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ENeuro Jun 2024CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function, and can be combined with genetically-encoded tools such as fluorescent...
CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function, and can be combined with genetically-encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs). To overcome these constraints, we developed an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus.We validated this strategy with three common tools in neuroscience: ChRonos, a channelrhodopsin, for studying synaptic transmission using optogenetics; GCaMP8f for recording Ca2+ transients using photometry, and mCherry for tracing axonal projections. We tested these tools in multiple brain regions and cell types, including GABAergic neurons in the nucleus accumbens, glutamatergic neurons projecting from the ventral pallidum to the lateral habenula, dopaminergic neurons in the ventral tegmental area, and proprioceptive neurons in the periphery. This flexible approach could help identify and test the function of novel genes affecting synaptic transmission, circuit activity, or morphology with a single viral injection. Our CRISPR/Cas9 approach is the first to use a single vector to both knock-down genes of interest and express tools to monitor, map, and manipulate neurons. We demonstrate its utility in the central nervous system and describe the first systemic CRISPR/Cas9 gene editing with co-expressed reporters in the peripheral nervous system. Our approach fills a significant gap in the neuronal gene editing toolkit, allowing high-throughput study of genes of unknown function in the nervous system, and has broad utility for loss-of-function studies in other biological fields. This tool has great translational potential: it can be used to screen risk factor genes identified through genome-wide association studies, or knock-down native gene expression and reintroduce mutant variants identified in clinical settings.
PubMed: 38871457
DOI: 10.1523/ENEURO.0438-23.2024 -
PLoS Computational Biology Jun 2024Humans are extremely robust in our ability to perceive and recognize objects-we see faces in tea stains and can recognize friends on dark streets. Yet,...
Humans are extremely robust in our ability to perceive and recognize objects-we see faces in tea stains and can recognize friends on dark streets. Yet, neurocomputational models of primate object recognition have focused on the initial feed-forward pass of processing through the ventral stream and less on the top-down feedback that likely underlies robust object perception and recognition. Aligned with the generative approach, we propose that the visual system actively facilitates recognition by reconstructing the object hypothesized to be in the image. Top-down attention then uses this reconstruction as a template to bias feedforward processing to align with the most plausible object hypothesis. Building on auto-encoder neural networks, our model makes detailed hypotheses about the appearance and location of the candidate objects in the image by reconstructing a complete object representation from potentially incomplete visual input due to noise and occlusion. The model then leverages the best object reconstruction, measured by reconstruction error, to direct the bottom-up process of selectively routing low-level features, a top-down biasing that captures a core function of attention. We evaluated our model using the MNIST-C (handwritten digits under corruptions) and ImageNet-C (real-world objects under corruptions) datasets. Not only did our model achieve superior performance on these challenging tasks designed to approximate real-world noise and occlusion viewing conditions, but also better accounted for human behavioral reaction times and error patterns than a standard feedforward Convolutional Neural Network. Our model suggests that a complete understanding of object perception and recognition requires integrating top-down and attention feedback, which we propose is an object reconstruction.
Topics: Humans; Attention; Neural Networks, Computer; Pattern Recognition, Visual; Computational Biology; Models, Neurological; Recognition, Psychology
PubMed: 38870125
DOI: 10.1371/journal.pcbi.1012159 -
Spine Surgery and Related Research May 2024Studies describing the relationship between the hip and spine have reported that corrective spinal surgery for adult spinal deformity (ASD) affects the orientation of...
INTRODUCTION
Studies describing the relationship between the hip and spine have reported that corrective spinal surgery for adult spinal deformity (ASD) affects the orientation of the acetabulum. However, the extent to which spinal correction in ASD affects acetabular anteversion in the standing position is unclear, especially after total hip arthroplasty, for which dislocation is a concern. The purpose of this study was to evaluate changes in anterior acetabular coverage in the upright position due to extensive correction surgery for ASD.
METHODS
Thirty-six consecutive patients who had undergone spinal corrective surgery from the thoracolumbar region to the pelvis were enrolled and evaluated. The ventral-central-acetabular (VCA) angle and anterior acetabular head index (AAHI) were measured with a false-profile view to evaluate the relationship between acetabular anteversion in the standing position and spinopelvic parameters before and after surgery. The spinopelvic parameters measured included thoracic kyphosis, pelvic incidence, pelvic tilt (PT), sacral slope, lumbar lordosis (LL), sagittal vertical axis, and global tilt.
RESULTS
The VCA angle and AAHI were significantly increased after spinal deformity correction (p<0.001). The changes in LL and PT were correlated with the VCA angle (LL: right, ρ=0.56; left, ρ=0.55, p<0.001; PT: right, ρ=-0.59; left, ρ=-0.64, p<0.001) and AAHI (LL: right, ρ=0.51; left, ρ=0.58, p<0.01; PT: right, ρ=-0.52; left, ρ=-0.59, p<0.01), respectively. Linear regression analysis revealed that a 10° increase in LL results in 1.4°-1.9° and 1.6%-2% increases in the VCA angle and AAHI, respectively.
CONCLUSIONS
Surgical correction for ASD significantly affects sagittal spinopelvic parameters, resulting in increased acetabular anteversion. The anterior coverage of the acetabulum in the postoperative standing position could be predicted with the intraoperatively measured LL, and evaluation using a false-profile was considered useful for treating ASD, particularly in patients after total hip arthroplasty.
PubMed: 38868798
DOI: 10.22603/ssrr.2023-0273 -
Spine Surgery and Related Research May 2024Idiopathic spinal cord herniation (ISCH) is a rare condition that is characterized by ventral herniation of the spinal cord through a defect in the dura mater into the... (Review)
Review
BACKGROUND
Idiopathic spinal cord herniation (ISCH) is a rare condition that is characterized by ventral herniation of the spinal cord through a defect in the dura mater into the epidural space, with no identifiable cause. ISCH is frequently underdiagnosed, and the information available in case reports is limited. To provide an overview of the clinical manifestations and diagnosis of this condition, this study aims to conduct a review of reported cases of ISCH.
METHODS
A literature review was carried out using seven databases. The search was conducted using the keywords "Idiopathic spinal cord herniation" OR "Idiopathic Ventral Spinal Cord Herniation" AND "Case report" OR "case series."
RESULTS
A total of 92 relevant papers reporting 224 cases, besides the index case, were determined. Of the cases, 58.5% were females and the mean age was 50.7 (SD 13.2) years. Symptoms, diagnoses, and outcomes were similar between genders. The most common clinical signs included motor symptoms (82.6%), instability (61.3%), hypoesthesia (59.2%), and disturbance of thermal sensitivity (47.3%). Brown-Séquard syndrome was observed in 27.2% of the cases, and surgical treatment was employed in 89.7% of the cases.
CONCLUSIONS
ISCH is a pathology that is principally treated with surgical approach. This study provides valuable insights into the clinical manifestations and diagnosis of ISCH, which can aid in the early recognition and treatment of this rare condition.
PubMed: 38868787
DOI: 10.22603/ssrr.2023-0102 -
IScience Jun 2024Cortical gradients in endogenous and stimulus-evoked neurodynamic timescales, and long-range cortical interactions, provide organizational constraints to the brain and...
Cortical gradients in endogenous and stimulus-evoked neurodynamic timescales, and long-range cortical interactions, provide organizational constraints to the brain and influence neural populations' roles in cognition. It is unclear how these functional gradients interrelate and which influence behavior. Here, intracranial recordings from 4,090 electrode contacts in 35 individuals map gradients of neural timescales and functional connectivity to assess their interactions along category-selective ventral temporal cortex. Endogenous and stimulus-evoked information processing timescales were not significantly correlated with one another suggesting that local neural timescales are context dependent and may arise through distinct neurophysiological mechanisms. Endogenous neural timescales correlated with functional connectivity even after removing the effects of shared anatomical gradients. Neural timescales and functional connectivity correlated with how strongly a population's activity predicted behavior in a simple visual task. These results suggest both interrelated and distinct neurophysiological processes give rise to different functional connectivity and neural timescale gradients, which together influence behavior.
PubMed: 38868193
DOI: 10.1016/j.isci.2024.110003 -
Nature Communications Jun 2024Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral...
Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.
Topics: Animals; Mice, Knockout; Male; Nerve Tissue Proteins; CA1 Region, Hippocampal; Autism Spectrum Disorder; Mice; Memory; Gene Editing; Social Behavior; Neurons; Dependovirus; Microfilament Proteins; Memory Disorders; Mice, Inbred C57BL
PubMed: 38866749
DOI: 10.1038/s41467-024-48430-x -
Journal of Affective Disorders Jun 2024While self-construal and posttraumatic stress disorder (PTSD) are independently associated with altered self-referential processes and underlying default mode network...
BACKGROUND
While self-construal and posttraumatic stress disorder (PTSD) are independently associated with altered self-referential processes and underlying default mode network (DMN) functioning, no study has examined how self-construal affects DMN connectivity in PTSD.
METHODS
A final sample of 93 refugee participants (48 with DSM-5 PTSD or sub-syndromal PTSD and 45 matched trauma-exposed controls) completed a 5-minute resting state fMRI scan to enable the observation of connectivity in the DMN and other core networks. A self-construal index was calculated by substracting scores on the collectivistic and individualistic sub-scales of the Self Construal Scale.
RESULTS
Independent components analysis identified 9 active networks-of-interest, and functional network connectivity was determined. A significant interaction effect between PTSD and self-construal index was observed in the anterior ventromedial DMN, with spatial maps localizing this to the left ventromedial prefrontal cortex (vmPFC), extending to the ventral anterior cingulate cortex. This effect revealed that connectivity in the vMPFC showed greater reductions in those with PTSD with higher levels of collectivistic self-construal.
LIMITATIONS
This is an observational study and causality cannot be assumed. The specialized sample of refugees means that the findings may not generalize to other trauma-exposed populations.
CONCLUSIONS
Such a finding indicates that self-construal may shape the core neural architecture of PTSD, given that functional disruptions to the vmPFC underpin the core mechanisms of extinction learning, emotion dysregulation and self-referential processing in PTSD. Results have important implications for understanding the universality of neural disturbances in PTSD, and suggest that self-construal could be an important consideration in the assessment and treatment of post-traumatic stress reactions.
PubMed: 38866252
DOI: 10.1016/j.jad.2024.06.009 -
Cell Reports Jun 2024In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light...
In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light treatment, the circuit mechanisms underlying the effects of light on itch-related behaviors remain poorly understood. In this study, we demonstrate that bright light treatment reduces itch-related behaviors in mice through a visual circuit related to the lateral parabrachial nucleus (LPBN). Specifically, a subset of retinal ganglion cells (RGCs) innervates GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which subsequently inhibit CaMKIIα neurons in the LPBN. Activation of both the vLGN/IGL-projecting RGCs and the vLGN/IGL-to-LPBN projections is sufficient to reduce itch-related behaviors induced by various pruritogens. Importantly, we demonstrate that the antipruritic effects of bright light treatment rely on the activation of the retina-vLGN/IGL-LPBN pathway. Collectively, our findings elucidate a visual circuit related to the LPBN that underlies the antipruritic effects of bright light treatment.
PubMed: 38865246
DOI: 10.1016/j.celrep.2024.114356 -
ELife Jun 2024A social memory pathway connecting the ventral hippocampus, the lateral septum and the ventral tegmental area helps to regulate how mice react to unknown individuals.
A social memory pathway connecting the ventral hippocampus, the lateral septum and the ventral tegmental area helps to regulate how mice react to unknown individuals.
Topics: Animals; Mice; Social Behavior; Ventral Tegmental Area; Hippocampus; Memory
PubMed: 38865180
DOI: 10.7554/eLife.99363 -
JAMA Surgery Jun 2024The prevalence of robotic-assisted anterior abdominal wall (ventral) hernia repair has increased dramatically in recent years, despite conflicting evidence of patient...
IMPORTANCE
The prevalence of robotic-assisted anterior abdominal wall (ventral) hernia repair has increased dramatically in recent years, despite conflicting evidence of patient benefit. Whether long-term hernia recurrence rates following robotic-assisted repairs are lower than rates following more established laparoscopic or open approaches remains unclear.
OBJECTIVE
To evaluate the association between robotic-assisted, laparoscopic, and open approaches to ventral hernia repair and long-term operative hernia recurrence.
DESIGN, SETTING, AND PARTICIPANTS
Secondary retrospective cohort analysis using Medicare claims data examining adults 18 years and older who underwent elective inpatient ventral, incisional, or umbilical hernia repair from January 1, 2010, to December 31, 2020. Data analysis was performed from January 2023 through March 2024.
EXPOSURE
Operative approach to ventral hernia repair, which included robotic-assisted, laparoscopic, and open approaches.
MAIN OUTCOMES AND MEASURES
The primary outcome was operative hernia recurrence for up to 10 years after initial hernia repair. To help account for potential bias from unmeasured patient factors (eg, hernia size), an instrumental variable analysis was performed using regional variation in the adoption of robotic-assisted hernia repair over time as the instrument. Cox proportional hazards modeling was used to estimate the risk-adjusted cumulative incidence of operative recurrence up to 10 years after the initial procedure, controlling for factors such as patient age, sex, race and ethnicity, comorbidities, and hernia subtype (ventral/incisional or umbilical).
RESULTS
A total of 161 415 patients were included in the study; mean (SD) patient age was 69 (10.8) years and 67 592 patients (41.9%) were male. From 2010 to 2020, the proportion of robotic-assisted procedures increased from 2.1% (415 of 20 184) to 21.9% (1737 of 7945), while the proportion of laparoscopic procedures decreased from 23.8% (4799 of 20 184) to 11.9% (946 of 7945) and of open procedures decreased from 74.2% (14 970 of 20 184) to 66.2% (5262 of 7945). Patients undergoing robotic-assisted hernia repair had a higher 10-year risk-adjusted cumulative incidence of operative recurrence (13.43%; 95% CI, 13.36%-13.50%) compared with both laparoscopic (12.33%; 95% CI, 12.30%-12.37%; HR, 0.78; 95% CI, 0.62-0.94) and open (12.74%; 95% CI, 12.71%-12.78%; HR, 0.81; 95% CI, 0.64-0.97) approaches. These trends were directionally consistent regardless of surgeon procedure volume.
CONCLUSIONS AND RELEVANCE
This study found that the rate of long-term operative recurrence was higher for patients undergoing robotic-assisted ventral hernia repair compared with laparoscopic and open approaches. This suggests that narrowing clinical applications and evaluating the specific advantages and disadvantages of each approach may improve patient outcomes following ventral hernia repairs.
PubMed: 38865153
DOI: 10.1001/jamasurg.2024.1696