Reliable execution of precise behaviors requires that brain circuits are resilient to variations in neuronal dynamics. Genetic perturbation of the majority of excitatory neurons in HVC, a brain region involved in song production, in adult songbirds with stereotypical songs triggered severe degradation of the song. The song fully recovered within 2 weeks, and substantial improvement occurred even when animals were prevented from singing during the recovery period, indicating that offline mechanisms enable recovery in an unsupervised manner. Song restoration was accompanied by increased excitatory synaptic input to neighboring, unmanipulated neurons in the same brain region. A model inspired by the behavioral and electrophysiological findings suggests that unsupervised single-cell and population-level homeostatic plasticity rules can support the functional restoration after large-scale disruption of networks that implement sequential dynamics. These observations suggest the existence of cellular and systems-level restorative mechanisms that ensure behavioral resilience.

Wang, B., Torok, Z., Duffy, A. et al. Unsupervised restoration of a complex learned behavior after large-scale neuronal perturbation. Nat Neurosci (2024).

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Researchers have mapped a tiny piece of the human brain in astonishing detail. The resulting cell atlas, which was described in Science and is available online, reveals new patterns of connections between brain neurons, as well as cells that wrap around themselves to form knots, and pairs of neurons that are almost mirror images of each other.

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Multiple sclerosis (MS) is a global health concern affecting around 2.6 million people. It is characterised by neural inflammation, myelin breakdown and cognitive decline. Cognitive impairment, especially reduced cognitive processing speed (CPS), which affects up to 67% of MS patients and frequently manifests before mobility concerns, is one of the disease’s most serious side effects. Effective adaptation and the application of cognitive rehabilitation treatments depend on the early diagnosis of cognitive impairment. Although pharmaceutical therapies have some drawbacks, endurance training has become a promising alternative. Intensity-controlled endurance exercise has the ability to delay the onset of MS symptoms and enhance cognitive function. Exercise has also been shown to have neuroprotective effects in a number of neurological disorders, including MS, Parkinson’s disease and stroke. This includes both aerobic and resistance training. A mix of aerobic exercise and weight training has shown promise, especially for people with mild cognitive impairment, but according to recent studies any amount of physical activity is beneficial to cognitive performance. In conclusion, this in-depth analysis highlights the crucial part endurance exercise plays in treating MS-related cognitive impairment. It improves not only neurological health in general but also cognitive performance. Exercise can help control MS in a way that dramatically improves quality of life and well-being.

Zameer U, Tariq A, Asif F, Kamran A. Empowering Minds and Bodies: The Impact of Exercise on Multiple Sclerosis and Cognitive Health. Ann Neurosci. 2024 Apr;31(2):121-123. doi: 10.1177/09727531241227674. Epub 2024 Feb 12. PMID: 38694717; PMCID: PMC11060125.

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SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3β activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3β in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3β. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.

Zhang GF, Zhu KL, Li Q, Zhang Y, Waddington JL, Du XD, Zhen XC. The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator. Acta Pharmacol Sin. 2024 Apr 11. doi: 10.1038/s41401-024-01256-1. Epub ahead of print. PMID: 38605179.

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Abstract: Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Zamecnik CR, Sowa GM, Abdelhak A, Dandekar R, Bair RD, Wade KJ, Bartley CM, Kizer K, Augusto DG, Tubati A, Gomez R, Fouassier C, Gerungan C, Caspar CM, Alexander J, Wapniarski AE, Loudermilk RP, Eggers EL, Zorn KC, Ananth K, Jabassini N, Mann SA, Ragan NR, Santaniello A, Henry RG, Baranzini SE, Zamvil SS, Sabatino JJ Jr, Bove RM, Guo CY, Gelfand JM, Cuneo R, von Büdingen HC, Oksenberg JR, Cree BAC, Hollenbach JA, Green AJ, Hauser SL, Wallin MT, DeRisi JL, Wilson MR. An autoantibody signature predictive for multiple sclerosis. Nat Med. 2024 Apr 19. doi: 10.1038/s41591-024-02938-3. Epub ahead of print. PMID: 38641750.

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Abstract: Parkinson’s disease and inflammatory bowel disease have been increasingly associated, implying shared pathophysiology. To explore biological explanations for the reported connection, we leveraged summary statistics of updated genome-wide association studies and characterized the genetic overlap between the two diseases. Aggregated genetic association data were available for 37 688 cases versus 981 372 controls for Parkinson’s disease and 25 042 cases versus 34 915 controls for inflammatory bowel disease. Genetic correlation was estimated with the high-definition likelihood method. Genetic variants with joint association to both diseases were identified by conditional false discovery rate framework and further annotated to reveal shared loci, genes, and enriched pathways. For both Crohn’s disease and ulcerative colitis, the two main subtypes of inflammatory bowel disease, we detected weak but statistically significant genetic correlations with Parkinson’s disease (Crohn’s disease: rg = 0.06, P = 0.01; ulcerative colitis: rg = 0.06, P = 0.03). A total of 1290 variants in 27 independent genomic loci were detected to associate with Parkinson’s disease and Crohn’s disease at conjunctional false discovery rate under 0.01 and 1359 variants in 15 loci were pleiotropic to Parkinson’s disease and ulcerative colitis. Among the identified pleiotropic loci, 23 are novel and have never been associated with both phenotypes. A mixture of loci conferring either same or opposing genetic effects on two phenotypes was also observed. Positional and expression quantitative trait loci mapping prioritized 296 and 253 genes for Parkinson’s disease with Crohn’s disease and ulcerative colitis, respectively, among which only <10% are differentially expressed in both colon and substantia nigra. These genes were identified to overrepresent in pathways regulating gene expression and post-translational modification beyond several immune-related pathways enriched by major histocompatibility complex genes. In conclusion, we found robust evidence for a genetic link between Parkinson’s disease and inflammatory bowel disease. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both synergistic and antagonistic pleiotropy. At the functional level, our findings implied a role of immune-centered mechanisms in the reported gut-brain connection.

Xiaoying Kang, Alexander Ploner, Yunzhang Wang, Jonas F Ludvigsson, Dylan M Williams, Nancy L Pedersen, Karin Wirdefeldt, Genetic overlap between Parkinson’s disease and inflammatory bowel disease, Brain Communications, Volume 5, Issue 1, 2023, fcad002,



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Editor’s summary: The autoimmune disease multiple sclerosis (MS) is a highly heterogeneous disease with many different treatment options. However, it is not clear whether certain features of MS are associated with distinct immune signatures or would benefit from particular therapies. Here, Gross et al. used peripheral blood mononuclear cells and serum collected from two independent cohorts of patients with MS to identify three endophenotypes of the disease. These peripheral blood immune signatures distinguished patients with distinct clinical disease trajectories and efficacy of interferon-β treatment. These data suggest that peripheral blood analysis could be used to guide personalized treatment regimens for patients with MS.

Abstract:  One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis (n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3–related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient’s blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.

Gross CC, Schulte-Mecklenbeck A, Steinberg OV, Wirth T, Lauks S, Bittner S, Schindler P, Baranzini SE, Groppa S, Bellmann-Strobl J, Bünger N, Chien C, Dawin E, Eveslage M, Fleischer V, Gonzalez-Escamilla G, Gisevius B, Haas J, Kerschensteiner M, Kirstein L, Korsukewitz C, Lohmann L, Lünemann JD, Luessi F, Meyer Zu Hörste G, Motte J, Ruck T, Ruprecht K, Schwab N, Steffen F, Meuth SG, Paul F, Wildemann B, Kümpfel T, Gold R, Hahn T, Zipp F, Klotz L, Wiendl H; German Competence Network Multiple Sclerosis (KKNMS). Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories. Sci Transl Med. 2024 Mar 27;16(740):eade8560. doi: 10.1126/scitranslmed.ade8560. Epub 2024 Mar 27. PMID: 38536936.

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Aims: According to Braak’s hypothesis, it is plausible that Parkinson’s disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons.

Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology.

Results: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach’s and Meissner’s plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD.

Conclusion: These results strongly support the plausibility of Braak’s hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

Espinosa-Oliva AM, Ruiz R, Soto MS, Boza-Serrano A, Rodriguez-Perez AI, Roca-Ceballos MA, García-Revilla J, Santiago M, Serres S, Economopoulus V, Carvajal AE, Vázquez-Carretero MD, García-Miranda P, Klementieva O, Oliva-Martín MJ, Deierborg T, Rivas E, Sibson NR, Labandeira-García JL, Machado A, Peral MJ, Herrera AJ, Venero JL, de Pablos RM. Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain. Neuropathol Appl Neurobiol. 2024 Feb;50(1):e12962. doi: 10.1111/nan.12962. PMID: 38343067.

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Abstract: The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RAgene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

Rohn TT, Radin D, Brandmeyer T, Linder BJ, Andriambeloson E, Wagner S, Kehler J, Vasileva A, Wang H, Mee JL, Fallon JH. Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice. PNAS Nexus. 2023 Jun 20;2(6):pgad170. doi: 10.1093/pnasnexus/pgad170. PMID: 37346271; PMCID: PMC10281383.



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Abstract: “Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.”

Ross, J.B., Myers, L.M., Noh, J.J. et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature (2024).

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