELISA kit, RT2 Profiler™ PCR array, and quantitative real-time PCR. The differential genes were subjected to Gene Ontology enrichment analysis and protein–protein interaction (PPI) network construction. Results Lipopolysaccharide profoundly aggravated the brain damage after 24 h post-MCAO. At the acute stage (ischemia/reperfusion 90 min/3 h), the brain homogenate gene expression of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and Interferon gamma-induced protein 10 (IP-10) was significantly up-regulated and the contents in plasma and brain homogenate were significantly increased in MCAO and MCAO + LPS group. IP-10 was the only gene with significant difference between MCAO and MCAO + LPS group, which was also in an important position with degrees of ≥ 14 in PPI network. Conclusions It was possible that trace LPS aggravated the ischemic brain injury by induction of excessive IP-10 secretion in the acute stage, leading to excessive inflammatory response, which consequently increased the infarct volume and edema degree 24 h post-MCAO.

BackgroundCognitive deficits are common in patients with bipolar disorder (BD). Abnormal high density lipoprotein (HDL) levels have been implicated in cognitive deficits associated with ageing and neurodegenerative disorders. The present study aimed to investigate serum HDL levels, cognitive deficits and their association in patients with BD.MethodsThirty-seven patients with BD and 37 gender- and age-matched healthy controls (HCs) were recruited in a case–control study. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum HDL levels were measured using enzymatic colourimetry.ResultsThere was no difference in serum HDL levels between patients with BD and HCs after adjusting for gender, age, education and body mass index (BMI). Cognitive test scores in patients with BD were significantly lower than those in HCs except for the visuospatial/constructional index after adjusting for confounding variables. Serum HDL levels were positively correlated with RBANS total score and language score in patients with BD. Stepwise multiple regression analysis showed that serum HDL levels were significantly correlated with RBANS total score and subscale scores on immediate memory and language in patients with BD after adjusting for confounding factors.ConclusionsOur findings suggest that patients with BD had poorer cognitive performance than HCs except for the visuospatial/constructional domain, and decreased serum HDL levels were correlated with cognitive deficits, especially in immediate memory and language domains in patients with BD.

Social functioning involves learning about the social networks in which we live and interact; knowing not just our friends, but also who is friends with our friends. Here we utilized a novel incidental learning paradigm and representational similarity analysis (RSA), a functional MRI multivariate pattern analysis technique, to examine the relationship between learning social networks and the brain's response to the faces within the networks. We found that accuracy of learning face pair relationships through observation is correlated with neural similarity patterns to those pairs in the left temporoparietal junction (TPJ), the left fusiform gyrus, and the subcallosal ventromedial prefrontal cortex (vmPFC), all areas previously implicated in social cognition. This model was also significant in portions of the cerebellum and thalamus. These results show that the similarity of neural patterns represent how accurately we understand the closeness of any two faces within a network, regardless of their true relationship. Our findings indicate that these areas of the brain not only process knowledge and understanding of others, but also support learning relations between individuals in groups.Significance StatementKnowledge of the relationships between people is an important skill that helps us interact in a highly social world. While much is known about how the human brain represents the identity, goals, and intentions of others, less is known about how we represent knowledge about social relationships between others. In this study, we used functional neuroimaging to demonstrate that patterns in human brain activity represent memory for recently learned social connections.

Background The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. Results Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. Conclusion Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

BackgroundNeurological complications may occur in patients with acute or chronic renal failure; however, in cases of acute renal failure, the signs and symptoms are usually more pronounced, and progressed rapidly. Oxidative stress and nitric oxide in the hippocampus, following kidney injury may be involved in cognitive impairment in patients with uremia. Although many women continue taking hormone therapy for menopausal symptom relief, but there are also some controversies about the efficacy of exogenous sex hormones, especially estrogen therapy alone, in postmenopausal women with kidney injury. Herein, to the best of our knowledge for the first time, spatial memory and synaptic plasticity at the CA1 synapse of a uremic ovariectomized rat model of menopause was characterized by estradiol replacement alone.ResultsWhile estradiol replacement in ovariectomized rats without uremia, promotes synaptic plasticity, it has an impairing effect on spatial memory through hippocampal oxidative stress under uremic conditions, with no change on synaptic plasticity. It seems that exogenous estradiol potentiated the deleterious effect of acute kidney injury (AKI) with increasing hippocampal oxidative stress.ConclusionsAlthough, estrogen may have some positive effects on cognitive function in healthy subjects, but its efficacy in menopause subjects under uremic states such as renal transplantation, needs to be further investigated in terms of dosage and duration.

Background Anxiety is associated with mood disorders including bipolar disorder. Two statistical modelling frameworks were compared to investigate the longitudinal relationship between repeatedly measured anxiety symptoms and the onset of depression and bipolar disorder in youth at confirmed familial risk. Methods Prospectively collected data on 156 offspring of a parent with confirmed bipolar disorder participating in the Canadian Flourish high-risk offspring longitudinal cohort study were used for this analysis. As part of the research protocol at approximately yearly visits, a research psychiatrist completed the HAM-A and a semi-structured diagnostic research interview following KSADS-PL format. Diagnoses using DSM-IV criteria were made on blind consensus review of all available clinical information. We investigated two statistical approaches, Cox model and Joint model, to evaluate the relationship between repeated HAM-A scores and the onset of major depressive or bipolar disorder. The Joint model estimates the trajectory of the longitudinal variable using a longitudinal sub-model and incorporates this estimated trajectory into a Cox sub-model. Results There was evidence of an increased hazard of major mood disorder for high-risk individuals with higher HAM-A scores under both modelling frameworks. After adjusting for other covariates, a one-unit increase in log-transformed HAM-A score was associated with a hazard ratio of 1.74 (95% CI (1.12, 2.72)) in the Cox model compared to 2.91(95% CI (1.29, 6.52)) in the Joint model. In an exploratory analysis there was no evidence that family clustering substantially affected the conclusions. Conclusions Estimated effects from the conventional Cox model, which is often the model of choice, were dramatically lower in this dataset, compared to the Joint model. While the Cox model is often considered the approach of choice for analysis, research has shown that the Joint model may be more efficient and less biased. Our analysis based on a Joint model suggests that the magnitude of association between anxiety and mood disorder in individuals at familial risk of developing bipolar disorder may be stronger than previously reported.

Background The Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In the present study we performed a systematic characterization of the spatio-temporal patterns of S- and M/L-opsin + cone outer segment and cell body degeneration in Rd1 mice, described the distribution and proportion of dual cones in Rd1 retinas, and examined the kinetics of microglial activation during the period of cone degeneration. Results Outer segments of S- and M/L-cones degenerated far more rapidly than their somas. Loss of both S- and M/L-opsin + outer segments was fundamentally complete by P21 in the central retina, and 90% complete by P45 in the peripheral retina. In comparison, degeneration of S- and M/L-opsin + cell bodies proceeded at a slower rate. There was a marked hemispheric asymmetry in the rate of S-opsin + and M/L-opsin + cell body degeneration. M/L-opsin + cones were more resilient to degeneration in the superior retina, whilst S-opsin + cones were relatively preserved in the inferior retina. In addition, cone outer segment and cell body degeneration occurred far more rapidly in the central than the peripheral retina. At P14, the superior retina comprised a minority of genuine S-cones with a much greater complement of genuine M/L-opsin cones and dual cones, whilst the other three retinal quadrants had broadly similar numbers of genuine S-cones, genuine M/L-cones and dual cones. At P60, approximately 50% of surviving cones in the superior, nasal and temporal quadrants were dual cones. In contrast, the inferior peripheral retina at P60 contained almost exclusively genuine S-cones with a tiny minority of dual cones. Microglial number and activity were stimulated during rod breakdown, remained relatively high during cone outer segment degeneration and loss of cone somas in the central retina, and decreased thereafter in the period coincident with slow degeneration of cone cell bodies in the peripheral retina. Conclusion The results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.

Publisher's version (útgefin grein), Background Electrical stimulation is widely used in experimental pain research but it lacks selectivity towards small nociceptive fibers. When using standard surface patch electrodes and rectangular pulses, large fibers are activated at a lower threshold than small fibers. Pin electrodes have been designed for overcoming this problem by providing a higher current density in the upper epidermis where the small nociceptive fibers mainly terminate. At perception threshold level, pin electrode stimuli are rather selectively activating small nerve fibers and are perceived as painful, but for high current intensity, which is usually needed to evoke sufficient pain levels, large fibers are likely co-activated. Long duration current has been shown to elevate the threshold of large fibers by the mechanism of accommodation. However, it remains unclear whether the mechanism of accommodation in large fibers can be utilized to activate small fibers even more selectively by combining pin electrode stimulation with a long duration pulse. Results In this study, perception thresholds were determined for a patch- and a pin electrode for different pulse shapes of long duration. The perception threshold ratio between the two different electrodes was calculated to estimate the ability of the pulse shapes to preferentially activate small fibers. The perception threshold ratios were compared between stimulation pulses of 5- and 50 ms durations and shapes of: exponential increase, linear increase, bounded exponential, and rectangular. Qualitative pain perception was evaluated for all pulse shapes delivered at 10 times perception threshold. The results showed a higher perception threshold ratio for long duration 50 ms pulses than for 5 ms pulses. The highest perception threshold ratio was found for the 50 ms, bounded exponential pulse shape. Results furthermore revealed different strength-duration relation between the bounded exponential- and rectangular pulse shapes. Pin electrode stimulation at high intensity was mainly described as "stabbing", "shooting", and "sharp". Conclusion These results indicate that long duration pulses with a bounded exponential increase preferentially activate the small nociceptive fibers with a pin electrode and concurrently cause elevated threshold of large non-nociceptive fibers with patch electrodes., Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121)., "Peer Reviewed"

Bipolar disorder is highly heritable and typically onsets in late adolescence or early adulthood. Evidence suggests that immune activation may be a mediating pathway between genetic predisposition and onset of mood disorders. Building on a prior study of mRNA and protein levels in high-risk offspring published in this Journal, we conducted a preliminary examination of methylation profiles in candidate immune genes from a subsample of well-characterized emergent adult (mean 20 years) offspring of bipolar parents from the Canadian Flourish high-risk cohort. Models were adjusted for variable age at DNA collection, sex and antidepressant and mood stabilizer use. On cross-sectional analysis, there was evidence of higher methylation rates for BDNF-1 in high-risk offspring affected (n = 27) and unaffected (n = 23) for mood disorder compared to controls (n = 24) and higher methylation rates in affected high-risk offspring for NR3C1 compared to controls. Longitudinal analyses (25 to 34 months) provided evidence of steeper decline in methylation rates in controls (n = 24) for NR3C1 compared to affected (n = 15) and unaffected (n = 11) high-risk offspring and for BDNF-2 compared to affected high-risk. There was insufficient evidence that changes in any of the candidate gene methylation rates were associated with illness recurrence in high-risk offspring. While preliminary, findings suggest that longitudinal investigation of epigenetic markers in well-characterized high-risk individuals over the peak period of risk may be informative to understand the emergence of bipolar disorder. Electronic supplementary material The online version of this article (10.1186/s40345-019-0152-1) contains supplementary material, which is available to authorized users.

Background Traumatic brain injury (TBI) is a widespread public health problem and a signature injury of our military in modern conflicts. Despite the long-term effects of even mild brain injuries, an effective treatment remains elusive. Coffee and several of its compounds, including caffeine, have been identified as having neuroprotective effects in studies of neurodegenerative disease. Given the molecular similarities between TBI and neurodegenerative disease, we have devised a study to test a nanocoffee extract in the treatment of a mouse model of mild TBI. Results After a single injury and two subsequent injections of nanocoffee, we identified treatment as being associated with improved behavioral outcomes, favorable molecular signaling changes, and dendritic changes suggestive of improved neuronal health. Conclusions We have identified coffee extracts as a potential viable multifaceted treatment approach to target the secondary injury associated with TBI.

Background Cardiovascular conditions contribute to brain volume loss, reduced cerebrovascular health, and increased dementia risk in aging adults. Altered hippocampal connectivity has also been observed in individuals with cardiovascular conditions, yet the functional consequences of these changes remain unclear. In the present study, we collected functional magnetic resonance imaging data during memory encoding and used a psychophysiological interaction analysis to examine whether cardiovascular burden, indexed using the Framingham risk score, was associated with encoding-related hippocampal connectivity and task performance in cognitively-intact older adults between 65 and 85 years of age. Our goal was to better understand the early functional consequences of vascular and metabolic dysfunction in those at risk for cognitive decline. Results High Framingham risk scores were associated with lower total brain volumes. In addition, those with high Framingham risk scores showed an altered relationship between left hippocampal-medial prefrontal coupling and task performance compared to those with low Framingham risk scores. Specifically, we found a significant interaction of Framingham risk and learning on connectivity between the left hippocampus and primarily left midline prefrontal regions comprising the left ventral anterior cingulate cortex and medial prefrontal cortex. Those with lower Framingham risk scores showed a pattern of weaker connectivity between left hippocampal and medial prefrontal regions associated with better task performance. Those with higher Framingham risk scores showed the opposite pattern; stronger connectivity was associated with better performance. Conclusions Findings from the current study show that amongst older adults with cardiovascular conditions, higher Framingham risk is associated with lower brain volume and altered left hippocampal-medial prefrontal coupling during task performance compared to those with lower Framingham risk scores. This may reflect a compensatory mechanism in support of memory function and suggests that older adults with elevated cardiovascular risk are vulnerable to early Alzheimer disease-like dysfunction within the episodic memory system.

Background Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3–6 months to induce chronic obesity. Results The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. Conclusions Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption. Electronic supplementary material The online version of this article (10.1186/s12868-019-0516-6) contains supplementary material, which is available to authorized users.

Background Animal responses to thermal stimuli involve intricate contributions of genetics, neurobiology and physiology, with temperature variation providing a pervasive environmental factor for natural selection. Thermal behavior thus exemplifies a dynamic trait that requires non-trivial phenotypic summaries to appropriately capture the trait in response to a changing environment. To characterize the deterministic and plastic components of thermal responses, we developed a novel micro-droplet assay of nematode behavior that permits information-dense summaries of dynamic behavioral phenotypes as reaction norms in response to increasing temperature (thermal tolerance curves, TTC). Results We found that C. elegans TTCs shift predictably with rearing conditions and developmental stage, with significant differences between distinct wildtype genetic backgrounds. Moreover, after screening TTCs for 58 C. elegans genetic mutant strains, we determined that genes affecting thermosensation, including cmk-1 and tax-4, potentially play important roles in the behavioral control of locomotion at high temperature, implicating neural decision-making in TTC shape rather than just generalized physiological limits. However, expression of the transient receptor potential ion channel TRPA-1 in the nervous system is not sufficient to rescue rearing-dependent plasticity in TTCs conferred by normal expression of this gene, indicating instead a role for intestinal signaling involving TRPA-1 in the adaptive plasticity of thermal performance. Conclusions These results implicate nervous system and non-nervous system contributions to behavior, in addition to basic cellular physiology, as key mediators of evolutionary responses to selection from temperature variation in nature. Electronic supplementary material The online version of this article (10.1186/s12868-019-0510-z) contains supplementary material, which is available to authorized users.

Background Recently, the use of traditional Chinese medicine (TCM) has become more generally accepted, including by the Food and Drug Administration. To expand the use of TCM worldwide, it is important to study the molecular mechanisms by which TCM and its active ingredients produce effects. Gastrodin is an active ingredient from Gastrodia elata Blume. It is reported that gastrodin has neuroprotective function in Parkinson’s disease. But its mechanisms of neuroprotection remain not clear in PD. Here, we build two C. elegans PD model using 6-OHDA and transgenic animal to observe the changes of PD worms treated with or without gastrodin to confirm the function of gastrodin, then utilize mutant worms to investigate DAF-2/DAF-16 signaling pathway, and finally verify the mechanism of gastrodin in PD. Results Gastrodin attenuates the accumulation of α-synuclein and the injury of dopaminergic neurons, improves chemotaxis behavior in Parkinson’s disease models, then recovers chemotaxis behavior by insulin-like pathway. DAF-2/DAF-16 is required for neuroprotective effect of dopamine neuron in PD. Conclusions Our study demonstrated that gastrodin rescued dopaminergic neurons and reduced accumulation of α-synuclein protein, and the activity of gastrodin against Parkinson’s disease depended on the insulin-like DAF-2/DAF-16 signaling pathway. Our findings revealed that this insulin-like pathway mediates neuroprotection of gastrodin in a Parkinson’s disease model. Electronic supplementary material The online version of this article (10.1186/s12868-019-0512-x) contains supplementary material, which is available to authorized users.

Aedes aegypti have a wide variety of sensory pathways that have supported success as a species as well as a highly competent vector of numerous debilitating infectious pathogens. Investigations into mosquito sensory systems and their effects on behavior are valuable resources for the advancement of mosquito control strategies. Numerous studies have elucidated key aspects of mosquito sensory systems, however there remains critical gaps within the field. In particular, compared to that of the adult form, there has been a lack of studies directed towards the immature life stages. Additionally, although numerous studies have pinpointed specific sensory receptors as well as relevant response behaviors, there has been a lack of studies able to monitor both concurrently. To begin filling aforementioned gaps, here we engineered Ae. aegypti to ubiquitously express a genetically encoded calcium indicator, GCaMP6s. Using this strain, combined with advanced confocal microscopy, we were able to simultaneously measure live stimulus-evoked calcium responses in both neuronal and muscle cells with a wide spatial range and resolution. Moreover, by coupling in vivo calcium imaging with behavioral assays we were able to gain functional insights into how stimulus-evoked neural and muscle activities are represented, modulated, and transformed in mosquito larvae enabling us to elucidate mosquito sensorimotor properties important for life-history-specific foraging strategies.Significance StatementUnderstanding mosquito sensory systems and resulting behavior has been a major factor in the advancement of mosquito control innovations. Aedes aegypti larvae offer an effective life stage for further elucidating information on mosquito sensory systems. Due to their relatively simplified nervous system, mosquito larvae are ideal for studying neural signal transduction, coding, and behavior. Moreover, a better understanding of the larval sensory system may enable the development of novel control methodologies able to target mosquitoes before they reach a vector-competent stage. Here we engineer Ae. aegypti to ubiquitously express a genetically encoded calcium indicator, GCaMP6s and use this tool to observe links between sensorimotor responses and behavior by exploiting live calcium imaging as well as live tracking based behavioral assays.

Background Neuropathic pain (NP) is a prevalent disease, which badly impairs the life quality of patients. The underlying mechanism of NP is still not fully understood. It has been reported that spinal Annexin A10 (ANXA10) contributes to NP. This study aims at exploring the underlying mechanisms of spinal ANXA10 in regulating NP in rats. Methods Spinal nerve ligation (SNL) was adopted to establish a NP model in rats. After SNL, paw withdrawal threshold and paw withdrawal latency were recorded to measure pain behaviors, RT-PCR was used to check the change of the expression of spinal ANXA10 mRNA, western blot analysis was used to detect the change of the protein level of ANXA10, nuclear factor kappa B (NF-κB), and maisrix metalloproteinase-9 (MMP-9) in the spinal cord. The levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukine-1β (IL-1β), and interleukine-6 (IL-6), were explored by ELISA kits. The effects of both knockdown of spinal ANXA10 and inhibition of NF-κB on pain behaviors and the expression of MMP-9 and proinflammatory cytokines were investigated. Results Our present findings highlighted that SNL caused pain hypersensitivity and increased the expression of spinal ANXA10/pNF-κB, TNF-α, IL-1β, and IL-6 both in the early and late phase of NP in rats, while spinal MMP-9 was only slightly increased in the early phase of NP. Knockdown of ANXA10 at the spinal cord level suppressed the SNL-induced hyperalgesia and blocked the activation of NF-κB, TNF-α and IL-1β both in the early and late phase of NP. Spinal ANXA10 knockdown could prevent the upregulation of spinal MMP-9 in the early phase and inhibit IL-6 expression in the late phase of SNL-induced NP. Conclusions In conclusion, spinal ANXA10/NF-κB/MMP-9 pathway, along with the activation of proinflammatory cytokines, was involved in the SNL-induced NP. MMP-9 may act as the downstream target of ANXA10/NF-κB pathway in the development rather than the maintenance of NP.

Sixty undergraduate students made category membership decisions for each of 132 candidate exemplar-category name pairs (e.g., chess - Sports) in each of two separate sessions. They were frequently inconsistent from one session to the next, both for nominal categories such as Sports and Fish, and ad hoc categories such as Things You Rescue from a Burning House. A mixture model analysis revealed that several of these inconsistencies could be attributed to criterial vagueness: participants adopting different criteria for membership in the two sessions. This finding indicates that categorization is a probabilistic process, whereby the conditions for applying a category label are not invariant. Individuals have various functional meanings of nominal categories at their disposal and entertain competing goals for ad hoc categories. ispartof: Open Mind (Camb) vol:3 pages:41-51 ispartof: location:United States status: published

Background Reports show that stressful events before injury exacerbates post-injury pain. The mechanism underlying stress-induced heightened thermal pain is unclear. Here, we examined the effects of chronic intermittent stress (CIS) on nociceptive behaviors and brain-derived nerve growth factor (BDNF) system in the prefrontal cortex (PFC) and hypothalamus of rats with and without thermal injury. Results Unstressed rats showed transient mechanical allodynia during stress exposure. Stressed rats with thermal injury displayed persistent exacerbated mechanical allodynia (P

Background The electroencephalogram (EEG) is a widely used laboratory technique in rodent models of epilepsy, traumatic brain injury (TBI), and other neurological diseases accompanied by seizures. Obtaining prolonged continuous EEG tracings over weeks to months is essential to adequately answer research questions related to the chronobiology of seizure emergence, and to the effect of potential novel treatment strategies. Current EEG recording methods include wired and the more recent but very costly wireless technologies. Wired continuous long-term EEG in rodents remains the mainstay approach but is often technically challenging due to the notorious frequent EEG cable disconnections from the rodent’s head, and to poor signal-to-noise ratio especially when simultaneously monitoring multiple animals. Premature EEG cable disconnections and cable movement-related artifacts result from the animal’s natural mobility, and subsequent tension on the EEG wires, as well as from potential vigorous and frequent seizures. These challenges are often accompanied by injuries to the scalp, and result in early terminations of costly experiments. Results Here we describe an enhanced customized swivel-balance EEG-cage system that allows tension-free rat mobility. The cage setup markedly improves the safety and longevity of current existing wired continuous long-term EEG. Prevention of EEG cable detachments is further enhanced by a special attention to surgical electrode anchoring to the skull. In addition to mechanically preventing premature disconnections, the detailed stepwise approach to the electrical shielding, wiring and grounding required for artifact-free high signal-to-noise ratio recordings is also included. The successful application of our EEG cage system in various rat models of brain insults and epilepsy is described with illustrative high quality tracings of seizures and electrographic patterns obtained during continuous and simultaneous monitoring of multiple rats early and up to 3 months post-brain insult. Conclusion Our simple-to-implement key modifications to the EEG cage setup allow the safe acquisition of substantial high quality wired EEG data without resorting to the still costly wireless technologies. Electronic supplementary material The online version of this article (10.1186/s12868-019-0490-z) contains supplementary material, which is available to authorized users.

The insula is important for the processing of pleasant aspects of touch whereas its role in the processing of emotionally neutral touch has been less explored. Here, we used a network approach to investigate the insular processing of pleasant stroking touch and emotionally neutral vibratory touch, analysing functional magnetic resonance imaging data from 23 healthy adult participants. Vibration and skin stroking activated areas in the posterior, middle and anterior insula. Psychophysiological interaction analyses suggested that skin stroking increased functional connectivity between the posterior and ventral anterior insula. Vibration instead increased functional connectivity between the posterior and dorsal anterior insula, and induced a stronger decrease of the default mode network activity compared to stroking. These results confirmed findings from previous studies showing that the posterior insula processes affective touch information. We suggest that this is accomplished by relaying tactile information from the posterior insula to ventral anterior insula, an area tightly connected to the emotional parts of the brain. However, our results also suggested that the insula processes tactile information with less emotional valence. A central hub in this processing seemed to be the right dorsal anterior insula. Keywords: Touch, fMRI, Insula, Resting state networks

Background Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War and has no known cause. Everyday symptoms include pain, fatigue, migraines, and dyscognition. A striking syndromic feature is post-exertional malaise (PEM). This is recognized as an exacerbation of everyday symptoms following a physically stressful or cognitively demanding activity. The underlying mechanism of PEM is unknown. We previously reported a novel paradigm that possibly captured evidence of PEM by utilizing fMRI scans taken before and after sub-maximal exercises. We hypothesized that A) exercise would be a sufficient physically stressful activity to induce PEM and B) Comparison of brain activity before and after exercise would provide evidence of PEM’s effect on cognition. We reported two-exercise induced GWI phenotypes with distinct changes in brain activation patterns during the completion of a 2-back working memory task (also known as two-back > zero-back). Results Here we report unanticipated findings from the reverse contrast (zero-back > two-back), which allowed for the identification of task-related deactivation patterns. Following exercise, patients developed a significant increase in deactivation patterns within the Default Mode Network (DMN) that was not seen in controls. The DMN is comprised of regions that are consistently down regulated during external goal-directed activities and is often altered within many neurological disease states. Conclusions Exercise-induced alterations within the DMN provides novel evidence of GWI pathophysiology. More broadly, results suggest that task-related deactivation patterns may have biomarker potential in Gulf War Illness. Electronic supplementary material The online version of this article (10.1186/s12868-019-0488-6) contains supplementary material, which is available to authorized users.

Highlights • Depressed mothers engage in less touching that is playful and interactive in nature. • Depressed mothers touch their infants less during face-to-face interactions. • Nondepressed mothers maintain high levels of touch following a perturbation period. • Depressed mothers decrease playful/stimulating touch after a perturbation period. • Implications for intervention programs of early touch stimulation for at-risk dyads., Touch is a critical channel of communication used by mothers to communicate and interact with their infants and to contribute to their infants’ socio-emotional development. The present study examined maternal touching in 41 mothers with and without depressive symptomatology. Mothers and their 4-month-old infants participated in the Still-Face (maternal emotional unavailability) and Separation (maternal physical unavailability) procedures. Maternal touching behaviours were video-recorded and coded using the Caregiver Infant Touch Scale (CITS). Results indicated that mothers with higher levels of depressive symptoms engaged in less touching following the perturbation period in the Still-Face procedure, whereas mothers with lower levels of depressive symptoms maintained stable levels of touching across both interaction periods. Mothers with higher levels of depressive symptoms displayed less playful/stimulating types of touching. Taken together, these results underscore the importance of touch and suggest key differences in touching behaviour between dyads with maternal depressive symptomatology and those without.

Increasing evidence shows that maternal touch may promote emotion regulation in infants, however less is known about how parental higher-order social cognition abilities are translated into tactile, affect-regulatory behaviours towards their infants. During 10 min book-reading, mother-infant sessions when infants were 12 months old (N = 45), we investigated maternal mind-mindedness (MM), the social cognitive ability to understand an infant’s mental state, by coding the contingency of maternal verbal statements towards the infants’ needs and desires. We also rated spontaneous tactile interactions in terms of their emotional contingency. We found that frequent non-attuned mind-related comments were associated with touch behaviours that were not contingent with the infant’s emotions; ultimately discouraging affective tactile responses from the infant. However, comments that were more appropriate to infant’s mental states did not necessarily predict more emotionally-contingent tactile behaviours. These findings suggest that when parental high-order social cognitive abilities are compromised, they are also likely to translate into inappropriate, tactile attempts to regulate infant’s emotions. Keywords: Mind-mindedness, Mother-infant interaction, Maternal touch, Infant touch, Contingency

The neural mechanisms facilitating the experience of vicarious social touch are largely unknown. The right inferior frontal gyrus (rIFG) has been suggested as part of a simulation observation-execution neural network that plays a key role in the perception of tactile stimuli. Considering that vicarious social touch involves vicarious sharing of emotions, we hypothesized that emotional empathy, i.e., the ability to feel what another individual is feeling, modulates the neural responses to vicarious touch. To examine the role of the rIFG in vicarious touch and its modulation by levels of emotional empathy, we used anodal transcranial direct current stimulation (tDCS) on forty participants who observed photos depicting social touch, nonsocial touch or no touch during tDCS or sham stimulation. The results show that while participants with high levels of emotional empathy exhibited no change in ratings of vicarious social touch, participants with low levels of emotional empathy rate human touch as more emotional following anodal stimulation of the rIFG than following sham stimulation. These findings indicate that emotional responses to vicarious social touch are associated with rIFG activity and are modulated by levels of emotional empathy. This result has major therapeutic potential for individuals with low empathic abilities, such as those with ASD. Keywords: Social touch, tDCS, Inferior frontal gyrus, Empathy, Interpersonal touch, Empathic concern

Touch provides more than sensory input for discrimination of what is on the skin. From early in development it has a rewarding and motivational value, which may reflect an evolutionary mechanism that promotes learning and affiliative bonding. In the present study we investigated whether affective touch helps infants tune to social signals, such as faces. Four-month-old infants were habituated to an individual face with averted gaze, which typically does not engage infants to the same extent as direct gaze does. As in a previous study, in the absence of touch, infants did not learn the identity of this face. Critically, 4-month-old infants did learn to discriminate this face when parents provided gentle stroking, but they did not when they experienced a non-social tactile stimulation. A preliminary follow-up eye-tracking study (Supplementary material) revealed no significant difference in the visual scanning of faces between touch and no-touch conditions, suggesting that affective touch may not affect the distribution of visual attention, but that it may promote more efficient learning of facial information. Keywords: Affective touch, Face processing, Infancy, Habituation

Highlights • The sense of touch enables parent-child communication from birth onward. • We theorized that parental touch would reduce children’s social vigilance. • Parental touch reduced children’s attention to social threat. • Parental touch increased trust, specifically among socially anxious children. • These effects occurred before (not after) the transition to adolescence., The sense of touch develops in utero and enables parent-child communication from the earliest moments of life. Research shows that parental touch (e.g., licking and grooming in rats, skin-to-skin care in humans) has organizing effects on the offspring’s stress system. Little is known, however, about the psychological effects of parental touch. Building on findings from ethology and psychology, we propose that parental touch—even as subtle as a touch on the shoulder—tells children that their environment is safe for exploration, thus reducing their social vigilance. We tested this hypothesis in late childhood (ages 8–10) and early adolescence (ages 11–14) in 138 parent-child dyads. Parents were randomly assigned to touch or not touch their child briefly and gently on the shoulder, right below the deltoid. Parental touch lowered children’s implicit attention to social threat. While parental touch lowered trust among socially non-anxious children, it raised trust among those who needed it the most: socially anxious children. The effects were observed only in late childhood, suggesting that parental touch loses its safety-signaling meaning upon the transition to adolescence. Our findings underscore the power of parental touch in childhood, especially for children who suffer from social anxiety.

Highlights • The infant brain is sensitive to gentle skin stroking within the first weeks of age. • The postcentral gyrus and posterior insular cortex are responsive to stroking. • Social touch activates both somatosensory and socio-affective brain areas in infancy., Physical expressions of affection play a foundational role in early brain development, but the neural correlates of affective touch processing in infancy remain unclear. We examined brain responses to gentle skin stroking, a type of tactile stimulus associated with affectionate touch, in young infants. Thirteen term-born infants aged 11–36 days, recruited through the FinnBrain Birth Cohort Study, were included in the study. Soft brush strokes, which activate brain regions linked to somatosensory as well as socio-affective processing in children and adults, were applied to the skin of the right leg during functional magnetic resonance imaging. We examined infant brain responses in two regions-of-interest (ROIs) known to process gentle skin stroking – the postcentral gyrus and posterior insular cortex – and found significant responses in both ROIs. These results suggest that the neonate brain is responsive to gentle skin stroking within the first weeks of age, and that regions linked to primary somatosensory as well as socio-affective processing are activated. Our findings support the notion that social touch may play an important role in early life sensory processing. Future research will elucidate the significance of these findings for human brain development.

Touch, such as a caress, can be interpreted as very pleasant. The emotional valence assigned to touch is likely related to certain bottom-up factors, such as optimal activation of C-tactile (CT) afferents. It is however unclear if besides somatosensory input, contextual factors related to the own body also play a role in the perceived pleasantness of touch. To test this, we manipulated visual appearance of the participant’s arm (veridical vision, no vision, pixelated moving statistic projected onto the arm (i.e. crawling skin)). We used slow velocity stroking (CT optimal stroking) with a soft brush to induce pleasant touch, and fast velocity stroking as a control condition. After each visual condition we asked participants (N = 23) to rate the emotional valence of the stroking they felt. After slow velocity stroking ratings on perceived pleasantness (but not on perceived unpleasantness) were modulated by visual condition, with veridical vision of the arm resulting in higher pleasantness ratings than both no vision and pixelated vision. We conclude that contextual processes affect the perceived pleasantness of touch. These findings shed a new light on the underlying mechanisms of how humans experience pleasant touch and show that pleasant touch not solely dependents on bottom up information. Keywords: Affective touch, Social touch, Interpersonal touch, CT afferents, Tactile perception

Background To prevent and control dementia, many scholars have focused on the transition stage between normal ageing and dementia, mild cognitive impairment (MCI) which is a key interventional target for dementia. Studies have shown that non-invasive brain stimulation (NIBS) is beneficial to improve cognitive function of MCI patients. However, whether NIBS is conducive to the protection of cognitive ability in MCI patients remains unknown due to limited evidence. The aim of the study was to systematically evaluate the modulation effect of NIBS on cognitive function (global cognitive ability and specific domains of cognition) in patients with MCI. Results A total of 11 RCTs comprising a total of 367 MCI participants. Meta-analysis showed that NIBS can significantly improve global cognition (n = 271, SMD = 0.94, 95% CI 0.47–1.41, p

Background Transcranial ultrasonic stimulation is a novel noninvasive tool for neuromodulation, and has high spatial resolution and deep penetration. Although it can increase excitation of neurons, its effects on neuron are poorly understood. This study was to evaluate effect of ultrasonic stimulation (US) on neurons in vitro. In this paper, the effect of US on the excitability and voltage-dependent \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ K^{ + } $$\end{document}K+ currents of CA1 pyramidal neurons in the rat hippocampus was studied using patch clamp. Results Our results suggest that US increased the spontaneous firing rate and inhibited transient outward potassium current (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{A}} $$\end{document}IA) and delayed rectifier potassium current (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{K}} ) $$\end{document}IK). Furthermore, US altered the activation of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{K}} $$\end{document}IK channels, inactivation and recovery properties of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{A}} $$\end{document}IA channels. After US, the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{K}} $$\end{document}IK activation curves significantly moved to the negative voltage direction and increased its slope factor. Moreover, the data showed that US moved the inactivation curve of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{A}} $$\end{document}IA to the negative voltage and increased the slope factor. Besides, US delayed the recovery of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{A}} $$\end{document}IA channel. Conclusions Our data indicate that US can increase excitation of neurons by inhibiting potassium currents. Different US decreased the voltage sensitivity of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{K}} $$\end{document}IK activation differentially. Moreover, the more time is needed for US to make the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \varvec{I}_{\varvec{A}} $$\end{document}IA channels open again after inactivating. US may play a physiological role by inhibiting voltage-dependent potassium currents in neuromodulation. Our research can provide a theoretical basis for the future clinical application of ultrasound in neuromodulation.