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Glutamatergic synapse: Glutamate determines neurotransmission by acting on postsynaptic receptors. EAATs, localized on the astrocytic membrane, rapidly terminate glutamatergic activity. EAAT activity is tightly coupled to glucose consumption, causing transient increase in lactate levels. Increased lactate may be an important immediate source of energy to firing neurons. Note the tight neuronal-astrocytic interaction, which is fundamental for the glutamate/glutamine coupling and the compartmentalization of glutamate. Glutamine synthesis in astrocytes is an important mechanism of ammonia detoxification. Note:—Pyr indicates pyruvate; Lac ϭ lactate; GS ϭ glutamine synthetase.
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Neurotransmitters are chemical substances that, by definition, allow communication between neurons and permit most neuronal-glial interactions in the CNS. Approximately 80% of all neurons use glutamate, and almost all interneurons use GABA. A third neurotransmitter, NAAG, modulates glutamatergic neurotransmission. Concentration changes in these mol...
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Context 1
... is a rapidly developing noninvasive technique that allows the clinician to assess the intact brain for neurochemical changes in a given brain region of interest. In the past 25 years, MRS has been an important clinically productive diagnostic tool. The detection of these molecules has been valuable in understanding the presence of neuronal elements (NAA), cell proliferation and degradation (choline), glial disease (myo-inositol), and energy states (Cr); but most changes in metabolite concentrations tend to be rather nonspecific. The 2 most abundant neurotransmitters in the human brain are glutamate and GABA. More recently, there is emerg- ing scientific interest in understanding the role of NAAG in neurologic diseases. A variety of pathologic alterations may arise from changes in the concentration of these neurotransmitters. These may occur due to alterations at several levels, including their synthesis, metabolism, and interaction with receptors. At present, neurologists have access to a vast reper- toire of drugs that modulate neurotransmitter activity in the brain for the treatment of diseases such as epilepsy, motor neuron diseases, and several chronic neurodegenerative disorders. However, complete remission of signs and symptoms is not consistently achieved. Glutamate, GABA, and NAAG are “visible” in H-MR spectroscopy. However, routine 1 H-MR spectroscopy se- quences do not allow the unequivocal detection of these neurotransmitters for several reasons: low spectral resolution, relatively low concentrations, and spectral contamination from other more dominant metabolites. To overcome these hur- dles, specific “editing” methods at high magnetic fields ( Ͼ 1.5T) are being developed and applied in clinical research, which provide a more reliable way for quantifying neurotransmitter levels in pathologic conditions. Because most acute and chronic neurologic disorders are associated with an imbalance of excitatory and inhibitory neurotransmission, it is exciting to consider a future role of 1 H-MR spectroscopy in providing a possible “biomarker” of disease and response to treatment. The aim of this review is the following: 1) to highlight the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG; and 2) to illustrate possible applications of editing 1 H-MR spectroscopy techniques in neurologic diseases, which can aid clinical practice, clinical trials, and neuroscience research. Almost 85% of all synapses in the brain are glutamatergic, making glutamate a central molecule in the brain. 1 Besides its role in neurotransmission, glutamate is a key molecule in synapse formation, dendrite pruning, cell migration, differentia- tion, and death. In addition, glutamate acts as a precursor for GABA in neurons and glutamine in astrocytes (Fig 1). Because the blood-brain barrier prevents entry of peripheral glutamate in the CNS, it is largely synthesized de novo in the neurons and astrocytes through 2 separate Krebs cycles, resulting in 2 glutamate pools (Fig 1). The larger neuronal pool of glutamate is characterized by a slow metabolic turnover, while the smaller astrocytic pool is characterized by a faster metabolic turnover. Glutamate released into the synaptic cleft is avidly taken up by the specific sodium-dependent receptor, EAAT, on astrocyte processes. Astrocytic glutamate undergoes 2 metabolic steps. First, it is rapidly converted to glutamine by a glial-specific ATP-dependent enzyme, glutamine synthetase. 2 This glutamine is released into the extracellular space and is taken up by neurons where neuron-specific PAG converts it back to glutamate. This forms the basis of the glutamate/glutamine cycling. Thus, opposite fluxes connect neurons and astrocytes, one transferring glutamate toward the smaller astrocytic pool and the other transferring glutamine toward the large neuronal pool, determining the directionality of glutamate transmission and rapid removal of excessive glutamate. Some of the major de- terminants of energy consumption by glutamatergic neurons in the cerebral cortex are linked to the glutamate/glutamine cycling. 3 Any pathologic condition with energy synthesis failure such as a mitochondrial dysfunction is also likely to affect glutamatergic neurotransmission. Second, glutamate uptake triggers glycolysis in astrocytes (aerobic glycolysis) and stimulates synthesis of lactate. 4 The cerebral metabolic rate of glucose oxidation and glutamate neurotransmitter cycling measured by using labeled carbon 13-MRS follows a stoichiometry of 1:1, suggesting a tight re- lationship between glutamatergic neurotransmission and energy metabolism. 5 In fact, glutamatergic activity is energeti- cally expensive, resulting in approximately 70%– 80% of total glucose consumption. 6 Higher rates of neuronal firing and rising concentrations of extracellular glutamate will cause more astrocytic glutamate to convert to lactate. In the astro- cyte-neuron-lactate shuttle hypothesis, the astrocyte-gener- ated lactate is shuttled into the neurons, providing a fast and preferential oxidative substrate during neuronal activity. 7 Glutamate-mediated neurotransmission occurs largely through 2 major receptor subtypes: ionotropic NMDAR and AMPAR and metabotropic glutamate receptors. The NMDAR is the most intensely studied glutamate receptor. Important properties of clinical interest include the following: large sin- gle-channel conductance, high calcium permeability, voltage- dependent block by magnesium, and an obligatory glycine co- activation. NMDAR has several subunits determined by different gene families ( NR1 , NR2A , NR2B , NR2C , NR2D , NR3A , and NR3B ). The NR1 with 1 of 4 possible NR2 subtypes and, in some cases, NR3 subtypes constitute the final functional NMDAR. Glutamate binds with high affinity to the NR2 subunit. Of great interest are second-messenger-linked metabotropic glutamate receptors. There are 3 groups of metabotropic glutamate receptors: I, II, and III. Groups II Ϫ and III Ϫ type metabotropic glutamate receptors act as autore- ceptors on glutamatergic neurons and have received maxi- mum attention. Their activation causes decreased glutamate release from neurons through mechanisms still largely un- known. 8 Indeed, agonists of group II metabotropic glutamate receptors are considered neuroprotective agents in knock-out mice. 9 The term “excitotoxicity” refers to a multifaceted pathway initiated by massive extracellular glutamate levels causing excessive calcium influx primarily through NMDAR, account- ing for neuronal cell death in several neurologic diseases. Glutamate is largely intracellular (5–10 mmol/kg wet weight depending on the brain region), and only a tiny fraction is present in the extracellular space (3– 4 mol/L). 10 The enor- mous quantity of glutamate in the human brain and the dan- gers of excessive extracellular glutamate, for powerful protec- tive mechanisms such as rapid uptake of glutamate by astrocytes are key for brain tissue vitality. High-affinity EAATs are transmembrane sodium-dependent receptors that involve a cotransport of 3Na ϩ ions for each molecule of glutamate uptake. This activity is linked to a Na ϩ -K ϩ adenosine triphos- phatase to maintain transmembrane concentration gradients. EAAT1 (also called GLAST) and EAAT2 (glutamate transporter 1) are subtypes found on glial cells, whereas EAAT3 (also called EAAC) is found on neuronal cells. 11 EAATs play a key role in maintaining excitatory glutamatergic neurotransmission by the following: 1) avidly removing glutamate from the synapse, 2) initiating glutamate/glutamine cycle, and 3) increasing astrocytic glucose consumption and production of lactate. In several neurodegenerative states, astrocytic control of glutamate homeostasis is profoundly ...
Context 2
... is a rapidly developing noninvasive technique that allows the clinician to assess the intact brain for neurochemical changes in a given brain region of interest. In the past 25 years, MRS has been an important clinically productive diagnostic tool. The detection of these molecules has been valuable in understanding the presence of neuronal elements (NAA), cell proliferation and degradation (choline), glial disease (myo-inositol), and energy states (Cr); but most changes in metabolite concentrations tend to be rather nonspecific. The 2 most abundant neurotransmitters in the human brain are glutamate and GABA. More recently, there is emerg- ing scientific interest in understanding the role of NAAG in neurologic diseases. A variety of pathologic alterations may arise from changes in the concentration of these neurotransmitters. These may occur due to alterations at several levels, including their synthesis, metabolism, and interaction with receptors. At present, neurologists have access to a vast reper- toire of drugs that modulate neurotransmitter activity in the brain for the treatment of diseases such as epilepsy, motor neuron diseases, and several chronic neurodegenerative disorders. However, complete remission of signs and symptoms is not consistently achieved. Glutamate, GABA, and NAAG are “visible” in H-MR spectroscopy. However, routine 1 H-MR spectroscopy se- quences do not allow the unequivocal detection of these neurotransmitters for several reasons: low spectral resolution, relatively low concentrations, and spectral contamination from other more dominant metabolites. To overcome these hur- dles, specific “editing” methods at high magnetic fields ( Ͼ 1.5T) are being developed and applied in clinical research, which provide a more reliable way for quantifying neurotransmitter levels in pathologic conditions. Because most acute and chronic neurologic disorders are associated with an imbalance of excitatory and inhibitory neurotransmission, it is exciting to consider a future role of 1 H-MR spectroscopy in providing a possible “biomarker” of disease and response to treatment. The aim of this review is the following: 1) to highlight the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG; and 2) to illustrate possible applications of editing 1 H-MR spectroscopy techniques in neurologic diseases, which can aid clinical practice, clinical trials, and neuroscience research. Almost 85% of all synapses in the brain are glutamatergic, making glutamate a central molecule in the brain. 1 Besides its role in neurotransmission, glutamate is a key molecule in synapse formation, dendrite pruning, cell migration, differentia- tion, and death. In addition, glutamate acts as a precursor for GABA in neurons and glutamine in astrocytes (Fig 1). Because the blood-brain barrier prevents entry of peripheral glutamate in the CNS, it is largely synthesized de novo in the neurons and astrocytes through 2 separate Krebs cycles, resulting in 2 glutamate pools (Fig 1). The larger neuronal pool of glutamate is characterized by a slow metabolic turnover, while the smaller astrocytic pool is characterized by a faster metabolic turnover. Glutamate released into the synaptic cleft is avidly taken up by the specific sodium-dependent receptor, EAAT, on astrocyte processes. Astrocytic glutamate undergoes 2 metabolic steps. First, it is rapidly converted to glutamine by a glial-specific ATP-dependent enzyme, glutamine synthetase. 2 This glutamine is released into the extracellular space and is taken up by neurons where neuron-specific PAG converts it back to glutamate. This forms the basis of the glutamate/glutamine cycling. Thus, opposite fluxes connect neurons and astrocytes, one transferring glutamate toward the smaller astrocytic pool and the other transferring glutamine toward the large neuronal pool, determining the directionality of glutamate transmission and rapid removal of excessive glutamate. Some of the major de- terminants of energy consumption by glutamatergic neurons in the cerebral cortex are linked to the glutamate/glutamine cycling. 3 Any pathologic condition with energy synthesis failure such as a mitochondrial dysfunction is also likely to affect glutamatergic neurotransmission. Second, glutamate uptake triggers glycolysis in astrocytes (aerobic glycolysis) and stimulates synthesis of lactate. 4 The cerebral metabolic rate of glucose oxidation and glutamate neurotransmitter cycling measured by using labeled carbon 13-MRS follows a stoichiometry of 1:1, suggesting a tight re- lationship between glutamatergic neurotransmission and energy metabolism. 5 In fact, glutamatergic activity is energeti- cally expensive, resulting in approximately 70%– 80% of total glucose consumption. 6 Higher rates of neuronal firing and rising concentrations of extracellular glutamate will cause more astrocytic glutamate to convert to lactate. In the astro- cyte-neuron-lactate shuttle hypothesis, the astrocyte-gener- ated lactate is shuttled into the neurons, providing a fast and preferential oxidative substrate during neuronal activity. 7 Glutamate-mediated neurotransmission occurs largely through 2 major receptor subtypes: ionotropic NMDAR and AMPAR and metabotropic glutamate receptors. The NMDAR is the most intensely studied glutamate receptor. Important properties of clinical interest include the following: large sin- gle-channel conductance, high calcium permeability, voltage- dependent block by magnesium, and an obligatory glycine co- activation. NMDAR has several subunits determined by different gene families ( NR1 , NR2A , NR2B , NR2C , NR2D , NR3A , and NR3B ). The NR1 with 1 of 4 possible NR2 subtypes and, in some cases, NR3 subtypes constitute the final functional NMDAR. Glutamate binds with high affinity to the NR2 subunit. Of great interest are second-messenger-linked metabotropic glutamate receptors. There are 3 groups of metabotropic glutamate receptors: I, II, and III. Groups II Ϫ and III Ϫ type metabotropic glutamate receptors act as autore- ceptors on glutamatergic neurons and have received maxi- mum attention. Their activation causes decreased glutamate release from neurons through mechanisms still largely un- known. 8 Indeed, agonists of group II metabotropic glutamate receptors are considered neuroprotective agents in knock-out mice. 9 The term “excitotoxicity” refers to a multifaceted pathway initiated by massive extracellular glutamate levels causing excessive calcium influx primarily through NMDAR, account- ing for neuronal cell death in several neurologic diseases. Glutamate is largely intracellular (5–10 mmol/kg wet weight depending on the brain region), and only a tiny fraction is present in the extracellular space (3– 4 mol/L). 10 The enor- mous quantity of glutamate in the human brain and the dan- gers of excessive extracellular glutamate, for powerful protec- tive mechanisms such as rapid uptake of glutamate by astrocytes are key for brain tissue vitality. High-affinity EAATs are transmembrane sodium-dependent receptors that involve a cotransport of 3Na ϩ ions for each molecule of glutamate uptake. This activity is linked to a Na ϩ -K ϩ adenosine triphos- phatase to maintain transmembrane concentration gradients. EAAT1 (also called GLAST) and EAAT2 (glutamate transporter 1) are subtypes found on glial cells, whereas EAAT3 (also called EAAC) is found on neuronal cells. 11 EAATs play a key role in maintaining excitatory glutamatergic neurotransmission by the following: 1) avidly removing glutamate from the synapse, 2) initiating glutamate/glutamine cycle, and 3) increasing astrocytic glucose consumption and production of lactate. In several neurodegenerative states, astrocytic control of glutamate homeostasis is profoundly affected due to dimin- ished EAAT activity or abnormal genetic splicing of their genes. 11 GABA in mature mammalian brain acts primarily as an inhibitory neurotransmitter. GABA is synthesized in a single step from its ...
Citations
... Magnetic resonance (MR) imaging on the other hand, is a safe, non-invasive, and non-irradiating imaging technique. MR-based molecular imaging methods, magnetic resonance spectroscopy (MRS) and chemical exchange saturation transfer (CEST), can quantify multiple metabolic functions and may provide promising endogenous contrast-based indices of synaptic health [21][22][23][24]. ...
In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer’s disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aβ) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer’s disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 μT and 5.9 μT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer’s disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aβ-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer’s disease in vivo.
... Excess Glu-has been associated with excitotoxicity which damages neurons and lead to reduced levels of N-acetyl-aspartate (NAA), indeed, high Glu-and low NAA have been suggested as biomarkers of glutamate neurotoxicity (Han and Ma, 2010). NAA is considered a marker for neuronal viability and mitochondrial energy metabolism (Agarwal and Renshaw, 2012) and high levels are suggestive for neuronal health. Low levels of NAA have been reported in BD patients (Aydin et al., 2016;Yildiz-Yesiloglu and Ankerst, 2006). ...
Bipolar disorder (BD) is associated with alterations in white matter (WM) microstructure, glutamatergic neurotransmission, and glia activity. Previous studies showed higher concentrations of glutamate (Glu), glutamate+glutamine (Glx), and reduced N-acetyl-aspartate (NAA) in BD. We investigated brain concentrations of Glu, Glx, NAA, mI as indirect marker of microglia activation, and Glx/NAA ratio as index of neuronal damage through ¹H-MR, and WM integrity with Tract-Based Spatial Statistics in 93 depressed BD patients and 58 healthy controls (HC).
We tested for linear effects of cited spectroscopic metabolites on DTI measures of WM integrity with general linear models for each group, then performing a conjunction analysis of Glx/NAA and mI concentration on the same measures. Statistical analyses (whole sample) revealed higher concentration of Glx/NAA, Glx and mI in BD patients compared to HC, and a positive association between mI and the ratio. DTI analyses (87 BD and 35 HC) showed a significant association of Glx/NAA ratio, and mI with WM microstructure. Conjunction analysis revealed a joint negative association between Glx/NAA and mI with fractional anisotropy.
This is the first study showing an association between brain metabolites involved in neuronal damage, and glial activation and the alterations in WM consistently reported in BD.
... Using standard 1 H-MRS sequences at 3T it is difficult to reliably estimate glutamine due to spectral overlap with glutamate [61], therefore we utilized the composite outcome measure Glx, which has been reported to be elevated in psychosisspectrum populations [62]. Studies at higher field strength or making use of acquisitions that have been optimized for estimating glutamine concentration could help to clarify whether FAAH activity is differently associated with glutamate or glutamine, or whether associations between FAAH activity and glutamine (rather than Glx) differ between patients and controls [62,63]. ...
Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108–2114; Biol. Psychiatry 88 (9), 727–735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen’s f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen’s f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.
... To overcome this drawback, other advanced MRI-based imaging techniques, along with nuclear medicine modalities, can provide additional and integrative information ( Table 1). A CNS biochemical profile can be explored by proton magnetic resonance spectroscopy (H1-MRS) [23,24]; nervous tissue microstructure integrity can be evaluated by diffusion-tensor imaging (DTI) [25,26] and magnetization transfer imaging (MTI) [27][28][29]; regional and whole brain perfusion can be assessed by perfusion weighted imaging (PWI) with or without contrast administration (dynamic susceptibility contrast imaging-DSC-MRI or dynamic contrast enhanced imaging-DCE-MRI, and three dimensional arterial spin labelled-3D ASL-MRI, respectively) [30]. Functional aspects such as regional brain activity and resting state networks or neuronal metabolism during tasks performance can be evaluated by different functional MRI (fMRI) modalities such as resting state fMRI (Rs-fMRI) or task-based fMRI [31,32]. ...
Diffusion-based magnetic resonance imaging (MRI) studies, namely diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI), have been performed in the context of systemic lupus erythematosus (SLE), either with or without neuropsychiatric (NP) involvement, to deepen cerebral microstructure alterations. These techniques permit the measurement of the variations in random movement of water molecules in tissues, enabling their microarchitecture analysis. While DWI is recommended as part of the initial MRI assessment of SLE patients suspected for NP involvement, DTI is not routinely part of the instrumental evaluation for clinical purposes, and it has been mainly used for research. DWI and DTI studies revealed less restricted movement of water molecules inside cerebral white matter (WM), expression of a global loss of WM density, occurring in the context of SLE, prevalently, but not exclusively, in case of NP involvement. More advanced studies have combined DTI with other quantitative MRI techniques, to further characterize disease pathogenesis, while brain connectomes analysis revealed structural WM network disruption. In this narrative review, the authors provide a summary of the evidence regarding cerebral microstructure analysis by DWI and DTI studies in SLE, focusing on lessons learned and future research perspectives.
... While the exact relationship between [ 18 F]FDG uptake and total glutamate levels is unknown, we suppose that glutamate is stored in the terminals of glutamatergic afferents in the mPFC, which are presumably thalamic or cortical inputs through the CSTC circuit, while NAAG is mainly located in interneurons [74]. Once released into the synapse, glutamate is taken up by astroglial cells and converted into glutamine, whereas NAAG is metabolized to NAA and glutamate [75,76]. In this scenario, the increased glutamate and NAAG levels measured by MR spectroscopy during chemogenetic activation may thus reflect elevated vesicular concentrations in thalamic or cortical afferent terminals, due to indirect inhibition via mDS dopaminergic activation of the indirect (no-go) pathway. ...
... Such an inhibition could account for the lower cortical [ 18 F]FDG uptake and consequently lower glutamatergic activity in the DS, resulting in increased vesicular glutamate content in DS. Furthermore, we suppose that mDS-DREADD stimulation also stimulates dopamine neurons that co-release glutamate [78,79], which in turn might favor the local astroglial conversion of glutamine to glutamate [75,76]. ...
Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [¹⁸F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [¹⁸F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).
... As Isaacson and Scanziani (2011) illustrate, inhibition plays a critical role in shaping spontaneous and sensory-evoked cortical activity, placing a particular importance on the ability to quantify GABA in understanding the relationship between neural activity and the excitation-inhibition balance. Furthermore, where glutamate serves a myriad of functions in addition to its role as a neurotransmitter, including its roles in energy metabolism, protein synthesis and as a precursor to GABA (Agarwal and Renshaw, 2012;Mangia et al., 2012), in the brain GABA is almost exclusively a neurotransmitter, suggesting that changes in GABA levels as measured with MRS are likely to be more closely related to changes in the excitation-inhibition balance and synaptic transmission. ...
The blood oxygen level dependent (BOLD) effect that provides the contrast in functional magnetic resonance imaging (fMRI) has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy (MRS) and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate (measured as Glx) and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex (OCC) of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods.
... In the mPFC, glutamate is stored in the terminals of glutamatergic afferents, which are presumably thalamic or cortical inputs to the mPFC, while NAAG is mainly located in interneurons (79). Once released into the synapse, glutamate is taken up by astroglial cells and converted into glutamine, whereas NAAG is metabolized to NAA and glutamate (80,81). Increased glutamate and NAAG levels measured by MR spectroscopy may reflect elevated vesicular concentrations due to lower neuronal activity. ...
... This inhibition might thus account for the increased glutamate levels in DMS after DS-DQ stimulation. Furthermore, we suppose that DS-DQ stimulation also stimulate dopamine neurons that co-release glutamate (83,84), which in turn might favor the astroglial conversion of glutamine to glutamate (80,81). There is no general model to connect glutamate levels measured with MRS to [ 18 F]FDG uptake, and these two markers did no correlate in WT mice, although there was a clear inverse relationship in mGluR5 KO mice (85). ...
Nigro-striatal dopamine transmission in the rat dorsomedial striatum (DMS) engages the cortico-striato-thalamo-cortical (CSTC) circuit. Modulation of the CSTC circuit can emulate behavioral and functional aspects of neuropsychiatric diseases, including obsessive compulsive disorder (OCD). Classical pharmacological and neurotoxic manipulations of brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations. In this study, we developed a chemogenetic method for selective activation of dopamine neurons innervating the rat DMS, and used this approach to investigate effects of targeted dopamine activation on CSTC circuit function. We monitored behavioral effects on locomotion, self-grooming, and prepulse inhibition of the startle response, which are stereotypic behaviors related to OCD, as well as effects on metabolic functional connectivity measured by [ ¹⁸ F]FDG PET, and regional concentrations of neurochemicals (i.e., glutamate, glutamine, N-acetylaspartate and N-acetylaspartateglutamate) measured by MR spectroscopy. We found that chemogenetic induced nigro-striatal dopamine transmission lowers some of the stereotypic behaviors that are considered hallmarks of OCD. It also disrupts functional connectivity between cortical areas and striatum, and increased total glutamate and N-acetylaspatateglutamate in cortical regions. The results thus establishes the importance of nigro-striatal dopamine transmission in modulation of CSTC function and emphasize DMS dopamine as a possible target for treatment of related neuropsychiatric disorders.
One Sentence Summary
Chemogenetic nigro-striatal dopamine activation modulates functional connectivity and behaviors related to cortico-striato-thalamo-cortical circuit – perspectives for the treatment of obsessive-compulsive disorder.
... Patients are diagnosed as having early MS (formerly clinicaly isolated syndrome suspected of being MS (CIS)), clinicaly definite multiple sclerosis (CDMS), relapsing-remitting multiple sclerosis (RRMS), progressive-relapsing MS (PRMS), and primary-and secondary-progressive multiple sclerosis (PPMS, SPMS) [2,4,10]. Moreover, the disease causes variable degrees of motor, sensory, behavioral, mental, emotional, and cognitive impairment [11][12][13]. ...
... However, whether the iron accumulation is the initial cause or a result of the pathology remains unknown. Neuronal dysfunction might also be initiated by enhanced glutamate neuro-excitation, so-called glutamate excitotoxicity [13,20]. In these specific circumstances, glutamate, an essential mediator of excitation, might be a co-founder of oxidative and metabolic stress and then contribute to neuronal damage in MS [12,21]. ...
... Various signals can be detected based on 1 H MRS (Figure 1): the signal attributable to N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), usually evaluated as the joint tNAA peak; the signal for creatine-containing compounds (i.e., creatine and phosphocreatine) referred as tCr; the signal from molecules contributing to the total choline (tCho) peak (i.e., phosphatidylcholine, glycerophosphatidylcholine, acetylcholine, and choline); the signal from myoInositol (mIns); the signals from neurotransmitters such as glutamate and glutamine (usually evaluated as one-peak Glx); and the signal from γ-aminobutyric acid (GABA) [11,13,25]. In general, approximately 25 additional compounds can be assessed throughout the brain: aspartate, glutathione, taurine, ethanolamine, histidine, glycogen, lactate (detectable only during pathological increment), or mobile lipids (i.e., triacylglycerol and cholesterol esters accumulated in lipid droplets) [26,[37][38][39][40]. ...
Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1 H and phosphorus 31 P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.
... At 4 and 6 years of age, no differences in frontal Glx concentrations were found between children born very preterm and term-born controls (27). Glutamate is mainly stored in neurons and acts as a precursor for GABA in neurons and glutamine in astrocytes (61,62). Together glutamate and glutamine form an important neurotransmitter cycle, but in addition, their roles in the brain may be far more complex (61,62). ...
... Glutamate is mainly stored in neurons and acts as a precursor for GABA in neurons and glutamine in astrocytes (61,62). Together glutamate and glutamine form an important neurotransmitter cycle, but in addition, their roles in the brain may be far more complex (61,62). During periods of brain development and maturation, glutamate plays an important role in different stages of neurogenesis including progenitor proliferation, migration, differentiation and survival, synaptogenesis and spinogenesis (63,64). ...
Executive function deficits in children born very preterm (VPT) have been linked to anatomical abnormalities in white matter and subcortical brain structures. This study aimed to investigate how altered brain metabolism contributes to these deficits in VPT children at school-age.
Fifty-four VPT participants aged 8–13 years and 62 term-born peers were assessed with an executive function test battery. Brain metabolites were obtained in the frontal white matter and the basal ganglia/thalami, using proton magnetic resonance spectroscopy (MRS). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, glutamate + glutamine (Glx)/Cr, and myo-Inositol (mI)/Cr were compared between groups and associations with executive functions were explored using linear regression.
In the frontal white matter, VPT showed lower Glx/Cr (mean difference: −5.91%, 95% CI [−10.50, −1.32]), higher Cho/Cr (7.39%, 95%-CI [2.68, 12.10]), and higher mI/Cr (5.41%, 95%-CI [0.18, 10.64]) while there were no differences in the basal ganglia/thalami. Lower executive functions were associated with lower frontal Glx/Cr ratios in both groups (β = 0.16, p = 0.05) and higher mI/Cr ratios in the VPT group only (interaction: β = −0.17, p = 0.02).
Long-term brain metabolite alterations in the frontal white matter may be related to executive function deficits in VPT children at school-age.
Very preterm birth is associated with long-term brain metabolite alterations in the frontal white matter.
Such alterations may contribute to deficits in executive function abilities.
Injury processes in the brain can persist for years after the initial insult.
Our findings provide new insights beyond structural and functional imaging, which help to elucidate the processes involved in abnormal brain development following preterm birth.
Ultimately, this may lead to earlier identification of children at risk for developing deficits and more effective interventions.
... Lower levels of Glutamate and GABA were found in areas rich in white matter. Glutamate levels were ~4 times higher than GABA, as expected for standard physiological levels in the brain 13,19,35,36 . Application of orCEST in water deprivation. ...
Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) is a molecular imaging methodology capable of mapping brain metabolites with relatively high spatial resolution. Specificity is the main goal of such experiments; yet CEST is confounded by spectral overlap between different molecular species. Here, we overcome this major limitation using a general framework termed overlap-resolved CEST (orCEST) - a kind of spectrally-edited experiment restoring specificity. First, we present evidence revealing that CEST experiments targeting the central nervous system's primary excitatory neurotransmitter, Glutamate (GluCEST) - is significantly contaminated by gamma-aminobutyric acid (GABA) - the primary inhibitory neurotransmitter in the CNS. Then, we harness the novel orCEST methodology to separate Glutamate and - for the first time - GABA signals, thus delivering the desired specificity. In-vivo orCEST experiments resolved the rat brain's primary neurotransmitters and revealed changes in Glutamate and GABA levels upon water deprivation in thirst-related areas. orCEST's features bode well for many applications in neuroscience and biomedicine.
