Journal of Neuroendocrinology
Cara, A;Henson, E;Beekly, B;Elias, C;
| DOI: 10.1111/jne.13063
Androgens are steroid hormones that play a critical role in brain development and sexual maturation by acting upon both androgen receptors (AR), and estrogen receptors (ERα/β) after aromatization. The contribution of estrogens from aromatized androgens in brain development and the central regulation of metabolism, reproduction, and behavior is well defined, but the role of androgens acting on AR has been unappreciated. Here we map the sex specific expression of _Ar_ in the adult and developing mouse brain. Postnatal days (PND) 12 and 21 were used to target a critical window of prepubertal development. Consistent with previous literature in adults, sex-specific differences in _Ar_ expression were most profound in the bed nucleus of the stria terminalis (BST), medial amygdala (MEA), and medial preoptic area (MPO). _Ar_ expression was also high in these areas in PND 12 and 21 of both sexes. In addition, we describe extra-hypothalamic and extra-limbic areas which show moderate, consistent, and similar _Ar_ expression in both sexes at both prepubertal time points. Briefly, _Ar_ expression was observed in olfactory areas of the cerebral cortex, in the hippocampus, several thalamic nuclei, and cranial nerve nuclei involved in autonomic sensory and motor function. To further characterize forebrain populations of _Ar_ expressing neurons and determine whether they also coexpress estrogen receptors, we examined expression of _Ar_, _Esr1_, and _Esr2_ in prepubertal mice in selected nuclei. We found populations of neurons in the BST, MEA, and MPO that coexpress _Ar_, but not _Esr1_ or _Esr2_, while others express a combination of the three receptors. Our findings indicate that various brain areas express _Ar_ during prepubertal development and may play an important role in female neuronal development and physiology.
Lotun, A;Li, D;Xu, H;Su, Q;Tuncer, S;Sanmiguel, J;Mooney, M;Baer, CE;Ulbrich, R;Eyles, SJ;Strittmatter, L;Hayward, LJ;Gessler, DJ;Gao, G;
PMID: 37149081 | DOI: 10.1016/j.pneurobio.2023.102460
Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.
Ling KK, Jackson M, Alkam D, Liu D, Allaire N, Sun C, Kiaei M, McCampbell A, Rigo F.
PMID: 29518482 | DOI: 10.1016/j.nbd.2018.03.002
Amyotrophic lateral sclerosis (ALS) is a fatal adult onset motor neuron disease characterized by progressive denervation and subsequent motor impairment. EphA4, a negative regulator of axonal growth, was recently identified as a genetic modifier in fish and rodent models of ALS. To evaluate the therapeutic potential of EphA4 for ALS, we examined the effect of CNS-directed EphA4 reduction in preclinical mouse models of ALS, and assessed if the levels of EPHA4 mRNA in blood correlate with disease onset and progression in human ALS patients. We developed antisense oligonucleotides (ASOs) to specifically reduce the expression of EphA4 in the central nervous system (CNS) of adult mice. Intracerebroventricular administration of an Epha4-ASO in wild-type mice inhibited Epha4 mRNA and protein in the brain and spinal cord, and promoted re-innervation and functional recovery after sciatic nerve crush. In contrast, lowering of EphA4 in the CNS of two mouse models of ALS (SOD1G93A and PFN1G118V) did not improve their motor function or survival. Furthermore, the level of EPHA4 mRNA in human blood correlated weakly with age of disease onset, and it was not a significant predictor of disease progression as measured by ALS Functional Rating Scores (ALSFRS). Our data demonstrates that lowering EphA4 in the adult CNS may not be a stand-alone viable strategy for treating ALS.
Uemura, M;Furuse, T;Yamada, I;Kushida, T;Abe, T;Imai, K;Nagao, S;Kudoh, M;Yoshizawa, K;Tamura, M;Kiyonari, H;Wakana, S;Hirano, S;
PMID: 35831353 | DOI: 10.1038/s41598-022-16106-5
Protocadherin 9 (Pcdh9) is a member of the cadherin superfamily and is uniquely expressed in the vestibular and limbic systems; however, its physiological role remains unclear. Here, we studied the expression of Pcdh9 in the limbic system and phenotypes of Pcdh9-knock-out mice (Pcdh9 KO mice). Pcdh9 mRNA was expressed in the fear extinction neurons that express protein phosphatase 1 regulatory subunit 1 B (Ppp1r1b) in the posterior part of the basolateral amygdala (pBLA), as well as in the Cornu Ammonis (CA) and Dentate Gyrus (DG) neurons of the hippocampus. We show that the Pcdh9 protein was often localised at synapses. Phenotypic analysis of Pcdh9 KO mice revealed no apparent morphological abnormalities in the pBLA but a decrease in the spine number of CA neurons. Further, the Pcdh9 KO mice were related to features such as the abnormal optokinetic response, less approach to novel objects, and reduced fear extinction during recovery from the fear. These results suggest that Pcdh9 is involved in eliciting positive emotional behaviours, possibly via fear extinction neurons in the pBLA and/or synaptic activity in the hippocampal neurons, and normal optokinetic eye movement in brainstem optokinetic system-related neurons.
Liu, QR;Zhu, M;Zhang, P;Mazucanti, CH;Huang, NS;Lang, DL;Chen, Q;Auluck, P;Marenco, S;O'Connell, JF;Ferrucci, L;Chia, CW;Egan, JM;
PMID: 34649926 | DOI: 10.2337/db21-0198
Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame (uORF) isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP and its amyloid formation was inhibited in vitro by Cα-peptide more efficiently than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus (T2DM) autopsy donors. Intriguingly, 100 years after the discovery of insulin we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.
Forrest, SL;Lee, S;Nassir, N;Martinez-Valbuena, I;Sackmann, V;Li, J;Ahmed, A;Tartaglia, MC;Ittner, LM;Lang, AE;Uddin, M;Kovacs, GG;
PMID: 37354322 | DOI: 10.1007/s00401-023-02604-x
Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau.
Dubois C, Rocks N, Blacher S, Primac I, Gallez A, García-Caballero M, Gérard C, Brouchet L, Noel A, Lenfant F, Cataldo D, Péqueux C.
PMID: 30444717 | DOI: 10.1530/ERC-18-0328
Estrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of estrogens in lung cancer development is a pre-requisite to support the development of sex-based treatments and to identify patients who could potentially benefit from anti-estrogen treatments. In this study, we highlight the contribution of lymphatic and blood endothelia in the sex-dependent modulation of lung cancer. The orthotopic graft of syngeneic lung cancer cells into immunocompetent mice showed that lung tumours grew faster in female mice than in males. Moreover, estradiol (E2) promoted tumour development in female mice and increased lymph/angiogenesis and levels of VEGFA and bFGF in lung tumours of females through an estrogen receptor (ER) alpha-dependent pathway. Furthermore, while treatment with ERbeta antagonist was inefficient, ERalpha antagonist (MPP) and tamoxifen decreased lung tumour volumes, altered blood and lymphatic vasculature and reduced VEGFA and bFGF levels in females, but not in males. Finally, the quantification of lymphatic and blood vasculature of lung adenocarcinoma biopsies from patients aged between 35 to 55 years old revealed more extensive lymphangiogenesis and angiogenesis in tumour samples issued from women than from men. In conclusion, our findings highlight an E2/ERalpha-dependent modulation of lymphatic and blood vascular components of lung tumour microenvironment. Our study has potential clinical implication in a personalised medicine perspective by pointing to the importance of estrogen status or supplementation on lung cancer development that should be considered to adapt therapeutic strategies.
Serafini, RA;Frere, JJ;Zimering, J;Giosan, IM;Pryce, KD;Golynker, I;Panis, M;Ruiz, A;tenOever, BR;Zachariou, V;
PMID: 37159520 | DOI: 10.1126/scisignal.ade4984
Although largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and chronic phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster model to characterize and compare the effects of infection with SARS-CoV-2 and influenza A virus (IAV) on the sensory nervous system. We detected SARS-CoV-2 transcripts but no infectious material in the cervical and thoracic spinal cord and dorsal root ganglia (DRGs) within the first 24 hours of intranasal virus infection. SARS-CoV-2-infected hamsters exhibited mechanical hypersensitivity that was milder but prolonged compared with that observed in IAV-infected hamsters. RNA sequencing analysis of thoracic DRGs 1 to 4 days after infection suggested perturbations in predominantly neuronal signaling in SARS-CoV-2-infected animals as opposed to type I interferon signaling in IAV-infected animals. Later, 31 days after infection, a neuropathic transcriptome emerged in thoracic DRGs from SARS-CoV-2-infected animals, which coincided with SARS-CoV-2-specific mechanical hypersensitivity. These data revealed potential targets for pain management, including the RNA binding protein ILF3, which was validated in murine pain models. This work elucidates transcriptomic signatures in the DRGs triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities.
Zahaf, A;Kassoussi, A;Hutteau-Hamel, T;Mellouk, A;Marie, C;Zoupi, L;Tsouki, F;Mattern, C;Bobé, P;Schumacher, M;Williams, A;Parras, C;Traiffort, E;
PMID: 36949062 | DOI: 10.1038/s41467-023-36846-w
Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
Lorsch ZS, Loh YHE, Purushothaman I, Walker DM, Parise EM, Salery M ,Cahill ME, Hodes GE, Pfau ML, Kronman H, Hamilton PJ, Issler O, Labonté B, Symonds AE, Zucker M, Zhang TY, Meaney MJ, Russo SJ, Shen L, Bagot RC, Nestler EJ.
PMID: 29549264 | DOI: 10.1038/s41467-018-03567-4
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
bioRxiv : the preprint server for biology
François, M;Delgado, IC;Lafond, A;Lewis, EM;Kuromaru, M;Hassouna, R;Deng, S;Thaker, VV;Dölen, G;Zeltser, LM;
PMID: 36824966 | DOI: 10.1101/2023.02.15.528679
Females are more sensitive to social exclusion, which could contribute to their heightened susceptibility to anxiety disorders. Chronic social isolation stress (CSIS) for at least 7 weeks after puberty induces anxiety-related behavioral adaptations in female mice. Here, we show that Arginine vasopressin receptor 1a ( Avpr1a )-expressing neurons in the central nucleus of the amygdala (CeA) mediate these sex-specific effects, in part, via projections to the caudate putamen. Loss of function studies demonstrate that AVPR1A signaling in the CeA is required for effects of CSIS on anxiety-related behaviors in females but has no effect in males or group housed females. This sex-specificity is mediated by AVP produced by a subpopulation of neurons in the posterodorsal medial nucleus of the amygdala that project to the CeA. Estrogen receptor alpha signaling in these neurons also contributes to preferential sensitivity of females to CSIS. These data support new therapeutic applications for AVPR1A antagonists in women.
Stein LM, Lhamo R, Cao A, Workinger J, Tinsley I, Doyle RP, Grill HJ, Hermann GE, Rogers RC, Hayes MR
PMID: 32152264 | DOI: 10.1038/s41398-020-0767-0
Previous studies identify a role for hypothalamic glia in energy balance regulation; however, a narrow hypothalamic focus provides an incomplete understanding of how glia throughout the brain respond to and regulate energy homeostasis. We examined the responses of glia in the dorsal vagal complex (DVC) to the adipokine leptin and high fat diet-induced obesity. DVC astrocytes functionally express the leptin receptor; in vivo pharmacological studies suggest that DVC astrocytes partly mediate the anorectic effects of leptin in lean but not diet-induced obese rats. Ex vivo calcium imaging indicated that these changes were related to a lower proportion of leptin-responsive cells in the DVC of obese versus lean animals. Finally, we investigated DVC microglia and astroglia responses to leptin and energy balance dysregulation in vivo: obesity decreased DVC astrogliosis, whereas the absence of leptin signaling in Zucker rats was associated with extensive astrogliosis in the DVC and decreased hypothalamic micro- and astrogliosis. These data uncover a novel functional heterogeneity of astrocytes in different brain nuclei of relevance to leptin signaling and energy balance regulation
