bioRxiv Subject Collection: Neuroscience's Journal
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Monday, December 2nd, 2024
| Time |
Event |
| 1:16a |
Optimizing femtosecond laser fabricating strategy of Nitinol hypotube for vascular interventional surgery
Guidewires and catheters are essential in minimally invasive procedures, particularly in accessing targets within the vascular system for neuron surgery. Femtosecond lasers can precisely cut nickel-titanium micro tubes, known as Nitinol hypotubes, serving as the heads of microguide wires while protecting their core tips.The quality and geometry of these hypotubes depend on the focus of the laser cutting system. We evaluated the cutting efficiency and quality of Nitinol hypotubes using objective lenses with three numerical apertures (NA). Quantitative analysis indicated that higher NA objectives yield better surface quality, resulting in lower debris. Additionally, cutting with high NA objectives produced significantly lower arithmetic mean surface roughness and enhanced mechanical properties. Using a two-temperature model, we simulated the interaction between femtosecond lasers and Nitinol, showing that higher NA objectives increase electron temperatures, thus improving material removal efficiency. This study also tested the optimized Nitinol hypotube performance in simulations of invasive neuron surgery. | | 9:47a |
Stress during puberty and adulthood pregnancy impact histone acetylation regulators in the hypothalamus
Undergoing stressful events during puberty puts women at risk for a variety of negative outcomes, and this risk is heightened if they become pregnant later in life. We previously demonstrated that stress during puberty combined with pregnancy in adulthood led to a blunted response of the hypothalamic-pituitary-adrenal stress axis in humans and mice. We have begun to understand the mechanisms underlying this effect by examining the paraventricular nucleus of the hypothalamus (PVN), a key regulator of the HPA axis. Prior studies uncovered an increase in chromatin openness within the PVN of the at-risk mice, with bioinformatic analyses implicating histone acetylation in this increased openness. Here, we measured the activity of histone acetyltransferase (HATs) and histone deacetylase (HDACs), the writers and erasers of histone acetylation, within the PVN to further characterize how stress during puberty and pregnancy may be interacting to produce a blunted stress response. We found that histone acetylation tone within the PVN is predictive of prior transcriptional and chromatin results, with pregnant, pubertally stressed females having a pro-acetylation tone within the PVN. These findings establish a role for regulators of acetylation in the open chromatin landscape characteristic in the PVN of pregnant, pubertally stressed females. Overall, this study provides insight into the epigenetic mechanisms underlying female-relevant risk for stress dysregulation, a central endophenotype of affective disorders. | | 10:16a |
The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty
The GluA1 subunit, encoded by the putative schizophrenia-associated gene GRIA1, is required for activity-regulated AMPA receptor (AMPAR) trafficking, and plays a key role in cognitive and affective function. The cytoplasmic, carboxy-terminal domain (CTD) is the most divergent region across AMPAR subunits. The GluA1 CTD has received considerable attention for its role during long-term potentiation (LTP) at CA1 pyramidal neuron synapses. However, its function at other synapses and, more broadly, its contribution to different GluA1-dependent processes, is poorly understood. Here, we used mice with a constitutive truncation of the GluA1 CTD to dissect its role regulating AMPAR localization and function as well as its contribution to cognitive and affective processes. We found that GluA1 CTD truncation affected AMPAR subunit levels and intracellular trafficking. {triangleup}CTD GluA1 mice exhibited no memory deficits, but presented exacerbated novelty-induced hyperlocomotion and dentate gyrus granule cell (DG GC) hyperactivity, among other behavioral alterations. Mechanistically, we found that AMPAR EPSCs onto DG GABAergic interneurons were significantly reduced, presumably underlying, at least in part, the observed changes in neuronal activity and behavior. In summary, this study dissociates CTD-dependent from CTD-independent GluA1 functions, unveiling the GluA1 CTD as a crucial hub regulating AMPAR function in a cell type-specific manner. | | 10:16a |
Cell Type Specific Enhancers for Dorsolateral Prefrontal Cortex.
The dorsolateral prefrontal cortex (DLPFC) is crucial to primate cognitive functions, but a paucity of cell type specific tools limits studies of DLPFC neurocomputational principles. Therefore, we set out to identify enhancers that fit inside Adeno-Associated Virus (AAV) vectors and that elicited functional, cell type specific gene expression in the non-human primate (NHP) DLPFC. We used single nucleus RNA-Seq and ATAC-Seq from rhesus macaque tissue samples to define DLPFC cell types and their associated open chromatin regions (OCRs). We trained machine learning (ML) models to recognize the unique regulatory grammar associated with each DLPFC neuron type, performed in silico screening of all OCRs, and identified candidate enhancers most likely to elicit cell type specific transgene expression in each neuron type. For layer 3 pyramidal neurons (L3PNs) and layer 5 extratelencephalic neurons (L5ETs), we cloned the top twelve identified candidates into AAVs and injected them into NHP DLPFC. In situ observation of enhancer-driven expression revealed the best performers, RMacL3-01 and RMacL5ET-01. We validated RMacL3-01 and RMacL5ET-01 using one-at-a-time injections in NHP DLPFC. RMacL3-01 restricted GFP expression to pyramidal neurons in layers 2 and 3, whereas RMacL5ET-01 restricted expression to POU3F1+ neurons in layer 5. RMacL3-01 elicited functional levels of channelrhodopsin expression that enabled optical activation of single- and multi-unit activity in NHP DLFPC. Together, these results and resources establish a solid foundation to study cell type specific principles of primate cognitive functions. | | 4:45p |
Electroretinograms as a functional readout of neuronal integrity in neurodegeneration models of Drosophila melanogaster
The current protocol leverages the intrinsic potential of electroretinograms (ERGs) in Drosophila melanogaster, extending their application by using aged flies and the GAL4- UAS system to attempt to understand human gene effects on neuronal transmission. ERGs model neuronal vulnerability and developmental changes, providing a robust tool for examining altered neurological states. The current protocols sheds insights into the strengths and pitfalls in the analysis of human gene pathways in progression of neurodegenerative states, with additional information on novel parameters that can be tapped. This technique enhances our ability to use neurophysiological recordings for gaining insights into the molecular mechanisms underlying the role of the gene in neuronal function, thus complementing ex vivo and in vitro systems using mouse and cell culture models. - Genetics and aging to studying neurodegeneration- Traditional ERG parameters - Additional parameters. Our technique builds on the robust background of several techniques to provide additional parameters such as aging the flies (1-5 weeks) and the response characteristics associated with creating transgenic models using the w1118 background. Lastly, we also provide a different way to explore the results by identifying zones and derivatives that may improve our electrophysiological of the genetic influences on neuronal responses better. | | 4:45p |
Purinergic Receptor P2Y13 Controls Activation and Mode of Division in Subependymal Adult Neural Stem Cells
The subependymal zone (SEZ) of the mammalian brain is the most active germinal area that continues to generate newborn neurons throughout life. This area harbors a population of neural stem cells (NSCs) that can be found in different states of activation, each differing in proliferative capacity and molecular signature: quiescent NSCs (qNSCs), primed NSCs and activated NSCs (aNSCs). There is currently a void in terms of the specific markers available to effectively discern between these transient states. Likewise, the molecular signaling mechanisms controlling the transition from quiescence to activation and the subsequent mode of division remain largely unexplored. Here, we present evidence that the metabotropic P2Y13 purinergic receptor plays a critical role in regulating adult neurogenesis. We found that P2Y13 is specifically expressed in NSCs within the adult SEZ and that its levels can be used to distinguish qNSCs from aNSCs. Moreover, we identified the metabotropic P2Y13 purinergic receptor as a pivotal modulator of NSC dynamics, influencing both the balance between NSC quiescence and activation and the mode of NSC division at the subependymal zone. | | 5:15p |
Emotion processing in mothers with bonding disorder during the first year postpartum: Results of an adapted fMRI emotional GoNoGo Task
Maternal bonding refers to the unique emotional connection between a mother and her baby that gradually develops during the pre- and postpartum period. However, 3-24% of women report bonding disorders (BD), often accompanied by constraints for the mother-infant relationship with consequences for child development. The underlying neural patterns are not clarified yet. Our present study investigates the neural and behavioral patterns that underlie the processing of emotional infant stimuli over the 1 year postpartum. Mothers with and without BD (N = 45) completed an adapted (newly developed) Emotional Infant GoNoGo Task while fMRI scanning at 3, 6 and 12 months postpartum. Our results show that response inhibition towards emotional infant faces elicits stronger results than towards adult faces in all mothers. While behavioral performance in BD is impaired, the neural responses to emotional infant faces as compared to neutral faces are increased at 3 months postpartum in limbic structures such as the anterior cingulate and insula, as well as nucleus caudatus. At 6 and 12 months behavioral reactions assimilate in BD to those of healthy controls, while differences in neural reactions between BD and healthy controls increase at 6 months and decrease again at 12 months. These effects are independent of depressive symptoms. Our findings point to an experience-based adaptive process of emotion processing and responses to infants affect during the first year postpartum as a specific characteristic of clinical bonding disorder and thus might point to potential or future therapeutic interventions targeting emotion processing and regulation in mothers with BD.
Key Findings We present an adapted version of an Emotional GoNoGo Task for fMRI with infant stimuli: Behavioral inhibition towards emotional infant faces leads to increased activity in emotion regulation networks compared to adult faces in women during the 1st year postpartum.
Women with postpartum bonding disorder (BD) show increased neural reactions (ACC, NCl Caudate, Insula) towards emotional baby faces (not adult faces, irrespectively of instructed inhibition and of valence) compared to a healthy control group (CG) at 3 months postpartum.
On a behavioural level, women with BD show increased reaction times to positive emotional adult faces and higher error rates during the inhibition of reaction towards emotional baby faces at 3 months.
Differences in neural reactions to emotional baby faces between BD and CG increase at 6 months and decrease again at 12 months, while behavioral reactions in BD assimilate to those of CG | | 6:04p |
Impact of a transient neonatal visual deprivation on the development of the ventral occipito-temporal cortex in humans
How does experience shape the development of visual brain regions? We demonstrate that a transient period of visual deprivation early in life in humans leads to permanent alteration in the function of the early visual cortex (EVC), while leaving the categorical coding of downstream ventral occipito-temporal cortex (VOTC) mostly unaffected. We used fMRI to characterize the brain response to five categories (faces, bodies, objects, buildings and words) in a rare group of cataract-reversal individuals who experienced a transient period of blindness early in life, and in matched participants with typical visual development. We show that the encoding of low-level visual properties is impaired in EVC in cataract-reversal participants, while the categorical response in the VOTC is preserved. When altering the visual properties of our stimuli to mimic in controls the deficit of EVC response of the cataract, we observe a cascading alteration of the categorical coding from EVC to VOTC that is not observed in the cataract-reversal group. Our results show that a typical visual categorical organization develops in VOTC despite a period of visual deprivation early in life and in the presence of impaired processing in EVC. A deep neural network exposed to a visual diet that emulates the experience of our participants reproduced our brain observations within an artificial system. These findings emphasize how specific visual regions are differently affected by a period of visual deprivation early in life, with information encoded in EVC being permanently affected, while the categorical coding in VOTC shows resilience to deprivation. | | 6:32p |
Normative models reveal distinct cortical abnormalities to dimensions of psychopathologies in preadolescents
Background: Evidence suggests a non-specific mapping between psychiatric disorders and underlying neurobiological substrates. A dimensional psychopathology framework may prove useful for organizing observed neurobiological alterations along broad psychopathological dimensions. Methods: We applied latent class analysis to identify clinical cohorts of symptomatic homogeneity to represent the clinical end of specific psychopathological dimensions (i.e., internalizing/externalizing, p-factor), using baseline data (N = 11860) from the Adolescent Brain and Cognitive Development (ABCD) Study. These cohorts were compared against neurotypical individuals in terms of deviations from the normality of cortical development, quantified using autoencoder-based normative models, to reveal cortical abnormalities. Results: We identified cortical thickness as an important MRI-derived index of psychopathology and revealed distinct structural abnormalities to broad psychopathological dimensions. Conclusion: This study highlights the value of person-centered analytic techniques, combined with normative modeling, to complement traditional associational methodologies in revealing neurobiological correlates of dimensional psychopathologies. |
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