Brian Collier (1940-2024).

Dr. Brian Collier, the former Editor-in-Chief of the Journal of Neurochemistry from 1996 to 2006, passed away January 4th, 2024. Brian's illustrious career spanned the fields of neurochemistry and pharmacology. He published his findings on mechanisms of acetylcholine synthesis and storage in the Journal of Neurochemistry, and his contributions remain landmarks in neurochemical research.

Fundamental Neurochemistry Review: At the intersection between the brain and the immune system: Non-coding RNAs spanning learning, memory and adaptive immunity.

Non-coding RNAs (ncRNAs) are highly plastic RNA molecules that can sequester cellular proteins and other RNAs, serve as transporters of cellular cargo and provide spatiotemporal feedback to the genome. Mounting evidence indicates that ncRNAs are central to biology, and are critical for neuronal development, metabolism and intra- and intercellular communication in the brain. Their plasticity arises from state-dependent dynamic structure states that can be influenced by cell type and subcellular environment, which can subsequently enable the same ncRNA with discrete functions in different contexts. Here, we highlight different classes of brain-enriched ncRNAs, including microRNA, long non-coding RNA and other enigmatic ncRNAs, that are functionally important for both learning and memory and adaptive immunity, and describe how they may promote cross-talk between these two evolutionarily ancient biological systems.

Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS). METHODS: Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior. RESULTS: MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease. INTERPRETATION: SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671.

Association Between Serum Neurofilament Light Chain and Neurochemistry Deficits in Patients with Spinocerebellar Ataxia Type 3.

Extensive evidence supports the claim that the serum neurofilament light chain (sNfL) can be used as a biomarker to monitor disease severity in patients with spinocerebellar ataxia type 3 (SCA3). However, little is known about the associations between sNfL levels and neurochemical alterations in SCA3 patients. In this study, we performed a cross-sectional study to analyze the association between sNfL and brain metabolic changes in SCA3 patients. The severity of ataxia was assessed by using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). The sNfL levels and brain metabolic changes, represented by N-acetyl aspartate (NAA)/creatine (Cr) and choline complex (Cho)/Cr ratios, were measured by a single-molecule array and proton magnetic resonance spectroscopy, respectively. In this cohort, we observed consistently elevated sNfL levels and reduced brain metabolites in the cerebellar hemispheres, dentate nucleus, and cerebellar vermis. However, this correlation was further validated in the cerebellar cortex after analysis using pairwise comparisons and a Bonferroni correction. Taken together, our results further confirmed that sNfL levels were increased in SCA3 patients and were negatively correlated with metabolic changes in the cerebellar cortex. Our data also support the idea that sNfL levels are a promising potential complementary biomarker for patients with SCA3.

Power spectra reveal distinct BOLD resting-state time courses in white matter.

Accurate characterization of the time courses of blood-oxygen-level-dependent (BOLD) signal changes is crucial for the analysis and interpretation of functional MRI data. While several studies have shown that white matter (WM) exhibits distinct BOLD responses evoked by tasks, there have been no comprehensive investigations into the time courses of spontaneous signal fluctuations in WM. We measured the power spectra of the resting-state time courses in a set of regions within WM identified as showing synchronous signals using independent components analysis. In each component, a clear separation between voxels into two categories was evident, based on their power spectra: one group exhibited a single peak, and the other had an additional peak at a higher frequency. Their groupings are location specific, and their distributions reflect unique neurovascular and anatomical configurations. Importantly, the two categories of voxels differed in their engagement in functional integration, revealed by differences in the number of interregional connections based on the two categories separately. Taken together, these findings suggest WM signals are heterogeneous in nature and depend on local structural-vascular-functional associations.

The Neurochemistry of Depression: The Good, The Bad and The Ugly.

A large constellation of experimental evidence suggests that neuroinflammation is involved in the onset of depression and neurodegenerative disorders. Many studies have shown impairments in tryptophan metabolism, the major pathway for the synthesis of serotonin, the mood regulating neurotransmitter. This article reviews the various metabolites generated in the competing pathways of tryptophan metabolism including the kynurenine pathway. Increased synthesis of the neurotoxic compound quinolinic acid occurs at the expense of the synthesis of the neuroprotective metabolite kynurenic acid. This shift in equilibrium plays a critical role in the induction of oxidative stress, neuroinflammation, and neurotoxicity. Sufficient protein intake with adequate amounts of tryptophan along with dietary antioxidants and flavonoids may offer protection against major depressive and neurodegenerative disorders.

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy.

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters' concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals' neurophysiological observations. At the second level, individuals' 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare alternative model evidence of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by individual differences in neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. Using within-subject split-sampling of the MEG dataset (i.e., validation by means of a held-out dataset), we show that model comparison for hypothesis testing can be highly reliable. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

Journal of Neurochemistry embraces Transparent Peer Review.

In this editorial we explain how the Journal of Neurochemistry will embrace Transparent Peer Review. Our goal is to enhance the experience for authors, readers, reviewers, and handling editors and to provide a sound platform for neurochemistry publications. This development is part of our ongoing drive to maintain and further increase the value of the Journal of Neurochemistry for the scientific community.

EDITOR SPOTLIGHT: Interview with Brain Proteostasis Special Issue Guest Editor Mychael Lourenco.

Mychael Lourenco is an Assistant Professor of Neuroscience at the Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro. Research in his lab focusses on understanding the molecular mechanisms underlying cognitive impairment in neurodegeneration and his research on Alzheimer's disease has been recognized by many awards both in Brazil and internationally. He serves as a Reviews Editor for the Journal of Neurochemistry and led this special issue on Brain Proteostasis as a Guest Editor. Here we interviewed him to hear his thoughts on the future of neuroscience and on career development and training.

In memoriam: Frode Fonnum (1937-2023).

Frode Fonnum died unexpectedly on 26th April 2023, at 86 years of age. He was a tower of strength-a primeval force-in neuroscience, neurochemistry and toxicology. His highly cited publications, comprised salient evidence for GABA and glutamate as brain neurotransmitters. He served as an expert, and as an organizer, including of European research cooperation and as President of the International Society for Neurochemistry (ISN). Photo credit: Per Kristian Opstad.

Fundamental neurochemistry review: Glutamatergic dysfunction as a central mechanism underlying flavivirus-induced neurological damage.

The Flaviviridae family comprises positive-sense single-strand RNA viruses mainly transmitted by arthropods. Many of these pathogens are especially deleterious to the nervous system, and a myriad of neurological symptoms have been associated with infections by Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) in humans. Studies suggest that viral replication in neural cells and the massive release of pro-inflammatory mediators lead to morphological alterations of synaptic spine structure and changes in the balance of excitatory/inhibitory neurotransmitters and receptors. Glutamate is the predominant excitatory neurotransmitter in the brain, and studies propose that either enhanced release or impaired uptake of this amino acid contributes to brain damage in several conditions. Here, we review existing evidence suggesting that glutamatergic dysfunction-induced by flaviviruses is a central mechanism for neurological damage and clinical outcomes of infection. We also discuss current data suggesting that pharmacological approaches that counteract glutamatergic dysfunction show benefits in animal models of such viral diseases.

Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain.

While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that activates the intestinal membrane receptor guanylyl cyclase C (GUCY2C). Clinical trials revealed that linaclotide relieves both constipation and visceral pain. We recently demonstrated that the analgesic effect of linaclotide reflects the overexpression of GUCY2C on neuropod cells, a specialized subtype of EECs. While this brings some clarity to the relationship between linaclotide and visceral analgesia, questions remain about the intracellular signaling mechanisms and neurotransmitters mediating this communication. In this Fundamental Neurochemistry Review, we discuss what is currently known about visceral nociceptors, enteroendocrine cells, and the gut-brain axis, and ongoing areas of research regarding that axis and visceral pain.

Fundamental Neurochemistry Review: GABAA receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy.

Epilepsy is a common neurological disorder associated with alterations of excitation-inhibition balance within brain neuronal networks. GABAA receptor neurotransmission is the most prevalent form of inhibitory neurotransmission and is strongly implicated in both the pathophysiology and treatment of epilepsy, serving as a primary target for antiseizure medications for over a century. It is now established that GABA exerts a multifaceted influence through an array of GABAA receptor subtypes that extends far beyond simply negating excitatory activity. As the role of GABAA neurotransmission within inhibitory circuits is elaborated, this will enable the development of precision therapies that correct the network dysfunction underlying epileptic pathology.

Fundamental Neurochemistry Review: Incorporating a greater diversity of cell types, including microglia, in brain organoid cultures improves clinical translation.

Brain organoids have the potential to improve clinical translation, with the added benefit of reducing any extraneous use of experimental animals. As brain organoids are three-dimensional in vitro constructs that emulate the human brain, they bridge in vitro and in vivo studies more appropriately than monocultures. Although many factors contribute to the failure of extrapolating monoculture-based information to animal-based experiments and clinical trials, for the purpose of this review, we will focus on glia (non-neuronal brain cells), whose functions and transcriptome are particularly abnormal in monocultures. As discussed herein, glia require signals from-and contact with-other cell types to exist in their homeostatic state, which likely contributes to some of the differences between data derived from monocultures and data derived from brain organoids and even two-dimensional co-cultures. Furthermore, we highlight transcriptomic differences between humans and mice in regard to aging and Alzheimer's disease, emphasizing need for a model using the human genome-again, a benefit of brain organoids-to complement data derived from animals. We also identify an urgency for guidelines to improve the reporting and transparency of research using organoids. The lack of reporting standards creates challenges for the comparison and discussion of data from different articles. Importantly, brain organoids mark the first human model enabling the study of brain cytoarchitecture and development.

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.

Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.

Fundamental neurochemistry review: Old brain stories - Influence of age and sex on the neurodegeneration-associated lipid changes.

Brain aging is a naturally occurring process resulting in the decline of cognitive functions and increased vulnerability to develop age-associated disorders. Fluctuation in lipid species is crucial for normal brain development and function. However, impaired lipid metabolism and changes in lipid composition in the brain have been increasingly recognized to play a crucial role in physiological aging, as well as in several neurodegenerative diseases. In the last decades, the role of sexual dimorphism in the vulnerability to develop age-related neurodegeneration has increased. However, further studies are warranted for detailed assessment of how age, sex, and additional non-biological factors may influence the lipid changes in brains. The aim of this work is to address the presence of sex differences in the brain lipid changes that occur along aging, and in the two most common age-related neurodegenerative disorders (Alzheimer's and Parkinson's diseases). We included the studies that assessed lipid-related alterations in the brain of both humans and experimental models. Additionally, we explored the influence of sex on lipid-lowering therapies. We conclude that sex exerts a notable effect on lipid modifications occurring with age and neurodegeneration, and in lipid-reducing interventions. Therefore, the application of sex as an experimental variable is strongly encouraged for future research in the field of precision medicine approach.

Fundamental Neurochemistry Review: Copper availability as a potential therapeutic target in progressive supranuclear palsy: Insight from other neurodegenerative diseases.

Since the first description of Parkinson's disease (PD) over two centuries ago, the recognition of rare types of atypical parkinsonism has introduced a spectrum of related PD-like diseases. Among these is progressive supranuclear palsy (PSP), a neurodegenerative condition that clinically differentiates through the presence of additional symptoms uncommon in PD. As with PD, the initial symptoms of PSP generally present in the sixth decade of life when the underpinning neurodegeneration is already significantly advanced. The causal trigger of neuronal cell loss in PSP is unknown and treatment options are consequently limited. However, converging lines of evidence from the distinct neurodegenerative conditions of PD and amyotrophic lateral sclerosis (ALS) are beginning to provide insights into potential commonalities in PSP pathology and opportunity for novel therapeutic intervention. These include accumulation of the high abundance cuproenzyme superoxide dismutase 1 (SOD1) in an aberrant copper-deficient state, associated evidence for altered availability of the essential micronutrient copper, and evidence for neuroprotection using compounds that can deliver available copper to the central nervous system. Herein, we discuss the existing evidence for SOD1 pathology and copper imbalance in PSP and speculate that treatments able to provide neuroprotection through manipulation of copper availability could be applicable to the treatment of PSP.

Functional imaging and neurochemistry identify in vivo neuroprotection mechanisms counteracting excitotoxicity and neurovascular changes in the hippocampus and visual cortex of obese and type 2 diabetic animal models.

Functional MRI (fMRI) with 1 H-MRS was combined on the hippocampus and visual cortex of animal models of obesity (high-fat diet, HFD) and type 2 diabetes (T2D) to identify the involved mechanisms and temporal evolution of neurometabolic changes in these disorders that could serve as potentially reliable clinical biomarkers. HFD rats presented elevated levels of N-acetylaspartylglutamate (NAAG) (p = 0.0365 vs. standard diet, SD) and glutathione (GSH) (p = 0.0494 vs. SD) in the hippocampus. NAAG and GSH levels in this structure proved to be correlated (r = 0.4652, p = 0.0336). This mechanism was not observed in diabetic rats. Combining MRS and fMRI-evaluated blood-oxygen-level-dependent (BOLD) response, elevated taurine (p = 0.0326 vs. HFD) and GABA type A receptor (GABAA R) (p = 0.0211 vs. SD and p = 0.0153 vs. HFD) were observed in the visual cortex of only diabetic rats, counteracting the elevated BOLD response and suggesting an adaptative mechanism against hyperexcitability observed in the primary visual cortex (V1) (p = 0.0226 vs. SD). BOLD amplitude was correlated with the glutamate levels (r = 0.4491; p = 0.0316). Therefore, here we found evidence for several biological dichotomies regarding excitotoxicity and neuroprotection in different brain regions, identifying putative markers of their different susceptibility and response to the metabolic and vascular insults of obesity and diabetes.

Motor cortex functional connectivity is associated with underlying neurochemistry in ALS.

OBJECTIVE: To identify structural and neurochemical properties that underlie functional connectivity impairments of the primary motor cortex (PMC) and how these relate to clinical findings in amyotrophic lateral sclerosis (ALS). METHODS: 52 patients with ALS and 52 healthy controls, matched for age and sex, were enrolled from 5 centres across Canada for the Canadian ALS Neuroimaging Consortium study. Resting-state functional MRI, diffusion tensor imaging and magnetic resonance spectroscopy data were acquired. Functional connectivity maps, diffusion metrics and neurometabolite ratios were obtained from the analyses of the acquired multimodal data. A clinical assessment of foot tapping (frequency) was performed to examine upper motor neuron function in all participants. RESULTS: Compared with healthy controls, the primary motor cortex in ALS showed reduced functional connectivity with sensory (T=5.21), frontal (T=3.70), temporal (T=3.80), putaminal (T=4.03) and adjacent motor (T=4.60) regions. In the primary motor cortex, N-acetyl aspartate (NAA, a neuronal marker) ratios and diffusion metrics (mean, axial and radial diffusivity, fractional anisotropy (FA)) were altered. Within the ALS cohort, foot tapping frequency correlated with NAA (r=0.347) and white matter FA (r=0.537). NAA levels showed associations with disturbed functional connectivity of the motor cortex. CONCLUSION: In vivo neurochemistry may represent an effective imaging marker of impaired motor cortex functional connectivity in ALS.

Systemic inflammation and cortical neurochemistry in never-medicated first episode-psychosis individuals.

Studies of cellular and cytokine profiles have contributed to the inflammation hypothesis of schizophrenia; however, precise markers of inflammatory dysfunction remain elusive. A number of proton magnetic resonance spectroscopy (1H-MRS) studies in patients with first-episode psychosis (FEP) have shown higher brain levels of metabolites such as glutamate, myo-inositol (mI) and choline-containing compounds (tCho), suggesting neuroinflammation. Here, we present peripheral inflammatory profiles in antipsychotic-naive FEP patients and age-and-sex matched healthy controls, as well as cortical glutamate, mI and tCho levels using 1H-MRS. Inflammatory profiles were analyzed using cytokine production by peripheral blood mononuclear cells, that were either spontaneous or stimulated, in 48 FEP patients and 23 controls. 1H-MRS of the medial prefrontal cortex was obtained in 29 FEP patients and 18 controls. Finally, 16 FEP patients were rescanned after 4 weeks of treatment (open-label) with Risperidone. FEP patients showed a higher proportion of proinflammatory Th1/Th17 subset, and an increased spontaneous production of Interleukin (IL)-6, IL-2 and IL-4 compared with the control group. Results obtained from 1H-MRS showed no significant difference in either glutamate, mI or tCho between FEP and control groups. At baseline, CD8% showed a negative correlation with glutamate in FEP patients; after 4 weeks of risperidone treatment, the FEP group exhibited a decrease in glutamate levels which positively correlated with CD4 + T cells. Nevertheless, these correlations did not survive correction for multiple comparisons. FEP patients show evidence of immune dysregulation, affecting both the innate and adaptive immune response, with a predominantly Th2 signature. These findings, along with the changes produced by antipsychotic treatment, could be associated with both systemic and central inflammatory processes in schizophrenia.