Neuronal Systems Research Articles

The evolving role of intraneuronal amyloid‐β in Alzheimer’s disease

AbstractBackgroundIn 1998 at the Alzheimer’s Association conference in Amsterdam, I first presented on the accumulation of Alzheimer’s disease (AD)‐linked amyloid‐β42 (Aβ42) in cultured neurons and human brains with early AD pathology (later published in Gouras GK et al., 2000). Despite much skepticism, this early work led to a revision of the role of Aβ in AD that for the past 2.5 decades has been at the center of our group’s attempt to better define the earliest cellular stages of AD. Our current scenario, including with new data, will be presented for the role of intraneuronal Aβ in the early endosomal and synaptic alterations that initiate the disease process.MethodAD transgenic (overexpression and knock‐in) mouse models at different ages and postmortem human brains are analyzed using amongst others, microscopy and biochemical approaches for APP metabolites, and other AD‐linked, endosome and synapse proteins, with a focus on the earliest detectable alterations within AD vulnerable neurons. Brain injections of prion‐like Aβ and tract tracing methods are used to model early anatomical and cellular progression of pathology. Further, primary brain cultures from AD mice are used to model early AD cellular alterations.ResultPrior to classical amyloid plaques, smaller accumulations of Aβ develop within the endosome‐lysosome system of AD vulnerable neurons, with preferential aggregation near axonal and dendritic synaptic terminals with AD pathogenesis. Ongoing work is centered on elucidating the early alterations of different pools of APP metabolites, ApoE and Tau in the early biological pathways that impact synapses.ConclusionOur understanding of the early cellular dysfunction and pathology has evolved significantly over the past few decades, with a better appreciation for the importance of other cell types (e.g. astrocytes, microglia) and factors in AD, and recent, albeit modest, success in therapy targeting Aβ. We see aging, along with genes and lifestyle, as promoting the earliest Aβ‐related dysfunction in endosomal biology at synapses and are working to piece together the links between key AD‐related proteins in the disease process.

Using an integrated multi‐omics approach to predict dementia: Explainable variational autoencoder (E‐VAE) classifier model

AbstractBackgroundAlzheimer’s disease (AD) and AD related dementias (ADRD) are complex multifactorial neurodegenerative diseases. Application of deep learning methods to analyze large scale whole genome‐wide SNP data and transcriptomic data may be a powerful approach to utilize early molecular changes for early detection of ADRD and elucidate the biological mechanisms in AD/ADRD.MethodWe harmonized the definition of dementia in the Health and Retirement Study (HRS) and an external study Religious Orders Study/Memory and Aging Project (ROSMAP) using a diagnostic algorithm previously validated in the HRS based on cognitive tests. The cognitive tests included immediate and delayed word recall, and backward counting that measure working memory and episodic memory. We developed an explainable variational autoencoder (E‐VAE) classifier model using genetic variants (genome‐wide SNP data, 5474 SNPs) and RNAseq data (592 differentially expresses genes in ADRD) from 204 study participants (102 participants with dementia and 102 controls) in the HRS to predict dementia. We validated the prediction performance in a test set of the HRS participants (26 participants with dementia and 26 controls), and further assessed the generalizability of the multi‐omics‐based VAE classifier model in the ROSMAP data (12 participants with dementia and 222 controls).ResultOur results showed a predictive accuracy of 0.73 (95% CI [0.61, 0.85]) with an AUC of 0.80 in the HRS validation data and an accuracy of 0.58 (95% CI [0.51, 0.64]) with an AUC of 0.66 in the ROSMAP study data. The E‐VAE model outperformed a penalized logistic regression model (Figure in supplementary file). We identified genes that involved in the apoptotic process, neuron and nervous system development were highly weighted in the multi‐omics‐based VAE model and found that genes in ‘Butyrophilin interactions pathway’ were over represented in ADRD (FDR adjusted p <0.05).ConclusionThis is the first study showing the generalizability of a deep learning prediction model for dementia in an independent dataset using an integrated multi‐omics approach. The more precise and definitive latent variables identified using E‐VAE can help us understand the complex biology in ADRD and characterize the disease status.

The T-type calcium channelosome.

T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.

Examining memory linking and generalization using scFLARE2, a temporally precise neuronal activity tagging system

How memories are organized in the brain influences whether they are remembered discretely versus linked with other experiences or whether generalized information is applied to entirely novel situations. Here, we used scFLARE2 (single-chain fast light- and activity-regulated expression 2), a temporally precise tagging system, to manipulate mouse lateral amygdala neurons active during one of two 3 min threat experiences occurring close (3 h) or further apart (27 h) in time. Silencing scFLARE2-tagged neurons showed that two threat experiences occurring at distal times are dis-allocated to orthogonal engram ensembles and remembered discretely, whereas the same two threat experiences occurring in close temporal proximity are linked via co-allocation to overlapping engram ensembles. Moreover, we found that co-allocation mediates memory generalization applied to a completely novel stimulus. These results indicate that endogenous temporal evolution of engram ensemble neuronal excitability determines how memories are organized and remembered and that this would not be possible using conventional immediate-early gene-based tagging methods.

Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure

Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer’s disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.

Spatiotemporal Assessment of Locus Coeruleus Integrity Predicting Cortical Tau and Cognition

AbstractBackgroundMisfolded tau protein, an Alzheimer’s Disease (AD) hallmark, accumulates decades before the emergence of cognitive decline. Autopsy and neuroimaging studies support the locus coeruleus (LC) as an early site of tau and its contribution to disease progression. However, whether tau in LC precedes cortical tau deposition remains unclear. Understanding the topography of tau progression and the biological factors making specific neuronal systems prone to AD‐related pathology is essential to target interventions appropriately. We examined the spatiotemporal relationships between LC integrity and cortical tau accumulation and its relevance to cognition.,MethodsWe combined longitudinal LC‐integrity (T1‐TSE‐imaging) and tau pathology (18F‐FTP‐PET) data from 77 adults (Fig1A). We used whole‐brain voxel‐wise GLM analysis to investigate the relationship between baseline LC‐integrity (inverted signal) and longitudinal tau accumulation and compared the correlation distributions in both directions. Robust regression analysis was used to examine whether the observed tau spreading pathway predicts PACC5 performance at follow‐up. We used neuropathological measures from 160 cognitively unimpaired or MCI/AD adults (Fig1B) to support the in‐vivo neuroimaging data. Spearman‐rank partial correlations were used to relate LC tangle density to tangles in temporal cortex areas. Using AHBA, the biological backgrounds underlying the connectomic‐genetic relationships related to LC were explored using a whole‐brain region‐wise transcriptomic similarity analysis.,ResultsCorrelations between baseline LC‐integrity and follow‐up tau were stronger than the inverse correlations, indicative of lower LC‐integrity preceding tau accumulation in MTL (Fig1C‐D). LC tangle density was strongly related to tangles in MTL structures (Fig1E). Longitudinal tau accumulation in the LC‐MTL axis is associated with lower cognitive performance (Fig2). Common neurogenetic profiles exist between LC and MTL/limbic regions, supporting a shared connectomic‐transcriptomic substrate. The genetic profile displays specific biological functions in protein transport regulation and lipid biosynthetic processes (Fig3).,ConclusionOur results suggest that changes in LC‐integrity may occur before tau spreads into the MTL, which jointly contributes to lower cognitive performance. The neurogenetic profiles can provide a biological framework for identifying individuals more likely to be at risk for AD disease progression. Future developments could examine the intersection between amyloid and LC‐related tau progression in the context of AD.

Therapeutic impact of music in young deaf patients with aggressive behavior disorder

In France metropolitan, 5 182 000 people have hearing loss (8.7% of the population), of which 4.1% are under 20 years of age. In children, hearing impairment is sought in the presence of depression, hyperactivity, impulsivity, instability accompanied by intense anger, and aggressive behavior. So far, the impact of dance and music on deaf people has been little studied. In this context, we recently initiated a project in mediated therapeutic workshops; Devoted to hearing-impaired adolescents or young adults with behavioral problems. The main objective of this project is to foster the adaptability of these young people with severe behavior problems. Protocol: 4 volunteers with moderate to profound deafness were included in this prospective study (2 F and 2 M, aged 19.5 ± 5.0 years). These patients exhibited daily behavioral disorders with stereotypies and aggressiveness with moderate to severe intensity according to the Behavior Problems Inventory (BPI-01). These young people attended weekly sessions lasting more than 12 months at the Music / Percussion Workshop in the presence of an instructor and nurse therapist. Outcome and Discussion: No voluntary withdrawal of the project was recorded. A very strong behavioral improvement was noted in 3/4 of the cases and a slight improvement in 1/4 of the cases. This study has shown that hearing loss is compensated by various adaptive processes, in particular by multi sensorial interactivity (such as the interactivity between touch and vision) and through mirror neuronal system. Conclusion: This study showed hearing impaired people are sensitive and receptive to the sound world and to rhythmic movement. This finding has been put to the benefit of rehabilitation through Music and Dance Therapies which has improved the behavioral disorder and blossoming of the group rehabilitation through Music and Dance Therapies of young people suffering from medium to profound deafness with severe behavior problems.

The physiological basis of leader-follower roles in the dyadic alternating tapping task

IntroductionCooperative and collaborative behaviors are important concepts for co-creative communication. One of the key elements for these behaviors is the leader-follower roles in human communication. Leaders are those who maintain their own pace and rhythm, on the contrary, followers are those who follow the pace and rhythm of the other. Well-coordinated leader-follower roles would produce better cooperative and collaborative behaviors, which could promote co-creative communication.MethodsHere, to explore the physiological basis for the leader-follower roles, we conducted the dyadic alternating tapping task with electrocardiographic and electroencephalographic recordings. The task would be stable for modeling human communication in the laboratory because it includes timing control in tens of milliseconds and turn-taking. Given that human communications are complex and constantly fluctuating, this study estimated the degree of leader-follower with the state-space model. This model allowed us to calculate two parameters independently for estimating the degree of leader-follower of each participant: αSelf (degree of one’s tap(n) was explained by one’s tap(n-1)) and αPair (degree of one’s tap(n) was explained by one’s tap (n-1) and pair’s tap (n-1)).ResultsThe result showed heart rate synchronization in the group in which both participants had high αPair. Also, the high-frequency component of heart rate variability was positively correlated with αPair. EEG analyses suggested the deactivation of the mirror neuron system (increasing φ1) in the participants with higher αSelf than lower ones. The activation of the mirror neuron system (increasing φ2) was shown in the participants with lower αPair than higher ones.DiscussionThese data of physiological basis for leader-follower roles could be useful for the constructivist approach to co-creative communication.

The Influence of Nucleoside Reverse Transcriptase Inhibitors on Mitochondrial Activity, Lipid Content, and Fatty-Acid-Binding Protein Levels in Microglial HMC3 Cells.

Despite the availability of a wide range of preventive measures and comprehensive treatment options following infection, the development of acquired immunodeficiency syndrome (AIDS) remains a persistent challenge. Nucleoside reverse transcriptase inhibitors (NRTIs) represent the most commonly utilized therapeutic approach, despite being on the pharmaceutical market for nearly four decades. During this time, a spectrum of side effects ranging from mild discomfort and hypersensitivity reactions to the more prevalent nephrotoxicity and hepatotoxicity has been documented. In light of these considerations, our study aimed to investigate the impacts of two NRTIs, lamivudine and zidovudine, on lipid metabolism in HMC3 microglial cells. Our findings revealed statistically significant reductions in the ATP levels (nearly 8%) and increased mitochondrial superoxide levels (around 10%) after 24 h of treatment with the maximum therapeutic concentration of zidovudine compared to the untreated microglial cells. Furthermore, the concentrations of fatty-acid-binding proteins 4 and 5 were significantly lower (approximately 40%) in the microglial cells that were exposed to NRTIs than in the untreated cells. Notably, the total lipid concentration within the microglial cells markedly increased following NRTI administration with a 13% rise after treatment with 10 µM lamivudine and a remarkable 70% surge following the administration of 6 µM zidovudine. These results suggest that the prolonged administration of NRTIs may potentially lead to lipid accumulation, posing a significant risk to the delicate homeostasis of the neuronal system and potentially triggering a pro-inflammatory response in microglial cells.

Effects of electric field on vibrational resonance in Izhikevich neuronal systems

In this paper, based on the Izhikevich neuron model, the effects of electric field (EF) on vibrational resonance (VR) of single neuron and bidirectionally coupled neurons system are investigated. It is found that multiple vibrational resonances (MVR) can be observed in a single Izhikevich neuron model whether EF is considered or not. After the introduction of EF, the system exhibits worse MVR and local vibrational anti-resonance can be observed. In coupled neuronal system, the effect of bidirectional coupling causes MVR to disappear and the system only exhibits the phenomenon of VR. When EF is not considered, the vibrational anti-resonance is also observed. Interestingly, the introduction of EF weakens both VR and anti-resonance in the system. In addition, the effects of system parameters such as the EF strength controller and coupling strength on the Fourier coefficients are also investigated, and it is found that these parameters can also cause changes in the number of resonance peaks, resulting in vibrational bi-resonance and vibrational triple-resonance. The EF plays an important role in attenuating VR in neuronal systems. Therefore, this study can provide new insights for further control of abnormal electrical activities and information transmission in neurons.

Exploring the neural basis and modulating factors of implicit altercentric spatial perspective-taking with fNIRS

Humans spontaneously take the perspective of others when encoding spatial information in a scene, especially with agentive action cues present. This functional near-infrared spectroscopy (fNIRS) study explored how action observation influences implicit spatial perspective-taking (SPT) by adapting a left–right spatial judgment task to investigate whether transformation strategies underlying altercentric SPT can be predicted on the basis of cortical activation. Strategies associated with two opposing neurocognitive accounts (embodied versus disembodied) and their proposed neural correlates (human mirror neuron system; hMNS versus cognitive control network; CCN) are hypothesized. Exploratory analyses with 117 subjects uncover an interplay between perspective-taking and post-hoc factor, consistency of selection, in regions alluding to involvement of the CCN. Descriptively, inconsistent altercentric SPT elicited greater activation than consistent altercentric SPT and/or inconsistent egocentric SPT in the left inferior frontal gyrus (IFG), left dorsolateral prefrontal cortex (DLPFC) and left motor cortex (MC), but not the inferior parietal lobules (IPL). Despite the presence of grasping cues, spontaneous embodied strategies were not evident during implicit altercentric SPT. Instead, neural trends in the inconsistent subgroups (22 subjects; 13 altercentric; 9 egocentric) suggest that inconsistency in selection modulates the decision-making process and plausibly taps on deliberate and effortful disembodied strategies driven by the CCN. Implications for future research are discussed.

Establishment of a Mathematical Model for Parkinson's Disease Based on Complex Neural Networks and Design of Deep Brain Electrical Stimulation Treatment Plans.

This article introduces the modeling idea of complex neural networks based on the analysis of Parkinson's disease(PD) seizures. According to the Hodgkin-Huxley model of neurons and the synaptic connection theory between neurons, a theoretical model of the basal ganglia circuit was established. To reveal the working mechanism of the brain during the attack of nervous system disease. On this basis, the neural system model is combined with the control theory. Finally, an intermittent adaptive feedback controller is proposed to effectively suppress the onset of Parkinson's disease by stimulating the neuronal system accordingly.

Artificial sensory system based on memristive devices

AbstractIn the biological nervous system, the integration and cooperation of parallel system of receptors, neurons, and synapses allow efficient detection and processing of intricate and disordered external information. Such systems acquire and process environmental data in real‐time, efficiently handling complex tasks with minimal energy consumption. Memristors can mimic typical biological receptors, neurons, and synapses by implementing key features of neuronal signal‐processing functions such as selective adaption in receptors, leaky integrate‐and‐fire in neurons, and synaptic plasticity in synapses. External stimuli are sensitively detected and filtered by “artificial receptors,” encoded into spike signals via “artificial neurons,” and integrated and stored through “artificial synapses.” The high operational speed, low power consumption, and superior scalability of memristive devices make their integration with high‐performance sensors a promising approach for creating integrated artificial sensory systems. These integrated systems can extract useful data from a large volume of raw data, facilitating real‐time detection and processing of environmental information. This review explores the recent advances in memristor‐based artificial sensory systems. The authors begin with the requirements of artificial sensory elements and then present an in‐depth review of such elements demonstrated by memristive devices. Finally, the major challenges and opportunities in the development of memristor‐based artificial sensory systems are discussed.

The Whole-Exome Sequencing of a Cohort of 19 Families with Adolescent Idiopathic Scoliosis (AIS): Candidate Pathways.

A significant genetic involvement has been known for decades to exist in adolescent idiopathic scoliosis (AIS), a spine deformity affecting 1-3% of the world population. However, though biomechanical and endocrinological theories have emerged, no clear pathophysiological explanation has been found. Data from the whole-exome sequencing performed on 113 individuals in 19 multi-generational families with AIS have been filtered and analyzed via interaction pathways and functional category analysis (Varaft, Bingo and Panther). The subsequent list of 2566 variants has been compared to the variants already described in the literature, with an 18% match rate. The familial analysis in two families reveals mutations in the BICD2 gene, supporting the involvement of the muscular system in AIS etiology. The cellular component analysis revealed significant enrichment in myosin-related and neuronal activity-related categories. All together, these results reinforce the suspected role of the neuronal and muscular systems, highlighting the calmodulin pathway and suggesting a role of DNA-binding activities in AIS physiopathology.

Empathy Modulates the Activity of the Sensorimotor Mirror Neuron System during Pain Observation.

The aim of this study is to analyze the brain activity patterns during the observation of painful expressions and to establish the relationship between this activity and the scores obtained on the Interpersonal Reactivity Index (IRI). The study included twenty healthy, right-handed subjects (10 women). We conducted a task-based and resting-state functional magnetic resonance imaging (fMRI) study. The task involved observing pictures displaying painful expressions. We performed a region of interest (ROI) analysis focusing on the core regions of the sensorimotor mirror neuron system (MNS). Resting-state fMRI was utilized to assess the functional connectivity of the sensorimotor MNS regions with the rest of the cortex using a seed-to-voxel approach. Additionally, we conducted a regression analysis to examine the relationship between brain activity and scores from the IRI subtests. Observing painful expressions led to increased activity in specific regions of the frontal, temporal, and parietal lobes. The largest cluster of activation was observed in the left inferior parietal lobule (IPL). However, the ROI analysis did not reveal any significant activity in the remaining core regions of the sensorimotor MNS. The regression analysis demonstrated a positive correlation between brain activity during the observation of pain and the "empathic concern" subtest scores of the IRI in both the cingulate gyri and bilateral IPL. Finally, we identified a positive relationship between the "empathic concern" subtest of the IRI and the functional connectivity (FC) of bilateral IPLs with the bilateral prefrontal cortex and the right IFG. Observing expressions of pain triggers activation in the sensorimotor MNS, and this activation is influenced by the individual's level of empathy.

Mitochondrial phosphagen kinases support the volatile power demands of motor nerve terminals.

Motor neurons are the longest neurons in the body, with axon terminals separated from the soma by as much as a meter. These terminals are largely autonomous with regard to their bioenergetic metabolism and must burn energy at a high rate to sustain muscle contraction. Here, through computer simulation and drawing on previously published empirical data, we determined that motor neuron terminals in Drosophilalarvae experience highly volatile power demands. It might not be surprising then, that we discovered the mitochondria in the motor neuron terminals of both Drosophilaand mice to be heavily decorated with phosphagen kinases - a key element in an energy storage and buffering system well-characterized in fast-twitch muscle fibres. Knockdown of arginine kinase 1 (ArgK1) in Drosophila larval motor neurons led to several bioenergetic deficits, including mitochondrial matrix acidification and a faster decline in the cytosol ATP to ADP ratio during axon burst firing. KEY POINTS: Neurons commonly fire in bursts imposing highly volatile demands on the bioenergetic machinery that generates ATP. Using a computational approach, we built profiles of presynaptic power demand at the level of single action potentials, as well as the transition from rest to sustained activity. Phosphagen systems are known to buffer ATP levels in muscles and we demonstrate that phosphagen kinases, which support such phosphagen systems, also localize to mitochondria in motor nerve terminals of fruit flies and mice. By knocking down phosphagen kinases in fruit fly motor nerve terminals, and using fluorescent reporters of the ATP:ADP ratio, lactate, pH and Ca2+ , we demonstrate a role for phosphagen kinases in stabilizing presynaptic ATP levels. These data indicate that the maintenance of phosphagen systems in motor neurons, and not just muscle, could be a beneficial initiative in sustaining musculoskeletal health and performance.

289 Postnatal Obesity Amplifies the Effect of Prenatal Testosterone Excess in Reducing the Progesterone Negative Feedback Sensitivity in First-Generation Ewes

Abstract Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women of reproductive age. Women with PCOS exhibit reduced sensitivity of the GnRH neuronal system to the inhibitory effects of both progesterone and estradiol. Additionally, obesity amplifies the severity of the PCOS phenotype. In sheep, testosterone (T) excess during gestational days (GD) 30-90 and 60-90 reduces neuroendocrine sensitivity to the progesterone negative feedback and recapitulates the PCOS phenotype. This study investigated the contribution of postnatal obesity in amplifying or mitigating the effects of mid-gestational T excess in disrupting the responsiveness to progesterone negative feedback in sheep. Suffolk ewes received T propionate (T; 100 mg i.m.) or corn oil (CO; vehicle) twice weekly from GD 60-90 (term = 147 d). At 5 mo of age, F1 T lambs were assigned randomly to either a maintenance (100% of NRC requirements) or overfed diet (130% of NRC requirements) and control lambs were fed the maintenance diet. At 22 mo of age, F1 ewes (n = 8/group) were synchronized with two injections of PGF2α 11 d apart. After the second PGF2α administration, blood samples were collected daily for 14 d and progesterone concentrations were determined via radioimmunoassay. Ewes that were confirmed to be cycling and in the mid-luteal phase based on progesterone concentrations (progesterone ≥ 1 ng/ml on day 10 and ≥ 0.5 ng/ml on days 8-9 and 11-12) were used for LH pulse characterization. On day 10 after PGF2α synchronization (mid-luteal phase), blood samples were collected every 15 min for 6 h to characterize LH pulsatile secretion via radioimmunoassay. Data were analyzed as one-way ANOVA with Tukey's HSD post-hoc analysis. Frequency of LH pulses was greater (P < 0.05) in T maintenance (3.75 ± 0.41 pulses/6h) and T overfed ewes (3.50 ± 0.34 pulses/6h) compared with controls (2.00 ± 0.37 pulses/6 h). Luteinizing hormone pulse amplitude was greater (P < 0.05) in T overfed (2.03 ± 0.15 ng/mL) compared with T maintenance (1.44 ± 0.17 ng/mL), but not to controls (1.74 ± 0.21 ng/mL). Also, average LH concentration was greater (P < 0.05) in T overfed (2.03 ± 0.24 ng/mL), but not T maintenance (1.31 ± 0.35 ng/mL), compared with controls (0.93 ± 0.30 ng/mLl). In conclusion, these findings demonstrate the activational role of postnatal obesity in amplifying prenatal T-induced alterations in tonic LH secretion during progesterone negative feedback. The activational effect of postnatal obesity in increasing LH secretion and consequently thecal androgen production is likely a contributor to the severity of hyperandrogenic status in women with PCOS. Research support: NIH-NICHD (R01HD099096).

Regulation of the proteostasis network by the neuronal system.

The protein homeostasis (proteostasis) network is a nexus of molecular mechanisms that act in concert to maintain the integrity of the proteome and ensure proper cellular and organismal functionality. Early in life the proteostasis network efficiently preserves the functionality of the proteome, however, as the organism ages, or due to mutations or environmental insults, subsets of inherently unstable proteins misfold and form insoluble aggregates that accrue within the cell. These aberrant protein aggregates jeopardize cellular viability and, in some cases, underlie the development of devastating illnesses. Hence, the accumulation of protein aggregates activates different nodes of the proteostasis network that refold aberrantly folded polypeptides, or direct them for degradation. The proteostasis network apparently functions within the cell, however, a myriad of studies indicate that this nexus of mechanisms is regulated at the organismal level by signaling pathways. It was also discovered that the proteostasis network differentially responds to dissimilar proteotoxic insults by tailoring its response according to the specific challenge that cells encounter. In this mini-review, we delineate the proteostasis-regulating neuronal mechanisms, describe the indications that the proteostasis network differentially responds to distinct proteotoxic challenges, and highlight possible future clinical prospects of these insights.

Azobenzene-based optoelectronic transistors for neurohybrid building blocks

Exploiting the light–matter interplay to realize advanced light responsive multimodal platforms is an emerging strategy to engineer bioinspired systems such as optoelectronic synaptic devices. However, existing neuroinspired optoelectronic devices rely on complex processing of hybrid materials which often do not exhibit the required features for biological interfacing such as biocompatibility and low Young’s modulus. Recently, organic photoelectrochemical transistors (OPECTs) have paved the way towards multimodal devices that can better couple to biological systems benefiting from the characteristics of conjugated polymers. Neurohybrid OPECTs can be designed to optimally interface neuronal systems while resembling typical plasticity-driven processes to create more sophisticated integrated architectures between neuron and neuromorphic ends. Here, an innovative photo-switchable PEDOT:PSS was synthesized and successfully integrated into an OPECT. The OPECT device uses an azobenzene-based organic neuro-hybrid building block to mimic the retina’s structure exhibiting the capability to emulate visual pathways. Moreover, dually operating the device with opto- and electrical functions, a light-dependent conditioning and extinction processes were achieved faithful mimicking synaptic neural functions such as short- and long-term plasticity.

Characterization of a Human Neuronal Culture System for the Study of Cofilin-Actin Rod Pathology.

Cofilactin rod pathology, which can initiate synapse loss, has been extensively studied in rodent neurons, hippocampal slices, and in vivo mouse models of human neurodegenerative diseases such as Alzheimer's disease (AD). In these systems, rod formation induced by disease-associated factors, such as soluble oligomers of Amyloid-β (Aβ) in AD, utilizes a pathway requiring cellular prion protein (PrPC), NADPH oxidase (NOX), and cytokine/chemokine receptors (CCR5 and/or CXCR4). However, rod pathways have not been systematically assessed in a human neuronal model. Here, we characterize glutamatergic neurons differentiated from human-induced pluripotent stem cells (iPSCs) for the formation of rods in response to activators of the PrPC-dependent pathway. Optimization of substratum, cell density, and use of glial-conditioned medium yielded a robust system for studying the development of Aβ-induced rods in the absence of glia, suggesting a cell-autonomous pathway. Rod induction in younger neurons requires ectopic expression of PrPC, but this dependency disappears by Day 55. The quantification of proteins within the rod-inducing pathway suggests that increased PrPC and CXCR4 expression may be factors in the doubling of the rod response to Aβ between Days 35 and 55. FDA-approved antagonists to CXCR4 and CCR5 inhibit the rod response. Rods were predominantly observed in dendrites, although severe cytoskeletal disruptions prevented the assignment of over 40% of the rods to either an axon or dendrite. In the absence of glia, a condition in which rods are more readily observed, neurons mature and fire action potentials but do not form functional synapses. However, PSD95-containing dendritic spines associate with axonal regions of pre-synaptic vesicles containing the glutamate transporter, VGLUT1. Thus, our results identified stem cell-derived neurons as a robust model for studying cofilactin rod formation in a human cellular environment and for developing effective therapeutic strategies for the treatment of dementias arising from multiple proteinopathies with different rod initiators.