Regular ArticleSteroid Hormones and Excitability in the Mammalian Brain
Abstract
Adrenocortical and gonadal steroid hormones can pass the blood–brain barrier and bind to intracellular receptors in the brain. In addition to steroid hormones binding to intracellular steroid receptors, metabolites of these steroids and steroid hormones produced in the brain (neurosteroids) are thought to bind to membrane recognition sites. Actions mediated by the intracellular receptors are generally delayed in onset and are of prolonged duration, whereas the hormones binding to membrane recognition sites induce fast effects. Both fast and delayed actions by steroid hormones potentially alter the electrical properties of neuronal membranes and thus the firing patterns of neurons carrying receptors for the hormones. We here review the fast and delayed actions by steroid hormones on single cell electrical properties in the mammalian nervous system. In general, fast effects by corticosteroids—presumably mediated by membrane receptors—induce inhibitory effects on cellular firing, although regional differences seem to exist. Delayed effects by corticosteroid hormones via mineralocorticoid receptors serve to maintain or enhance fast transmission in the brain, while modulatory inputs are suppressed. By contrast, corticosteroids acting through glucocorticoid receptors suppress transmission carried by amino acids, particularly when the activity is elevated in comparison to resting level; modulatory inputs are enhanced. Prolonged activation of glucocorticoid receptors can implicate the integrity of neuronal circuits by allowing considerable influx of calcium ions during depolarization. Of the gonadal hormones, estradiol mainly exerts excitatory actions, in both a rapid and a delayed mode. Progesterone on the other hand is predominantly inhibitory, usually with a short delay in onset. The effect of androgens on neuronal excitability has not yet been studied in great detail. Finally, neurosteroids and A-ring reduced steroids in general induce rapid effects on firing patterns, probably by acting on ligand gated ion channels. The diverse actions of steroid hormones on single cell activity have consequences for the excitability in local circuits in which these cells participate. This is illustrated in this review for two processes that depend on circuit rather than single cell function, i.e., long term potentiation and epilepsy. The diverging character of steroid hormones with regard to the time frame, space, and nature of their effects is also reflected in the functional processes that are linked to the activity of the networks responding to steroids. In this way steroid hormones add an essentially new aspect to the regulation of functional processes in the brain, during physiological conditions but also when networks are implicated during diseases and disorders. Future research on steroid modulation of cellular excitability will gain considerably from attempts to either link the changed excitability to the underlying molecular events or study the effects on cellular activity in close connection with behavioral functions.
References (0)
Cited by (254)
Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome
2022, Journal of Dental SciencesSex differences in the nervous system have gained recent academic interest. While the prominent differences are observed in mood and anxiety disorders, growing number of evidences also suggest sex difference in pain perception. This review focuses on estrogen as the key molecule underlying such difference, because estrogen plays many functions in the nervous system, including modulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3), two important nociceptive receptors. Estrogen was shown in various studies to up-regulate TRPV1 expression through two distinct pathways, resulting in pro-nociceptive effect. However, estrogen alleviated pain in other studies, by down-regulating nerve growth factor (NGF)–activated pathways and TRPV1. Estrogen may also attenuate nociception by inhibiting P2X3 receptors and ATP-signaling. Understanding the mechanism underlying the pro- and anti-nociceptive effect of estrogen might be crucial to understand pathophysiology of the burning mouth syndrome (BMS), a common chronic orofacial pain disorder in menopausal women. The involvement of TRPV1 is strongly suspected because of burning sensation. Reduced estrogen level of the BMS patient might have caused increased activity of P2X3 receptors. Interestingly, the increased expression of TRPV1 and P2X3 in oral mucosa of BMS patients was reported. The combinational impact of differential modulation of TRPV1/P2X3 during menopause might be an important contributing factor of etiology of BMS. Understanding the estrogen-dependent regulation of nociceptive receptors may provide a valuable insight toward the peripheral mechanism of sex-difference in pain perception.
Juvenile hormone drives the maturation of spontaneous mushroom body neural activity and learned behavior
2021, NeuronMature behaviors emerge from neural circuits sculpted by genetic programs and spontaneous and evoked neural activity. However, how neural activity is refined to drive maturation of learned behavior remains poorly understood. Here, we explore how transient hormonal signaling coordinates a neural activity state transition and maturation of associative learning. We identify spontaneous, asynchronous activity in a Drosophila learning and memory brain region, the mushroom body. This activity declines significantly over the first week of adulthood. Moreover, this activity is generated cell-autonomously via Cacophony voltage-gated calcium channels in a single cell type, α′/β′ Kenyon cells. Juvenile hormone, a crucial developmental regulator, acts transiently in α′/β′ Kenyon cells during a young adult sensitive period to downregulate spontaneous activity and enable subsequent enhanced learning. Hormone signaling in young animals therefore controls a neural activity state transition and is required for improved associative learning, providing insight into the maturation of circuits and behavior.
Hypothalamic-pituitary-adrenal axis targets for the treatment of epilepsy
2021, Neuroscience LettersStress is a common seizure trigger in persons with epilepsy. The body’s physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and involves a hormonal cascade that includes corticotropin releasing hormone (CRH), adrenocorticotropin releasing hormone (ACTH) and the release of cortisol (in humans and primates) or corticosterone (in rodents). The prolonged exposure to stress hormones may not only exacerbate pre-existing medical conditions including epilepsy, but may also increase the predisposition to psychiatric comorbidities. Hyperactivity of the HPA axis negatively impacts the structure and function of the temporal lobe of the brain, a region that is heavily involved in epilepsy and mood disorders like anxiety and depression. Seizures themselves damage temporal lobe structures, further disinhibiting the HPA axis, setting off a vicious cycle of neuronal damage and increasing susceptibility for subsequent seizures and psychiatric comorbidity. Treatments targeting the HPA axis may be beneficial both for epilepsy and for associated stress-related comorbidities such as anxiety or depression. This paper will highlight the evidence demonstrating dysfunction in the HPA axis associated with epilepsy which may contribute to the comorbidity of psychiatric disorders and epilepsy, and propose treatment strategies that may dually improve seizure control as well as alleviate stress related psychiatric comorbidities.
Pubertal stress decreases sexual motivation and supresses the relation between cerebral theta rhythms and testosterone levels in adult male rats
2020, Brain ResearchThis study evaluated the effect of stress during puberty on sexual motivation and the correlation between serum testosterone levels (T) and the absolute power of the theta electroencephalographic rhythms, recorded in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of adult male rats. Thirty males of the stressed group (SG, housed 1 per cage from days 25–50) and 30 controls (CG, housed 5 per cage), were tested in copulatory interactions at 90 days of age. The above mentioned physiological parameters were obtained during the awake-quiet state in a sub-group without sexual motivation (WSM, n = 15, stimulated with a nonreceptive female) and a sub-group with sexual motivation (SM, n = 15, stimulated with a receptive-female). Pearson correlations (r) between these parameters were calculated for each sub-group and brain structure and then compared between sub-groups. SG presented higher mount and intromission latencies than CG. While CG-WSM showed a positive r between T levels and theta band (0.23-0.59), those CG-SM presented a negative r (−0.23 to −0.67). An r that tended towards zero (−0.31 to 0.29) was obtained in both stressed sub-groups. This study shows that pubertal stress suppresses the relation between serum T levels and theta rhythms in the mPFC and BLA in adult male rats. This is one of the first studies evaluating the association between these two physiological parameters specifically in the context of sexual motivation; thus increasing our understanding of the effect of pubertal stress on prefrontal-amygdaline functioning during the sexually-motivated state in male rats.
Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis
2020, Epilepsy and BehaviorWe investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy.
We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau–Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum–albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥ 50% for three months after the first course of MP.
Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01).
Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.
Reproductive state and water deprivation increase plasma corticosterone in a capital breeder
2020, General and Comparative EndocrinologyPlasma corticosterone (CORT) concentrations fluctuate in response to homeostatic demands. CORT is widely recognized as an important hormone related to energy balance. However, far less attention has been given to the potential role of CORT in regulating salt and water balance or responding to osmotic imbalances. We examined the effects of reproductive and hydric states on CORT levels in breeding Children’s pythons (Antaresia childreni), a species with substantial energetic and hydric costs associated with egg development. Using a 2 × 2 experimental design, we examined how reproduction and water deprivation, both separately and combined, impact CORT levels and how these changes correlate with hydration (plasma osmolality) and energy levels (blood glucose). We found that reproduction leads to increased CORT levels, as does dehydration induced by water deprivation. The combined impact of reproduction and water deprivation led to the largest increases in CORT levels. Additionally, we found significant positive relationships among CORT levels, plasma osmolality, and blood glucose. Our results provide evidence that both reproductive activity and increased plasma osmolality can lead to increased plasma CORT in an ectotherm, which could be explained by either CORT having a role as a mineralocorticoid or CORT being elevated as part of a stress response to resource imbalances.