Publications by authors named "Harbinder S Dhillon"

5 Publications

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Synaptic vesicle fusion is modulated through feedback inhibition by dopamine auto-receptors.

Synapse 2020 01 23;74(1):e22131. Epub 2019 Sep 23.

Department of Biological Sciences, Delaware State University, Dover, Delaware.

Mechanisms of synaptic vesicular fusion and neurotransmitter clearance are highly controlled processes whose finely-tuned regulation is critical for neural function. This modulation has been suggested to involve pre-synaptic auto-receptors; however, their underlying mechanisms of action remain unclear. Previous studies with the well-defined C. elegans nervous system have used functional imaging to implicate acid sensing ion channels (ASIC-1) to describe synaptic vesicle fusion dynamics within its eight dopaminergic neurons. Implementing a similar imaging approach with a pH-sensitive fluorescent reporter and fluorescence resonance after photobleaching (FRAP), we analyzed dynamic imaging data collected from individual synaptic termini in live animals. We present evidence that constitutive fusion of neurotransmitter vesicles on dopaminergic synaptic termini is modulated through DOP-2 auto-receptors via a negative feedback loop. Integrating our previous results showing the role of ASIC-1 in a positive feedback loop, we also put forth an updated model for synaptic vesicle fusion in which, along with DAT-1 and ASIC-1, the dopamine auto-receptor DOP-2 lies at a modulatory hub at dopaminergic synapses. Our findings are of potential broader significance as similar mechanisms are likely to be used by auto-receptors for other small molecule neurotransmitters across species.
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http://dx.doi.org/10.1002/syn.22131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336876PMC
January 2020

Assessment of the Effects of Endocrine Disrupting Compounds on the Development of Vertebrate Neural Network Function Using Multi-electrode Arrays.

J Vis Exp 2018 04 26(134). Epub 2018 Apr 26.

Department of Biological Sciences, Delaware State University;

Bis-phenols, such as bis-phenol A (BPA) and bis-phenol-S (BPS), are polymerizing agents widely used in the production of plastics and numerous everyday products. They are classified as endocrine disrupting compounds (EDC) with estradiol-like properties. Long-term exposure to EDCs, even at low doses, has been linked with various health defects including cancer, behavioral disorders, and infertility, with greater vulnerability during early developmental periods. To study the effects of BPA on the development of neuronal function, we used an in vitro neuronal network derived from the early chick embryonic brain as a model. We found that exposure to BPA affected the development of network activity, specifically spiking activity and synchronization. A change in network activity is the crucial link between the molecular target of a drug or compound and its effect on behavioral outcome. Multi-electrode arrays are increasingly becoming useful tools to study the effects of drugs on network activity in vitro. There are several systems available in the market and, although there are variations in the number of electrodes, the type and quality of the electrode array and the analysis software, the basic underlying principles, and the data obtained is the same across the different systems. Although currently limited to analysis of two-dimensional in vitro cultures, these MEA systems are being improved to enable in vivo network activity in brain slices. Here, we provide a detailed protocol for embryonic exposure and recording neuronal network activity and synchrony, along with representative results.
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http://dx.doi.org/10.3791/56300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100960PMC
April 2018

Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants.

J Vis Exp 2018 03 6(133). Epub 2018 Mar 6.

Department of Biological Sciences, Delaware State University;

Bisphenols, such as bisphenol A (BPA) and bisphenol S (BPS) are polymerizing agents widely used in the production of plastics and numerous everyday-use products. Based on their chemical structure and estradiol-like biological properties, they have been classified as endocrine disrupting compounds (EDC). Long-term exposure to EDCs, even at low doses, has been linked to various health defects including cancer, behavioral disorders and infertility, with greater vulnerability indicated during early developmental periods. Cellular and molecular studies with the genetically tractable nematode model Caenorhabditis elegans have demonstrated that exposure to BPA causes apoptosis, embryonic lethality and disruption in the DNA repair mechanisms. We have previously reported that exposure of C. elegans embryos to low doses of different bisphenols decreases fecundity. In addition, we have shown that the effects of exposure during the very early stages of development persist into adulthood as assayed by quantifying habituation behavior, a form of non-associative learning. Here, we provide detailed protocols for embryonic exposure to low-dose EDCs as well as the associated fecundity and anterior touch habituation assays, along with representative results.
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http://dx.doi.org/10.3791/56771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931445PMC
March 2018

Effects of BPA and BPS exposure limited to early embryogenesis persist to impair non-associative learning in adults.

Behav Brain Funct 2015 Sep 17;11:27. Epub 2015 Sep 17.

Department of Biological Sciences, Delaware State University, Dover, DE, 19901, USA.

Background: Bisphenol-A (BPA) is a polymerizing agent used in plastic bottles and several routinely used consumer items. It is classified among endocrine disrupting chemicals suspected to cause adverse health effects in mammals ranging from infertility and cancer to behavioral disorders. Work with the invertebrate lab model Caenorhabditis elegans has shown that BPA affects germ cells by disrupting double-stranded DNA break repair mechanisms. The current study utilizes this model organism to provide insight into low-dose and long-term behavioral effects of BPA and bisphenol-S (BPS), a supposed safer replacement for BPA.

Findings: Experiments presented in our report demonstrate that the effects of embryonic exposure to considerably low levels of BPA persist into adulthood, affecting neural functionality as assayed by measuring habituation to mechano-sensory stimuli in C. elegans. These results are noteworthy in that they are based on low-dose exposures, following the rationale that subtler effects that may not be morphologically apparent are likely to be discernible through behavioral changes. In addition, we report that embryonic exposure to BPS follows a pattern similar to BPA.

Conclusions: Building upon previous observations using the C. elegans model, we have shown that exposure of embryos to BPA and BPS affects their behavior as adults. These long-term effects are in line with recommended alternate low-dose chemical safety testing approaches. Our observation that the effects of BPS are similar to BPA is not unexpected, considering their structural similarity. This, to our knowledge, is the first reported behavioral study on low-dose toxicity of any endocrine disrupting chemical in C. elegans.
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http://dx.doi.org/10.1186/s12993-015-0071-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573949PMC
September 2015

A synergistic approach towards understanding the functional significance of dopamine receptor interactions.

J Mol Signal 2013 Dec 5;8(1):13. Epub 2013 Dec 5.

Department of Biological Sciences, Center for Neuroscience Research, Delaware State University, Dover, DE 19901, USA.

The importance of the neurotransmitter dopamine (DA) in the nervous system is underscored by its role in a wide variety of physiological and neural functions in both vertebrates and invertebrates. Binding of dopamine to its membrane receptors initiates precise signaling cascades that result in specific cellular responses. Dopamine receptors belong to a super-family of G-protein coupled receptors (GPCRs) that are characterized by seven trans-membrane domains. In mammals, five dopamine receptors have been identified which are grouped into two different categories D1- and D2-like receptors. The interactions of DA receptors with other proteins including specific G╬▒ subunits are critical in deciding the fate of downstream molecular events carried out by effector proteins. In this mini-review we provide a synopsis of known protein-protein interactions of DA receptors and a perspective on the potential synergistic utility of Caenorhabditis elegans as a model eukaryote with a comparatively simpler nervous system to gain insight on the neuronal and behavioral consequences of the receptor interactions.
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http://dx.doi.org/10.1186/1750-2187-8-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878971PMC
December 2013