Excitatory Effects Research Articles

The orexinergic system mediates the excitatory effects of caffeine on the arousal and sympathetic activity

ObjectiveCaffeine is a non-selective adenosine receptor antagonist with pro-arousal and pro-sympathetic nervous system excitatory effects, and these pharmacological effects fit well with the physiological functions of orexin. The purpose of this study was to investigate the role of the orexinergic nervous system in the pharmacological effects of caffeine. MethodsAn animal model of sleepiness caused by adenosine accumulation was established by sleep deprivation, and caffeine's effects on the spontaneous activity and sympathetic nervous system of the model animals were evaluated by using the open-field experiment and gastrointestinal peristaltic observation, respectively, and the intervention of orexin receptor antagonists on the pharmacological effects of caffeine was also observed. ResultsMice with 8 h of sleep deprivation showed a significant decrease in spontaneous activity and a significant increase in gastrointestinal push distance. After caffeine intervention, the spontaneous activities of sleep-deprived mice significantly increased and gastrointestinal peristalsis significantly decreased dose-dependent, while orexin receptors antagonist blocked the pro-arousal and inhibitory gastrointestinal peristalsis effects of caffeine on sleep-deprived mice. ConclusionsOrexinergic nervous system mediated caffeine's excitatory effects on the pro-arousal and pro-sympathetic nervous systems. Orexin is likely to be an important performer in the pharmacological effects of caffeine.

Effect of transcranial direct current stimulation on postpartum depression: A study protocol for a randomized controlled trial.

Postpartum depression (PPD) is a complex combination of physiological, emotional, and behavioral alterations associated with postpartum chemical, social, and psychological variations. It does harm to the relationship between family members that could potentially last for years. However, standard depression treatments are not ideal for PPD, and the outcomes of these treatments are debatable. Transcranial direct current stimulation (tDCS) is an emerging technology that could provide patients with PPD with a safe and non-pharmacological treatment. tDCS can relieve depression by directly stimulating the prefrontal cortex through the excitatory effect of the anode. It may also ease depression indirectly by promoting the production and release of the neurotransmitter GABA. The mechanism of tDCS makes it an ideal therapeutic approach to treat PPD, although it has not been widely used, and its effect has not been evaluated systematically and effectively. A double-blind, randomized controlled trial will be conducted involving 240 tDCS-naive patients with PPD, who will be randomly divided into two groups. One group will receive routine clinical treatment and care with active tDCS, and the other group will receive routine clinical treatment and care with sham tDCS. Each group of patients will receive a 3-week intervention during which they will receive 20 min of active or sham tDCS 6 days per week. The Montgomery-Åsberg Depression Rating Scale will be administered before the intervention as a baseline and on each weekend throughout the intervention phase. Before and after the intervention, the Perceived Stress Scale and the Positive and Negative Affect Schedule will be evaluated. Side effects and abnormal reactions will be recorded during each treatment. As antidepressants are banned in the study, the results will not be affected by drugs and will therefore be more accurate. Nonetheless, this experiment will be conducted in a single center as a small sample experiment. Therefore, future studies are required to confirm the effectiveness of tDCS in treating PPD.

Asymptotic solutions to nonlinear Hawkes processes: A systematic classification of the steady-state solutions

Hawkes point processes are first-order non-Markovian stochastic models of intermittent bursty dynamics with applications to physical, seismic, epidemic, biological, financial, and social systems. While accounting for positive feedback loops that may lead to critical phenomena in complex systems, the standard linear Hawkes process only describes excitative phenomena. To describe the co-existence of excitatory and inhibitory effects (or negative feedbacks), extensions involving nonlinear dependences of the intensity as a function of past activity are needed. However, such nonlinear Hawkes processes have been found hitherto to be analytically intractable due to the interplay between their non-Markovian and nonlinear characteristics, with no analytical solutions available. Here, we present various exact and robust asymptotic solutions to nonlinear Hawkes processes using the field master equation approach. We report explicit power law formulas for the steady state intensity distributions $P_{\mathrm{ss}}(\lambda)\propto \lambda^{-1-a}$, where the tail exponent $a$ is expressed analytically as a function of parameters of the nonlinear Hawkes models. We present three robust interesting characteristics of the nonlinear Hawkes process: (i) for one-sided positive marks (i.e., in the absence of inhibitory effects), the nonlinear Hawkes process can exhibit any power law relation either as intermediate asymptotics ($a\leq 0$) or as true asymptotics ($a>0$) by appropriate model selection; (ii) for distribution of marks with zero mean (i.e., for balanced excitatory and inhibitory effects), the Zipf law ($a\approx 1$) is universally observed for a wide class of nonlinear Hawkes processes with fast-accelerating intensity map; (iii) for marks with a negative mean, the asymptotic power law tail becomes lighter with an exponent increasing above 1 ($a>1$) as the mean mark becomes more negative.

Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC.

Investigation of Neuromodulatory Effect of Anodal Cerebellar Transcranial Direct Current Stimulation on the Primary Motor Cortex Using Functional Near-Infrared Spectroscopy.

Cerebellar brain inhibition (CBI), a neural connection between the cerebellum and primary motor cortex (M1), has been researched as a target pathway for neuromodulation to improve clinical outcomes in various neurological diseases. However, conflicting results of anodal cerebellar transcranial direct current stimulation (acb-tDCS) on M1 excitability indicate that additional investigation is required to examine its precise effect. This study aimed to gather evidence of the neuromodulatory effect of acb-tDCS on the M1 using functional near-infrared spectroscopy (fNIRS). Sixteen healthy participants were included in this cross-over study. Participants received real and sham acb-tDCS randomly, with a minimum 1-week washout period between them. The anode and cathode were placed on the right cerebellum and the right buccinator muscle, respectively. Stimulation lasted 20min at an intensity of 2mA, and fNIRS data were recorded for 42min (including a 4-min baseline before stimulation and an 18-min post-stimulation duration) using eight channels attached bilaterally on the M1. acb-tDCS induced a significant decrease in oxyhemoglobin (HbO) concentration (inhibitory effect) in the left (contralateral) M1, whereas it induced a significant increase in HbO concentration (excitatory effect) in the right (ipsilateral) M1 compared to sham tDCS during (p < 0.05) and after stimulation (p < 0.01) in a group level analysis. At the individual level, variations in response to acb-tDCS were observed. Our findings demonstrate the neuromodulatory effects of acb-tDCS on the bilateral M1 in terms of neuronal hemodynamics.

Ketamine administration in idiopathic epileptic and healthy control dogs: Can we detect differences in brain metabolite response with spectroscopy?

In recent years ketamine has increasingly become the focus of multimodal emergency management for epileptic seizures. However, little is known about the effect of ketamine on brain metabolites in epileptic patients. Magnetic resonance spectroscopy (MRS) is a non-invasive technique to estimate brain metabolites in vivo. Our aim was to measure the effect of ketamine on thalamic metabolites in idiopathic epileptic (IE) dogs using 3 Tesla MRS. We hypothesized that ketamine would increase the glutamine-glutamate (GLX)/creatine ratio in epileptic dogs with and without antiseizure drug treatment, but not in control dogs. Furthermore, we hypothesized that no different responses after ketamine administration in other measured brain metabolite ratios between the different groups would be detected. In this controlled prospective experimental trial IE dogs with or without antiseizure drug treatment and healthy client-owned relatives of the breeds Border Collie and Greater Swiss Mountain Dog, were included. After sedation with butorphanol, induction with propofol and maintenance with sevoflurane in oxygen and air, a single voxel MRS at the level of the thalamus was performed before and 2 min after intravenous administration of 1 mg/kg ketamine. An automated data processing spectral fitting linear combination model algorithm was used to estimate all commonly measured metabolite ratios. A mixed ANOVA with the independent variables ketamine administration and group allocation was performed for all measured metabolites. A p < 0.05 was considered statistically significant. Twelve healthy control dogs, 10 untreated IE and 12 treated IE dogs were included. No significant effects for GLX/creatine were found. However, increased glucose/creatine ratios were found (p < 0.001) with no effect of group allocation. Furthermore, increases in the GABA/creatine ratio were found in IEU dogs. MRS was able to detect changes in metabolite/creatine ratios after intravenous administration of 1 mg/kg ketamine in dogs and no evidence was found that excitatory effects are induced in the thalamus. Although it is beyond the scope of this study to investigate the antiseizure potential of ketamine in dogs, results of this research suggest that the effect of ketamine on the brain metabolites could be dependent on the concentrations of brain metabolites before administration.

The Dopamine System in Mediating Alcohol Effects in Humans.

Brain-imaging studies show that the development and maintenance of alcohol use disorder (AUD) is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Altered reward processing, complex conditioning processes, impaired reinforcement learning, and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with stress, cognition, and emotion processing.

Dynamic mechanism of epileptic seizures induced by excitatory pyramidal neuronal population

&lt;abstract&gt;&lt;p&gt;The pyramidal neuronal population (PY) in the cerebral cortex is closely related to epilepsy, while the excitability of PY is directly affected by the excitatory interneurons (EIN), the inhibitory interneurons (IN), and the thalamic relay nucleus (TC). Based on this, we use the thalamocortical neural field model to explore the dynamic mechanism of system transition by taking the synaptic connection strengths of the above three nuclei on PY as the main factor affecting seizures. The results show that the excitatory effects of EIN on PY induce transitions from 1-spike and wave discharges (SWDs) to 2-spike and wave discharges (2-SWDs), the inhibitory effects of IN on PY induce transitions from saturated state to tonic oscillation state, and the excitatory effects of TC on PY induce transitions from clonic oscillation state to saturated state. According to the single-parameter bifurcation analysis, it is found that Hopf and fold limit cycle bifurcations are the key factors leading to the state transition. In addition, the state analysis of the three pathways is carried out in pairs. The results show that the system produces more types of epileptic seizures with the combined action of EIN and TC on PY. According to the two-parameter bifurcation curve, we obtain the stable parameter areas of tonic-clonic oscillations, SWDs, 2-SWDs and saturated discharges, and clearly find the reasonable transition path between tonic-clonic seizures and absence seizures. This may provide some theoretical guidance for the transmission and evolution of seizures.&lt;/p&gt;&lt;/abstract&gt;

Role of synthetical amynoquinone ethyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-ylamino) acetate in inhibition of Ehrlich’s tumor

Quinones are naturally or synthetically occurring secondary metabolites that have various bio-dynamics, highlighting their antitumor potential. This has been explored through their selective cytotoxicity, and studies in medicinal chemistry about the relation between biological activity versus chemical structure may lead to the solution of the toxicity problems associated with quinones. In this context, the antitumor effect of a synthetic naphthoquinone, named Ethyl 2-(1,4-Dioxo-1,4-Dihydronaphthalen-2-Ylamino) Acetate, was tested using mice transplanted with Ehrlich ascitic tumor as an experimental model. The acute toxicity test was performed using 30 mice that received the aminoquinone at doses of 100, 200, 300, and 600mg/kg. After evaluation of the clinical findings in the spontaneous activity tests, the LD50 calculation for the test substance showed low levels of toxicity at doses lower than 244.11±23.29mg/kg. Thus, three experimental groups were established, where animals transplanted with tumor cells received NaCl vehicle solution (control, n=6), and the others were treated with 71.7mg/kg of Methotrexate (n=6) or 20mg/kg of Aminoquinone (n=6). All administrations were intraperitoneal, in a single dose. Three days after the implantation of the tumor cells the animals were weighed daily and evaluated for tumor biometry and development. The treatments occurred five days after the implantation of the tumor cells and were extended for 7 more days. At the end of the 12-day experimental period, all animals were euthanized for biochemical and histopathological analyses of the tumors and vital organs. The spontaneous activity test showed that the amount of responses associated with the nervous system tends to increase with the increase in dosage, highlighting the excitatory effect on the central nervous system in almost all dosages employed, followed by depressant activities on this system. There was a significant tumor reduction, both in animals treated with methotrexate (71.7 %) and in those treated with aminoquinone (91.6 %) in the control group. There was no significant difference in tumor volume between the animals treated with aminoquinone or methotrexate. The histopathological analysis revealed that in both treatments there were fewer mitoses in the tumor mass compared to the control group. However, there was apparent toxicity to the liver, heart, and left kidney in the treatment with methotrexate compared to aminoquinone. The significant capacity for tumor reduction presented by aminoquinone allows pointing it as a promising alternative for the development of a more efficient drug to control tumor development, being necessary for the development of new studies to deepen the knowledge about its mechanisms of action.

Effects of the Co-Administration of Morphine and Lipopolysaccharide on Toll-Like Receptor-4/Nuclear Factor Kappa β Signaling Pathway of MDA-MB-231 Breast Cancer Cells.

The Toll-like receptor 4 (TLR4) gene promotes migration in adenocarcinoma cells. Morphine is an agonist for TLR4 that has a dual role in cancer development. The promoter or inhibitor role of morphine in cancer progression remains controversial. This study aims to evaluate the effects of morphine on the TLR4, myeloid differentiation primary response protein 88-dependent (MyD88), and nuclear factor-kappa B (NF-κB) expressions in the human MDA-MB-231 breast cancer cell line. The cells were examined after 24 hours of incubation with morphine using the Boyden chamber system. TLR4, MyD88, and NF-κB mRNA expressions were assessed using quantitative real-time polymerase chain reaction (RT-PCR). The concentration of interleukin-2 beta was also measured using the ELISA assay. According to the findings, three doses of morphine (0.25, 1.25, and 0.025 μM) increased the expression of the TLR4 and NF-κB genes, whereas no significant change was observed in the mRNA expression of MyD88. Furthermore, treatment with morphine and lipopolysaccharide (LPS) significantly decreased the expression of TLR4, MyD88, and NF-κB. However, no significant change was observed in interleukin 2 beta concentration. These findings confirmed the excitatory effects of morphine on TRL4 expression and the MYD88 signaling pathway in vitro.

Synaptic Processes in Raphe Magnus Nucleus under Activation Periaqueductal Gray Matter on the Model of Parkinson’s Disease.

The electrophysiological studies on 4 Albino rats (230 ± 30?.) on the rotenone model of Parkinson’s disease (PD), induced by unilateral injection of rotenone and kept 4 weeks has been conducted. The extracellular online recording of spike activity of 149 single neurons of the Raphe Magnus (RMG) at high frequency stimulation (HFS) of Periaqueductal gray (PAG) had produced. The programmed mathematical analysis of spikes averaged frequency, with recalculation in interpulse intervals and frequencies to assess of degree of manifestation depressor and excitatory effects as well as the frequency of pre- and post-stimulus activation degree of manifestation in terms of diagrams of averaged frequency spikes are used. On the model of PD a significant reduction in quantity of RMG neurons, evoked at HFS PAG by depressor and depressor–excitatory manifestations of activity had been revealed. On the model of PD, the significant reduction in the number of neurons RMG, responding at PAG HFS by depressor and depressor-excitatory manifestations of activity has been revealed. Analysis of relative degree of intensity of depressor and excitatory effects, by way of example diagrams average frequency of spikes, led to the conclusion. It has been discovered the prevalence of excitatory post stimulus manifestations of activity over depressive (on the order of 1.63- and 2.0-multiple). The pre stimulus frequency of activity substantially prevailed in neurons, responding by excitatory effects (on the order of 2.46- and 17.0-multiple in uni- and multidirectional successions, respectively). As regards to post stimulus frequency, the difference is even higher proved– on the order of 14.6 and even 56.5-multiple for uni- and multidirectional sequences, respectively. Besides, especially larger for multidirectional successions. In other words, under PD excitotoxicity revealed, promoting the powerful frequency growth of pre- and post-stimulus activity in both excitatory sequences, testifying about deep neurodegenerative defeat of important ant nociceptive structure – RMG and promotes the emergence of resistant chronic pain.

Mechanism of Oxytocin-Induced Contraction in Rat Gastric Circular Smooth Muscle

Oxytocin produces an excitatory effect on gastric muscle through the activation of receptors present on stomach smooth muscle cells. However, the intracellular mechanisms that mediate oxytocin excitatory effects are still largely unknown. Therefore, we aimed to investigate the signaling pathways involved in oxytocin-induced contractions in gastric smooth muscle, shedding light on phospholipase C (PLC)-β1 signaling and its downstream molecules, including inositol 1,4,5- trisphosphate (IP3) and myosin light chain kinase (MLCK). The contractions of gastric smooth muscle from male rats were measured in an organ bath set up in response to exogenous oxytocin 10-7 M, in the presence and absence of inhibitors of the indicated signaling molecules. Oxytocin (10-9-10-5 M) induced dose-dependent stomach smooth muscle contraction. Pre-incubation with atosiban, an oxytocin receptor inhibitor, abolished the oxytocin-induced contraction. Moreover, PLC β1 inhibitor (U73122) and IP3 inhibitor Xestospongin C inhibited oxytocin-induced muscle contraction to various degrees. Verapamil, a calcium channel blocker, inhibited oxytocin-induced contraction, and pre-incubation of the strips, with both verapamil and Xestospongin C, further inhibited the excitatory effect of oxytocin. Chelation of intracellular calcium with BAPT-AM (1,2-bis-(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid) significantly inhibited the effect of oxytocin on muscle contraction. Finally, pre-incubation of the strips with the Ca2+/calmodulin-dependent protein kinase selective inhibitor STO-609 significantly inhibited the contraction induced by oxytocin. These results suggest that oxytocin directly stimulates its cell surface receptor to activate PLC β1, which in turn liberates IP3, which eventually elevates intracellular calcium, the prerequisite for smooth muscle contraction.

Decoding subject's own name in the primary auditory cortex.

Current studies have shown that perception of subject's own name (SON) involves multiple multimodal brain regions, while activities in unimodal sensory regions (i.e., primary auditory cortex) and their interaction with multimodal regions during the self-processing remain unclear. To answer this, we combined multivariate pattern analysis and dynamic causal modelling analysis to explore the regional activation pattern and inter-region effective connection during the perception of SON. We found that SON and other names could be decoded from the activation pattern in the primary auditory cortex. In addition, we found an excitatory effect of SON on connections from the anterior insula/inferior frontal gyrus to the primary auditory cortex, and to the temporoparietal junction. Our findings extended the current knowledge of self-processing by showing that primary auditory cortex could discriminate SON from other names. Furthermore, our findings highlighted the importance of influence of the insula on the primary auditory cortex during self-processing.

Neurotransmitters Regulation and Food Intake: The Role of Dietary Sources in Neurotransmission

Neurotransmitters (NTs) are biologically active chemicals, which mediate the electrochemical transmission between neurons. NTs control numerous organic functions particularly crucial for life, including movement, emotional responses, and the physical ability to feel pleasure and pain. These molecules are synthesized from simple, very common precursors. Many types of NTs have both excitatory and inhibitory effects. Neurotransmitters' imbalance can cause many diseases and disorders, such as Parkinson's disease, depression, insomnia, increased anxiety, memory loss, etc. Natural food sources containing NTs and/or their precursors would be a potential option to help maintain the balance of NTs to prevent brain and psychiatric disorders. The level of NTs could be influenced, therefore, by targeting dietary habits and nutritional regimens. The progressive implementation of nutritional approaches in clinical practice has made it necessary to infer more about some of the nutritional NTs in neuropsychiatry. However, the importance of the intake of nutritional NTs requires further understanding, since there are no prior significant studies about their bioavailability, clinical significance, and effects on nerve cells. Interventional strategies supported by evidence should be encouraged.

Identification of Spinal Inhibitory Interneurons Required for Attenuating Effect of Duloxetine on Neuropathic Allodynia-like Signs in Rats.

Neuropathic pain is a chronic pain condition that occurs after nerve damage; allodynia, which refers to pain caused by generally innocuous stimuli, is a hallmark symptom. Although allodynia is often resistant to analgesics, the antidepressant duloxetine has been used as an effective therapeutic option. Duloxetine increases spinal noradrenaline (NA) levels by inhibiting its transporter at NAergic terminals in the spinal dorsal horn (SDH), which has been proposed to contribute to its pain-relieving effect. However, the mechanism through which duloxetine suppresses neuropathic allodynia remains unclear. Here, we identified an SDH inhibitory interneuron subset (captured by adeno-associated viral (AAV) vectors incorporating a rat neuropeptide Y promoter; AAV-NpyP+ neurons) that is mostly depolarized by NA. Furthermore, this excitatory effect was suppressed by pharmacological blockade or genetic knockdown of α1B-adrenoceptors (ARs) in AAV-NpyP+ SDH neurons. We found that duloxetine suppressed Aβ fiber-mediated allodynia-like behavioral responses after nerve injury and that this effect was not observed in AAV-NpyP+ SDH neuron-selective α1B-AR-knockdown. These results indicate that α1B-AR and AAV-NpyP+ neurons are critical targets for spinal NA and are necessary for the therapeutic effect of duloxetine on neuropathic pain, which can support the development of novel analgesics.

Adenosine A1 receptor agonist, N6-cyclohexyladenosine, attenuates Huntington's disease via stimulation of TrKB/PI3K/Akt/CREB/BDNF pathway in 3-nitropropionic acid rat model

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive impairments. Intrastriatal injection of 3- nitropropionic acid (3NP) was used to induce HD-like symptoms by inhibiting succinate dehydrogenase enzyme (SDH) in the mitochondrial complex II. The adenosine A1 receptor has long been known to have a crucial role in neuroprotection, mainly by blocking Ca2+ influx, which causes inhibition of glutamate (Glu) and a decline in its excitatory effects at the postsynaptic level. To this end, this study investigated the possible involvement of TrKB/PI3K/Akt/CREB/BDNF pathway in mediating protection afforded by the central N6-cyclohexyladenosine (CHA), an adenosine A1 receptor agonist. A single intrastriatal CHA injection (6.25 nM/1 μL); 45min after 3-NP injection, attenuated neuronal death, and improved cognitive and motor deficits caused by 3-NP neurotoxin. This effect was shown to parallel an enhanced activation of PI3K/Akt/CREB/BDNF axis as well as boosting pERK1/2 levels. Moreover, CHA attenuated neuroinflammatory and oxidative stress status via reducing NFκB p65, TNFα and iNOS contents and increasing SOD. Furthermore, immunohistochemical data showed a reduction in the glial fibrillary acidic protein (GFAP) immunoreactivity to a marker for astrocyte and microglia activation following CHA treatment. The results of this study suggest that CHA may have protective effect against HD via modulating oxidative stress, excitotoxic and inflammatory pathways.

Awareness Creation of Neurotoxins‐induced Wallerian‐type degeneration causing brain Acetylcholine‐imbalance and frank Alzheimer disease

AbstractBackgroundPresence Environmentally Mediated Intellectual Decline Neurotoxins ('presence‐EMIDN') threats from 'bounded', 'unbounded' and 'pervasive' sources puts everyone at risk of developing neurodegenerative diseases (eg. Alzheimer) once specific lipophilic‐neurotoxins breach the blood‐brain and nose‐brain barriers to reach the brain and build up to harmful thresholds. Such neurotoxins exist; how they provoke Wallerian‐type degeneration to cause FAD have been threaded together from experimental evidenced‐based reviews. My intent/interest is to create awareness and establish the aetiology for FAD, which has remained idiopathic since 1906, when the German Neurologist, Alois Alzheimer, discovered the disease.MethodThrough threaded literature reviews from multiple sourcesResultsMany neurotoxins produce Wallerian‐type degeneration: organophosphorus compounds (DFP, TOCP), acrylamide, n‐hexane and some of its metabolites. Wallerian‐type degeneration have been demonstrated in animals: hens, cats, rats, rabbits. Changes during Wallerian‐type degeneration can be grouped into two (Histopathological and Biochemical): it describes the cascade of events taking place in the distal part of an axon that has been cut or crushed. The histopathological changes occur in stages in the following order of succession: stage a: primary degeneration of axon followed by secondary degeneration of myelin in these order: axon swelling; axon disintegration; loss of normal myelin structures with swelling; tumefaction; and breakdown of myelin sheaths; followed by stage b: Cellular proliferation; and then stage c: Fibrosis. The biochemical changes result from liberations of normal biochemical constituents of axon and myelin. There is specifically a decrease in the CNS neurotransmitter's Acetylcholine content, in stage a (causing deficiency‐imbalance), increase in collagen in stage c, and other stage b changes.ConclusionThere are evidences showing that symptoms of FAD is due to 'Acetylcholine deficiency‐imbalance in the brain' where it exercises Excitatory and Inhibitory effects which progressively kick‐starts FAD with fatalities after 5 years. Establishing this aetiology brings vistas of new hope/challenges for possible therapeutic interventions developments.

CRISPR/SaCas9 mutagenesis of stromal interaction molecule 1 in proopiomelanocortin neurons increases glutamatergic excitability and protects against diet-induced obesity

ObjectiveProopiomelanocortin (POMC) neurons are the key anorexigenic hypothalamic neuron for integrating metabolic cues to generate the appropriate output for maintaining energy homeostasis and express the requisite channels as a perfect synaptic integrator in this role. Similar to the metabolic hormones leptin and insulin, glutamate also excites POMC neurons via group I metabotropic glutamate receptors (mGluR1 and 5, mGluR1/5) that activate Transient Receptor Potential Canonical (TRPC 5) Channels to cause depolarization. A key modulator of TRPC 5 channel activity is stromal interaction molecule 1 (STIM1), which is involved in recruitment of TRPC 5 channels from receptor-operated to store-operated calcium entry following depletion of calcium from the endoplasmic reticulum. MethodsWe used a single adeno-associated viral (AAV) vector containing a recombinase-dependent Staphylococcus aureus Cas9 (SaCas) and a single guide RNA (sgRNA) to mutate Stim1 in POMCCre neurons in male mice, verified by qPCR of Stim1 mRNA expression in single POMC neurons. Whole-cell patch clamp experiments were conducted to validate the effects of Stim1 mutagenesis. Body weight and food intake were measured in male mice to assess disruptions in energy balance. ResultsReduced Stim1 expression augmented the efficacy of the mGluR1/5 agonist 3, 5-Dihydroxyphenylglycine (DHPG) to depolarize POMC neurons via a Gαq-coupled signaling pathway, which is an essential part of excitatory glutamatergic input in regulating energy homeostasis. The TRPC 5 channel blockers HC070 and Pico145 antagonized the excitatory effects of DHPG. As proof of principle, mutagenesis of Stim1 in POMC neurons reduced food intake, attenuated weight gain, reduced body fat and fat pad mass in mice fed a high fat diet. ConclusionsUsing CRISPR technology we have uncovered a critical role of STIM1 in modulating glutamatergic activation of TRPC 5 channels in POMC neurons, which ultimately is important for maintaining energy balance.

The role of the bed nucleus of the stria terminalis in the motivational control of instrumental action.

We review recent studies assessing the role of the bed nucleus of the stria terminalis (BNST) in the motivational control of instrumental conditioning. This evidence suggests that the BNST and central nucleus of the amygdala (CeA) form a circuit that modulates the ventral tegmental area (VTA) input to the nucleus accumbens core (NAc core) to control the influence of Pavlovian cues on instrumental performance. In support of these claims, we found that activity in the oval region of BNST was increased by instrumental conditioning, as indexed by phosphorylated ERK activity (Experiment 1), but that this increase was not due to exposure to the instrumental contingency or to the instrumental outcome per se (Experiment 2). Instead, BNST activity was most significantly incremented in a test conducted when the instrumental outcome was anticipated but not delivered, suggesting a role for BNST in the motivational effects of anticipated outcomes on instrumental performance. To test this claim, we examined the effect of NMDA-induced cell body lesions of the BNST on general Pavlovian-to-instrumental transfer (Experiment 3). These lesions had no effect on instrumental performance or on conditioned responding during Pavlovian conditioning to either an excitory conditioned stimulus (CS) or a neutral CS (CS0) but significantly attenuated the excitatory effect of the Pavlovian CS on instrumental performance. These data are consistent with the claim that the BNST mediates the general excitatory influence of Pavlovian cues on instrumental performance and suggest BNST activity may be central to CeA-BNST modulation of a VTA-NAc core circuit in incentive motivation.

CNSC-24. THE EPILEPTIC LANDSCAPE OF IDH MUTANT GLIOMAS

Abstract Tumor-associated epilepsy (TAE) is a frequent complication of diffusely infiltrative gliomas, and impairs quality-of-life. We previously showed that isocitrate dehydrogenase 1 mutant (IDHmut) gliomas were associated with preoperative seizures, and that D2HG increased synchronized bursts in cultured neurons (PMID: 28404805). But the mechanism whereby this occurs, whether IDHmut inhibitors can block this, and whether seizure risk varies by IDHmut status post-operatively, are unknown. We discovered that exogenous 3 mM D2HG had a 150% greater effect on the firing rate of cultured mouse cortical neurons when nonneoplastic glia cells were present versus when they were absent (P=0.002). Coculture with patient-derived IDHmut glioma cells increased the firing rate of human cortical neuron/astrocyte spheroids by up to 272%, and the IDHmut inhibitor AG881 reduced the excitatory effect of IDHmut glioma cells on spheroids by 79% (P=0.0008). Using a novel in vivo model of TAE, wherein EEG recordings were taken of immunocompetent mice engrafted with isogenic mouse glioma lines (NRAS/ATRX/TP53mut ± IDHmut), we found that IDHmut gliomas produced 7.6-fold more epileptiform spikes than IDHwt gliomas (P=0.004). RNA-Seq analysis of the peritumoral mouse brain tissue showed that this increase in spikes was associated with significantly increased expression of key genes known to be upregulated in epilepsy, including SLC12A5, THSB1, VEGFA, FOSL2, and SYNPO. Treatment with 5 mg/kg AG881 by daily oral gavage reduced those spikes in IDHmut-engrafted mice by 51% within three days (P=0.027), whereas vehicle control had no effect (P=0.33). Among 247 patients with grade 2–4 adult-type diffuse gliomas, multivariable time-to-event analysis showed that post-operative seizure risk was positively associated with pre-operative seizures, subtotal resection, and IDHmut astrocytoma. Together, these data show that (i) the D2HG product of IDHmut gliomas increases neuronal excitation in a glial-dependent manner; (ii) IDHmut also affects post-operative seizure risk; (iii) IDHmut inhibitors may improve TAE control.