Abstract: “Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABAA receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABAA receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment.”

Neumann S, Boothman-Burrell L, Gowing EK, Jacobsen TA, Ahring PK, Young SL, Sandager-Nielsen K and Clarkson AN: The Delta-Subunit Selective GABAA Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism.  Frontiers in Neurosci., 29 October 2019 | https://doi.org/10.3389/fnins.2019.01133.

https://www.frontiersin.org/articles/10.3389/fnins.2019.01133/full

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Journal Club: “The presentation and development of psychiatric illnesses is affected by interindividual variability in brain morphology and genetics. Epigenetic factors and early life experiences can also alter brain development and influence psychiatric illness susceptibility. For example, interactions between genetic and environmental factors may alter gene expression, resulting in neuroplastic and functional modifications that lead to anxiety and depression. …”

Vonderwalde I: DNA Methylation within the Amygdala Early in Life Increases Susceptibility for Depression and Anxiety Disorders. J. Neurosci. 39 (45) 8828-8830 (2019).

https://www.jneurosci.org/content/39/45/8828

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The present study provides evidence for a prodromal phase of multiple sclerosis, with implications for studying disease aetiology and underscoring the limitations of therapies that solely target inflammation. The findings also suggest an opportunity to apply secondary prevention strategies at the very earliest stages of the disease. Specifically, the authors studied whether serum neurofilament light chain (sNfL) levels are elevated before clinical multiple sclerosis onset. Results indicated that levels of sNfL were increased 6 years before clinical multiple sclerosis onset, indicating that multiple sclerosis may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Bjornevik K, Munger KL, Cortese M, Barro C, Healy BC, Niebuhr DW, Scher Al, Kuhle J and Ascherio A: Serum Neurofilament Light Chain Levels in Patients with presymptomatic Multiple Sclerosis. JAMA Neurol. [Epub ahead of print, Sept. 13, 2019; doi: 10.1001/jamaneurol.2019.3238.].

https://www.ncbi.nlm.nih.gov/pubmed/31515562

https://www.ncbi.nlm.nih.gov/pubmed/31654040

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Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain’s energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. An increasing amount of evidence suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. The authors describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data, and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. The authors consider potential mechanisms by which metabolic abnormalities could generate attacks and highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions.

Key points

  • Prevalent triggers of migraine attacks can all be linked to unbalanced cerebral energy metabolism and/or oxidative stress.
  • Magnetic resonance spectroscopy studies have shown that mitochondrial phosphorylation potential and ATP are decreased in the brains of people with migraine between attacks. Glucose (and lipid) metabolism and mitochondrial functions are abnormal in the peripheral blood.
  • Among patients with migraine, various single nucleotide polymorphisms are present in non-coding mitochondrial DNA and nuclear-encoded mitochondrial proteins; common variants associated with migraine are functionally involved in mitochondrial metabolism.
  • Metabolic enhancers, such as riboflavin and coenzyme Q10, and dietary or pharmacological ketogenesis improve migraine but novel, more efficient metabolic strategies are needed.
  • Experimental studies indicate a link between cerebral energy disequilibrium and cortical spreading depression and/or trigeminovascular system activation; calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide could also help restore energy homeostasis.
  • Migraine can be regarded as a conserved, adaptive response that occurs in individuals with a genetic predisposition and a mismatch between the brain’s energy reserve and workload.

Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J: The metabolic face of migraine – from pathophysiology to treatment. Nature Rev. Neurol. [Epub ahead of print, Oct. 4, 2019; doi: 10.1038/s41582-019-0255-4].

https://www.ncbi.nlm.nih.gov/pubmed/31586135

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To analyze music preferences in human subjects, Gold and colleagues built a computer model to analyze songs quantitatively. The researchers fed the model a large musical repertoire, including Canadian and German folk songs and Bach compositions. This training allowed the model to measure a trait that the researchers call ‘complexity’, which includes qualities such as how surprising a song would sound to listeners accustomed to Western music.

The results showed that the human brain favors songs that are neither too simple nor too complex. Surprising twists and turns in a piece of music can influence its appeal to the brain. The researchers asked people to rate how much they liked various musical clips, including excerpts from Georges Bizet’s opera ‘Carmen’ and the Japanese traditional song ‘Sakura’. Participants preferred songs of medium complexity to simple and highly complex tunes. When participants were uncertain about how a song would unfold, they preferred fewer surprises. But if people thought they knew what would happen next in a song, they enjoyed being surprised.

The results support existing theories that in many types of art, intermediate complexity maximizes curiosity and enjoyment.

Gold BP, Pearce MT, Mas-Herrero E, Dagher A and Zatorre RJ: Predictability and uncertainty in the pleasure of music: a reward for learning? J. Neurosci. [Epub ahead of print, 21 October 2019;  0428-19; DOI: https://doi.org/10.1523/JNEUROSCI.0428-19.2019].

https://www.ncbi.nlm.nih.gov/pubmed/31636112

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Previous studies identified several separate risk factors for stress-induced disorders. The authors of the present study tested whether they could use an integrated approach to predict susceptibility or resilience to social defeat stress (SDS) in mice and whether administration of acetyl-L-carnitine promoted resilience in the SDS paradigm.

Their findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The co-presence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, they provided initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience in the SDS paradigm.

They feel that these results provide the starting point for in vivo models which predict development of neurobiological and behavioral deficits after stress exposure. This approach may lead to novel therapeutic strategies which promote resilience in susceptible individuals.

Nasca C, Menard C, Hodes Gm Bigio B, Pena C, Lorsch Z, Zelli D, Ferris A, Kana V, Purushothaman I, Dobbin J, Nassim M, DeAngelis P, Merad M, Rasgon N, Meaney M, Nestler EJ, McEwen BS and Russo SJ: Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress. Biol. Psychiatry 86 (6): 483-491 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31466563

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The purpose of this study was to estimate the percentage contribution of genetic and environmental factors to Autism Spectrum Disorder (ASD). Children from Denmark, Finland, Sweden, Israel, and Western Australia who were born between January 1, 1998, and December 31, 2011, were followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018. The sample consisted of 2,001,631 individuals, of whom 1,027,546 (51.3%) were male. 22,156 subjects were diagnosed with ASD.

Based on population data from these 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences. Maternal effects were minimal and ranged from 0.4% to 1.6%. The results suggest possible modest differences in the sources of ASD risk between countries.

Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, Glasson E, Mahjani B, Suominen A, Leonard H, Gissler M, Buxbaum JD, Wong K, Schendel D, Kodesh A, Breshnahan M, Levine SZ, Parner ET, Hansen SN, Hultman C, Reichenberg A, Sandin S: Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort. JAMA Psychiatry [Epub ahead of print, July 17, 2019; doi: 10.1001/jamapsychiatry.2019.1411 ].

https://www.ncbi.nlm.nih.gov/pubmed/31314057

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Abstract: “Mitochondria vary in morphology and function in different tissues; however, little is known about their molecular diversity among cell types. Here we engineered MitoTag mice, which express a Cre recombinase-dependent green fluorescent protein targeted to the outer mitochondrial membrane, and developed an isolation approach to profile tagged mitochondria from defined cell types. We determined the mitochondrial proteome of the three major cerebellar cell types (Purkinje cells, granule cells and astrocytes) and identified hundreds of mitochondrial proteins that are differentially regulated. Thus, we provide markers of cell-type-specific mitochondria for the healthy and diseased mouse and human central nervous systems, including in amyotrophic lateral sclerosis and Alzheimer’s disease. Based on proteomic predictions, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neuronal mitochondria. We also characterize cell-type differences in mitochondrial calcium buffering via the mitochondrial calcium uniporter (Mcu) and identify regulator of microtubule dynamics protein 3 (Rmdn3) as a determinant of endoplasmic reticulum-mitochondria proximity in Purkinje cells. Our approach enables exploring mitochondrial diversity in many in vivo contexts.”

Fecher C, Trovò L, Müller SA, Snaidero N, Wettmarshausen J, Heink S, Ortiz O, Wagner I, Kühn R, Hartmann J, Karl RM, Konnerth A, Korn T, Wurst W, Merkler D, Lichtenthaler SF, Perocchi F, Misgeld T: Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity. Nature Neurosci. 22(10): 1731-1742 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31501572

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Chronic pain is associated with anxio-depressive comorbidities, but the neuroanatomical substrates remain unknown. A specific serotonergic pathway from the dorsal raphe nucleus to the lateral habenula via the central amygdala is now uncovered as a key neural circuit governing comorbid depressive symptoms in chronic pain.

Specifically, the authors identified a novel pathway involving 5-hydroxytryptamine projections from the dorsal raphe nucleus to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala. The SOM neurons in the amygdala projected directly to the lateral habenula, an area known to be involved in depression. Manipulation of this pathway using pharmacological or optogenetic approaches modulated depression-like behavior in laboratory animals.

Zhou W, Jin Y, Meng Q, Zhu X, Bai T, Tian Y, Mao Y, Wang L, Xie W, Zhong H, Zhang N, Luo MH, Tao W, Wang H, Li J, Li J, Qiu BS, Zhou JN, Li X, Xu H, Wang K, Zhang X, Liu Y, Levin GR, Xu L and Zhang Z: A neural circuit for comorbid depressive symptoms in chronic pain. Nature Neurosci. 22(10): 1649-1658 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31451801

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Patients with brain tumours have a range of symptoms that can vary in severity, from headaches to a decline in cognitive function. The symptoms depend on the tumour type and its size, location and growth rate. Understanding what controls the growth rate of brain tumours might therefore lead to the development of therapies that slow cancer progression and improve the quality of life of people who have this type of cancer. In this report, Venkataramani and colleagues show that cancer cells form excitatory synaptic connections with neurons in the central nervous system. This connection accelerates tumour growth rate and lethality. Specifically, these neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour “microtubes”, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Tumour invasion and growth were reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgöz AA, Herrmannsdörfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hänggi D, Liu HK, Wick W, Winkler F, Kuner T: Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573(7775):532-538 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/31534219

https://www.ncbi.nlm.nih.gov/pubmed/31534222

https://www.nature.com/articles/d41586-019-02746-7

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