Scholarly Works, School of Neuroscience

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Research articles, presentations, and other scholarship

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Astrocytes require perineuronal nets to maintain synaptic homeostasis in mice
Tewari, Bhanu P.; Woo, AnnaLin M.; Prim, Courtney E.; Chaunsali, Lata; Patel, Dipan C.; Kimbrough, Ian F.; Engel, Kaliroi; Browning, Jack L.; Campbell, Susan L.; Sontheimer, Harald (Nature Portfolio, 2024-08-01)
Perineuronal nets (PNNs) are densely packed extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. PNNs stabilize synapses inhibiting synaptic plasticity. Here we show that synaptic terminals of fast-spiking interneurons localize to holes in the PNNs in the adult mouse somatosensory cortex. Approximately 95% of holes in the PNNs contain synapses and astrocytic processes expressing Kir4.1, glutamate and GABA transporters. Hence, holes in the PNNs contain tripartite synapses. In the adult mouse brain, PNN degradation causes an expanded astrocytic coverage of the neuronal somata without altering the axon terminals. The loss of PNNs impairs astrocytic transmitter and potassium uptake, resulting in the spillage of glutamate into the extrasynaptic space. Our data show that PNNs and astrocytes cooperate to contain synaptically released signals in physiological conditions. Their combined action is altered in mouse models of Alzheimer's disease and epilepsy where PNNs are disrupted. Perineuronal nets stabilize synapses inhibiting synaptic plasticity. Here, the authors show that perineuronal nets act as a diffusion barrier facilitating astrocytic clearance of synaptically released ions and neurotransmitters.
Expression and localization of the neuropeptide Y-Y4 receptor in the chick spleen: mRNA upregulation by high ambient temperature
Nishimura, Haruka; Elhussiny, Mohamed Z.; Ouchi, Yoshimitsu; Haraguchi, Shogo; Itoh, Taichi Q.; Gilbert, Elizabeth R.; Cline, Mark A.; Nishimura, Shotaro; Hosaka, Yoshinao Z.; Takahashi, Eiki; Cockrem, John F.; Bungo, Takashi; Chowdhury, Vishwajit S. (Elsevier, 2024-10-01)
High ambient temperatures (HT) can increase diencephalic neuropeptide Y (NPY) expression, and central injection of NPY attenuates heat stress responses while inducing an antioxidative state in the chick spleen. However, there is a lack of knowledge about NPY receptor expression, and its regulation by HT, in the chick spleen. In the current study, male chicks were used to measure the expression of NPY receptors in the spleen and other immune organs under acute (30 vs. 40 f 1 degrees C for 3 h) or chronic (30 vs. 40 f 1 degrees C for 3 h/day for 3 days) exposure to HT and in response to central injection of NPY (47 pmol, 188 pmol, or 1 nmol). We found that NPYY4 receptor mRNA was expressed in the spleen, but not in other immune organs studied. Immunofluorescence staining revealed that NPY-Y4 receptors were localized in the splenic pulp. Furthermore, NPY-Y4 receptor mRNA increased in the chick spleen under both acute and chronic exposure to HT. Central NPY at two dose levels (47 and 188 pmol) and a higher dose (1 nmol) did not increase splenic NPY-Y4 receptor mRNA expression or splenic epinephrine under HT (35 f 1 degrees C), and significantly increased 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations under HT (40 f 1 degrees C). In conclusion, increased expression of NPY-Y4 receptor mRNA in the spleen under HT suggest that Y4 receptor may play physiological roles in response to HT in male chicks.
Age-related dysregulation of proteasome-independent K63 polyubiquitination in the hippocampus and amygdala
Bae, Yeeun; Venkat, Harshini; Preveza, Natalie; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (Pergamon-Elsevier, 2025-08-06)
Cognitive decline with aging is a complex process involving multiple brain regions and molecular mechanisms. While the role of the canonical protein degradation function of the ubiquitin–proteasome system (UPS) has been well studied in the context of aging and age-associated memory loss, the non-proteolytic functions of ubiquitin activity remain poorly understood. Here, we investigated the role of lysine-63 (K63) polyubiquitination, the most abundant form of proteasome-independent ubiquitination, in aged rats, focusing on the hippocampus and amygdala, two brain regions reported to have cellular and molecular alterations with age that are associated with age-related memory loss. Using an unbiased proteomic approach, we observed a significant increase of K63 polyubiquitination in the hippocampus across the lifespan. Reducing K63 polyubiquitination in the hippocampus of aged male rats using the CRISPR-dCas13 RNA editing system enhanced contextual fear memory, while similar manipulations in middle-aged rats, which typically have normal memory, had no effect, emphasizing the age-dependent role of K63 polyubiquitination in memory formation. Conversely, the amygdala showed a consistent reduction of K63 polyubiquitination protein targets across the lifespan, and further reductions of K63 polyubiquitination improved memory retention in aged, but not middle-aged, male rats. Together, our findings reveal the dynamic and region-specific functions of K63 polyubiquitination in the brain aging process, providing novel insights into its contribution to age-associated memory decline.
Increased DNA methylation of Igf2 in the male hippocampus regulates age-related deficits in synaptic plasticity and memory
Kincaid, Shannon; Stickling, Courtney P.; Farrell, Kayla; Bae, Yeeun; Patrick, Morgan B.; Bhanot, Gitali; Cummings, Adam; Abraham, Jennifer; Alisesky, Abby; Ferrara, Nicole; Rosenkranz, J. Amiel; Jarome, Timothy J. (Elsevier, 2025-10-01)
The aging process is characterized by a general decline in cognitive abilities, which affects nearly 33 % of U.S. adults over the age of 70 and is a risk factor for the development of dementia and Alzheimer's disease. Numerous studies have reported increased neuroinflammation and impaired synaptic plasticity and memory with age in the hippocampus, a major brain region involved in the formation and storage of most memories. However, much remains unknown about the mechanisms that contribute to age-related deficits in synaptic plasticity and memory. The Insulin-like growth factor 2 (Igf2) is a genomic imprinted gene that is expressed from a single allele in all species. Though IGF2 has been shown to be important in development, synaptic plasticity, and memory formation in the hippocampus and administration of IGF2 can improve memory late in life, whether changes in regulation of this gene contribute to age-related memory decline have yet to be explored. Here, we show that aged (24 months) male rats have increased CpG-site specific promoter methylation and reduced expression of Igf2 in the hippocampus relative to young adult (3 months) and middle-aged (12 months) rats. Importantly, CRISPR-dCas9 mediated increase of DNA 5-hydroxymethylation, an active transcriptional mark, of the Igf2 promoter in the hippocampus improved memory and long-term potentiation in aged, but not middle-aged, rats. These data indicate that increased DNA methylation of Igf2 in the hippocampus contributes to age-related deficits in synaptic plasticity and memory.
Antimicrobial Resistance and Genomic Characterization of an Escherichia coli Strain Harboring p0111 and an IncX1-Type Plasmid, Isolated from the Brain of an Ostrich
Hu, Jing; Zhou, Jiahe; Wang, Leping; Chen, Zhongwei; Tan, Yizhou; Yin, Yangyan; Pei, Zhe; Li, Changting; Bai, Huili; Ma, Chunxia; Teng, Ling; Feng, Yongcui; Li, Xian; Wei, Yingyi; Peng, Hao (MDPI, 2025-08-22)
An outbreak characterized by clinical signs of diarrhea and paralysis, occasionally progressing to fatal outcomes, occurred at an ostrich breeding facility. Conventional antibiotic treatments proved ineffective. To investigate the etiology of the disease, brain and liver specimens were collected for diagnostic analysis. An Escherichia coli (E. coli) isolate, designated strain HZDC01, was obtained from cerebral tissues, and whole-genome sequencing was performed for genomic characterization. Genomic analysis revealed that the chromosomal DNA harbors numerous resistance genes, conferring multidrug resistance through complex mechanisms. Furthermore, a p0111-type plasmid carrying the bla_CTX-M-55 gene and an IncX1-type plasmid harboring rmtB, sul1, APH(6)-Id, tet(A), AAC(3)-IIc, aadA2, bla_TEM-1B, and floR genes were identified. These plasmids carry numerous mobile genetic elements that can disseminate via horizontal gene transfer, thereby amplifying the risk of resistance-gene spread within bacterial populations. Additionally, the ibeB and ibeC genes, which encode proteins involved in the invasion of brain microvascular endothelial cells, were identified. These genes may facilitate E. coli penetration of the blood–brain barrier, potentially leading to meningitis and posing a life-threatening risk to the host. This is the first report of the isolation and characterization of extended-spectrum beta-lactamase E. coli from the brain of an ostrich with paralysis. The findings provide valuable genomic insights into the antimicrobial resistance profiles and pathogenic mechanisms of ostrich-derived E. coli isolates.
Caudate serotonin signaling during social exchange distinguishes essential tremor and Parkinson’s disease patients
Hartle, Alec E.; Kishida, Kenneth T.; Sands, L. Paul; Batten, Seth R.; Barbosa, Leonardo S.; Bang, Dan; Lohrenz, Terry; White, Jason P.; Sohrabi, Arian K.; Calafiore, Rebecca L.; DiFeliceantonio, Alexandra G.; Laxton, AdrianW.; Tatter, Stephen B.; Witcher, Mark R.; Montague, P. Read; Howe, W. Matt (Springer Nature, 2025-09-02)
Dynamic changes in dopamine, noradrenaline, and serotonin release are believed to causally contribute to the neural computations that support reward-based decision making. Accordingly, changes in signaling by these systems are hypothesized to underwrite multiple cognitive and behavioral symptoms observed in many neurological disorders. Here,we characterize the release of these neurotransmitters measured concurrently in the caudate of patients with Parkinson’s disease or essential tremor undergoing deep brain stimulation surgery as they played a social exchange game. We show that violations in the expected value of monetary offers are encoded by opponent patterns of dopamine and serotonin release in essential tremor, but not Parkinson’s disease, patients. We also demonstrate that these changes in serotonin signaling comprise a neurochemical boundary that subsegments these two neuromotor diseases. Our combined results point to a neural signature of altered reward processing that can be used to understand the signaling deficiencies that underwrite these diseases.
Elevated EGR1 binding at enhancers in excitatory neurons correlates with neuronal subtype-specific epigenetic regulation
Yin, Liduo; Xu, Xiguang; Conacher, Benjamin; Lin, Yu; Carrillo, Gabriela L.; Cun, Yupeng; Fox, Michael A.; Lu, Xuemei; Xie, Hehuang (2025-08-11)
Background: Brain development and neuronal cell specification are accompanied by epigenetic changes that enable the regulation of diverse gene expression patterns. During these processes, transcription factors interact with cell-type-specific epigenetic marks, binding to unique sets of cis-regulatory elements in different cell types. However, the detailed mechanisms through which cell-type-specific gene regulation is established in neurons remain to be explored. Results: In this study, we conducted a comparative histone modification analysis between excitatory and inhibitory neurons. Our results revealed that neuronal cell-type-specific histone modifications are enriched in super enhancer regions that contain abundant EGR1 motifs. Further CUT&RUN assay confirmed that excitatory neurons exhibit more EGR1 binding sites, primarily located in enhancers. Integrative analysis demonstrated that EGR1 binding is strongly correlated with various epigenetic markers of open chromatin regions and is linked to distinct gene pathways specific to neuronal subtypes. In inhibitory neurons, most genomic regions containing EGR1 binding sites become accessible during early embryonic stages, whereas super enhancers in excitatory neurons, which also host EGR1 binding sites, gain accessibility during postnatal stages. Conclusions: This study highlights the crucial role of transcription factor binding, such as EGR1, to enhancer regions, which may be key to establishing cell-type-specific gene regulation in neurons.
Metrics of glycemic control but not body weight influence flavor nutrient conditioning in humans
Baugh, Mary Elizabeth; Ahrens, Monica L.; Burns, Amber K.; Sullivan, Rhianna M.; Valle, Abigail N.; Hanlon, Alexandra L.; DiFeliceantonio, Alexandra G. (Elsevier, 2025-07)
The modern food landscape, marked by a rising prevalence of highly refined, ultra-processed, and highly palatable foods, combined with genetic and environmental susceptibilities, is widely considered a key factor driving obesity at the population level. Gaining insight into the physiological and behavioral mechanisms that shape food preferences and choices is crucial for understanding obesity's development and informing prevention strategies. One factor influencing habitual eating patterns, which may impact body weight, is flavor-nutrient learning. Research suggests that post-oral signaling is diminished in both animals and humans with obesity, potentially affecting flavor-nutrient learning. By analyzing pooled data from two similar preliminary studies, we found that markers of glycemic control-specifically fasting glucose and HbA1C-rather than BMI, were negatively correlated with changes in flavor liking in our flavor-nutrient learning task. These findings contribute to the expanding body of research on flavor-nutrient learning and underscore the variability in individual responses to these paradigms. Obesity is increasingly recognized as a complex and heterogeneous condition with diverse underlying mechanisms. Together, our findings and existing evidence emphasize the importance of further investigating how phenotypic factors interact to shape food preferences and eating behaviors.
Spatial Transcriptomics Reveals Regional and Temporal Dynamics of Gene Expression in the Mouse Brain Across Development and Aging
Conacher, Benjamin; Moore, Amanda; Yin, Liduo; Lin, Yu; Xu, Xiguang; Mao, Qinwen; Xie, Hehuang (MDPI, 2025-06-18)
Investigating transcriptomic changes during healthy development and aging provides insights into the molecular mechanisms that regulate the maturation of brain functions and drive age-related decline. Although it has been speculated that aging may represent a reversal of late-stage brain development, direct molecular comparisons between these two processes have remained limited. This study employs spatial transcriptomics to analyze the mouse brain at three key timepoints: postnatal day 21 (P21), 3 months (adult), and 28 months (aged), to identify region-specific differential gene expression dynamics. We identify widespread transcriptional changes across both brain development and aging, with all brain regions exhibiting distinct, region-specific gene expression dynamics that reflect divergent regulatory trajectories across the lifespan. During development, gene expression patterns were strongly enriched for neurogenesis, synaptic plasticity, and myelination, reflecting active circuit formation and white matter maturation. In contrast, aging was characterized by a decline in myelination-related gene expression and a pronounced increase in inflammatory and glial activation pathways, particularly within the hippocampus. While both development and aging involved changes in myelination-associated genes, the underlying mechanisms appear distinct: developmental upregulation supports circuit establishment and refinement, whereas aging-related downregulation may reflect secondary consequences of neuroinflammation and reactive gliosis. These findings underscore that, despite some overlap in affected pathways, neural maturation and age-related decline are driven by fundamentally different regulatory programs. These findings establish a novel spatial transcriptomic reference for brain development and aging, offering a valuable data resource for investigating neurodevelopmental and neurodegenerative mechanisms.
Guinea Pigs Are Not a Suitable Model to Study Neurological Impacts of Ancestral SARS-CoV-2 Intranasal Infection
Joyce, Jonathan D.; Moore, Greyson A.; Thompson, Christopher K.; Bertke, Andrea S. (MDPI, 2025-05-15)
Neurological symptoms involving the central nervous system (CNS) and peripheral nervous system (PNS) are common complications of acute COVID-19 as well as post-COVID conditions. Most research into these neurological sequalae focuses on the CNS, disregarding the PNS. Guinea pigs were previously shown to be useful models of disease during the SARS-CoV-1 epidemic. However, their suitability for studying SARS-CoV-2 has not been experimentally demonstrated. To assess the suitability of guinea pigs as models for SARS-CoV-2 infection and the impact of SARS-CoV-2 infection on the PNS, and to determine routes of CNS invasion through the PNS, we intranasally infected wild-type Dunkin-Hartley guinea pigs with ancestral SARS-CoV-2 USA-WA1/2020. We assessed PNS sensory neurons (trigeminal ganglia, dorsal root ganglia), autonomic neurons (superior cervical ganglia), brain regions (olfactory bulb, brainstem, cerebellum, cortex, hippocampus), lungs, and blood for viral RNA (RT-qPCR), protein (immunostaining), and infectious virus (plaque assay) at three- and six-days post infection. We show that guinea pigs, which have previously been used as a model of SARS-CoV-1 pulmonary disease, are not susceptible to intranasal infection with ancestral SARS-CoV-2, and are not useful models in assessing neurological impacts of infection with SARS-CoV-2 isolates from the early pandemic.
Systematic evaluation of parameters in RNA bisulfite sequencing data generation and analysis
Johnson, Zachary; Xu, Xiguang; Pacholec, Christina; Xie, Hehuang (Oxford University Press, 2022-03-31)
The presence of 5-methylcytosine (m5C) in RNA molecules has been known for decades and its importance in regulating RNA metabolism has gradually become appreciated. Despite recent advances made in the functional and mechanistic understanding of RNA m5C modifications, the detection and quantification of methylated RNA remains a challenge. In this study, we compared four library construction procedures for RNA bisulfite sequencing and implemented an analytical pipeline to assess the key parameters in the process of m5C calling. We found that RNA fragmentation after bisulfite conversion increased the yield significantly, and an additional high temperature treatment improved bisulfite conversion efficiency especially for sequence reads mapped to the mitochondrial transcriptome. Using Unique Molecular Identifiers (UMIs), we observed that PCR favors the amplification of unmethylated templates. The low sequencing quality of bisulfite-converted bases is a major contributor to the methylation artifacts. In addition, we found that mitochondrial transcripts are frequently resistant to bisulfite conversion and no p-m5C sites with high confidence could be identified on mitochondrial mRNAs. Taken together, this study reveals the various sources of artifacts in RNA bisulfite sequencing data and provides an improved experimental procedure together with analytical methodology.
Dynamics of RNA m⁵C modification during brain development
Johnson, Zachary; Xu, Xiguang; Lin, Yu; Xie, Hehuang (Elsevier, 2023-05)
Post-transcriptional RNA modifications have been recognized as key regulators of neuronal differentiation and synapse development in the mammalian brain. While distinct sets of 5-methylcytosine (m5C) modified mRNAs have been detected in neuronal cells and brain tissues, no study has been performed to characterize methylated mRNA profiles in the developing brain. Here, together with regular RNA-seq, we performed transcriptome-wide bisulfite sequencing to compare RNA cytosine methylation patterns in neural stem cells (NSCs), cortical neuronal cultures, and brain tissues at three postnatal stages. Among 501 m5C sites identified, approximately 6% are consistently methylated across all five conditions. Compared to m5C sites identified in NSCs, 96% of them were hypermethylated in neurons and enriched for genes involved in positive transcriptional regulation and axon extension. In addition, brains at the early postnatal stage demonstrated substantial changes in both RNA cytosine methylation and gene expression of RNA cytosine methylation readers, writers, and erasers. Furthermore, differentially methylated transcripts were significantly enriched for genes regulating synaptic plasticity. Altogether, this study provides a brain epitranscriptomic dataset as a new resource and lays the foundation for further investigations into the role of RNA cytosine methylation during brain development.
Monoubiquitination of histone H2B is a crucial regulator of the transcriptome during memory formation
Navabpour, Shaghayegh; Farrell, Kayla; Kincaid, Shannon E.; Omar, Nour; Musaus, Madeline; Lin, Yu; Xie, Hehuang; Jarome, Timothy J. (Cold Spring Harbor Laboratory Press, 2024-03)
Posttranslational modification of histone proteins is critical for memory formation. Recently, we showed that monoubiquitination of histone H2B at lysine 120 (H2Bub) is critical for memory formation in the hippocampus. However, the transcriptome controlled by H2Bub remains unknown. Here, we found that fear conditioning in male rats increased or decreased the expression of 86 genes in the hippocampus but, surprisingly, siRNA-mediated knockdown of the H2Bub ligase, Rnf20, abolished changes in all but one of these genes. These findings suggest that monoubiquitination of histone H2B is a crucial regulator of the transcriptome during memory formation.
Increasing H2B Monoubiquitination Improves the Transcriptome and Memory in the Aged Hippocampus
Kincaid, Shannon; Setenet, Gueladouan; Preveza, Natalie J.; Arndt, Kaiser C.; Gwin, Phillip; Lin, Yu; Xie, Hehuang; Jarome, Timothy J. (Society for Neuroscience, 2025-04)
A decline in cognitive abilities is associated with the aging process, affecting nearly 33% of US adults over the age of 70, and is a risk factor for the development of dementia and Alzheimer's disease. Several studies have reported age-related alterations in the transcriptome in the hippocampus, a major site of memory storage that is among the first regions impacted with age, dementia, and Alzheimer's disease. However, much remains unknown about why these transcriptional changes exist in the aged hippocampus and how this impacts memory late in life. Here, we show that monoubiquitination of histone H2B (H2Bubi), an epigenetic mechanism recently reported to be major regulator of the epigenome and transcriptome during memory formation in the young adult brain, decreases with age in the hippocampus of male rats. In vivo CRISPR-dCas9-mediated upregulation of Rnf20, the only ubiquitin E3 ligase for H2B, in the hippocampus significantly improved memory retention in aged rats. Remarkably, RNA-seq analysis revealed that in addition to the 18 genes typically upregulated in the aged rat hippocampus following contextual fear conditioning, Rnf20 upregulation caused learning-related increases and decreases in 40 and 11 unique genes, respectively, suggesting that these 51 genes may be among those most critical for improving memory in advanced age. Together, these data suggest that H2B monoubiquitination is a significant regulator of age-related dysregulation of the transcriptome and impairments in memory.
Indirectly acquired fear memories have distinct, sex-specific molecular signatures from directly acquired fear memories
Navabpour, Shaghayegh; Patrick, Morgan B.; Omar, Nour A.; Kincaid, Shannon E.; Bae, Yeeun; Abraham, Jennifer; McGrew, Jacobi; Musaus, Madeline; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (PLOS, 2024-12-23)
Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects women more than men. About 30% of patients suffering from PTSD develop the disorder by witnessing a traumatic event happen to someone else. However, as the focus has remained on those directly experiencing the traumatic event, whether indirectly acquired fear memories that underlie PTSD have the same molecular signature as those that are directly acquired remains unknown. Here, using a rodent indirect fear learning paradigm where one rat (observer) watches another rat (demonstrator) associate an auditory cue with foot shock, we found that fear can be indirectly acquired by both males and females regardless of the sex or novelty (familiarity) of the demonstrator animal. However, behaviorally, indirectly acquired fear responses resemble those of pseudoconditioning, a behavioral response that is thought to not represent learning. Despite this, using unbiased proteomics, we found that indirectly acquired fear memories have distinct protein degradation profiles in the amygdala and anterior cingulate cortex (ACC) relative to directly acquired fear memories and pseudoconditioning, which further differed significantly by sex. Additionally, Egr2 and c-fos expression in the retrosplenial cortex of observer animals resembled that of demonstrator rats but was significantly different than that of pseudoconditioned rats. Together, these findings reveal that indirectly acquired fear memories have sex-specific molecular signatures that differ from those of directly acquired fear memories or pseudoconditioning. These data have important implications for understanding the neurobiology of indirectly acquired fear memories that may underlie bystander PTSD.
Neural Signatures of Cognitive Control Predict Future Adolescent Substance Use Onset and Frequency
Chen, Ya-Yun; Lindenmuth, Morgan; Lee, Tae-Ho; Lee, Jacob; Casas, Brooks; Kim-Spoon, Jungmeen (Elsevier, 2024-11-29)
BACKGROUND: Adolescent substance use is a significant predictor of future addiction and related disorders. Understanding neural mechanisms underlying substance use initiation and frequency during adolescence is critical for early prevention and intervention. METHODS: The current longitudinal study followed 91 substance-naïve adolescents annually for 7 years from ages 14 to 21 years to identify potential neural precursors that predict substance use initiation and frequency. Cognitive control processes were examined using the Multi-Source Interference Task to assess functional neural connectivity. A questionnaire was used to assess substance use frequency. RESULTS: Stronger connectivity between the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC) at time 1 predicted a delayed onset of substance use, indicative of a protective effect. A notable decline in this dACC–dlPFC connectivity was observed 1 year prior to substance use initiation. Conversely, lower connectivity of the dACC with the supplementary motor area and heightened connectivity of the anterior insula with the dorsal medial prefrontal cortex and angular gyrus were predictive of greater frequency of future substance use. These findings remained after controlling for demographic and socioeconomic covariates. CONCLUSIONS: This study highlights the critical role of cognitive control–related neural connectivity in predicting substance use initiation and frequency during adolescence. The results imply that efforts to strengthen and monitor the development of the top-down cognitive control system in the brain from early adolescence can be protective and deter progression into problematic substance use. Furthermore, for adolescents with heightened frequency of substance use, interventions may prove more effective by targeting interoceptive processes in cognitive control training.
Making an Effective Flipped Neuroscience Lab by Approaching Students from Their Limbic Brain
Fu, Zhuo (Faculty for Undergraduate Neuroscience, 2024-07-21)
During the pandemic, we filmed our neuroscience labs, and now the videos provide a great resource to flip the lab. Our lab, however, covers a wide range of complicated topics, ranging from gross anatomy, immunohistochemistry (IHC) staining, and fluorescence imaging to cockroach microscopic surgery and measuring nerve conduction velocity on worms and human subjects, and it is challenging to get students to finish watching these complicated experiments. The biggest challenge that students face while watching these experiment demonstrations is their own emotions. When we were editing the films of the labs, we did not reduce the complexity, but we explained concepts by using concepts and objects that students are already familiar with so we do not trigger anxiety. To reduce boredom, we employed three major methods: questioning, humor, and increasing the pace. To address potential anxiety or reluctance about the in-person part of the lab, we mention at the beginning of every lab session that making mistakes is completely acceptable and, as they make mistakes, we help them understand what went wrong and how to correct it. We also introduce additional activities in some lab sessions to pique their interest. For instance, we ask students to test the effects of Red Bull on crickets and investigate whether students who play more video games have higher conduction velocities in the median nerve. Thus far, our flipped lab has been quite successful in terms of maintaining video retention rates and in-person attendance rates. A notable example of the effectiveness of improved hands-on skills is the cockroach microscopic surgery. Before implementing the flipped lab, only 10% of students were able to successfully complete the surgery and acquire nerve activity recordings. With the flipped lab, 90% of students were able to obtain a recording independently.
The Predictive Value of Plasma Bioactive Lipids on Craving in Human Volunteers With Alcohol Use Disorder
Miliano, Cristina; Natividad, Luis A.; Quello, Susan; Stoolmiller, Mike; Gregus, Ann M.; Buczynski, Matthew W.; Mason, Barbara J. (Elsevier, 2024-07-26)
Background: Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by alcohol seeking and consumption despite negative consequences. Despite the availability of multiple treatments, patients continue to exhibit high relapse rates. Thus, biomarkers that can identify patients at risk for heightened craving are urgently needed. Mounting preclinical and clinical evidence implicates perturbations in bioactive lipid signaling in the neurobiology of craving in AUD. We hypothesize that these lipids are potential biomarkers for predicting alcohol craving in patients with AUD. Methods: This study used archival deidentified clinical data and corresponding plasma specimens from 157 participants in 3 clinical studies of AUD. We evaluated plasma levels of 8 lipid species as predictors of craving in response to in vivo alcohol and affective cues during abstinence. Results: Participants were 109 men and 48 women who met DSM-5 criteria for severe AUD. We found that plasma levels of 12- and 15-HETE, 12/15-lipoxygenase–produced proinflammatory lipids, and palmitoylethanolamide, an anti-inflammatory fatty acid amide hydrolase–regulated lipid metabolite, were differentially correlated with alcohol craving during abstinence, predicting higher craving independent of demographics, alcohol use history, and multiple therapeutic treatments. Conclusions: Our findings highlight the promise of these lipid metabolites as biomarkers of heightened alcohol craving. The results open a novel opportunity for further research and clinical evaluation of these biomarkers to optimize existing treatments and develop new therapeutics for AUD.
Effect of chronic vapor nicotine exposure on affective and cognitive behavior in male mice
Murdaugh, Laura B.; Miliano, Cristina; Chen, Irene; Faunce, Christine L.; Natividad, Luis A.; Gregus, Ann M.; Buczynski, Matthew W. (Nature Portfolio, 2024-03-19)
Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.
Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal
Buzzi, Belle; Koseli, Eda; Alkhlaif, Yasmin; Parker, Abigail; Mustafa, Mohammed A.; Lichtman, Aron H.; Buczynski, Matthew W.; Damaj, M. Imad (Elsevier, 2023-07-11)
Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), alters nicotinic dependence behaviors in rodents. This study, using transgenic knock-out (KO) mice, evaluated the role of the two 2-AG biosynthesis enzymes, (Diacylglycerol lipase-α) DAGL-α and DAGL-β in spontaneous nicotine withdrawal. DAGL-α deletion prevents somatic and affective signs of nicotine withdrawal, while DAGL-β deletion plays a role in hyperalgesia due to nicotine withdrawal. These results suggest a differential role of these enzymes in the various signs of nicotine withdrawal. Our behavioral findings relate to the distribution of these enzymes with DAGL-β being highly expressed in macrophages and DAGL-α in neurons. This study offers new potential targets for smoking cessation therapies.

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