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Untangling Appetite Circuits with Optogenetics and Chemogenetics
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Interestingly, the termination of feeding behavior as a result of diphtheria-toxin directed deletion of ARCAgRP neurons can be rescued by the delivery of the GABAA receptor partial agonist bretazenil, specifically to the PBN, suggesting that hyperactivity within the PBN following loss of GABAergic input from ARCAgRP neurons promotes anorexia (Wu, Boyle, and Palmiter 2009). Of note, although ARCAgRP neurons are monosynaptically connected to PBN cells, optogenetic photostimulation of this discrete terminal field was insufficient to orchestrate food intake (Atasoy et al. 2012). However, these ARCAgRP ablation studies unveiled the PBN as a critical structural relay in signaling satiety. It is hypothesized that the loss of GABA signaling from ARCAgRP within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. A pivotal study uncovered the source of excitatory inputs to the PBN coming from glutamatergic neurons, marked by vesicular glutamate transporter 2 (vGLUT2) in the NTS. These NTSvGLUT2 neurons, via a caudal serotonergic signaling pathway, project to and control the excitability of PBN neurons and inhibit feeding. Further strengthening these results, genetic inactivation of glutamatergic signaling by the NTS onto N-methyl-d-aspartate-type glutamate receptors (NMDARs) in the PBN prevents starvation (Wu, Clark, and Palmiter 2012).
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
After glutamate is synthesized in the neuron, it is transported into the synaptic vesicles via a transporter. The vesicular glutamate transporter protein is apparently the same transporter that moves inorganic phosphate ions across the cell membrane, but the one found in synaptic vesicles of glutamatergic neurons has been called VGLUT.173 Three subtypes of VGLUT are expressed in the brain (VGLUT1–3).168 Glutamate is released from neurons in a calcium-dependent manner by exocytosis.58,168 Zinc is colocalized with glutamate in a subpopulation of synaptic vesicles in the brain and is released together with glutamate, allowing it to have a modulatory effect on some glutamate receptors.168
Phytochemical, Pharmacological and Therapeutic Profile of Bacopa monnieri
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Muhammad Shahid, Fazal Subhan, Nazar Ul Islam, Ihsan Ullah, Javaid Alam, Nisar Ahmad, Gowhar Ali
Bacopa monnieri is a well-known nootropic drug (Kasture et al. 2007) that has the potential to improve cognition – particularly the speed of attention (Kongkeaw et al. 2014). It produces enhanced memory retention and spatial learning performance (Vollala et al. 2010; Promsuban et al. 2017). The cognitive-enhancing effect of Bacopa monnieri is mediated through increased cerebral blood flow (Kamkaew et al. 2012); inhibition of acetylcholinesterase (Das et al. 2002); increased expression of serotonin reuptake transporter with increased synthesis (Charles et al. 2011) and level of serotonin (Dulcy and Rajan 2009); upregulation of the 5-HT3A receptor that facilitates the release of acetylcholine in the hippocampus and may activate GABAergic neurons – which enhances GABA release (Rajan et al. 2011); decreased neuronal degeneration, plasma corticosterone, oxidative stress and increased cytochrome-c activity, with concomitant increase in the ATP levels (Hota et al. 2009); increased protein kinase activity with increased protein content; decreased norepinephrine level; downregulation of Hif-1α and upregulation of Fmr-1 expression; increased levels of antioxidant enzymes and differential regulation of the activity of histone acetylation and protein phosphatases (PP1a, PP2A) in the hippocampus (Dhawan and Singh 1996; Khan et al. 2014; Preethi et al. 2014; Rani and Prasad 2015); increased synaptic plasticity (Preethi et al. 2012); stimulation of thyroid function (Kar et al. 2002); restoration of NR1 expression and binding of REST/NRSF to NR1 promoter (Verma et al. 2015); and increased vesicular glutamate transporter type 2 (VGLUT2) in the prefrontal cortex (Piyabhan and Wetchateng 2014). Moreover, Bacopa monnieri restores the cognitive deficits related to cerebral ischemia, and this protective effect has been attributed in part to the presence of bacopaside-I via PKC and PI3K/Akt mechanisms (Le et al. 2015).
Genetic and epigenetic studies of opioid abuse disorder – the potential for future diagnostics
Published in Expert Review of Molecular Diagnostics, 2023
Sarah Abdulmalek, Gary Hardiman
As global deletion of the oprm1 gene resulted in reduced self-administration of cocaine, amphetamine, nicotine, and cannabinoid, it also impaired the animals’ behavior where they displayed signs of autistic-like behavior [3,58]. Furthermore, selective approaches in gene manipulation revealed more potentials. Recent studies have shown that conditional knockout (KO) of oprm1 in the forebrain GABAergic neurons reduced the consumption of alcohol and decreased alcohol-associated conditioned place preference (CPP) in mice [59]. CPP is an experimental technique that is used to monitor the rewarding effect of drugs. A recent study by Reeves and colleagues showed that conditional knockout of MOR in the thalamo-striatal type 2 vesicular glutamate transporter-expressing synapses (vGluT2) inhibited glutamate transmission at those synapses and disrupted oxycodone-related CPP without interfering with its antinociceptive properties [60]. Interestingly, these mice did not show withdrawal symptoms following treatment with naloxone. Meanwhile, activation of MORs in the NAc shell has been reported to regulate the appetitive behavior [61].
Glutamatergic dysregulation in mood disorders: opportunities for the discovery of novel drug targets
Published in Expert Opinion on Therapeutic Targets, 2020
Panek Małgorzata, Kawalec Paweł, Malinowska Lipień Iwona, Tomasz Brzostek, Pilc Andrzej
Glutamate is the main stimulatory neurotransmitter in the central nervous system. Glu is the anion of glutamic acid and is the predominant form in physiological conditions. It plays an important role in the maturation of neurons, regulating their proliferation and migration processes during nervous system development. Additionally, it has a significant impact on cognition (e.g. learning and memory) as well as many other processes (e.g. it regulates the conduction of pain sensation in the spinal cord and brain). Glu is synthesized from glutamine in glutamatergic neurons by the mitochondrial enzyme glutaminase. With the aid of the vesicular glutamate transporter, Glu enters synaptic vesicles. During neuronal depolarization, the released Glu enters the synaptic space, stimulating numerous receptors. After its release, glutamate does not undergo enzymatic decomposition but is intercepted into the neighboring glial cells through the EAAT. Then, under the influence of the glutamine synthetase enzyme, it is converted into glutamine [13,25] Centelles et al. [25] depicted graphically the exact metabolism of glutamate)
Excitatory transmission from ventral pallidum to lateral habenula mediates depression
Published in The World Journal of Biological Psychiatry, 2020
Bin Liu, Yurong Cao, Jing Wang, Jicheng Dong
LHb receives presynaptic inputs from several brain regions of limbic and basal ganglion structures, including ventral pallidum (VP), paraventricular nucleus (PVN), etc., and these pathways modulate emotion related behaviours (Yang et al. 2018b). In particular, VP is a key convergent point for input from various brain structures related to reward, motivation and hedonics, and thus plays an important role in depression (Smith et al. 2009). Previous studies found that chronic social defeat stress (CSDS)-induced depressed mice showed increased activity of VP parvalbumin-positive (PV) neurons. Furthermore, they revealed a PVVP→LH projection and found that silencing this circuit attenuated depressive-like behavioural despair in the CSDS model (Knowland et al. 2017). On the other hand, a substantial proportion of VP neurons are glutamatergic (expressing vesicular glutamate transporter 2 (VGluT2) mRNA), especially in the ventromedial VP (Root et al. 2015). The VP are found to project to LHb (Tripathi et al. 2013). However, whether the glutamatergic VP neurons project to LHb remains unclear. This study investigated the glutamatergic VP→LH projection and the function of this circuit in negative emotions and depression-like behaviour.