Phosphine Catalyzed Michael-Type Additions: The Synthesis of Glutamic Acid Derivatives from Arylidene-α-amino Esters.

The reaction of arylidene-α-amino esters with electrophilic alkenes to yield Michael-type addition compounds is optimized using several phosphines as organocatalysts. The transformation is very complicated due to the generation of several final compounds, including those derived from the 1,3-dipolar cycloadditions. For this reason, the selection of the reaction conditions is a very complex task and the slow addition of the acrylic system is very important to complete the process. The study of the variation in the structural components of the starting imino ester is performed as well as the expansion of other electron-poor alkenes. The crude products have a purity higher than 90% in most cases without any purification. A plausible mechanism is detailed based on the bibliography and the experimental results. The synthesis of pyroglutamate entities, after the reduction of the imino group and cyclization, is performed in high yields. In addition, the hydrolysis of the imino group, under acidic media, represents a direct access to glutamate surrogates.

Decreased γ-aminobutyric acid levels in the brainstem in patients with possible sleep bruxism: A pilot study.

BACKGROUND: An increasing number of studies have indicated that the central and autonomic nervous systems play roles in the genesis of sleep bruxism (SB). The role of specific neurochemicals in SB has been a subject of interest. OBJECTIVE: In this study, we use proton magnetic resonance spectroscopy (1 H-MRS) to determine whether the levels of γ-aminobutyric acid (GABA) and glutamate (Glu) are different in the brainstem and bilateral cortical masticatory area (CMA) between possible sleep bruxism (SB) patients and controls, and discuss whether the brainstem or cortical networks which may affect the central masticatory pathways are under the genesis of SB. METHODS: Twelve possible SB patients and twelve age- and gender-matched controls underwent 1 H-MRS using the "MEGA-Point Resolved Spectroscopy Sequence" (MEGA-PRESS) technique in the brainstem and bilateral CMA. Proton magnetic resonance spectroscopy data were processed using LCModel. Because the signal detected by MEGA-PRESS includes contributions from GABA, macromolecules (primarily proteins) and homocarnosine, the GABA signal is referred to as "GABA+". The glutamate complex (Glx) signal contains both glutamate (Glu) and glutamine (Gln), which mainly reflect glutamatergic metabolism. RESULTS: Edited spectra were successfully obtained from the bilateral CMA in all subjects. There were no significant differences in neurochemical levels between the left and right CMA in possible SB patients and controls. In the brainstem, significantly lower GABA+ levels were found in possible SB patients than in controls (P = .011), whereas there was no significant difference (P = .307) in Glx levels between the 2 groups. CONCLUSIONS: SB patients may possess abnormalities in the GABAergic system of brainstem networks.

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke.

Background: Remote ischemic postconditioning (RIPostC) may protect the brain from ischemia/reperfusion (I/R) injury. The association between RIPostC and obesity has not yet been extensively studied. Methods: Twelve-week-old male Zucker diabetic fatty (ZDF; n=68) and Zucker diabetic lean (ZDL; n=51) rats were subjected to focal cerebral ischemia for 90 minutes, followed by 24 hours of reperfusion. RIPostC was performed with 5-minute I/R cycles using a tourniquet on the right hind limb. Results: The results showed a negative association between obesity and neurological impairment in ischemic animals. We observed a 70% greater infarct size in ZDF rats compared with their lean counterparts, as evaluated by 2,3,5-triphenyltetrazolium chloride staining. To measure the total fragmented DNA in peripheral lymphocytes, comet assay was performed. Obese rats exhibited higher levels of DNA damage (by approximately 135%) in peripheral blood lymphocytes even before the induction of stroke. RIPostC did not attenuate oxidative stress in the blood in obese rats subjected to ischemia. Focal cerebral ischemia increased core and penumbra tissue glutamate release in the brain and decreased it in the blood of ischemic ZDL rats, and these changes improved following RIPostC treatment. However, changes in blood and tissue glutamate content were not detected in ischemic ZDF rats or after RIPostC intervention. Conclusion: Our findings suggest that obese animals respond more severely to ischemia-reperfusion brain injury. However, obese animals did not achieve neuroprotective benefits of RIPostC treatment.

Evaluation of the antinociceptive effect of valerian and hops combination in experimental animal models: Involvement of the opioid system.

Pain is a common undertreated worldwide complaint. The need to explore the antinociceptive potential of alternative herbal products is essential. Although used as a mild sedative, limited evidence focused on the potential antinociceptive effect of valerian and hops combination. The present study was carried out to evaluate the in vivo anti-nociceptive effect of the valerian-hops combination to justify its use as an effective and safe analgesic agent. Anti-nociceptive effects of valerian-hops combination (50, 100, and 200 mg/kg) were assessed in swiss albino mice for performing the acetic acid-induced writhing test, the paw licking test using formalin, the paw licking test using glutamate, and the tail immersion test. The effects were compared to those of diclofenac or morphine in the presence or absence of the opioid receptor antagonist naloxone. Valerian-hops" extract of 100 and 200 mg/kg demonstrated a significant reduction in the number of writhing episodes induced by acetic acid compared to the control (p < 0.05), a significant reduction in the licking number at doses of 100 and 200 mg/kg in the late phase formalin-induced paw licking, significantly reduced the number of lickings after glutamate injection compared to control (p < 0.05). And significantly increased pain reaction after 60 and 90 min of tail immersion test, this effect was opposed by naloxone treatment. The valerian-hops combination produced a significant antinociceptive effect that involved the opioid system. Further studies are required to fully uncover the underlying active constituents and their mechanisms.

Dietary Exposure to Glutamates of 2- to 5-Year-Old Toddlers in China Using the Duplicate Diet Method.

A duplicate diet collection method was used to estimate dietary exposure to glutamates in children aged 2-5 years in selected provinces of China. Daily duplicate diet samples were collected from 86 healthy toddlers over three consecutive days. Glutamates were analyzed using ultra-high-pressure liquid chromatography-MS/MS (UHPLC-MS/MS). Results showed that the highest glutamates content was found in mixed meals, at 5.12 mg/kg, followed by powdered formula (3.89 mg/kg), and milk and dairy products (2.29 mg/kg). The total mean daily dietary exposure for subjects was 0.20 mg/kg BW, and P95 daily dietary exposure was 0.44 mg/kg BW, both below the acceptable daily intake (ADI) (120 mg/kg BW) recommended by the Joint (FAO/WHO) Expert Committee on Food Additives (JECFA) and the ADI (30 mg/kg BW) set by the European Food Safety Authority (EFSA). Hence it can be considered that glutamates exposure would cause low risk in this group.

Ketamine and Other Glutamate Receptor Modulating Agents for Treatment-Resistant Depression: A Systematic Review of Randomized Controlled Trials.

Objective: Available treatments of depression have limited efficacy and unsatisfactory remission rates. This study aims to review randomized controlled trials (RCTs) investigating effects of glutamate receptor modulators in treating patients with resistant depression. Method : The study protocol was registered in PROSPERO (CRD42021225516). Scopus, ISI Web of Science, Embase, Cochrane Library, Google Scholar, and three trial registries were searched up to September 2020 to find RCTs evaluating glutamate receptor modulators for resistant depression. The difference between intervention and control groups in changing depression scores from baseline to endpoint was considered the primary outcome. Version 2 of the Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the RCTs. No funding was received. Results: Thirty-eight RCTs were included. Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK-0657); the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo. A limited number of studies were available that addressed drugs other than ketamine. Conclusion: The study cannot determine the difference between statistical and clinical significance between the agents and placebo due to high heterogeneity among the RCTs. Nevertheless, ketamine could be used as an efficacious drug in TRD; still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression.

Change of Extracellular Glutamate Level in Striatum during Deep Brain Stimulation of the Entopeduncular Nucleus in Rats.

OBJECTIVE: Globus pallidus interna (GPi) is acknowledged as an essential treatment for advanced Parkinson's disease (PD). Nonetheless, the neurotransmitter study about its results is undiscovered. The goal of this research was to examine influences of entopeduncular nucleus (EPN) stimulation, identical to human GPi, in no-lesioned (NL) rat and 6-hydroxydopamine (6-HD)-lesioned rat on glutamate change in the striatum. METHODS: Extracellular glutamate level changes in striatum of NL category, NL with deep brain stimulation (DBS) category, 6-HD category, and 6-HD with DBS category were examined using microdialysis and high-pressure liquid chromatography. Tyrosine hydroxylase (TH) immunoreactivities in substantia nigra and striatum of the four categories were also analyzed. RESULTS: Extracellular glutamate levels in the striatum of NL with DBS category and 6-HD with DBS category were significantly increased by EPN stimulation compared to those in the NL category and 6-HD category. EPN stimulation had no significant effect on the expression of TH in NL or 6-HD category. CONCLUSION: Clinical results of GPi DBS are not only limited to direct inhibitory outflow to thalamus. They also include extensive alteration within basal ganglia.

Growth Response of Lactobacillus rhamnosus Chloramphenicol-Resistant Strain ATCC 27773 to Pteroyl-Mono- and -Di-Glutamates.

This study investigated the effect of various concentrations of pteroyl-mono-γ-glutamate (PteGlu1) and pteroyl-di-γ-glutamate (PteGlu2) on the growth of Lactobacillus rhamnosus strains ATCC 7469 (wild-type strain) and ATCC 27773 (chloramphenicol-resistant strain) used for folate microbiological assays. At concentrations of 0.025-0.20 nmol/L, the growth of the chloramphenicol-resistant strain was stimulated to a greater extent by PteGlu1 than by PteGlu2, but the wild-type strain did not show such phenomena. L. rhamnosus ATCC 27773 bioassays were used to determine the total folate content of various foods treated with a chicken pancreas folate conjugase. This showed a significantly lower value when PteGlu1 was used as a calibrator than with PteGlu2. These results indicated that PteGlu2 should be the standard folate compound when chicken pancreas folate conjugase is used in preparing samples for L. rhamnosus ATCC 27773 bioassay.

Decreased Serum Glutamate Levels in Male Adults with Internet Gaming Disorder: A Pilot Study.

OBJECTIVE: Alteration in glutamatergic neurotransmission and dopaminergic dysfunction has been implicated in both the initiation and expression of addiction related behaviors. This pilot study was aimed to investigate the serum levels of glutamate and dopamine in adults with internet gaming disorder (IGD). METHODS: We measured serum levels of glutamate and dopamine in male participants with IGD (n=26) and age-matched healthy controls (n=25). Clinical interviews were performed to identify IGD and to rule out psychiatric comorbidities. Serum levels of glutamate and dopamine were examined by enzyme immunoassays using ELISA Kits. RESULTS: Serum levels of glutamate were lower among IGD than control (IGD: 24.184±12.303 µg/ml; control: 33.676±12.413 µg/ml; t=2.742, p=0.008), while levels of dopamine did not differ between. Serum glutamate and dopamine levels did not correlate with gaming hours and exposure to game in the IGD group. But serum glutamate levels were positively correlated with the dopamine levels (r=0.360, p=0.013). CONCLUSION: Our results suggest that altered glutamatergic neurotransmission may contribute to the pathophysiology of IGD.

A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways.

BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

Effects of Antipsychotic Administration on Brain Glutamate in Schizophrenia: A Systematic Review of Longitudinal 1H-MRS Studies.

Schizophrenia is associated with brain glutamate dysfunction, but it is currently unclear whether antipsychotic administration can reduce the extent of glutamatergic abnormality. We conducted a systematic review of proton magnetic resonance spectroscopy (1H-MRS) studies examining the effects of antipsychotic treatment on brain glutamate levels in schizophrenia. The Medline database was searched to identify relevant articles published until December 2016. Inclusion required that studies examined longitudinal changes in brain glutamate metabolites in patients with schizophrenia before and after initiation of first antipsychotic treatment or a switch in antipsychotic treatment. The searches identified eight eligible articles, with baseline and follow-up measures in a total of 168 patients. The majority of articles reported a numerical reduction in brain glutamate metabolites with antipsychotic treatment, and the estimated overall mean reduction of 6.5% in Glx (the combined signal from glutamate and glutamine) across brain regions. Significant reductions in glutamate metabolites in at least one brain region were reported in four of the eight studies, and none of the studies reported a significant glutamatergic increase after antipsychotic administration. Relationships between the degree of change in glutamate and the degree of improvement in symptoms have been inconsistent but may provide limited evidence that antipsychotic response may be associated with lower glutamate levels before treatment and a greater extent of glutamatergic reduction during treatment. Further longitudinal, prospective studies of glutamate and antipsychotic response are required to confirm these findings.

The Inhibitory Effect of α/ß-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that α/ß-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6's inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1-3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor's effects are mediated through the binding with the GluAs C-terminal regions.

Effects of DARPP-32 Genetic Variation on Prefrontal Cortex Volume and Episodic Memory Performance.

Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral correlates in humans are scarce. Post mortem findings suggest genotype specific expressions of DARPP-32 in the dorsal frontal lobes. Therefore, we investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (♀54%). The major homozygote G, T, or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352, the two latter in complete linkage disequilibrium), at the DARPP-32 regulating PPP1R1B gene, influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had an overall larger prefrontal volume in addition to greater EM recall accuracy after accounting for the influence of age. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in young adults and selective to this group for EM. Our findings suggest that genomic variation maps onto individual differences in frontal brain volumes and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality.

Shiga toxin type-2 (Stx2) induces glutamate release via phosphoinositide 3-kinase (PI3K) pathway in murine neurons.

Shiga toxin-producing Escherichia coli (STEC) can cause central nervous system (CNS) damage resulting in paralysis, seizures, and coma. The key STEC virulence factors associated with systemic illness resulting in CNS impairment are Shiga toxins (Stx). While neurons express the Stx receptor globotriaosylceramide (Gb3) in vivo, direct toxicity to neurons by Stx has not been studied. We used murine neonatal neuron cultures to study the interaction of Shiga toxin type 2 (Stx2) with cell surface expressed Gb3. Single molecule imaging three dimensional STochastic Optical Reconstruction Microscopy-Total Internal Reflection Fluorescence (3D STORM-TIRF) allowed visualization and quantification of Stx2-Gb3 interactions. Furthermore, we demonstrate that Stx2 increases neuronal cytosolic Ca(2+), and NMDA-receptor inhibition blocks Stx2-induced Ca(2+) influx, suggesting that Stx2-mediates glutamate release. Phosphoinositide 3-kinase (PI3K)-specific inhibition by Wortmannin reduces Stx2-induced intracellular Ca(2+) indicating that the PI3K signaling pathway may be involved in Stx2-associated glutamate release, and that these pathways may contribute to CNS impairment associated with STEC infection.

A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons.

We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury.

Quantitation of various indolinyl caged glutamates as their o-phthalaldehyde derivatives by high performance liquid chromatography coupled with tandem spectroscopic detections: derivatization, stoichiometry and stability studies.

Quantification, stability and unique spectroscopic properties of indolinyl-caged glutamates (ICGs), with the o-phthalaldehyde-3-mercaptopropionic acid (OPA-MPA) reagent, were described, at first. As new principle to the field, reactivity and stoichiometry of variously substituted OPA-MPA derivatized ICGs, such as 4-methoxy-7-nitroindolinyl-(MNI-Glu), 4-methoxy-5,7-dinitroindolinyl-(DNI-Glu), 2-dimethylamino-propoxy and dimethylamino-isobutoxy alternatives (2DMA-1PO-DNI-Glu, 1DMA-2P-DNI-Glu and 3DMA-1iBU-DNI-Glu), was demonstrated. Derivatives' stability was determined using high performance liquid chromatography (HPLC) applying simultaneous photodiode array (DAD) and fluorescence (Fl) detections, while their structural identity was confirmed by HPLC-time of flight mass spectrometry (HPLC-TOF-MS). The SH-additive of the reagents was also varied. ICGs react unequivocally, with one OPA-SH-group molecule, in the molar ratios of ([OPA-SH-additive]/[ICG]=1/1, resulting in species with the characteristic isoindole spectral property (EEx/EEm=337/454nm; λmax=337nm). ICGs' isoindole derivatives, due to their sandwich structure, are manifesting the π-π-stacking phenomenon: they fail to show fluorescence. ICGs' stability decreased in the order of MNI-Glu, 2DMA-1PO/1DMA-2PO, 3DMA-1iBU and DNI-Glu, correspondingly, resulting in increasing order of free glutamic acid (GA), as their decomposition product. GA and ICGs were determined as their OPA/MPA derivatives while uncaged species (MNI, DNI and its substituted alternatives) in their initial forms. The practical utility of the method was confirmed analyzing ICGs and their decomposition products, simultaneously. Quantifications' reliability and reproducibility were characterized with the relative standard deviation percentages of responses (RSDs%): for GA 0.41-12 RSD% for ICGs 0.057-7.0 RSD% were obtained. Stability properties of variously substituted, recently introduced ICGs, prepared in laboratories of Institute of Experimental Medicine, were defined.

Hyperactivation of the habenula as a link between depression and sleep disturbance.

Depression occurs frequently with sleep disturbance such as insomnia. Sleep in depression is associated with disinhibition of the rapid eye movement (REM) sleep. Despite the coincidence of the depression and sleep disturbance, neural substrate for depressive behaviors and sleep regulation remains unknown. Habenula is an epithalamic structure regulating the activities of monoaminergic neurons in the brain stem. Since the imaging studies showed blood flow increase in the habenula of depressive patients, hyperactivation of the habenula has been implicated in the pathophysiology of the depression. Recent electrophysiological studies reported a novel role of the habenular structure in regulation of REM sleep. In this article, we propose possible cellular mechanisms which could elicit the hyperactivation of the habenular neurons and a hypothesis that dysfunction in the habenular circuit causes the behavioral and sleep disturbance in depression. Analysis of the animals with hyperactivated habenula would open the door to understand roles of the habenula in the heterogeneous symptoms such as reduced motor behavior and altered REM sleep in depression.

Trichotillomania: a good response to treatment with N-acetylcysteine

Abstract: Trichotillomania is considered a behavioral disorder and is characterized by the recurring habit of pulling one's hair, resulting in secondary alopecia. It affects 1% of the adult population, and 2 to 4.4% of psychiatric patients meet the diagnostic criteria. It can occur at any age and is more prevalent in adolescents and females. Its occurrence in childhood is not uncommon and tends to have a more favorable clinical course. The scalp, eyebrows and eyelashes are the most commonly affected sites. Glutamate modulating agents, such as N-acetylcysteine, have been shown to be a promising treatment. N-acetylcysteine acts by reducing oxidative stress and normalizing glutaminergic transmission. In this paper, we report a case of trichotillomania with an excellent response to N-acetylcysteine.

Biological sources of inflexibility in brain and behavior with aging and neurodegenerative diseases.

Almost unequivocally, aging and neurodegeneration lead to deficits in neural information processing. These declines are marked by increased neural noise that is associated with increased variability or inconsistency in behavioral patterns. While it is often viewed that these problems arise from dysregulation of dopamine (DA), a monoamine modulator, glutamate (GLU), an excitatory amino acid that interacts with DA, also plays a role in determining the level of neural noise. We review literature demonstrating that neural noise is highest at both high and low levels of DA and GLU, allowing their interaction to form a many-to-one solution map for neural noise modulation. With aging and neurodegeneration, the range over which DA and GLU can be modulated is decreased leading to inflexibility in brain activity and behavior. As the capacity to modulate neural noise is restricted, the ability to shift noise from one brain region to another is reduced, leading to greater uniformity in signal-to-noise ratios across the entire brain. A negative consequence at the level of behavior is inflexibility that reduces the ability to: (1) switch from one behavior to another; and (2) stabilize a behavioral pattern against external perturbations. In this paper, we develop a theoretical framework where inflexibility across brain and behavior, rather than inconsistency and variability is the more important problem in aging and neurodegeneration. This theoretical framework of inflexibility in aging and neurodegeneration leads to the hypotheses that: (1) dysfunction in either or both of the DA and GLU systems restricts the ability to modulate neural noise; and (2) levels of neural noise and variability in brain activation will be dedifferentiated and more evenly distributed across the brain; and (3) changes in neural noise and behavioral variability in response to different task demands and changes in the environment will be reduced.