scholarly journals Behavioral and Gene Regulatory Responses to Developmental Drug Exposures in Zebrafish

2022 ◽  
Vol 12 ◽  
Author(s):  
Aleksandra M. Mech ◽  
Munise Merteroglu ◽  
Ian M. Sealy ◽  
Muy-Teck Teh ◽  
Richard J. White ◽  
...  

Developmental consequences of prenatal drug exposure have been reported in many human cohorts and animal studies. The long-lasting impact on the offspring—including motor and cognitive impairments, cranial and cardiac anomalies and increased prevalence of ADHD—is a socioeconomic burden worldwide. Identifying the molecular changes leading to developmental consequences could help ameliorate the deficits and limit the impact. In this study, we have used zebrafish, a well-established behavioral and genetic model with conserved drug response and reward pathways, to identify changes in behavior and cellular pathways in response to developmental exposure to amphetamine, nicotine or oxycodone. In the presence of the drug, exposed animals showed altered behavior, consistent with effects seen in mammalian systems, including impaired locomotion and altered habituation to acoustic startle. Differences in responses seen following acute and chronic exposure suggest adaptation to the presence of the drug. Transcriptomic analysis of exposed larvae revealed differential expression of numerous genes and alterations in many pathways, including those related to cell death, immunity and circadian rhythm regulation. Differential expression of circadian rhythm genes did not correlate with behavioral changes in the larvae, however, two of the circadian genes, arntl2 and per2, were also differentially expressed at later stages of development, suggesting a long-lasting impact of developmental exposures on circadian gene expression. The immediate-early genes, egr1, egr4, fosab, and junbb, which are associated with synaptic plasticity, were downregulated by all three drugs and in situ hybridization showed that the expression for all four genes was reduced across all neuroanatomical regions, including brain regions implicated in reward processing, addiction and other psychiatric conditions. We anticipate that these early changes in gene expression in response to drug exposure are likely to contribute to the consequences of prenatal exposure and their discovery might pave the way to therapeutic intervention to ameliorate the long-lasting deficits.

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sujeenthar Tharmalingam ◽  
Sandhya Khurana ◽  
Alyssa Murray ◽  
Jeremy Lamothe ◽  
T. C. Tai

Abstract Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. We have previously demonstrated that antenatal dexamethosone (DEX) administration in Wistar-Kyoto dams results in offspring with increased blood pressure coupled with elevated plasma epinephrine levels. In order to elucidate the molecular mechanisms responsible for prenatal DEX-mediated programming of hypertension, a whole-transcriptome analysis was performed on DEX programmed WKY male adrenal glands using the Rat Gene 2.0 microarray. Differential gene expression (DEG) analysis of DEX-exposed offspring compared with saline-treated controls revealed 142 significant DEGs (109 upregulated and 33 downregulated genes). DEG pathway enrichment analysis demonstrated that genes involved in circadian rhythm signaling were most robustly dysregulated. RT-qPCR analysis confirmed the increased expression of circadian genes Bmal1 and Npas2, while Per2, Per3, Cry2 and Bhlhe41 were significantly downregulated. In contrast, gene expression profiling of Spontaneously Hypertensive (SHR) rats, a genetic model of hypertension, demonstrated decreased expression of Bmal1 and Npas2, while Per1, Per2, Per3, Cry1, Cry2, Bhlhe41 and Csnk1D were all upregulated compared to naïve WKY controls. Taken together, this study establishes that glucocorticoid programmed adrenals have impaired circadian signaling and that changes in adrenal circadian rhythm may be an underlying molecular mechanism responsible for the development of hypertension.


2020 ◽  
Vol 174 (2) ◽  
pp. 210-217
Author(s):  
Theodore A Slotkin ◽  
Samantha Skavicus ◽  
Edward D Levin ◽  
Frederic J Seidler

Abstract Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.


2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 157-158
Author(s):  
Wellison Jarles Da Silva Diniz ◽  
Lawrence P Reynolds ◽  
Alison K Ward ◽  
Pawel P Borowicz ◽  
Kevin K K Sedivec ◽  
...  

Abstract Vitamins and minerals are essential for proper fetal and placental development and function. However, the impact of micronutrient supplementation on placental function and gene expression remains unclear. Herein, we performed a transcriptomic analysis to determine the impact of pre-breeding maternal micronutrient supplementation on the gene expression of placental caruncles (CAR; maternal placenta). Crossbred Angus beef heifers were supplemented (VTM, n = 7) or not (CON, n = 7) with 113 g•heifer-1•d-1 of mineral premix (Purina® Wind & Rain® Storm® All-Season 7.5 Complete) from d 71 to 148 before breeding and until d 83 of gestation. After breeding, heifers were fed a diet to gain 0.79 kg/d. Uteroplacental tissues were collected at d 83. The largest placentome closest to the fetus was collected, and CAR was manually dissected from the cotyledon. Total RNA was isolated from CAR, and gene expression was measured with RNA-Seq. After data quality control and read mapping, differential expression was performed using DESeq2. We identified 46 upregulated and 19 downregulated genes in the VTM group (adj.Pval < 0.1). ShinyGO pathway analysis software was used to identify genes in the Ca and CGMP-PKG signaling pathways, including CALM2 and CAMK2G, which were down and upregulated, respectively. Calcium-mediated systems may activate steroidogenic activity in bovine placentomes, while the cGMP-PKG pathway plays a key role in vascular homeostasis mediated by nitric oxide and decreased Ca concentrations. Furthermore, biological processes underlying blood circulation were among those over-represented. Previous studies report that maternal nutrition may impact placental vascularity and uterine blood flow. ATP2B, that is upregulated in the VTM group, is a calcium/calmodulin-regulated, magnesium-dependent protein involved in intracellular Ca homeostasis. In summary, pre-breeding and early gestation maternal micronutrient supplementation leads to differential expression of genes involved in Ca homeostasis and has a putative effect on placenta vascular function.


Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1614
Author(s):  
Subramaniam Jayanthi ◽  
Michael T. McCoy ◽  
Jean Lud Cadet

Methamphetamine (METH)-use disorder (MUD) is a very serious, potentially lethal, biopsychosocial disease. Exposure to METH causes long-term changes to brain regions involved in reward processing and motivation, leading vulnerable individuals to engage in pathological drug-seeking and drug-taking behavior that can remain a lifelong struggle. It is crucial to elucidate underlying mechanisms by which exposure to METH leads to molecular neuroadaptive changes at transcriptional and translational levels. Changes in gene expression are controlled by post-translational modifications via chromatin remodeling. This review article focuses on the brain-region specific combinatorial or distinct epigenetic modifications that lead to METH-induced changes in gene expression.


1998 ◽  
Vol 25 (1) ◽  
pp. 169-194 ◽  
Author(s):  
Carol L. Wagner ◽  
Lakshmi D. Katikaneni ◽  
Toby H. Cox ◽  
Rita M. Ryan

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Diego Marques-Coelho ◽  
◽  
Lukas da Cruz Carvalho Iohan ◽  
Ana Raquel Melo de Farias ◽  
Amandine Flaig ◽  
...  

AbstractAlzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Yet, the pathophysiological processes involved in AD onset and progression are still poorly understood. Among numerous strategies, a comprehensive overview of gene expression alterations in the diseased brain could contribute for a better understanding of the AD pathology. In this work, we probed the differential expression of genes in different brain regions of healthy and AD adult subjects using data from three large transcriptomic studies: Mayo Clinic, Mount Sinai Brain Bank (MSBB), and ROSMAP. Using a combination of differential expression of gene and isoform switch analyses, we provide a detailed landscape of gene expression alterations in the temporal and frontal lobes, harboring brain areas affected at early and late stages of the AD pathology, respectively. Next, we took advantage of an indirect approach to assign the complex gene expression changes revealed in bulk RNAseq to individual cell types/subtypes of the adult brain. This strategy allowed us to identify previously overlooked gene expression changes in the brain of AD patients. Among these alterations, we show isoform switches in the AD causal gene amyloid-beta precursor protein (APP) and the risk gene bridging integrator 1 (BIN1), which could have important functional consequences in neuronal cells. Altogether, our work proposes a novel integrative strategy to analyze RNAseq data in AD and other neurodegenerative diseases based on both gene/transcript expression and regional/cell-type specificities.


2015 ◽  
Vol 9s2 ◽  
pp. SART.S23544 ◽  
Author(s):  
Carolien Konijnenberg

Prenatal drug exposure is a common public health concern that can result in perinatal complications, birth defects, and developmental disorders. The growing literature regarding the effects of prenatal exposure to specific drugs such as tobacco, alcohol, cocaine, and heroin is often conflicting and constantly changing. This review discusses several reasons why the effects of prenatal drug exposure are so difficult to determine, including variations in dose, timing, duration of exposure, polydrug use, unreliable measures of drug exposure, latent or “sleeper” effects, genetic factors, and socioenvironmental influences. In addition to providing research guidelines, this review also aims to help clinicians and policy makers to identify the strengths and weaknesses in studies investigating the effects of prenatal drug exposure. This knowledge may be used to make better informed decisions regarding the appropriate treatment for pregnant, drug-dependent women and their children.


2021 ◽  
Author(s):  
C Figueroa ◽  
H Yang ◽  
J DiSpirito ◽  
JR Bourgeois ◽  
G Kalyanasundaram ◽  
...  

AbstractDrug and alcohol use during adolescence is common, and data in both humans and preclinical animal models clearly indicate drug exposure during adolescence increases the risk of substance use and other mental health disorders later in life. Adolescence is a period of social, emotional, and cognitive development, and is characterized by increased exploratory behavior, risk-taking, and peer-centered social interactions. These are thought to be behavioral manifestations of developmental plasticity in ‘reward’ regions of the brain. Human data indicate that adolescence is not a unitary developmental period, but rather different neural and behavioral sequelae can be observed in early vs. late adolescence. However, most studies with rodent models examine a single adolescent age compared to a mature adult age, and often only in males. Herein, we sought to determine whether the acute response to the opioid morphine would also differ across adolescence, and by sex. By quantifying c-Fos positive cells, a proxy for neural activity, at different stages during adolescence (pre-, early, mid-, and late adolescence) and in multiple reward regions (prefrontal cortex, nucleus accumbens, caudate/putamen), we determined that acute morphine can either reduce or increase c-Fos expression dependent on adolescent age, sex, and brain region. These data suggest that heterogeneity in the consequences of adolescent opioid exposure may be due to the interaction between age- and sex-specific developmental profiles of reward processing in individual brain regions. In future studies, it will be important to add age within adolescence as an independent variable to fully capture the consequences of healthy or abnormal reward-related neural development.


2021 ◽  
Author(s):  
JG Ramaekers ◽  
NL Mason ◽  
SW Toennes ◽  
EL Theunissen ◽  
E Amico

AbstractResting state fMRI has been employed to identify alterations in functional connectivity within or between brain regions following acute and chronic exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive component in cannabis. Most studies focused a priori on a limited number of local brain areas or circuits, without considering the impact of cannabis on wholebrain network organization. The present study attempted to identify changes in the wholebrain human functional connectome as assessed with ultra-high field (7T) resting state scans of occasional (N=12) and chronic cannabis users (N=14) during placebo and following vaporization of cannabis. Two distinct data-driven methodologies, i.e. network-based statistics (NBS) and connICA, were used to identify changes in functional connectomes associated with acute cannabis intoxication and chronic cannabis use. Both methodologies revealed a broad state of hyperconnectivity within the entire range of major brain networks in chronic cannabis users compared to occasional cannabis users, which might be reflective of an adaptive network reorganization following prolonged cannabis exposure. The connICA methodology also extracted a distinct spatial connectivity pattern of hypoconnectivity involving the dorsal attention, limbic, subcortical and cerebellum networks and of hyperconnectivity between the default mode and ventral attention network, that was associated with the feeling of subjective high during THC intoxication across both user groups. Whole-brain network approaches identified spatial patterns in functional brain connectomes that distinguished acute from chronic cannabis use, and offer an important utility for probing the interplay between short and long-term alterations in functional brain dynamics when progressing from occasional to chronic use of cannabis.


2021 ◽  
Author(s):  
Z Yan Wang ◽  
Grace C. McKenzie-Smith ◽  
Weijie Liu ◽  
Hyo Jin Cho ◽  
Talmo D Pereira ◽  
...  

Social isolation, particularly in early life, leads to deleterious physiological and behavioral outcomes. Few studies, if any, have been able to capture the behavioral and neurogenomic consequences of early life social isolation together in a single social animal system. Here, we leverage new high-throughput tools to comprehensively investigate the impact of isolation in the bumblebee (Bombus impatiens) from behavioral, molecular, and neuroanatomical perspectives. We reared newly emerged bumblebees either in complete isolation, small groups, or in their natal colony, and then analyzed their behaviors while alone or paired with another bee. We find that when alone, individuals of each rearing condition show distinct behavioral signatures. When paired with a conspecific, bees reared in small groups or in the natal colony express similar behavioral profiles. Isolated bees, however, showed increased social interactions. To identify the neurobiological correlates of these differences, we quantified brain gene expression and measured the volumes of key brain regions for a subset of individuals from each rearing condition. Overall, we find that isolation increases social interactions and disrupts gene expression and brain development. Limited social experience in small groups is sufficient to preserve typical patterns of brain development and social behavior.


Sign in / Sign up

Export Citation Format

Share Document