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de Assis GG, de Sousa MBC, Murawska-Ciałowicz E. Sex Steroids and Brain-Derived Neurotrophic Factor Interactions in the Nervous System: A Comprehensive Review of Scientific Data. Int J Mol Sci 2025; 26:2532. [PMID: 40141172 PMCID: PMC11942429 DOI: 10.3390/ijms26062532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/28/2025] Open
Abstract
Sex steroids and the neurotrophin brain-derived neurotrophic factor (BDNF) participate in neural tissue formation, phenotypic differentiation, and neuroplasticity. These processes are essential for the health and maintenance of the central nervous system. AIM The aim of our review is to elucidate the interaction mechanisms between BDNF and sex steroids in neuronal function. METHOD A series of searches were performed using Mesh terms for androgen/receptors, estrogen/receptors, and BDNF/receptors, and a collection of the scientific data available on PubMed up to February 2025 about mechanical interactions between BDNF and sex steroids was included in this literature review. DISCUSSION This review discussed the influence of sex steroids on the formation and/or maintenance of neural circuits via different mechanisms, including the regulation of BDNF expression and signaling. Estrogens exert a time- and region-specific effect on BDNF synthesis. The nuclear estrogen receptor can directly regulate BDNF expression, independently of the presence of estrogen, in neuronal cells, whereas progesterone and testosterone upregulate BDNF expression via their specific nuclear receptors. In addition, testosterone has a positive effect on BDNF release by glial cells, which lack androgen receptors.
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Affiliation(s)
- Gilmara Gomes de Assis
- Escola Superior Desporto e Lazer, Instituto Politécnico de Viana do Castelo, Rua Escola Industrial e Comercial de Nun’Álvares, 4900-347 Viana do Castelo, Portugal
- Sport Physical Activity and Health Research & Innovation Center, 4900-347 Viana do Castelo, Portugal
| | | | - Eugenia Murawska-Ciałowicz
- Department of Physiology and Biomechanics, Wroclaw University of Health and Sport Sciences, 51-612 Wrocław, Poland;
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Li J, Xiao WH, Ye F, Tang XW, Jia QF, Zhang XB. Brain-derived neurotrophic factor, sex hormones and cognitive decline in male patients with schizophrenia receiving continuous antipsychotic therapy. World J Psychiatry 2023; 13:995-1004. [PMID: 38186728 PMCID: PMC10768483 DOI: 10.5498/wjp.v13.i12.995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/04/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
BACKGROUND There are systematic differences in clinical features between women and men with schizophrenia (SCZ). The regulation of sex hormones may play a potential role in abnormal neurodevelopment in SCZ. Brain-derived neurotrophic factor (BDNF) and sex hormones have complex interacting actions that contribute to the etiology of SCZ. AIM To investigate the influence of BDNF and sex hormones on cognition and clinical symptomatology in chronic antipsychotic-treated male SCZ patients. METHODS The serum levels of follicle-stimulating hormone, luteinizing hormone (LH), estradiol (E2), progesterone, testosterone (T), prolactin (PRL) and BDNF were compared between chronic antipsychotic-treated male (CATM) patients with SCZ (n = 120) and healthy controls (n = 120). The Positive and Negative Syndrome Scale was used to quantify SCZ symptoms, while neuropsychological tests were used to assess cognition. Neuropsychological tests, such as the Digit Cancellation Test (DCT), Semantic Verbal Fluency (SVF), Spatial Span Test (SS), Paced Auditory Serial Addition Test (PASAT), Trail Making Task (TMT-A), and Block Design Test (BDT), were used to assess executive functions (BDT), attention (DCT, TMT-A), memory (SS, PASAT), and verbal proficiency (SVF). RESULTS Although E2 levels were significantly lower in the patient group compared to the healthy controls, T, PRL, and LH levels were all significantly higher. Additionally, the analysis revealed that across the entire sample, there were positive correlations between E2 Levels and BDNF levels as well as BDNF levels and the digital cancellation time. In CATM patients with SCZ, a significant correlation between the negative symptoms score and PRL levels was observed. CONCLUSION Sex hormones and BDNF levels may also be linked to cognitive function in patients with chronic SCZ.
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Affiliation(s)
- Jin Li
- Department of Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
| | - Wen-Huan Xiao
- Department of Psychiatry, Affiliated Wutaishan Hospital of Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Fei Ye
- Department of Psychiatry, Affiliated Wutaishan Hospital of Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Xiao-Wei Tang
- Department of Psychiatry, Affiliated Wutaishan Hospital of Medical College of Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Qiu-Fang Jia
- Department of Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
| | - Xiao-Bin Zhang
- Department of Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou 215137, Jiangsu Province, China
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Androgen receptors and muscle: a key mechanism underlying life history trade-offs. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2017; 204:51-60. [DOI: 10.1007/s00359-017-1222-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 10/05/2017] [Accepted: 10/08/2017] [Indexed: 12/18/2022]
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Verhovshek T, Sengelaub DR. Androgen action at the target musculature regulates brain-derived neurotrophic factor protein in the spinal nucleus of the bulbocavernosus. Dev Neurobiol 2013; 73:587-98. [PMID: 23512738 DOI: 10.1002/dneu.22083] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/22/2013] [Accepted: 03/12/2013] [Indexed: 02/07/2023]
Abstract
We have previously demonstrated that brain-derived neurotrophic factor (BDNF) interacts with testosterone to regulate dendritic morphology of motoneurons in the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB). Additionally, in adult male rats testosterone regulates BDNF in SNB motoneurons and its target muscle, the bulbocavernosus (BC). Because BDNF is retrogradely transported from skeletal muscles to spinal motoneurons, we hypothesized that testosterone could regulate BDNF in SNB motoneurons by acting locally at the BC muscle. To test this hypothesis, we restricted androgen manipulation to the SNB target musculature. After castration, BDNF immunolabeling in SNB motoneurons was maintained at levels similar to those of gonadally intact males by delivering testosterone treatment directly to the BC muscle. When the same implant was placed interscapularly in castrated males it was ineffective in supporting BDNF immunolabeling in SNB motoneurons. Furthermore, BDNF immunolabeling in gonadally intact adult males given the androgen receptor blocker hydroxyflutamide delivered directly to the BC muscle was decreased compared with that of gonadally intact animals that had the same hydroxyflutamide implant placed interscapularly, or when compared with castrated animals that had testosterone implants at the muscle. These results demonstrate that the BC musculature is a critical site of action for the androgenic regulation of BDNF in SNB motoneurons and that it is both necessary and sufficient for this action. Furthermore, the local action of androgens at the BC muscle in regulating BDNF provides a possible mechanism underlying the interactive effects of testosterone and BDNF on motoneuron morphology. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 587-598, 2013.
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Affiliation(s)
- Tom Verhovshek
- Department of Neurological Surgery, Indiana Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA.
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Steroid hormones and BDNF. Neuroscience 2013; 239:271-9. [PMID: 23380505 DOI: 10.1016/j.neuroscience.2013.01.025] [Citation(s) in RCA: 301] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Revised: 12/29/2012] [Accepted: 01/09/2013] [Indexed: 11/23/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin abundantly expressed in several areas of the central nervous system (CNS) and is known to induce a lasting potentiation of synaptic efficacy, to enhance specific learning and memory processes. BDNF is one of the key molecules modulating brain plasticity and it affects cognitive deficit associated with aging and neurodegenerative disease. Several studies have shown an altered BDNF production and secretion in a variety of neurodegenerative diseases like Alzheimer's and Parkinson's diseases but also in mood disorders like depression, eating disorders and schizophrenia. Plasma BDNF is also a biomarker of impaired memory and general cognitive function in aging women. Gonadal steroids are involved in the regulation of several CNS processes, specifically mood, affective and cognitive functions during fertile life and reproductive aging. These observations lead many scientists to investigate a putative co-regulation between BDNF and gonadal and/or adrenal steroids and their relationship with gender difference in the incidence of mental diseases. This overview aims to summarize the current knowledge on the correlation between BDNF expression/function and both gonadal (progesterone, estrogens, and testosterone) and adrenal hormones (mainly cortisol and dehydroepiandrosterone (DHEA)) with relevance in clinical application.
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Ottem EN, Bailey DJ, Jordan CL, Breedlove SM. With a little help from my friends: androgens tap BDNF signaling pathways to alter neural circuits. Neuroscience 2012; 239:124-38. [PMID: 23262234 DOI: 10.1016/j.neuroscience.2012.12.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 12/03/2012] [Accepted: 12/05/2012] [Indexed: 12/20/2022]
Abstract
Gonadal androgens are critical for the development and maintenance of sexually dimorphic regions of the male nervous system, which is critical for male-specific behavior and physiological functioning. In rodents, the motoneurons of the spinal nucleus of the bulbocavernosus (SNB) provide a useful example of a neural system dependent on androgen. Unless rescued by perinatal androgens, the SNB motoneurons will undergo apoptotic cell death. In adulthood, SNB motoneurons remain dependent on androgen, as castration leads to somal atrophy and dendritic retraction. In a second vertebrate model, the zebra finch, androgens are critical for the development of several brain nuclei involved in song production in males. Androgen deprivation during a critical period during postnatal development disrupts song acquisition and dimorphic size-associated nuclei. Mechanisms by which androgens exert masculinizing effects in each model system remain elusive. Recent studies suggest that brain-derived neurotrophic factor (BDNF) may play a role in androgen-dependent masculinization and maintenance of both SNB motoneurons and song nuclei of birds. This review aims to summarize studies demonstrating that BDNF signaling via its tyrosine receptor kinase (TrkB) receptor may work cooperatively with androgens to maintain somal and dendritic morphology of SNB motoneurons. We further describe studies that suggest the cellular origin of BDNF is of particular importance in androgen-dependent regulation of SNB motoneurons. We review evidence that androgens and BDNF may synergistically influence song development and plasticity in bird species. Finally, we provide hypothetical models of mechanisms that may underlie androgen- and BDNF-dependent signaling pathways.
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Affiliation(s)
- E N Ottem
- Department of Biology, Northern Michigan University, Marquette, MI 49855, USA.
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Verhovshek T, Rudolph LM, Sengelaub DR. Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems. Neuroscience 2012; 239:103-14. [PMID: 23103213 DOI: 10.1016/j.neuroscience.2012.10.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 08/20/2012] [Accepted: 10/13/2012] [Indexed: 12/15/2022]
Abstract
Neurotrophic factors and steroid hormones interact to regulate a variety of neuronal processes such as neurite outgrowth, differentiation, and neuroprotection. The coexpression of steroid hormone and neurotrophin receptor mRNAs and proteins, as well as their reciprocal regulation provides the necessary substrates for such interactions to occur. This review will focus on androgen brain-derived neurotrophic factor (BDNF) interactions in the spinal cord, describing androgen regulation of BDNF in neuromuscular systems following castration, androgen manipulation, and injury. Androgens interact with BDNF during development to regulate normally-occurring motoneuron death, and in adulthood, androgen-BDNF interactions are involved in the maintenance of several features of neuromuscular systems. Androgens regulate BDNF and trkB expression in spinal motoneurons. Androgens also regulate BDNF levels in the target musculature, and androgenic action at the muscle regulates BDNF levels in motoneurons. These interactions have important implications for the maintenance of motoneuron morphology. Finally, androgens interact with BDNF after injury, influencing soma size, dendritic morphology, and axon regeneration. Together, these findings provide further insight into the development and maintenance of neuromuscular systems and have implications for the neurotherapeutic/neuroprotective roles of androgens and trophic factors in the treatment of motoneuron disease and recovery from injury.
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Affiliation(s)
- T Verhovshek
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute and Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Fraley GS, Steiner RA, Lent KL, Brenowitz EA. Seasonal changes in androgen receptor mRNA in the brain of the white-crowned sparrow. Gen Comp Endocrinol 2010; 166:66-71. [PMID: 19686750 PMCID: PMC2824064 DOI: 10.1016/j.ygcen.2009.08.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Revised: 07/30/2009] [Accepted: 08/11/2009] [Indexed: 11/23/2022]
Abstract
In songbirds, neurons that regulate learned song behavior undergo extensive seasonal plasticity in their number and size in relation to the bird's reproductive status. Seasonal plasticity of these brain regions is primarily regulated by changes in circulating concentrations of testosterone. Androgen receptors are present in all of the major song nuclei, but it is unknown whether levels of androgen receptor mRNA in the telencephalic song regions HVC, the robust nucleus of the arcopallium, and the lateral magnocellular nucleus of the anterior nidopallium change as a function of season in white-crowned sparrows. To determine whether seasonal changes in levels of androgen receptor mRNA are specific to the song control system, we also measured levels of androgen receptor mRNA in a limbic nucleus, the lateral division of the bed nucleus of the stria terminalis (the lateral division of the bed nucleus of the stria terminalis). We found that levels of androgen receptor mRNA were higher in HVC and the lateral division of the bed nucleus of the stria terminalis of birds in the breeding condition compared with the nonbreeding condition; however, we observed no seasonal differences in levels of androgen receptor mRNA in either the robust nucleus of the arcopallium or the lateral magnocellular nucleus of the anterior nidopallium. These results are consistent with previous observations that seasonal plasticity of the song nuclei results from testosterone acting directly on HVC, which then exerts transsynaptic trophic effects on its efferent targets. The seasonal change in the expression of androgen receptor in HVC may be one component of the cellular mechanisms underlying androgenic effects on seasonal plasticity of the song control nuclei.
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Affiliation(s)
- Gregory S Fraley
- Department of Biology & Neuroscience Program, Hope College, Holland, MI 49423, USA
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Verhovshek T, Cai Y, Osborne MC, Sengelaub DR. Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature. Endocrinology 2010; 151:253-61. [PMID: 19880806 PMCID: PMC2803156 DOI: 10.1210/en.2009-1036] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Trophic factors maintain motoneuron morphology and function in adulthood. Brain-derived neurotrophic factor (BDNF) interacts with testosterone to maintain dendritic morphology of spinal motoneurons. In addition, testosterone regulates BDNF's receptor (trkB) in motoneurons innervating the quadriceps muscles as well as in motoneurons of the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB). Given these interactive effects, we examined whether androgen might also regulate BDNF in quadriceps and SNB motoneurons and their corresponding target musculature. In both motoneuron populations, castration of males reduced BDNF immunolabeling, and this effect was prevented with testosterone replacement. ELISA for BDNF in the target musculature of quadriceps (vastus lateralis, VL) and SNB (bulbocavernosus, BC) motoneurons revealed that BDNF in the VL and BC muscles was also regulated by androgen. However, although castration significantly decreased BDNF concentration in the VL muscle, BDNF concentration in the BC muscle was significantly increased in castrates. Treatment of castrated males with testosterone maintained BDNF levels at those of intact males in both sets of muscles. Together, these results demonstrate that androgens regulate BDNF in both a sexually dimorphic, highly androgen-sensitive neuromuscular system as well as a more typical somatic neuromuscular system. Furthermore, in addition to the regulation of trkB, these studies provide another possible mechanism for the interactive effects of testosterone and BDNF on motoneuron morphology. More importantly, by examining both the motoneurons and the muscles they innervate, these results demonstrate that within a neural system, BDNF levels in different components are differentially affected by androgen manipulation.
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Affiliation(s)
- Tom Verhovshek
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
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Lin JW, Shih CM, Chen YC, Lin CM, Tsai JT, Chiang YH, Shih R, Chiu PL, Hung KS, Yeh YS, Wei L, Chiu WT, Yang LY. Biochemical alteration in cerebrospinal fluid precedes behavioral deficits in Parkinsonian rats induced by 6-hydroxydopamine. ACTA ACUST UNITED AC 2009; 72 Suppl 2:S55-65; discussion S65. [DOI: 10.1016/j.wneu.2009.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Accepted: 09/06/2009] [Indexed: 12/25/2022]
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Fargo KN, Foecking EM, Jones KJ, Sengelaub DR. Neuroprotective actions of androgens on motoneurons. Front Neuroendocrinol 2009; 30:130-41. [PMID: 19393684 PMCID: PMC2726741 DOI: 10.1016/j.yfrne.2009.04.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Revised: 04/03/2009] [Accepted: 04/14/2009] [Indexed: 01/30/2023]
Abstract
Androgens have a variety of protective and therapeutic effects in both the central and peripheral nervous systems. Here we review these effects as they related specifically to spinal and cranial motoneurons. Early in development, androgens are critical for the formation of important neuromuscular sex differences, decreasing the magnitude of normally occurring cell death in select motoneuron populations. Throughout the lifespan, androgens also protect against motoneuron death caused by axonal injury. Surviving motoneurons also display regressive changes to their neurites as a result of both direct axonal injury and loss of neighboring motoneurons. Androgen treatment enhances the ability of motoneurons to recover from these regressive changes and regenerate both axons and dendrites, restoring normal neuromuscular function. Androgens exert these protective effects by acting through a variety of molecular pathways. Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from motoneuron injury.
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Affiliation(s)
- Keith N. Fargo
- Research and Development Service; Edward Hines, Jr. VA Hospital; Hines, Illinois USA
- Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago; Maywood, Illinois, USA
| | - Eileen M. Foecking
- Research and Development Service; Edward Hines, Jr. VA Hospital; Hines, Illinois USA
- Department of Otolaryngology--Head and Neck Surgery, Loyola University Chicago; Maywood, Illinois, USA
| | - Kathryn J. Jones
- Research and Development Service; Edward Hines, Jr. VA Hospital; Hines, Illinois USA
- Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago; Maywood, Illinois, USA
- Department of Otolaryngology--Head and Neck Surgery, Loyola University Chicago; Maywood, Illinois, USA
| | - Dale R. Sengelaub
- Department of Psychological and Brain Sciences, and Program in Neuroscience, Indiana University, Bloomington, Indiana USA
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Hamson DK, Morris JA, Breedlove SM, Jordan CL. Time course of adult castration-induced changes in soma size of motoneurons in the rat spinal nucleus of the bulbocavernosus. Neurosci Lett 2009; 454:148-51. [PMID: 19429073 PMCID: PMC2688770 DOI: 10.1016/j.neulet.2009.02.059] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2009] [Revised: 02/18/2009] [Accepted: 02/18/2009] [Indexed: 11/28/2022]
Abstract
The spinal nucleus of the bulbocavernosus (SNB) innervates striated muscles, the bulbocavernosus and levator ani (BC/LA), which control penile reflexes. Castration results in shrinkage in the size of SNB somata and dendrites, as well as BC/LA muscle mass. However, there is no information about how quickly these regressive changes occur compared to the rapid effects of castration upon penile reflexes, which are greatly diminished a few days after surgery. Therefore we examined the time course of change in the size of SNB somata after castration of adult male rats. Males were sacrificed 2, 14, or 28 days after either castration or sham surgery and somata were measured in the SNB and in a control population of motoneurons, the retrodorsolateral nucleus (RDLN). BC/LA weight was reduced in castrates compared to intact males 14 and 28 days post surgery, but SNB somata were significantly smaller in castrates only at 28 days after surgery. As has been previously observed, castration did not affect soma size in the RDLN. These data indicate that SNB somata respond more slowly after castration than BC/LA mass or penile reflexes, suggesting that the size of SNB somata cannot account for the loss of penile reflexes. Androgenic effects on SNB somata may contribute to aspects of reproductive behavior that are not apparent in penile reflexes tested ex copula.
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Affiliation(s)
- Dwayne K Hamson
- Neuroscience Program and Department of Psychology, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824, United States.
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Osborne MC, Verhovshek T, Sengelaub DR. Androgen regulates trkB immunolabeling in spinal motoneurons. J Neurosci Res 2007; 85:303-9. [PMID: 17131419 DOI: 10.1002/jnr.21122] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Neurotrophic factors and steroid hormones have been shown to have neuroprotective/neurotherapeutic effects, and it has been shown previously that brain-derived neurotrophic factor (BDNF) and testosterone have a combinatorial effect in the maintenance of motoneurons. Given that gonadal hormones regulate the BDNF receptor, tyrosine receptor kinase B (trkB), we hypothesized that such a regulatory effect could mediate the interactive effects of BDNF and testosterone. Using immunohistochemical methods, we examined the frequency of cells immunolabeled for trkB receptors in two populations of spinal motoneurons, the hormone-sensitive, sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus (SNB) and the nondimorphic motoneurons innervating the muscles of the quadriceps. In both the highly androgen-sensitive SNB motoneurons and the more typical somatic motoneurons innervating the quadriceps, the frequency of motoneurons intensely immunolabeled for trkB receptors was regulated by the presence of testosterone. Castrated animals deprived of testosterone showed a reduced frequency of intensely labeled motoneurons compared with intact animals or castrated animals given testosterone replacement. This finding suggests that the combinatorial effect of BDNF and testosterone in the maintenance of motoneurons could occur at least in part through an androgen-mediated expression of the BDNF receptor.
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Affiliation(s)
- M C Osborne
- Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, Indiana 47405, USA
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Matsumoto A. Testosterone prevents synaptic loss in the perineal motoneuron pool in the spinal cord in male rats exposed to chronic stress. Stress 2005; 8:133-40. [PMID: 16019604 DOI: 10.1080/10253890500140642] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Chronic stress is known to induce disorders of reproductive neuroendocrine functions. Motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in male rats play an important role in copulatory behavior. In the present study, it was examined whether chronic stress would alter synaptic organization of the SNB motoneurons and whether androgen would modify the changes under chronic stress. Five male rats were under restraint stress for 5 days per week for 3 weeks, and five males implanted subcutaneously with Silastic capsules containing testosterone were also exposed to stress. Five males served as unstressed controls. After 3 weeks of restraint stress, cholera toxin-horseradish peroxidase (CT-HRP) was injected into the bulbocavernosus muscles and animals were killed 2 days later. The spinal cords containing the SNB were dissected, processed with a modified tetramethylbenzidine (TMB) method for visualization of retrogradely transported CT-HRP, and examined ultrastructurally. Neuronal structures apposing the membranes of 150 SNB motoneurons (total for three groups) were analyzed by measuring the percentage of somatic membranes covered by synaptic contacts. The mean percentage of somatic membranes covered by synapses in males exposed to chronic stress was significantly less than that in controls or stressed males treated with testosterone. Size and number of synaptic contacts per unit length of somatic membranes in males exposed to stress were also significantly less than those in controls or stressed males treated with testosterone. There was no significant difference in any of the parameters between controls and stressed males treated with testosterone. Changes in plasma levels of testosterone showed the same profile as changes in the synaptic contacts. These results suggest that the SNB motoneurons of male rats exposed to chronic stress retain a considerable synaptic plasticity in response to androgen, and that androgen treatment can rescue the SNB system in male rats when under chronic restraint stress.
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Affiliation(s)
- Akira Matsumoto
- Department of Anatomy, Juntendo University School of Medicine, Hongo, Tokyo, Japan.
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Chen X, Agate RJ, Itoh Y, Arnold AP. Sexually dimorphic expression of trkB, a Z-linked gene, in early posthatch zebra finch brain. Proc Natl Acad Sci U S A 2005; 102:7730-5. [PMID: 15894627 PMCID: PMC1140405 DOI: 10.1073/pnas.0408350102] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2004] [Indexed: 12/23/2022] Open
Abstract
Sexual differentiation of the zebra finch (Taeniopygia guttata) neural song circuit is thought to be initiated by sex differences in sex chromosome gene expression in brain cells. One theory is that Z-linked genes, present in the male's ZZ genome at double the dose of females' (ZW), are expressed at higher levels and trigger masculine patterns of development. We report here that trkB (tyrosine kinase receptor B) is Z-linked in zebra finches. trkB is the receptor for neurotrophic factors BDNF and neurotrophin 4, and mediates their influence on neuronal survival, migration, and specification. trkB mRNA is expressed at a higher level in the male telencephalon or whole brain than in corresponding regions of the female in adulthood, and at posthatch day (P) 6, when the song circuit is undergoing sexual differentiation. Moreover, this expression is higher in the song nucleus high vocal center (HVC) than in the surrounding telencephalon at P6, and in males relative to females. In addition, trkB protein is expressed more highly in male than female whole brain at P6. These results establish trkB as a candidate factor that contributes to masculine differentiation of HVC because of its Z-linkage, which leads to sex differences in expression. BDNF is known to be stimulated by estrogen and to be expressed at higher levels in males than females at later ages in HVC. Thus, the trkB-BDNF system may be a focal point for convergent masculinizing influences of Z-linked factors and hormones.
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Affiliation(s)
- Xuqi Chen
- Department of Physiological Science, University of California, Los Angeles, CA 90095, USA
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Tabori NE, Stewart LS, Znamensky V, Romeo RD, Alves SE, McEwen BS, Milner TA. Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation. Neuroscience 2005; 130:151-63. [PMID: 15561432 DOI: 10.1016/j.neuroscience.2004.08.048] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2004] [Indexed: 11/18/2022]
Abstract
Like estrogens in female rats, androgens can affect dendritic spine density in the CA1 subfield of the male rat hippocampus [J Neurosci 23:1588 (2003)]. Previous light microscopic studies have shown that androgen receptors (ARs) are present in the nuclei of CA1 pyramidal cells. However, androgens may also exert their effects through rapid non-genomic mechanisms, possibly by binding to membranes. Thus, to investigate whether ARs are at potential extranuclear sites of ARs, antibodies to ARs were localized by light and electron microscopy in the male rat hippocampal formation. By light microscopy, AR immunoreactivity (-ir) was found in CA1 pyramidal cell nuclei and in disperse, punctate processes that were most dense in the pyramidal cell layer. Additionally, diffuse AR-ir was found in the mossy fiber pathway. Ultrastructural analysis revealed AR-ir at several extranuclear sites in all hippocampal subregions. AR-ir was found in dendritic spines, many arising from pyramidal and granule cell dendrites. AR-ir was associated with clusters of small, synaptic vesicles within preterminal axons and axon terminals. Labeled preterminal axons were most prominent in stratum lucidum of the CA3 region. AR-containing terminals formed asymmetric synapses or did not form synaptic junctions in the plane of section analyzed. AR-ir also was detected in astrocytic profiles, many of which apposed terminals synapsing on unlabeled dendritic spines or formed gap junctions with other AR-labeled or unlabeled astrocytes. Collectively, these results suggest that ARs may serve as both a genomic and non-genomic transducer of androgen action in the hippocampal formation.
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Affiliation(s)
- N E Tabori
- Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 411 East 69th Street, New York, NY 10021, USA
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Abstract
The ovarian steroid hormones have numerous effects on the brain, many of which are mediated, at least in part, by interaction with intracellular steroid hormone receptors acting as regulators of transcription. These intracellular steroid hormone receptors have often been considered to be activated solely by cognate hormone. However, during the past decade, numerous studies have shown that the receptors can be activated by neurotransmitters and intracellular signaling systems, through a process that does not require hormone. Although most of these have been in vitro experiments, others have been in vivo. Evidence from a wide variety of tissues and cells suggests that steroid hormone receptors are transcription factors that can be activated by a wide variety of factors, only one of which is cognate hormone. Furthermore, ligand-independent activation of neural steroid hormone receptors, rather than being a pharmacological or in vitro curiosity, seems to be a process that occurs in the normal physiology of animals. Thinking of steroid hormone receptors only as ligand-activated proteins may constrain our thinking about the many factors that may activate the receptors and cause receptor-dependent changes in neural gene expression and neuroendocrine function.
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Affiliation(s)
- Jeffrey D Blaustein
- Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003, USA.
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Zoubina EV, Smith PG. Distributions of estrogen receptors alpha and beta in sympathetic neurons of female rats: enriched expression by uterine innervation. JOURNAL OF NEUROBIOLOGY 2002; 52:14-23. [PMID: 12115890 DOI: 10.1002/neu.10064] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Estrogen modulates many features of the sympathetic nervous system, including cell numbers and ganglion synapses, and can induce uterine sympathetic nerve degeneration. However, distributions of estrogen receptors alpha and beta within sympathetic neurons have not been described, and their regulation by target tissue or estrogen levels has not been explored. We used immunofluorescence and retrograde tracing to define estrogen receptor expression in sympathetic neurons at large in pre- and paravertebral ganglia and in those projecting to the uterine horns. Estrogen receptor alpha immunoreactivity was present in 29 +/- 1%, while estrogen receptor beta was expressed by 92 +/- 1% of sympathetic neurons at large. The proportions of neurons expressing these receptors were comparable in the superior cervical and thoraco-lumbar paravertebral ganglia from T11 through L5, and in the suprarenal, celiac, and superior mesenteric prevertebral ganglia. Injections of FluoroGold into the uterine horns resulted in labeled neurons, with peak occurrences in T13, L1, and the suprarenal ganglion. Uterine-projecting neurons showed small but significantly greater incidence of estrogen receptor beta expression relative to the neuronal population at large, whereas the proportion of uterine-projecting neurons with estrogen receptor alpha-immunoreactivity was nearly threefold greater. Numbers of estrogen receptor-expressing neurons were not altered by acute estrogen administration. We conclude that the vast majority of sympathetic neurons express estrogen receptor beta immunoreactive protein, whereas a smaller, presumably overlapping subset expresses the estrogen receptor alpha. Expression of the latter apparently can be enhanced by target-mediated mechanisms.
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Affiliation(s)
- Elena V Zoubina
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City 66160, USA
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Abstract
Target-derived neurotrophic factors are assumed to regulate motoneuron cell death during development but remain unspecified. Motoneuron cell death in the spinal nucleus of the bulbocavernosus (SNB) of rats extends postnatally and is controlled by androgens. We exploited these features of the SNB system to identify endogenously produced trophic factors regulating motoneuron survival. Newborn female rat pups were treated with the androgen, testosterone propionate, or the oil vehicle alone. In addition, females received trophic factor antagonists delivered either into the perineum (the site of SNB target muscles) or systemically. Fusion molecules that bind and sequester the neurotrophins (trkA-IgG, trkB-IgG, and trkC-IgG) were used to block activation of neurotrophin receptors, and AADH-CNTF was used to antagonize signaling through the ciliary neurotrophic factor receptor-alpha (CNTFRalpha). An acute blockade of trkB, trkC, or CNTFRalpha prevented the androgenic sparing of SNB motoneurons when antagonists were delivered to the perineum. Trophic factor antagonists did not significantly reduce SNB motoneuron number when higher doses were injected systemically. These findings demonstrate a requirement for specific, endogenously produced trophic factors in the androgenic rescue of SNB motoneurons and further suggest that trophic factor interactions at the perineum play a crucial role in masculinization of this neural system.
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Abstract
Ten aged male rats (24 months of age) were castrated and implanted subcutaneously with Silastic capsules containing testosterone (T)(5 males) or nothing (5 males). Five sham-castrated males (25 months of age) served as controls. Four weeks after castration, cholera toxin-horseradish peroxidase (CT-HRP) was injected into the bulbocavernosus muscles and animals were killed 2 days later. The spinal cords containing the spinal nucleus of the bulbocavernosus (SNB) were dissected, processed with a modified tetramethylbenzidine method for visualization of retrogradely transported CT-HRP, and examined ultrastructurally. Neuronal structures apposing the membranes of 150 CT-HRP-labeled SNB motoneurons were analyzed by measuring the percentage of somatic membranes covered by synaptic contacts, synaptoid contacts, and neuron-neuron contacts. Most of the neuronal structures in the control and experimental SNB motoneurons consisted of synaptic contacts. The mean percentage of somatic membranes covered by synapses in castrated, aged males treated with T was significantly greater than that in control or castrated animals. Size and number of synaptic contacts per unit length of somatic membranes in castrated, aged males treated with T were also significantly greater than those in control or castrated animals. Plasma levels of T in castrated, aged males treated with T were significantly greater than that in controls. These results suggest that the SNB motoneurons of aged male rats retain a considerable synaptic plasticity in response to androgen, and that androgen may be, at least in part, involved in the process of aging of the SNB system in male rats.
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Affiliation(s)
- A Matsumoto
- Department of Anatomy, Juntendo University School of Medicine, Hongo, Tokyo 113-0033, Japan.
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Yang LY, Arnold AP. Interaction of BDNF and testosterone in the regulation of adult perineal motoneurons. JOURNAL OF NEUROBIOLOGY 2000; 44:308-19. [PMID: 10942884 DOI: 10.1002/1097-4695(20000905)44:3<308::aid-neu2>3.0.co;2-m] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In androgen-sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB), we investigated the interaction of BDNF (brain-derived neurotrophic factor) and testosterone to understand whether each factor gates the ability of the other to regulate androgen receptor expression and soma size, and whether each factor requires the presence of the other for its action. We axotomized SNB motoneurons and applied BDNF or PBS (phosphate-buffered saline) to the cut ends of the axons in rats that were castrated and treated with either testosterone or placebo. Control groups were either not castrated or not axotomized, or had intact SNB axons and were castrated and treated with testosterone or placebo. We found that testosterone determined the expression of nuclear androgen receptor, and this effect was enhanced by both BDNF and contact with the target muscles. The effect of BDNF on androgen receptor expression was seen only when testosterone was present. In the regulation of soma size, BDNF dominated. The application of BDNF completely compensated for the loss of testosterone in castrated males so that the testosterone effect on soma size was seen only in intact SNB motoneurons and in axotomized motoneurons treated with PBS. Moreover, testosterone increased androgen receptor and soma size in axotomized SNB motoneurons, indicating that testosterone can act on sites other than the target muscles of the SNB to regulate each of these. These results indicate that the regulation of androgen receptor by testosterone does not require BDNF, but the regulation of androgen receptor by BDNF does require testosterone. The regulation of soma size by BDNF does not require high expression of nuclear androgen receptor.
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Affiliation(s)
- L Y Yang
- Department of Physiological Science, 621 Charles E. Young Drive South, University of California, Los Angeles, California 90095-1527, USA.
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