Scholarly Works, School of Neuroscience

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Antibiotic exposure is associated with decreased risk of psychiatric disorders
Kerman, Ilan A.; Glover, Matthew E.; Lin, Yezhe; West, Jennifer L.; Hanlon, Alexandra L.; Kablinger, Anita S.; Clinton, Sarah M. (Frontiers, 2024-01-08)
Objective: This study sought to investigate the relationship between antibiotic exposure and subsequent risk of psychiatric disorders. Methods: This retrospective cohort study used a national database of 69 million patients from 54 large healthcare organizations. We identified a cohort of 20,214 (42.5% male; 57.9 ± 15.1 years old [mean ± SD]) adults without prior neuropsychiatric diagnoses who received antibiotics during hospitalization. Matched controls included 41,555 (39.6% male; 57.3 ± 15.5 years old) hospitalized adults without antibiotic exposure. The two cohorts were balanced for potential confounders, including demographics and variables with potential to affect: the microbiome, mental health, medical comorbidity, and overall health status. Data were stratified by age and by sex, and outcome measures were assessed starting 6 months after hospital discharge. Results: Antibiotic exposure was consistently associated with a significant decrease in the risk of novel mood disorders and anxiety and stressor-related disorders in: men (mood (OR 0.84, 95% CI 0.77, 0.91), anxiety (OR 0.88, 95% CI 0.82, 0.95), women (mood (OR 0.94, 95% CI 0.89,1.00), anxiety (OR 0.93, 95% CI 0.88, 0.98), those who are 26–49 years old (mood (OR 0.87, 95% CI 0.80, 0.94), anxiety (OR 0.90, 95% CI 0.84, 0.97)), and in those ≥50 years old (mood (OR 0.91, 95% CI 0.86, 0.97), anxiety (OR 0.92, 95% CI 0.87, 0.97). Risk of intentional harm and suicidality was decreased in men (OR 0.73, 95% CI 0.55, 0.98) and in those ≥50 years old (OR 0.67, 95% CI 0.49, 0.92). Risk of psychotic disorders was also decreased in subjects ≥50 years old (OR 0.83, 95 CI: 0.69, 0.99). Conclusion: Use of antibiotics in the inpatient setting is associated with protective effects against multiple psychiatric outcomes in an age- and sex-dependent manner.
Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy
Browning, Jack L.; Wilson, Kelsey A.; Shandra, Oleksii; Wei, Xiaoran; Mahmutovic, Dzenis; Maharathi, Biswajit; Robel, Stefanie; VandeVord, Pamela J.; Olsen, Michelle L. (MDPI, 2024-03-01)
Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE⁺), those without epilepsy (PTE⁻), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE⁺ and PTE⁻ relative to sham. Focusing on protein pathways unique to PTE⁺, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE⁻. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.
Risk of Excess Maternal Folic Acid Supplementation in Offspring
Xu, Xiguang; Zhang, Ziyu; Lin, Yu; Xie, Hehuang (MDPI, 2024-03-06)
Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.
NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia
Chen, Irene; Murdaugh, Laura B.; Miliano, Cristina; Dong, Yuyang; Gregus, Ann M.; Buczynski, Matthew W. (Elsevier, 2023-06-14)
N-acyl-ethanolamine (NAEs) serve as key endogenous lipid mediators as revealed by manipulation of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for metabolizing NAEs. Preclinical studies focused on FAAH or NAE receptors indicate an important role for NAE signaling in nociception and affective behaviors. However, there is limited information on the role of NAE biosynthesis in these same behavioral paradigms. Biosynthesis of NAEs has been attributed largely to the enzyme N-acylphosphatidylethanolamine Phospholipase D (NAPE-PLD), one of three pathways capable of producing these bioactive lipids in the brain. In this report, we demonstrate that Nape-pld knockout (KO) mice displayed reduced sucrose preference and consumption, but other baseline anxiety-like or depression-like behaviors were unaltered. Additionally, we observed sex-dependent responses in thermal nociception and other baseline measures in wildtype (WT) mice that were absent in Nape-pld KO mice. In the Complete Freund's Adjuvant (CFA) model of inflammatory arthritis, WT mice exhibited sex-dependent changes in paw edema that were lost in Nape-pld KO mice. However, there was no effect of Nape-pld deletion on arthritic pain-like behaviors (grip force deficit and tactile allodynia) in either sex, indicating that while NAPE-PLD may alter local inflammation, it does not contribute to pain-like behaviors associated with inflammatory arthritis. Collectively, these findings indicate that chronic and systemic NAPE-PLD inactivation will likely be well-tolerated, warranting further pharmacological evaluation of this target in other disease indications.
Prognostic Factors and Nomogram for Choroid Plexus Tumors: A Population-Based Retrospective Surveillance, Epidemiology, and End Results Database Analysis
Bhutada, Abhishek S.; Adhikari, Srijan; Cuoco, Joshua A.; In, Alexander; Rogers, Cara M.; Jane, John A.; Marvin, Eric A. (MDPI, 2024-01-31)
Background: Choroid plexus tumors (CPTs) are rare neoplasms found in the central nervous system, comprising 1% of all brain tumors. These tumors include choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Although gross total resection for choroid plexus papillomas (CPPs) is associated with long-term survival, there is a scarcity of prospective data concerning the role and sequence of neoadjuvant therapy in treating aCPP and CPC. Methods: From the years 2000 to 2019, 679 patients with CPT were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Among these patients, 456 patients had CPP, 75 patients had aCPP, and 142 patients had CPC. Univariate and multivariable Cox proportional hazard models were run to identify variables that had a significant impact on the primary endpoint of overall survival (OS). A predictive nomogram was built for patients with CPC to predict 5-year and 10-year survival probability. Results: Histology was a significant predictor of OS, with 5-year OS rates of 90, 79, and 61% for CPP, aCPP, and CPC, respectively. Older age and African American race were prognostic for worse OS for patients with CPP. Older age was also associated with reduced OS for patients with aCPP. American Indian/Alaskan Native race was linked to poorer OS for patients with CPC. Overall, treatment with gross total resection or subtotal resection had no difference in OS in patients with CPP or aCPP. Meanwhile, in patients with CPC, gross total resection (GTR) was associated with significantly better OS than subtotal resection (STR) only. However, there is no difference in OS between patients that receive GTR and patients that receive STR with adjuvant therapy. The nomogram for CPC considers types of treatments received. It demonstrates acceptable accuracy in estimating survival probability at 5-year and 10-year intervals, with a C-index of 0.608 (95% CI of 0.446 to 0.77). Conclusions: This is the largest study on CPT to date and highlights the optimal treatment strategies for these rare tumors. Overall, there is no difference in OS with GTR vs. STR in CPP or aCPP. Furthermore, OS is equivalent for CPC with GTR and STR plus adjuvant therapy.
Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
Legon, Wynn; Strohman, Andrew; In, Alexander; Payne, Brighton (Wolters Kluwer Health, Inc., 2024-02-01)
The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.
TACI: An ImageJ Plugin for 3D Calcium Imaging Analysis
Omelchenko, Alisa A.; Bai, Hua; Hussain, Sibtain; Tyrrell, Jordan J.; Klein, Mason; Ni, Lina (Journal of Visualized Experiments, 2022-12-16)
Research in neuroscience has evolved to use complex imaging and computational tools to extract comprehensive information from data sets. Calcium imaging is a widely used technique that requires sophisticated software to obtain reliable results, but many laboratories struggle to adopt computational methods when updating protocols to meet modern standards. Difficulties arise due to a lack of programming knowledge and paywalls for software. In addition, cells of interest display movements in all directions during calcium imaging. Many approaches have been developed to correct the motion in the lateral (x/y) direction. This paper describes a workflow using a new ImageJ plugin, TrackMate Analysis of Calcium Imaging (TACI), to examine motion on the z-axis in 3D calcium imaging. This software identifies the maximum fluorescence value from all the z-positions a neuron appears in and uses it to represent the neuron's intensity at the corresponding t-position. Therefore, this tool can separate neurons overlapping in the lateral (x/ y) direction but appearing on distinct z-planes. As an ImageJ plugin, TACI is a user-friendly, open-source computational tool for 3D calcium imaging analysis. We validated this workflow using fly larval thermosensitive neurons that displayed movements in all directions during temperature fluctuation and a 3D calcium imaging dataset acquired from the fly brain.
A collection of 157 individual neuromelanin-sensitive images accompanied by non-linear neuromelanin-sensitive atlas and a probabilistic locus coeruleus atlas
Lee, Tae-Ho; Kim, Sun Hyung; Neal, Joshua; Katz, Benjamin; Kim, Il Hwan (2024-02)
The current dataset aims to support and enhance the research reliability of neuromelanin regions in the brain- stem, such as locus coeruleus (LC), by offering raw neuromelanin-sensitive images. The dataset includes raw neuromelanin-sensitive images from 157 healthy individuals (8–64 years old). In addition, leveraging individual neuromelanin-sensitive images, a non-linear neuromelanin- sensitive atlas, generated through an iterative warping pro- cess, is included to tackle the common challenge of a limited field of view in neuromelanin-sensitive images. Finally, the dataset encompasses a probabilistic LC atlas generated through a majority voting approach with pre-existing multiple atlas-based segmentations. This process entails warping pre-existing atlases onto individual spaces and identifying voxels with a majority consensus of over 50 % across the atlases. This LC probabilistic atlas can minimize uncertainty variance associated with choosing a specific single atlas.
Hedgehog-interacting protein acts in the habenula to regulate nicotine intake
Caligiuri, Stephanie P. B.; Howe, William M.; Wills, Lauren; Smith, Alexander C. W.; Lei, Ye; Bali, Purva; Heyer, Mary P.; Moen, Janna K.; Ables, Jessica L.; Elayouby, Karim S.; Williams, Maya; Fillinger, Clementine; Oketokoun, Zainab; Lehmann, Vanessa E.; DiFeliceantonio, Alexandra G.; Johnson, Paul M.; Beaumont, Kristin; Sebra, Robert P.; Ibanez-Tallon, Ines; Kenny, Paul J. (National Academy of Sciences, 2022-11-08)
Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.
Immunoregulatory and neutrophil-like monocyte subsets with distinct single-cell transcriptomic signatures emerge following brain injury
Gudenschwager Basso, Erwin K.; Ju, Jing; Soliman, Eman; de Jager, Caroline; Wei, Xiaoran; Pridham, Kevin J.; Olsen, Michelle L.; Theus, Michelle H. (2024-02-03)
Monocytes represent key cellular elements that contribute to the neurological sequela following brain injury. The current study reveals that trauma induces the augmented release of a transcriptionally distinct CD115+/Ly6Chi monocyte population into the circulation of mice pre-exposed to clodronate depletion conditions. This phenomenon correlates with tissue protection, blood–brain barrier stability, and cerebral blood flow improvement. Uniquely, this shifted the innate immune cell profile in the cortical milieu and reduced the expression of pro-inflammatory Il6, IL1r1, MCP-1, Cxcl1, and Ccl3 cytokines. Monocytes that emerged under these conditions displayed a morphological and gene profile consistent with a subset commonly seen during emergency monopoiesis. Single-cell RNA sequencing delineated distinct clusters of monocytes and revealed a key transcriptional signature of Ly6Chi monocytes enriched for Apoe and chitinase-like protein 3 (Chil3/Ym1), commonly expressed in pro-resolving immunoregulatory monocytes, as well as granule genes Elane, Prtn3, MPO, and Ctsg unique to neutrophil-like monocytes. The predominate shift in cell clusters included subsets with low expression of transcription factors involved in monocyte conversion, Pou2f2, Na4a1, and a robust enrichment of genes in the oxidative phosphorylation pathway which favors an anti-inflammatory phenotype. Transfer of this monocyte assemblage into brain-injured recipient mice demonstrated their direct role in neuroprotection. These findings reveal a multifaceted innate immune response to brain injury and suggest targeting surrogate monocyte subsets may foster tissue protection in the brain.
Linking drug and food addiction via compulsive appetite
Laque, Amanda; Wagner, Grant E.; Matzeu, Alessandra; De Ness, Genna L.; Kerr, Tony M.; Carroll, Ayla M.; de Guglielmo, Giordano; Nedelescu, Hermina; Buczynski, Matthew W.; Gregus, Ann M.; Jhou, Thomas C.; Zorrilla, Eric P.; Martin-Fardon, Remi; Koya, Eisuke; Ritter, Robert C.; Weiss, Friedbert; Suto, Nobuyoshi (Wiley, 2022-06)
Background and Purpose: ‘Food addiction’ is the subject of intense public and research interest. However, this nosology based on neurobehavioural similarities among obese individuals, patients with eating disorders and those with substance use disorders (drug addiction) remains controversial. We thus sought to determine which aspects of disordered eating are causally linked to preclinical models of drug addiction. We hypothesized that extensive drug histories, known to cause addiction-like brain changes and drug motivation in rats, would also cause addiction-like food motivation. Experimental Approach: Rats underwent extensive cocaine, alcohol, caffeine or obesogenic diet histories and were subsequently tested for punishment-resistant food self-administration or ‘compulsive appetite’, as a measure of addiction-like food motivation. Key Results: Extensive cocaine and alcohol (but not caffeine) histories caused compulsive appetite that persisted long after the last drug exposure. Extensive obesogenic diet histories also caused compulsive appetite, although neither cocaine nor alcohol histories caused excess calorie intake and bodyweight during abstinence. Hence, compulsive appetite and obesity appear to be dissociable, with the former sharing common mechanisms with preclinical drug addiction models. Conclusion and Implications: Compulsive appetite, as seen in subsets of obese individuals and patients with binge-eating disorder and bulimia nervosa (eating disorders that do not necessarily result in obesity), appears to epitomize ‘food addiction’. Because different drug and obesogenic diet histories caused compulsive appetite, overlapping dysregulations in the reward circuits, which control drug and food motivation independently of energy homeostasis, may offer common therapeutic targets for treating addictive behaviours across drug addiction, eating disorders and obesity.
Presynaptic inhibition selectively suppresses leg proprioception in behaving Drosophila
Dallmann, Chris; Agrawal, Sweta; Cook, Andrew; Brunton, Bingni; Tuthill, John (Cold Spring Harbor Laboratory, 2023-10-23)
The sense of proprioception is mediated by internal mechanosensory neurons that detect joint position and movement. To support a diverse range of functions, from stabilizing posture to coordinating movements, proprioceptive feedback to limb motor control circuits must be tuned in a context-dependent manner. How proprioceptive feedback signals are tuned to match behavioral demands remains poorly understood. Using calcium imaging in behaving Drosophila , we find that the axons of position-encoding leg proprioceptors are active across behaviors, whereas the axons of movementencoding leg proprioceptors are suppressed during walking and grooming. Using connectomics, we identify a specific class of interneurons that provide GABAergic presynaptic inhibition to the axons of movement-encoding proprioceptors. These interneurons are active during self-generated but not passive leg movements and receive input from descending neurons, suggesting they are driven by predictions of leg movement originating in the brain. Predictively suppressing expected proprioceptive feedback provides a mechanism to attenuate reflexes that would otherwise interfere with voluntary movement.
The two-body problem: Proprioception and motor control across the metamorphic divide
Agrawal, Sweta; Tuthill, John C. (Elsevier, 2022-05-02)
Like a rocket being propelled into space, evolution has engineered flies to launch into adulthood via multiple stages. Flies develop and deploy two distinct bodies, linked by the transformative process of metamorphosis. The fly larva is a soft hydraulic tube that can crawl to find food and avoid predators. The adult fly has a stiff exoskeleton with articulated limbs that enable long-distance navigation and rich social interactions. Because the larval and adult forms are so distinct in structure, they require distinct strategies for sensing and moving the body. The metamorphic divide thus presents an opportunity for comparative analysis of neural circuits. Here, we review recent progress toward understanding the neural mechanisms of proprioception and motor control in larval and adult Drosophila. We highlight commonalities that point toward general principles of sensorimotor control and differences that may reflect unique constraints imposed by biomechanics. Finally, we discuss emerging opportunities for comparative analysis of neural circuit architecture in the fly and other animal species.
Functional architecture of neural circuits for leg proprioception in Drosophila
Chen, Chenghao; Agrawal, Sweta; Mark, Brandon; Mamiya, Akira; Sustar, Anne; Phelps, Jasper S.; Lee, Wei-Chung Allen; Dickson, Barry J.; Card, Gwyneth M.; Tuthill, John C. (Cell Press, 2021-10-11)
To effectively control their bodies, animals rely on feedback from proprioceptive mechanosensory neurons. In the Drosophila leg, different proprioceptor subtypes monitor joint position, movement direction, and vibration. Here, we investigate how these diverse sensory signals are integrated by central proprioceptive circuits. We find that signals for leg joint position and directional movement converge in second-order neurons, revealing pathways for local feedback control of leg posture. Distinct populations of second-order neurons integrate tibia vibration signals across pairs of legs, suggesting a role in detecting external substrate vibration. In each pathway, the flow of sensory information is dynamically gated and sculpted by inhibition. Overall, our results reveal parallel pathways for processing of internal and external mechanosensory signals, which we propose mediate feedback control of leg movement and vibration sensing, respectively. The existence of a functional connectivity map also provides a resource for interpreting connectomic reconstruction of neural circuits for leg proprioception.
Complete loss of the X-linked gene CASK causes severe cerebellar degeneration
Patel, Paras A.; Hegert, Julia; Cristian, Ingrid; Kerr, Alicia; LaConte, Leslie E. W.; Fox, Michael A.; Srivastava, Sarika; Mukherjee, Konark (BMJ, 2022-02-11)
Background Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration. Method Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum. Result The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration. Conclusion We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.
Phosphorylation of RPT6 Controls Its Ability to Bind DNA and Regulate Gene Expression in the Hippocampus of Male Rats during Memory Formation
Farrell, Kayla; Auerbach, Aubrey; Musaus, Madeline; Navabpour, Shaghayegh; Liu, Catherine; Lin, Yu; Xie, Hehuang; Jarome, Timothy J. (Society for Neuroscience, 2024-01)
Memory formation requires coordinated control of gene expression, protein synthesis, and ubiquitin–proteasome system (UPS)-mediated protein degradation. The catalytic component of the UPS, the 26S proteasome, contains a 20S catalytic core surrounded by two 19S regulatory caps, and phosphorylation of the 19S cap regulatory subunit RPT6 at serine 120 (pRPT6-S120) has been widely implicated in controlling activity-dependent increases in proteasome activity. Recently, RPT6 was also shown to act outside the proteasome where it has a transcription factor-like role in the hippocampus during memory formation. However, little is known about the proteasome-independent function of “free” RPT6 in the brain or during memory formation and whether phosphorylation of S120 is required for this transcriptional control function. Here, we used RNA-sequencing along with novel genetic approaches and biochemical, molecular, and behavioral assays to test the hypothesis that pRPT6-S120 functions independently of the proteasome to bind DNA and regulate gene expression during memory formation. RNA-sequencing following siRNA-mediated knockdown of free RPT6 revealed 46 gene targets in the dorsal hippocampus of male rats following fear conditioning, where RPT6 was involved in transcriptional activation and repression. Through CRISPR-dCas9-mediated artificial placement of RPT6 at a target gene, we found that RPT6 DNA binding alone may be important for altering gene expression following learning. Further, CRISPR-dCas13-mediated conversion of S120 to glycine on RPT6 revealed that phosphorylation at S120 is necessary for RPT6 to bind DNA and properly regulate transcription during memory formation. Together, we reveal a novel function for phosphorylation of RPT6 in controlling gene transcription during memory formation.
NAK-associated protein 1/NAP1 activates TBK1 to ensure accurate mitosis and cytokinesis
Paul, Swagatika; Sarraf, Shireen; Nam, K. H.; Zavar, Leila; DeFoor, Nicole; Biswas, Sahitya; Fritsch, Lauren; Yaron, Tomer; Johnson, Jared; Huntsman, Emily; Cantley, Lewis; Ordureau, Alban; Pickrell, Alicia M. (Rockefeller University Press, 2023-12-07)
Subcellular location and activation of Tank Binding Kinase 1 (TBK1) govern precise progression through mitosis. Either loss of activated TBK1 or its sequestration from the centrosomes causes errors in mitosis and growth defects. Yet, what regulates its recruitment and activation on the centrosomes is unknown. We identified that NAK-associated protein 1 (NAP1) is essential for mitosis, binding to and activating TBK1, which both localize to centrosomes. Loss of NAP1 causes several mitotic and cytokinetic defects due to inactivation of TBK1. Our quantitative phosphoproteomics identified numerous TBK1 substrates that are not only confined to the centrosomes but are also associated with microtubules. Substrate motifs analysis indicates that TBK1 acts upstream of other essential cell cycle kinases like Aurora and PAK kinases. We also identified NAP1 as a TBK1 substrate phosphorylating NAP1 at S318 to promote its degradation by the ubiquitin proteasomal system. These data uncover an important distinct function for the NAP1-TBK1 complex during cell division.
The Role of STING Signaling in Central Nervous System Infection and Neuroinflammatory Disease
Fritsch, Lauren; Kelly, Colin; Pickrell, Alicia M. (Wiley, 2023-01-12)
The cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is a critical innate immune mechanism for detecting the presence of double-stranded DNA (dsDNA) and prompting a robust immune response. Canonical cGAS-STING activation occurs when cGAS, a predominantly cytosolic pattern recognition receptor, binds microbial DNA to promote STING activation. Upon STING activation, transcription factors enter the nucleus to cause the production of Type I interferons, inflammatory cytokines whose primary function is to prime the host for viral infection by producing a number of antiviral interferon-stimulated genes. While the pathway was originally described in viral infection, more recent studies have implicated cGAS-STING signaling in a number of different contexts, including autoimmune disease, cancer, injury, and neuroinflammatory disease. This review focuses on how our understanding of the cGAS-STING pathway has evolved over time with an emphasis on the role of STING-mediated neuroinflammation and infection in the nervous system. We discuss recent findings on how STING signaling contributes to the pathology of pain, traumatic brain injury, and stroke, as well as how mitochondrial DNA may promote STING activation in common neurodegenerative diseases. We conclude by commenting on the current knowledge gaps that should be filled before STING can be an effective therapeutic target in neuroinflammatory disease. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology Immune System Diseases > Molecular and Cellular Physiology.
Sex linked behavioral and hippocampal transcriptomic changes in mice with cell-type specific Egr1 loss
Swilley, Cody; Lin, Yu; Zheng, Yuze; Xu, Xiguang; Liu, Min; Jarome, Timothy J.; Hodes, Georgia E.; Xie, Hehuang (Frontiers, 2023-10-19)
The transcription factor EGR1 is instrumental in numerous neurological processes, encompassing learning and memory as well as the reaction to stress. Egr1 complete knockout mice demonstrate decreased depressive or anxiety-like behavior and impaired performance in spatial learning and memory. Nevertheless, the specific functions of Egr1 in distinct cell types have been largely underexplored. In this study, we cataloged the behavioral and transcriptomic character of Nestin-Cre mediated Egr1 conditional knockout (Egr1cKO) mice together with their controls. Although the conditional knockout did not change nociceptive or anxiety responses, it triggered changes in female exploratory activity during anxiety testing. Hippocampus-dependent spatial learning in the object location task was unaffected, but female Egr1cKO mice did exhibit poorer retention during testing on a contextual fear conditioning task compared to males. RNA-seq data analyses revealed that the presence of the floxed Egr1 cassette or Nestin-Cre driver alone exerts a subtle influence on hippocampal gene expression. The sex-related differences were amplified in Nestin-Cre mediated Egr1 conditional knockout mice and female mice are more sensitive to the loss of Egr1 gene. Differentially expressed genes resulted from the loss of Egr1 in neuronal cell lineage were significantly associated with the regulation of Wnt signaling pathway, extracellular matrix, and axon guidance. Altogether, our results demonstrate that Nestin-Cre and the loss of Egr1 in neuronal cell lineage have distinct impacts on hippocampal gene expression in a sex-specific manner.
Brain Similarity as a Protective Factor in the Longitudinal Pathway Linking Household Chaos, Parenting, and Substance Use
Kim-Spoon, Jungmeen; Lee, Tae-Ho; Clinchard, Claudia; Lindenmuth, Morgan; Brieant, Alexis; Steinberg, Laurence; Deater-Deckard, Kirby; Casas, Brooks (Elsevier, 2023-04-29)
Background: Socioecological factors such as family environment and parenting behaviors contribute to the development of substance use. While biobehavioral synchrony has been suggested as the foundation for resilience that can modulate environmental effects on development, the role of brain similarity that attenuates deleterious effects of environmental contexts has not been clearly understood. We tested whether parent-adolescent neural similarity—the level of pattern similarity between parent-adolescent functional brain connectivity representing the level of attunement within each dyad—moderates the longitudinal pathways in which household chaos (a stressor) predicts adolescent substance use directly and indirectly via parental monitoring. Methods: In a sample of 70 parent-adolescent dyads, similarity in resting-state brain activity was identified using multipattern connectivity similarity estimation. Adolescents and parents reported on household chaos and parental monitoring, and adolescent substance use was assessed at a 1-year follow-up. Results: The moderated mediation model indicated that for adolescents with low neural similarity, but not high neural similarity, greater household chaos predicted higher substance use over time directly and indirectly via lower parental monitoring. Our data also indicated differential susceptibility in the overall association between household chaos and substance use: Adolescents with low neural similarity exhibited high substance use under high household chaos but low substance use under low household chaos. Conclusions: Neural similarity acts as a protective factor such that the detrimental effects of suboptimal family environment and parenting behaviors on the development of adolescent health risk behaviors may be attenuated by neural similarity within parent-adolescent bonds.

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