Astrocyte-derived thrombospondin induces cortical synaptogenesis in a sex-specific manner

AbstractThe regulation of synaptic connectivity in the brain is vital to proper functioning and development of the central nervous system (CNS). Formation of neural networks in the CNS has been shown to be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process is different between males and females has not been thoroughly investigated. In this study, we found that cortical neurons purified from newborn male rats showed a significantly more robust synaptogenic response compared to female-derived cells when exposed to factors secreted from astrocytes. This difference was driven largely by the neuronal response to TSP2, which increased synapses in male neurons while showing no effect on female neurons. Blockade of endogenous 17β-estradiol production with letrozole normalized the TSP response between male and female cells, indicating a level of regulation by estrogen signaling. Our results suggest that TSP-induced synaptogenesis is critical for the development of male but not female cortical synapses, contributing to sex differences in astrocyte-mediated synaptic connectivity.

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Risk-based Decision Making in Rats: Modulation by Sex and Amphetamine

10.1101/2020.03.09.981563 ◽

2020 ◽

Author(s):

Dannia Islas-Preciado ◽

Steven R. Wainwright ◽

Julia Sniegocki ◽

Stephane E. Lieblich ◽

Shunya Yagi ◽

...

Keyword(s):

Decision Making ◽

Sex Differences ◽

Gonadal Hormones ◽

Risky Choice ◽

Female Rats ◽

Male Rats ◽

Risky Decision Making ◽

Risky Decision ◽

17Β Estradiol ◽

Males And Females

AbstractDecision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17β-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17β-estradiol benzoate (0.3 μg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17β-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias towards larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

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Tactile Stimulation in Adult Rats Modulates Dopaminergic Molecular Parameters in the Nucleus Accumbens Preventing Amphetamine Relapse.

10.21203/rs.3.rs-1247241/v1 ◽

2022 ◽

Author(s):

Domênika Rubert Rossato ◽

Higor Zuchetto Rosa ◽

Jéssica Leandra Oliveira Rosa ◽

Laura Hautrive Milanesi ◽

Vinícia Garzella Metz ◽

...

Keyword(s):

Nucleus Accumbens ◽

Tactile Stimulation ◽

Male Rats ◽

Adult Rats ◽

Delta Fosb ◽

The Central Nervous System ◽

Molecular Assessment ◽

Drug Abstinence ◽

The Brain ◽

Abstinence Period

Abstract Amphetamine (AMPH) is a psychostimulant drug frequently related to addiction, which is characterized by functional and molecular changes in the brain reward system, favoring relapse development and pharmacotherapies have shown low effectiveness. Considering the beneficial influences of tactile stimulation (TS) in different diseases that affect the central nervous system (CNS), here we evaluated if TS applied in adult rats could prevent or minimize the AMPH-relapse behavior also accessing molecular neuroadaptations in the Nucleus accumbens (NAc). Following AMPH conditioning in the conditioned place preference (CPP) paradigm, male rats were submitted to TS (15-min session, 3 times a day, for 8 days) during the drug abstinence period, which were re-exposed to the drug in the CPP paradigm for additional 3 days for relapse observation and molecular assessment. Our findings showed that besides AMPH relapse; TS prevented the dopamine transporter (DAT), dopamine 1 receptor (D1R), tyrosine hydroxylase (TH), mu opioid receptor (MOR) increase and AMPH-induced delta FosB (ΔFosB). Based on these outcomes, we propose TS as a useful tool to treat psychostimulant addiction, which subsequent to clinical studies; it could be included in detoxification programs together with pharmacotherapies and psychological treatments already conventionally established.

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Local Cerebral Glucose Utilization in Normal Female Rats: Variations during the Estrous Cycle and Comparison with Males

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1985.54 ◽

1985 ◽

Vol 5 (3) ◽

pp. 393-400 ◽

Cited By ~ 44

Author(s):

Astrid Nehlig ◽

Linda J. Porrino ◽

Alison M. Crane ◽

Louis Sokoloff

Keyword(s):

Estrous Cycle ◽

Glucose Utilization ◽

Brain Regions ◽

Female Rats ◽

Male Rats ◽

Normal Male ◽

Normal Female ◽

Female Rat ◽

Males And Females ◽

The Brain

The quantitative 2-[14C]deoxyglucose autoradiographic method was used to study the fluctuations of energy metabolism in discrete brain regions of female rats during the estrous cycle. A consistent though statistically nonsignificant cyclic variation in average glucose utilization of the brain as a whole was observed. Highest levels of glucose utilization occurred during proestrus and metestrus, whereas lower rates were found during estrus and diestrus. Statistically significant fluctuations were found specifically in the hypothalamus and in some limbic structures. Rates of glucose utilization in the female rat brain were compared with rates in normal male rats. Statistically significant differences between males and females at any stage of the estrous cycle were confined mainly to hypothalamic areas known to be involved in the control of sexual behavior. Glucose utilization in males and females was not significantly different in most other cerebral structures.

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A Possible Mechanism for the Action of Adrenomedullin in Brain to Stimulate Stress Hormone Secretion

Endocrinology ◽

10.1210/en.2004-0806 ◽

2004 ◽

Vol 145 (11) ◽

pp. 4890-4896 ◽

Cited By ~ 20

Author(s):

Meghan M. Taylor ◽

Willis K. Samson

Keyword(s):

Hpa Axis ◽

Hormone Secretion ◽

Plasma Corticosterone ◽

Male Rats ◽

Stress Hormone ◽

Elevated Plasma ◽

The Central Nervous System ◽

Neuroendocrine Responses ◽

The Brain

Abstract Adrenomedullin (AM) has been reported to have actions at each level of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that the peptide plays a role in the organization of the neuroendocrine responses to stress. We examined the mechanism by which AM regulates the central nervous system branch of the HPA axis as well as the possible role of AM in the modulation of the releases of two other hormones, prolactin and GH, whose secretions also are altered by stress. Intracerebroventricular administration of AM led to elevated plasma corticosterone levels in unrestrained, conscious male rats. This effect was abrogated by pretreatment with a CRH antagonist, suggesting that AM activates the HPA axis by causing the release of CRH into hypophyseal portal vessels. In addition, AM given intracerebroventricularly stimulated the release of prolactin but did not alter the secretion of GH. We propose that AM produced in the brain may be an important neuromodulator of the hormonal stress response.

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Neuroinvasion of SARS-CoV-2 in human and mouse brain

Journal of Experimental Medicine ◽

10.1084/jem.20202135 ◽

2021 ◽

Vol 218 (3) ◽

Cited By ~ 4

Author(s):

Eric Song ◽

Ce Zhang ◽

Benjamin Israelow ◽

Alice Lu-Culligan ◽

Alba Vieites Prado ◽

...

Keyword(s):

Cortical Neurons ◽

Immune Cell ◽

Multiple Organ ◽

Type I ◽

Organ Systems ◽

The Central Nervous System ◽

Interferon Responses ◽

The Brain ◽

Immune Cell Infiltrates

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

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Astrocytic and microglial response and histopathological changes in the brain of horses with experimental chronic Trypanosoma evansi infection

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652008000400011 ◽

2008 ◽

Vol 50 (4) ◽

pp. 243-249 ◽

Cited By ~ 9

Author(s):

Karen Regina Lemos ◽

Luiz Carlos Marques ◽

Lucia Padilha Cury Thomaz Aquino ◽

Antonio Carlos Alessi ◽

Rosangela Zacarias Zacarias

Keyword(s):

Nervous System ◽

Mononuclear Cells ◽

Trypanosoma Evansi ◽

Control Group ◽

Reactive Microglia ◽

The Central Nervous System ◽

Males And Females ◽

Microglial Response ◽

The Brain ◽

Experimental Group

This study aimed to characterize astrocytic and microglial response in the central nervous system (CNS) of equines experimentally infected with T. evansi. The experimental group comprised males and females with various degrees of crossbreeding, ages between four and seven years. The animals were inoculated intravenously with 10(6) trypomastigotes of T. evansi originally isolated from a naturally infected dog. All equines inoculated with T. evansi were observed until they presented symptoms of CNS disturbance, characterized by motor incoordination of the pelvic limbs, which occurred 67 days after inoculation (DAI) and 124 DAI. The animals in the control group did not present any clinical symptom and were observed up to the 125th DAI. For this purpose the HE histochemical stain and the avidin biotin peroxidase method was used. Lesions in the CNS of experimentally infected horses were those of a wide spread non suppurative meningoencephalomyelitis.The severity of lesions varied in different parts of the nervous system, reflecting an irregular distribution of inflammatory vascular changes. The infiltration of mononuclear cells was associated with anisomorphic gliosis and reactive microglia was identified. The intensity of the astrocytic response in the CNS of the equines infected by T. evansi characterizes the importance of the performance of these cells in this trypanosomiasis. The characteristic gliosis observed in the animals in this experiment suggests the ability of these cells as mediators of immune response. The parasite, T. evansi, was not identified in the nervous tissues.

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CNS-Selective Estrogen Therapy

Proceedings ◽

10.3390/proceedings2019022031 ◽

2019 ◽

Vol 22 (1) ◽

pp. 31

Author(s):

Katalin Prokai-Tatrai ◽

Laszlo Prokai

Keyword(s):

Psychiatric Symptoms ◽

Estrogen Therapy ◽

The Body ◽

Therapeutic Interventions ◽

Eye Health ◽

The Central Nervous System ◽

17Β Estradiol ◽

Hormonal Exposure ◽

Bioanalytical Assays ◽

The Brain

17β-Estradiol (E2), the main human estrogen, has been known to exert multiple actions throughout the body, including in the central nervous system (CNS). In particular, it has been shown that E2 is gender-independently needed for brain and eye health. Lack of E2 due to normal aging and/or pathological processes leads to neurological and psychiatric diseases as well as accelerated neurodegeneration. Current estrogen replacement therapies, however, cannot be used as therapeutic interventions to treat these maladies due to a profound, unwanted hormonal exposure to the rest of the body. In this presentation, we show that the small-molecule bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) produces E2 only in the CNS but remains inert in the rest of the body, both upon chronic systemic and topical administrations, thereby avoiding the detrimental side-effects of the hormone, such as stimulation of the uterus and tumor growth. The highly localized production of E2 in the CNS will be shown through a series of bioanalytical assays and efficacy studies using animal models of estrogen-responsive maladies pertaining to the brain and the retina. Owing to DHED’s significantly more favorable physicochemical properties than the highly lipophilic parent E2 for transport through biological membranes such as the blood-brain barrier or the cornea, a highly effective E2 therapy can be achieved in rodents upon prodrug administration, which further enhances therapeutic safety. Altogether, our patented DHED approach shows unprecedented selectivity to deliver E2 into the CNS and, thus, promises a high translation value in terms of efficacious and safe treatment against neurodegeneration as well as neurological and psychiatric symptoms arising from estrogen deficiency.

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Further evidence that brain histamine H2 receptors are stimulatory in the control of prolactin in the rat

Acta Endocrinologica ◽

10.1530/acta.0.1190488 ◽

1988 ◽

Vol 119 (4) ◽

pp. 488-492 ◽

Cited By ~ 7

Author(s):

Carmela Netti ◽

Valeria Sibilia ◽

Francesca Guidobono ◽

Isabella Villa ◽

Paola Franco ◽

...

Keyword(s):

Prolactin Secretion ◽

Male Rats ◽

Normal Male ◽

Brain Histamine ◽

H2 Receptors ◽

The Central Nervous System ◽

Brain Ventricle ◽

The Brain ◽

Chemical Analogue ◽

Stimulation Of

Abstract. The effects of administration into the brain ventricle of H2 receptor agonists (4-methylhistamine, 0.8 μmol/rat; dimaprit, 0.4–0.8 μmol/rat), H2 antagonists (cimetidine, 0.8 μmol/rat; ranitidine, 0.4–0.8 μmol/rat; famotidine, 0.03 μmol/rat) and of the dimaprit chemical analogue SK&F 91487 (0.4 μmol/rat) on unstimulated and histamine-stimulated prolactin secretion in normal male rats were studied. The H2 agonist 4-methylhistamine caused a significant increase in unstimulated blood PRL, whereas dimaprit, SK&F 91487, and the H2 antagonists tested did not change PRL levels. 4-Methylhistamine significantly enhanced the stimulatory effects of histamine on prolactin, whereas all the H2 antagonists inhibited histamine-induced prolactin release. The inhibition of histamine-induced prolactin secretion by the H2 agonist dimaprit is nonspecific, since its chemical analogue SK&F 91487, which has no H2 agonist activity, also inhibits it. These results indicate that stimulation of the H2 receptors in the central nervous system is facilitatory for PRL secretion, suggesting that the activation of H2 receptors may contribute to the PRL-releasing effects of histamine.

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What happens to your brain on the way to Mars

Science Advances ◽

10.1126/sciadv.1400256 ◽

2015 ◽

Vol 1 (4) ◽

pp. e1400256 ◽

Cited By ~ 106

Author(s):

Vipan K. Parihar ◽

Barrett Allen ◽

Katherine K. Tran ◽

Trisha G. Macaraeg ◽

Esther M. Chu ◽

...

Keyword(s):

Cortical Neurons ◽

Charged Particles ◽

Radiation Sensitivity ◽

Galactic Cosmic Rays ◽

Spine Density ◽

Neuronal Structure ◽

Prefrontal Cortical ◽

Radiation Induced ◽

The Central Nervous System ◽

The Brain

As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.

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Neuroinvasion of SARS-CoV-2 in human and mouse brain

10.1101/2020.06.25.169946 ◽

2020 ◽

Cited By ~ 22

Author(s):

Eric Song ◽

Ce Zhang ◽

Benjamin Israelow ◽

Alice Lu-Culligan ◽

Alba Vieites Prado ◽

...

Keyword(s):

Cortical Neurons ◽

Immune Cell ◽

Multiple Organ ◽

Cns Infection ◽

Type I ◽

Organ Systems ◽

Pathologic Features ◽

The Central Nervous System ◽

The Brain

SummaryAlthough COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

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