Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring

2020 ◽  
Vol 174 (2) ◽  
pp. 210-217
Author(s):  
Theodore A Slotkin ◽  
Samantha Skavicus ◽  
Edward D Levin ◽  
Frederic J Seidler
Keyword(s):  
Brain Development ◽  
Choline Acetyltransferase ◽  
Drug Exposure ◽  
Brain Regions ◽  
Synaptic Function ◽  
Male Rats ◽  
High Dose ◽  
Age Related ◽  
The Impact ◽  
Ach Receptors

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.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals Function of Neuromuscular Synapses in the Zebrafish Choline-Acetyltransferase Mutant bajan

2008 ◽  
Vol 100 (4) ◽  
pp. 1995-2004 ◽  
Author(s):  
Meng Wang ◽  
Hua Wen ◽  
Paul Brehm
Keyword(s):  
Choline Acetyltransferase ◽  
Residual Activity ◽  
Direct Consequence ◽  
Synaptic Function ◽  
Congenital Myasthenic Syndrome ◽  
Quantal Content ◽  
Quantal Size ◽  
Gene Coding ◽  
Myasthenic Syndrome ◽  
The Impact

We have identified a zebrafish mutant line, bajan, in which compromised motility and fatigue result from a point mutation in the gene coding choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis. Although the mutation predicts loss of ChAT function, bajan inexplicably retains low levels of neuromuscular transmission. We exploited this residual activity and determined the consequences for synaptic function. The attenuated synaptic responses were a direct consequence of a decrease in both resting mean quantal size and quantal content. To replicate behavioral fatigue in swimming, motorneurons were stimulated at high frequencies. A prominent reduction in quantal content, reflecting vesicle depletion, was coincident with a small additional reduction in quantal size. In humans, defective ChAT leads to episodic apnea, a form of congenital myasthenic syndrome characterized by use-dependent fatigue. In contrast to bajan, however, afflicted individuals exhibit a normal resting quantal size and quantal content. The fatigue in humans results from a pronounced long-lasting drop in quantal size with little or no change in quantal content. These differences have important implications for interpreting fatigue as well as on understanding the impact of ACh availability on vesicle filling and recycling.

Growth and development of the organism and immunophysiological indices of blood of male F2 rats, affected by different doses of nanogermanium citrate

2017 ◽  
Vol 4 (2) ◽  
pp. 14-22 ◽  
Author(s):  
R. Fedoruk ◽  
U. Tesarivska ◽  
M. Khrabko ◽  
M. Tsap
Keyword(s):  
Growth And Development ◽  
Male Rats ◽  
Lower Content ◽  
Internal Organs ◽  
Hematological Indices ◽  
Age Related ◽  
Coeffi Cients ◽  
Group Ii ◽  
The Impact ◽  
Different Doses

Aim. To study age-related changes in the bodyweight, internal organs, and immunophysiological indices of blood for male F 2 rats, affected by different doses of nanogermanium citrate. Methods. Physiological, immunological, clinical, colorimetric, and statistical methods were applied; automatic veterinary analyzer Orphee Mythic 18 Vet (Germany) was used to determine hematological indices. Results. The decade-wise dynamics of changes in the bodyweight, the weight of heart, liver, kidneys, testicles, lungs, spleen, and weight coeffi cients of these organs at the age of 2–3 and 4–5 months demonstrated that there were intergroup dose-dependent and age-related differences in the intensity of growth and development of the organism of male rats. The highest gain of bodyweight was registered for male rates, which received 10 μg Ge/kg of bodyweight 30 days after weaning, this tendency was kept for the lower level of these indices in groups ІІІ and IV at the effect of 20 and 200 μg Ge. On days 97, 107, and 117, males of group II and IV demonstrated non-reliably lower indices of bodyweight, whereas in group III their values did not differ much from those for the control. Reliably higher indices of weight of liver and spleen were demonstrated along with their weight coeffi cients for younger males, but they were lower at the age of 4–5 months compared to the control. The blood of 2–3 m.o. group II males had reliably lower content of hemoglobin and hematocrit index as well as the tendency to the decrease in the number of erythrocytes. At the age of 4–5 months, there was an evident decrease in the number of leukocytes and their forms – lymphocytes, monocytes, and granulocytes, which was more expressed in the blood of group II and IV males compared to the control. At the impact of nanogermanium citrate (NGeC), the blood of males of experimental groups of both age periods demonstrated higher content of immunoglobulins, circulating immune complexes, hexoses, bound to proteins, and ceruloplasmin (except for group II animals at the age of 4 months). The effect of applied doses of NGeC inhibited the input of acute phase proteins into the blood which was evident in the reliably lower content of mean mass molecules at the age of 2–3 months with its staying at the level of the control group of animals at the age of 4– months. Conclusions. The biological effect of NGeC in the doses of 10, 20, and 200 μg Ge/kg of bodyweight was demonstrated in differently directed changes in the intensity of organism growth and development, specifi c internal organs, and hematological indices, which was more expressed for animals, receiving 10 μg Ge, as well as in the differences in immunophysiological indices of blood of males of the experimental groups of both age periods, which indicated the activation of immunobiological reactivity of their organism at the age of 2–3 and 4–5 months.

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

1991 ◽  
Vol 9 (10) ◽  
pp. 1811-1820 ◽  
Author(s):  
J L Grem ◽  
N McAtee ◽  
R F Murphy ◽  
F M Balis ◽  
S M Steinberg ◽  
...  
Keyword(s):  
Pilot Study ◽  
Drug Exposure ◽  
High Dose ◽  
Gastrointestinal Carcinoma ◽  
Time Curve ◽  
Recombinant Interferon ◽  
Dose Dependent Decrease ◽  
Grade 3 ◽  
The Impact ◽  
Dose Dependent

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

scholarly journals Neuroscience Research on Human Visual Path Integration: Empirical Overview and Strategic Considerations

2021 ◽  
Author(s):  
Jimmy Y. Zhong
Keyword(s):  
Path Integration ◽  
Hippocampal Formation ◽  
Brain Activity ◽  
Brain Regions ◽  
Neural Basis ◽  
Age Related ◽  
Neuroscience Research ◽  
Integration Strategies ◽  
The Impact ◽  
The Brain

Over the past two decades, many neuroimaging studies have attempted uncover the brain regions and networks involved in path integration and identify the underlying neurocognitive mechanisms. Although these studies made inroads into the neural basis of path integration, they have yet to offer a full disclosure of the functional specialization of the brain regions supporting path integration. In this paper, I reviewed notable neuroscientific studies on visual path integration in humans, identified the commonalities and discrepancies in their findings, and incorporated fresh insights from recent path integration studies. Specifically, this paper presented neuroscientific studies performed with virtual renditions of the triangle/path completion task and addressed whether or not the hippocampus is necessary for human path integration. Based on studies that showed evidence supporting and negating the involvement of the hippocampal formation in path integration, this paper introduces the proposal that the use of different path integration strategies may determine the extent to which the hippocampus and entorhinal cortex are engaged during path integration. To this end, recent studies that investigated the impact of different path integration strategies on behavioral performance and functional brain activity were discussed. Methodological concerns were raised with feasible recommendations for improving the experimental design of future strategy-related path integration studies, which can cover cognitive neuroscience research on age-related differences in the role of the hippocampal formation in path integration and Bayesian modelling of the interaction between landmark and self-motion cues. The practical value of investigating different path integration strategies was also discussed briefly from a biomedical perspective.

scholarly journals High Caloric Diet Induces Memory Impairment and Disrupts Synaptic Plasticity in Aged Rats

2021 ◽  
Vol 43 (3) ◽  
pp. 2305-2319
Author(s):  
Sara L. Paulo ◽  
Catarina Miranda-Lourenço ◽  
Rita F. Belo ◽  
Rui S. Rodrigues ◽  
João Fonseca-Gomes ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Memory Impairment ◽  
Overweight And Obesity ◽  
Synaptic Function ◽  
Male Rats ◽  
Standard Diet ◽  
Aged Rats ◽  
High Caloric Diet ◽  
The Impact

The increasing consumption of sugar and fat seen over the last decades and the consequent overweight and obesity, were recently linked with a deleterious effect on cognition and synaptic function. A major question, which remains to be clarified, is whether obesity in the elderly is an additional risk factor for cognitive impairment. We aimed at unravelling the impact of a chronic high caloric diet (HCD) on memory performance and synaptic plasticity in aged rats. Male rats were kept on an HCD or a standard diet (control) from 1 to 24 months of age. The results showed that under an HCD, aged rats were obese and displayed significant long-term recognition memory impairment when compared to age-matched controls. Ex vivo synaptic plasticity recorded from hippocampal slices from HCD-fed aged rats revealed a reduction in the magnitude of long-term potentiation, accompanied by a decrease in the levels of the brain-derived neurotrophic factor receptors TrkB full-length (TrkB-FL). No alterations in neurogenesis were observed, as quantified by the density of immature doublecortin-positive neurons in the hippocampal dentate gyrus. This study highlights that obesity induced by a chronic HCD exacerbates age-associated cognitive decline, likely due to impaired synaptic plasticity, which might be associated with deficits in TrkB-FL signaling.

scholarly journals Abnormal brain development in child and adolescent carriers of mutant huntingtin

Neurology ◽  
2019 ◽  
Vol 93 (10) ◽  
pp. e1021-e1030 ◽  
Author(s):  
Ellen van der Plas ◽  
Douglas R. Langbehn ◽  
Amy L. Conrad ◽  
Timothy R. Koscik ◽  
Alexander Tereshchenko ◽  
...  
Keyword(s):  
Brain Development ◽  
Longitudinal Design ◽  
Structural Mri ◽  
Child And Adolescent ◽  
Brain Regions ◽  
Clinical Onset ◽  
Age Related ◽  
Cag Expansion ◽  
Accelerated Longitudinal Design ◽  
Abnormal Brain

ObjectiveThe huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development.MethodsChildren and adolescents (age 6–18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated.ResultsAge-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions.ConclusionOur results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.

scholarly journals Antioxidant Effects ofSatureja hortensisL. Attenuate the Anxiogenic Effect of Cisplatin in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Igor Kumburovic ◽  
Dragica Selakovic ◽  
Tatjana Juric ◽  
Nemanja Jovicic ◽  
Vladimir Mihailovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Anxiolytic Effect ◽  
Optimal Dose ◽  
Brain Regions ◽  
Male Rats ◽  
High Dose ◽  
Tissue Samples ◽  
Anxiogenic Effect ◽  
Antioxidant Effects

Numerous adverse effects of cisplatin-based therapy are usually accompanied by enhanced oxidative damage and cell apoptosis in various tissues. Even neurotoxic manifestations of cisplatin administration, such as the anxiogenic effect, appear along with the increased oxidative stress and apoptotic indicators in certain brain regions. Thirty-five Wistar albino male rats were divided into seven groups: control, cisplatin (received a single dose of cisplatin: 7.5 mg/kg), three groups with oral administration ofSatureja hortensisL. methanolic extract (SH) (low: 50 mg/kg, middle: 100 mg/kg, and high dose: 200 mg/kg) along with cisplatin application, a group with the extract in high dose alone, and a silymarin group (cisplatin and silymarin: 100 mg/kg), in order to evaluate the antioxidant effects of SH on cisplatin-induced increase in the anxiety level. After completing 10-day pretreatments, behavioral testing was performed in the open field and the elevated plus maze, followed by an investigation of oxidative stress and apoptosis parameters in hippocampal tissue samples. Cisplatin administration resulted in anxiogenic-like behavior, increased lipid peroxidation, and proapoptotic markers accompanied by the decline in antioxidant and antiapoptotic defense. The administration of extract alone did not significantly alter any of the estimated parameters. When applied along with cisplatin, SH in a dose of 100 mg/kg induced the significant anxiolytic effect with concomitant recovery of antioxidant and antiapoptotic activity indicators, while both lower and higher doses of the extract failed to improve the adverse effects of cisplatin administration. The beneficial effects of the middle dose of SH were equivalent to the same dose of silymarin, as a “golden standard.” Our results indicate that the antioxidant supplementation with SH in an optimal dose significantly improved the oxidative status and it had antiapoptotic effect in the rat hippocampus disturbed by cisplatin administration, which was accompanied with attenuation of cisplatin-induced anxiogenic effect.

scholarly journals Hyperexcitability and Homeostasis in Fragile X Syndrome

2022 ◽  
Vol 14 ◽  
Author(s):  
Xiaopeng Liu ◽  
Vipendra Kumar ◽  
Nien-Pei Tsai ◽  
Benjamin D. Auerbach
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Inhibitory Neuron ◽  
Cell Types ◽  
Developmental Time ◽  
Brain Regions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Neuron Activity ◽  
The Impact

Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability, resulting from a mutation in the FMR1 gene and subsequent loss of its protein product FMRP. Despite this simple genetic origin, FXS is a phenotypically complex disorder with a range of physical and neurocognitive disruptions. While numerous molecular and cellular pathways are affected by FMRP loss, there is growing evidence that circuit hyperexcitability may be a common convergence point that can account for many of the wide-ranging phenotypes seen in FXS. The mechanisms for hyperexcitability in FXS include alterations to excitatory synaptic function and connectivity, reduced inhibitory neuron activity, as well as changes to ion channel expression and conductance. However, understanding the impact of FMR1 mutation on circuit function is complicated by the inherent plasticity in neural circuits, which display an array of homeostatic mechanisms to maintain activity near set levels. FMRP is also an important regulator of activity-dependent plasticity in the brain, meaning that dysregulated plasticity can be both a cause and consequence of hyperexcitable networks in FXS. This makes it difficult to separate the direct effects of FMR1 mutation from the myriad and pleiotropic compensatory changes associated with it, both of which are likely to contribute to FXS pathophysiology. Here we will: (1) review evidence for hyperexcitability and homeostatic plasticity phenotypes in FXS models, focusing on similarities/differences across brain regions, cell-types, and developmental time points; (2) examine how excitability and plasticity disruptions interact with each other to ultimately contribute to circuit dysfunction in FXS; and (3) discuss how these synaptic and circuit deficits contribute to disease-relevant behavioral phenotypes like epilepsy and sensory hypersensitivity. Through this discussion of where the current field stands, we aim to introduce perspectives moving forward in FXS research.

scholarly journals Isolation disrupts social interactions and destabilizes brain development in bumblebees

2021 ◽  
Author(s):  
Z Yan Wang ◽  
Grace C. McKenzie-Smith ◽  
Weijie Liu ◽  
Hyo Jin Cho ◽  
Talmo D Pereira ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Development ◽  
Social Interactions ◽  
Social Isolation ◽  
Small Groups ◽  
Early Life ◽  
Brain Regions ◽  
Brain Gene Expression ◽  
Rearing Condition ◽  
The Impact

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.

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