Browsing by Author "Guo, Changyong"

Now showing 1 - 7 of 7
  • Thumbnail Image
    Item
    Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors
    (Springer Nature, 2022) Guo, Changyong; Wen, Di; Zhang, Yihong; Mustaklem, Richie; Mustaklem, Basil; Zhou, Miou; Ma, Tao; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    It is essential to identify the neuronal mechanisms of Alzheimer’s Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.
  • Thumbnail Image
    Item
    Calcium Permeable-AMPA Receptors and Excitotoxicity in Neurological Disorders
    (Frontiers Media, 2021-08-17) Guo, Changyong; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca2+ influx-triggered excitotoxicity through Ca2+-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.
  • Thumbnail Image
    Item
    CalTrig: A GUI-Based Machine Learning Approach for Decoding Neuronal Calcium Transients in Freely Moving Rodents
    (bioRxiv, 2024-10-01) Lange, Michal A.; Chen, Yingying; Fu, Haoying; Korada, Amith; Guo, Changyong; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    Advances in in vivo C⁢a2+ imaging using miniatured microscopes have enabled researchers to study single-neuron activity in freely moving animals. Tools such as MiniAN and CalmAn have been developed to convert C⁢a2+ visual signals to numerical information, collectively referred to as CalV2N. However, substantial challenges remain in analyzing the large datasets generated by CalV2N, particularly in integrating data streams, evaluating CalV2N output quality, and reliably and efficiently identifying Ca2+ transients. In this study, we introduce CalTrig, an open-source graphical user interface (GUI) tool designed to address these challenges at the post-CalV2N stage of data processing. CalTrig integrates multiple data streams, including C⁢a2+ imaging, neuronal footprints, C⁢a2+ traces, and behavioral tracking, and offers capabilities for evaluating the quality of CalV2N outputs. It enables synchronized visualization and efficient C⁢a2+ transient identification. We evaluated four machine learning models (i.e., GRU, LSTM, Transformer, and Local Transformer) for C⁢a2+ transient detection. Our results indicate that the GRU model offers the highest predictability and computational efficiency, achieving stable performance across training sessions, different animals and even among different brain regions. The integration of manual, parameter-based, and machine learning-based detection methods in CalTrig provides flexibility and accuracy for various research applications. The user-friendly interface and low computing demands of CalTrig make it accessible to neuroscientists without programming expertise. We further conclude that CalTrig enables deeper exploration of brain function, supports hypothesis generation about neuronal mechanisms, and opens new avenues for understanding neurological disorders and developing treatments.
  • Thumbnail Image
    Item
    Contrasting Effects of Adolescent and Early-Adult Ethanol Exposure on Prelimbic Cortical Pyramidal Neurons
    (Elsevier, 2020) Galaj, Ewa; Guo, Changyong; Huang, Donald; Ranaldi, Robert; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    Background: Adolescence and early-adulthood are vulnerable developmental periods during which binge drinking can have long-lasting effects on brain function. However, little is known about the effects of binge drinking on the pyramidal cells of the prelimbic cortex (PrL) during early and protracted withdrawal periods. Methods: In the present study, we performed whole-cell patch clamp recordings and dendritic spine staining to examine the intrinsic excitability, spontaneous excitatory post-synaptic currents (sEPSCs), and spine morphology of pyramidal cells in the PrL from rats exposed to chronic intermittent ethanol (CIE) during adolescence or early-adulthood. Results: Compared to chronic intermittent water (CIW)-treated controls, the excitability of PrL-L5 pyramidal neurons was significantly increased 21 days after adolescent CIE but decreased 21 days after early-adult CIE. No changes of excitability in PrL Layer (L) 5 were detected 2 days after either adolescent or early-adulthood CIE. Interestingly, decreases in sEPSC amplitude and increases in thin spines ratio were detected 2 days after adolescent CIE. Furthermore, decreased frequency and amplitude of sEPSCs, accompanied by a decrease in the density of total spines and non-thin spines were observed 21 days after adolescent CIE. In contrast, increased frequency and amplitude of sEPSCs, accompanied by increased densities of total spines and non-thin spines were found 21 days after early adult CIE. Conclusion: CIE produced prolonged neuronal and synaptic alterations in PrL-L5, and the developmental stage, i.e., adolescence vs. early-adulthood when subjects receive CIE, is a key factor in determining the direction of these changes.
  • Thumbnail Image
    Item
    Limited versus extended cocaine intravenous self‐administration: Behavioral effects and electrophysiological changes in insular cortex
    (Wiley, 2021-02) Luo, Yi-Xiao; Huang, Donald; Guo, Changyong; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    Aims: Limited vs extended drug exposure has been proposed as one of the key factors in determining the risk of relapse, which is the primary characteristic of addiction behaviors. The current studies were designed to explore the related behavioral effects and neuronal alterations in the insular cortex (IC), an important brain region involved in addiction. Methods: Experiments started with rats at the age of 35 days, a typical adolescent stage when initial drug exposure occurs often in humans. The drug-seeking/taking behaviors, and membrane properties and intrinsic excitability of IC pyramidal neurons were measured on withdrawal day (WD) 1 and WD 45-48 after limited vs extended cocaine intravenous self-administration (IVSA). Results: We found higher cocaine-taking behaviors at the late withdrawal period after limited vs extended cocaine IVSA. We also found minor but significant effects of limited but not extended cocaine exposure on the kinetics and amplitude of action potentials on WD 45, in IC pyramidal neurons. Conclusion: Our results indicate potential high risks of relapse in young rats with limited but not extended drug exposure, although the adaptations detected in the IC may not be sufficient to explain the neural changes of higher drug-taking behaviors induced by limited cocaine IVSA.
  • Thumbnail Image
    Item
    Prenatal Alcohol Exposure Reduces Posterior Dorsomedial Striatum Excitability and Motivation in a Sex- and Age-Dependent Fashion
    (Elsevier, 2020-12) Roselli, Victoria; Guo, Changyong; Huang, Donald; Wen, Di; Zona, Daniel; Liang, Tiebing; Ma, Yao-Ying; Pharmacology and Toxicology, School of Medicine
    Prenatal alcohol exposure (PAE)-induced clinical symptoms have been widely reported but effective treatments are not yet available due to our limited knowledge of the neuronal mechanisms underlying behavioral outputs. Operant behaviors, including both goal-directed and habitual actions, are essential for everyday life. The dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) have been identified as mediating each type of instrumental behavior, respectively. The current studies were designed to evaluate the effects of PAE (i.e., 3 g/kg, twice a day on gestational days 17-20) on goal-directed vs. habitual behaviors in both females and males during their adolescent and adult stages. We found that PAE-treated adult, but not adolescent, males display similar habitual oral sucrose self-administration but reduced goal-directed sucrose self-administration, compared to those treated by prenatal control (water) exposure (PCE). There were no differences in either habitual or goal-directed sucrose taking between PCE- vs. PAE-treated adolescent and adult females. These results indicate sex- and age-specific effects of PAE on operant behaviors. Further, whole-cell patch clamp recordings showed that the excitability of medium-sized spiny neurons (MSNs) in the posterior DMS (pDMS), but not the anterior DMS (aDMS), was significantly decreased in PAE-treated adult male rats. Notably, chemogenetic enhancement of MSN excitability in the pDMS by the DREADD agonist, compound 21, rescued the motivation of PAE-treated male adult rats. These data suggest that the pDMS may be a key neuronal substrate mediating the PAE-induced low motivation in male adults.
  • Thumbnail Image
    Item
    Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways
    (MDPI, 2023-12-31) Williams, Kent E.; Zou, Yi; Qiu, Bin; Kono, Tatsuyoshi; Guo, Changyong; Garcia, Dawn; Chen, Hanying; Graves, Tamara; Lai, Zhao; Evans-Molina, Carmella; Ma, Yao-Ying; Liangpunsakul, Suthat; Yong, Weidong; Liang, Tiebing; Medicine, School of Medicine
    High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by Fkbp5 is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. Fkbp5 has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured Fkbp5 KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of Fkbp5 KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female Fkbp5 KO and WT mice. Differentially expressed genes (DEGs) were identified between Fkbp5 KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, Fkbp5 plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes.