Role of Sex Steroids on the Survival, Neuritic Outgrowth of Neurons, and Dopamine Neurons in Cultured Preoptic Area and Hypothalamus

doi:10.1006/hbeh.1994.1026

Hormones and Behavior

Volume 28, Issue 4, December 1994, Pages 305-312

https://doi.org/10.1006/hbeh.1994.1026 Get rights and content

Abstract

Morphological sex differences in some discrete brain regions are thought to be developed by the influence of circulating androgen during the perinatal period. In order to know whether the effect of androgen is a direct one, cells derived from neonatal rat preoptic area (POA) and/or hypothalamus were cultured in a serum-free medium, and the effects on survival, process growth of neurons, and dopaminergic function were examined. When the POA cells were exposed to testosterone (T), neuronal survival was greater than the controls, and the frequency distribution of total process length and the number of process branchings were significantly deviated from the controls. Estradiol-17β (E₂) and 5α-dihydrotestosterone had less significant effects on these parameters than T. Moreover, the addition of T increased the dopamine (DA) contents of cells and medium DA in the hypothalamic culture. E₂ also greatly increased DA content of the medium. These steroids failed to alter the DA levels in the POA cell cultures. These results generally conform to the notion of previous investigators that T has direct effects on the expansion of dendritic elements of the POA and the development of sex difference in the hypothalamic DA neurons, although the effect of T after conversion to E₂ cannot be excluded.

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Age-related decline in testosterone levels has also been associated with increased AD risk in men [12]. Testosterone exerts neuroprotective effects by inhibiting Aβ accumulation; promoting neuronal growth, synaptic function, and axonal regeneration; and protecting against neuronal loss [19,30]. Various genes involved in the biosynthesis and metabolism of sex steroids have been linked to AD; one of these, CYP17A1, is responsible for testosterone and estrogen production.
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Such beneficial neural actions of androgens include: (1) promotion of neuron growth, axonal regeneration, and synaptic function, (2) protection against neuron cell loss, and (3) regulation of AD-related pathology including Aβ accumulation. In the first case, androgens have a variety of growth-promoting and maturational effects on neurons in a range of paradigms (Arai, 1991; Brannvall et al., 2005; Cooke et al., 1998; Gorski, 1985; Kawashima and Takagi, 1994; Lustig, 1994; Matsumoto, 1991). In addition, androgens are potent facilitators of spine density and synaptic function, including regulation of long-term potentiation in the hippocampus (Garcia-Segura et al., 1994; Hajszan et al., 2008; Hatanaka et al., 2009; MacLusky et al., 2004; Matsumoto, 2001; Matsumoto et al., 1988; Pouliot et al., 1996; Schulz and Korz, 2010).
This article is part of a Special Issue "Hormones & Neurotrauma".
Age-related loss of sex steroid hormones is a established risk factor for the development of Alzheimer's disease (AD) in women and men. While the relationships between the sex steroid hormones and AD are not fully understood, findings from both human and experimental paradigms indicate that depletion of estrogens in women and androgens in men increases vulnerability of the aging brain to AD pathogenesis. We review evidence of a wide range of beneficial neural actions of sex steroid hormones that may contribute to their hypothesized protective roles against AD. Both estrogens and androgens exert general neuroprotective actions relevant to a several neurodegenerative conditions, some in a sex-specific manner, including protection from neuron death and promotion of select aspects of neural plasticity. In addition, estrogens and androgens regulate key processes implicated in AD pathogenesis, in particular the accumulation of β-amyloid protein. We discuss evidence of hormone-specific mechanisms related to the regulation of the production and clearance of β-amyloid as critical protective pathways. Continued elucidation of these pathways promises to yield effective hormone-based strategies to delay development of AD.
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Dörner et al. (1991) have suggested that prenatal stress may operate in male-typical sexual behavior in a similar manner in humans. Sexual dimorphisms have been identified in the size of the preoptic nucleus, stria terminalis, amygdala, hippocampus (Kawashima & Takagi, 1994), anterior commissure (Jones et al., 1997) and certain nuclei of the ventromedial nucleus of the hypothalamus (VMH) (Flanagan-Cato, 2000), all of which suggests numerous structural sexual dimorphisms. Certain other cell types in the brain exhibit dimorphic properties as well.
Introduction: Numerous studies employing various animal models have found that perinatal stress, encountered in utero during sensitive developmental stages or shortly after birth, disrupts both sexual differentiation and sexual behavior in offspring. The biochemical, cellular, genetic and epigenetic events which are involved in the organismal response to perinatal stress are currently under investigation. Methods, Results and Discussion: In this review, the reader is introduced to perinatal stressors as a toxicological phenomenon, and several recently characterized epigenetic responses to said stressors are discussed.
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While there is some evidence for a degenerative role of androgens in development and sexual differentiation [9], there appear to be many more reports confirming the neuroprotective properties of androgens in vitro and in adult model systems. Several in vitro studies demonstrate that dehydroepiandrosterone (DHEA) enhances neuronal and glial survival [201,32], while testosterone (T) increases neuronal survival, the number and receptive field of neurite processes, and neurotransmitter output [130,248]. Also, T has been shown to increase neurite length [199], angiogenesis [133], and neurogenesis [133,7,143].
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The sexual differentiation of reproductive physiology and behavior in the rodent brain is largely determined by estradiol aromatized from testicular androgens. The cellular mechanisms by which estradiol masculinizes the brain are beginning to emerge and revealing novel features of brain development that are highly region-specific. In the preoptic area, the major site controlling male sexual behavior, estradiol increases the level of the COX-2 enzyme and its product, prostaglandin E2 which promotes dendritic spine synaptogenesis. In the ventromedial nucleus of the hypothalamus, the major site controlling female reproductive behavior, estradiol promotes glutamate release from synaptic terminals, activating NMDA receptors and the MAP kinase pathway. In the arcuate nucleus, a major regulator of anterior pituitary function, estradiol increases GABA synthesis, altering the morphology of neighboring astrocytes and reducing formation of dendritic spines synapses. Glutamate, GABA and the importance of neuronal-astrocytic cross-talk are emerging as common aspects of masculinization. Advances are also being made in the mechanistic basis of female brain development, although the challenges are far greater.
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Seven-day treatments with IGF-I in PC12-ER and PC12-C cells, and with E2 in PC12-ER cells, increased the percentage of process-bearing cells and the absolute neurite length per cell. PC12 cells transfected with the pCMV-neo vector, without the ERα gene, also elaborated neurites in response to IGF-I. Although studies in dissociated cells and in vivo have demonstrated that IGF-I [1,35,36] or E2 alone [1,20,27,28,30] can stimulate process outgrowth, our new data demonstrate that crosstalk between ER and IGF-IR is necessary for E2- and IGF-I-stimulated neurite outgrowth within this homogenous cell system. Specifically, inhibition of ER with the antagonist ICI blocks the neurite promoting effects of both E2 and IGF-I. Likewise, inhibition of IGF-IR with the antagonist JB1 blocks the neurite promoting effects of both IGF-I and E2.
Estradiol (E₂) and insulin-like growth factor-I (IGF-I) can act independently or in concert to promote neurite outgrowth in vivo and in cultured neurons. This study examined the role of crosstalk between estrogen receptor (ER)α and the IGF-I receptor as a critical mediator of hormone- and growth factor-dependent neurite outgrowth in a homogenous cell system. We used control PC12 cells and PC12 cells stably transfected with ERα, both of which express IGF-I receptor. Cells were treated for 1 week with vehicle, 1 nM E₂ or 100 ng/ml IGF-I alone or with E₂ or IGF-I in the presence of either the IGF-I receptor antagonist JB1 or the ER antagonist ICI 182,780. IGF-I significantly increased neurite outgrowth, as measured by the percentage of process-bearing cells, and absolute neurite length per cell in both control and ERα-transfected PC12 cells. In contrast, E₂ increased process formation and extension only in PC12 cells that were stably transfected with ERα. ICI 182,780 and JB1 blocked the IGF-I-induced increases in neurite length in both cell types. The efficacy of ICI 182,780 in control PC12 cells may have been due to the upregulation of ERα in these cells by the 7-day treatment with IGF-I. The ER and IGF-I receptor antagonists similarly blocked the E₂-induced increase in neurite lengths in ERα-transfected cells. Immunofluorescent analysis of the cellular distribution of an axonal marker, phospho-neurofilament, verified that the processes extended by PC12 cells were neurites. These data suggest that receptor crosstalk between IGF-I receptors and ERα has an important role in neurite formation and extension even in a single-cell system.

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Regular ArticleRole of Sex Steroids on the Survival, Neuritic Outgrowth of Neurons, and Dopamine Neurons in Cultured Preoptic Area and Hypothalamus

Abstract

Regular Article
Role of Sex Steroids on the Survival, Neuritic Outgrowth of Neurons, and Dopamine Neurons in Cultured Preoptic Area and Hypothalamus