Abstract
Dendritic spines, key sites for neural plasticity, are influenced by gonadal steroids. In this chapter, we review the effects of gonadal steroids on dendritic spine density in areas important to cognitive function, the hippocampus, and prefrontal cortex. Most of these animal model studies investigated the effects of estrogen in females, but we also include more recent data on androgen effects in both males and females. The underlying genomic and non-genomic mechanisms related to gonadal steroid-induced spinogenesis are also reviewed. Subsequently, we discuss possible reasons for the observed sex differences in many neuropsychiatric diseases, which appear to be caused, in part, by aberrant synaptic connections that may involve dendritic spine pathology. Overall, knowledge concerning the regulation of dendritic spines by gonadal hormones has grown since the initial discoveries in the 1990s, and current research points to a potential role for aberrant spine functioning in many neuropsychiatric disorders.
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8.1 Introduction
Dendritic spines are an important site of neural plasticity. As such, many factors, including gonadal steroid hormones, which are the primary focus of this chapter, influence spine density. Most of the work reviewed here focuses on the effects of estrogens on dendritic spine plasticity in the context of mediating cognition. Although less well studied, androgens have also been shown to alter spine density and impact cognition, and therefore, they will be reviewed as well. In addition, it is becoming increasingly evident that dendritic spines play a role in neuropsychiatric disorders, and given that gonadal steroids influence spine plasticity, we will speculate on the potential role that gonadal steroids may play in mediating neural dysfunction.
8.2 Dendritic Spines
In general, dendrites are covered extensively by dendritic spines, which, as they are sites for synaptic contact, have a prominent post-synaptic density that contains actin and scaffolding proteins that are activated or deactivated depending on physiological state (Calabrese et al. 2006; Chidambaram et al. 2019). The number of dendritic spines increases with development to a critical point (Urbanska et al. 2012), and following the establishment of connectivity between neurons, dendritic spine turnover actively continues until adulthood when spines achieve relative stability and less turnover (Koleske 2013). In the adult, several distinct dendritic spine subtypes have been described, with thin filopodial types presumed to be immature spines capable of plasticity, and larger, mushroom-shaped spines that are more stable and are the sites of functioning synapses (Bourne and Harris 2007; Von Bohlen Und Halbach 2009).
Although relatively stable in adulthood as compared to development, dendritic spines do exhibit plasticity, including alterations in number and spine subtype, in adult mammals in response to varied stimuli, including denervation/reinnervation (Deller et al. 2006; Parnavelas et al. 1974), hormonal changes (Luine and Frankfurt 2020b; Frankfurt and Luine 2015), drug exposure (Frankfurt et al. 2011; Robinson et al. 2001; Kolb and Gibb 2015), environmental stimuli (Kolb et al. 2003), learning and memory (Luine and Frankfurt 2020c; Kasai et al. 2010a), and stress (Watanabe et al. 1992). Notably, spine plasticity varies during the lifespan. During adolescence, pruning of dendritic spines occurs in the neocortex (Kolb et al. 2012; Holtmaat et al. 2005; Khanal and Hotulainen 2021). Pruning at this stage suggests a refinement of synapses such that weaker connections are eliminated, and stronger ones are maintained. In the aging brain, dendritic spines and synapse density decrease. There are decreases in dendritic spine density in the cortex (Dickstein et al. 2013; Dumitriu et al. 2010) and dendritic spines and axospinous synapses in the hippocampus with aging (Geinisman et al. 1992; Von Bohlen Und Halbach et al. 2006). Given that during adolescence and aging there is significant change in steroid hormone levels and function, dendritic spine plasticity during these times may be more susceptible to hormonal influences.
Dendritic spine plasticity is essential for learning and memory (Koleske 2013; Chidambaram et al. 2019; Khanal and Hotulainen 2021), which has also been demonstrated to be influenced by gonadal steroids (Luine and Frankfurt 2020a, c; Luine et al. 2018, 2022). The hippocampus and the medial prefrontal cortex (mPFC) are integral to learning and memory (Churchwell and Kesner 2011; Churchwell et al. 2010) and changes in dendritic spine density in these areas play a critical role in these cognitive processes (Jedlicka et al. 2008; Leuner et al. 2003). For this reason, alterations in spine density in the hippocampus and mPFC have been studied more than in other brain regions (Fig. 8.1). Many studies have demonstrated estrogen-dependent enhancements in learning and memory, and these enhancements are associated with increases in spine density on apical and basal dendrites in pyramidal cells in the CA1 region of the hippocampus (CA1) and mPFC in rodents (Luine and Frankfurt 2012, 2013, 2020a, b; Luine 2015, 2016). Therefore, estrogen-induced dendritic spine plasticity has been more extensively studied in the mPFC and CA1 than in other brain regions.
8.2.1 Steroids and Dendritic Spine Plasticity: Estrogens
Early studies demonstrated that dendritic spine density on pyramidal cells in CA1 in gonadally intact female rats fluctuated over the estrous cycle (Woolley et al. 1990; Woolley and McEwen 1992) with the highest levels in proestrus when estrogen levels are also highest. Initial results in the hippocampus were supported by later studies (Kinsley et al. 2006; Gonzalez-Burgos et al. 2005). Alterations in spine density during the estrous cycle have also been demonstrated in other brain regions including the ventromedial nucleus of hypothalamus (Frankfurt et al. 1990; Gonzalez-Burgos et al. 2015), the amygdala (Rasia-Filho et al. 2012), and pyramidal cells in layers III and V of the sensorimotor cortex (Chen et al. 2009). In general, spine density was greatest when estrogen levels were highest apart from the medial nucleus of the amygdala where spine density was lowest on neurons when estrogen levels were high (Rasia-Filho et al. 2012). Alterations in spine density during the estrous cycle in these regions may underlie lordosis and other reproductive behaviors.
The data on intact cycling rats are supported by studies that show a decrease in spine density in ovariectomized (OVX) rats in CA1 (Gould et al. 1990b) that was subsequently restored by administration of estrogen for different time periods (Fig. 8.2), acute (<2 h) to subchronic (2–7 days). In initial studies, subchronic estrogen was shown to reverse the OVX-induced decrease in spine density on pyramidal cells in CA1 (Gould et al. 1990b; Luine and Frankfurt 2013). Spine synapses in the hippocampi of OVX monkeys (Leranth et al. 2002) and rats (Woolley and McEwen 1992) are also restored after subchronic estrogen administration. More recently, acute estradiol or estrogen agonists, given for less than 2 h, have been found to induce rapid increases in spine density in gonadectomized female (Inagaki et al. 2012; Luine and Frankfurt 2020a; Phan et al. 2012; Phan et al. 2011; Phan et al. 2015) and male rats (Jacome et al. 2016). A decrease in spine density after OVX has also been shown in CA1 and the mPFC (Wallace et al. 2006). Dendritic spines are decreased in both CA1 and the mPFC in aged females that have lower levels of estrogen (Wallace et al. 2007; Luine et al. 2011). Moreover, when OVX rats are fed a diet low in phytoestrogens, spine density in both CA1 and the mPFC is lower than those fed a high phytoestrogen diet (Luine et al. 2006). Finally, chronic exposure to high levels of estrogen during and after pregnancy increases spine density in CA1 pyramidal cells in rats (Kinsley et al. 2006).
As with the estrous cycle, most studies have been done in the hippocampus, but dendritic spine density in other brain regions is also altered when estrogen fluctuates. In the rat, OVX-induced decreases in spine density in the ventromedial nucleus of the hypothalamus (Frankfurt et al. 1990), amygdala (Rasia-Filho et al. 2012), and layers III and V of the somatosensory cortex (Chen et al. 2009) are reversed by estradiol administration (Fig. 8.2). Ye et al. (2019) found that pyramidal cells in layer V of the frontal, motor, and somatosensory cortex in the OVX mouse have decreased spine density that is also reversed when estradiol is given (Ye et al. 2019). The fact that spine density is altered in many brain areas by estrogen illustrates that many neurons are probably sensitive to hormonal alterations, and this understanding may shed light on the observation of sex differences in many neuropsychiatric diseases.
8.2.2 Gonadal Steroids and Dendritic Spine Plasticity: Androgens
Many neurons in the central nervous system are also sensitive to circulating androgens. Although far fewer studies have addressed the interaction between androgens and dendritic spines, it has been clearly demonstrated that various androgens and several androgenic metabolites function similarly to estrogens in terms of their ability to increase spine synapse and dendritic spine density. In gonadectomized male and female rats, both testosterone propionate (TP) and dehydroepiandrosterone (DHEA) increased dendritic spine density on pyramidal cells in CA1 and the mPFC (Luine et al. 2022; Jacome et al. 2016). Similarly, spine synapse density decreases in CA1 after gonadectomy are reversed in rats of both sexes after TP, dihydrotestosterone (DHT), and DHEA administration (Hajszan et al. 2004; Maclusky et al. 2004; Leranth et al. 2004; Atwi et al. 2016). In adult male mouse hippocampus, testosterone (T) increased spine density (Li et al. 2012), and in rats, castration (CAS) reduced, while administration of DHT or estradiol increased spine synapse density in the mPFC (Hajszan et al. 2007). Neurons in the brains of females are also sensitive to androgens as subchronic TP, and DHEA increased spine density on pyramidal cells in the mPFC and CA1 of adult OVX female rats (Luine et al. 2022). Again, as with estrogens, most studies use subchronic treatments, but rapid effects of androgens have also been shown. Acute administration of both T and DHT increases spine density in CA1 in gonadectomized male and female rats (Jacome et al. 2016; Luine et al. 2022) and in hippocampal slices taken from male rats (Murakami et al. 2018). Thus, both spine synapses and synapse density fluctuate with changing androgen levels (Fig. 8.2).
Consistent with the estrogen studies, there are reports of androgens increasing spine density in brain regions other than the hippocampus and mPFC. Syrian hamsters had decreased dendritic spine density in the medial preoptic area 9 weeks after gonadectomy compared to intact male hamsters and gonadectomized hamsters treated with T for 9 weeks (Garelick and Swann 2014). Gonadectomy decreased spine density in the medial preoptic nucleus and medial amygdala, and this effect was reversed by DHT 24 h after injection (Huijgens et al. 2021). Androgen-induced alterations in spine density in these regions may underlie regulation of male sexual behavior.
8.3 Mechanism of Gonadal Steroid Action on Dendritic Spines
Gonadal steroids exert their effects via receptors that mediate both nuclear, genomic, and membrane, non-genomic, mechanisms (Fig. 8.3). Estrogen receptors (ER) α and β are found within cell nuclei and on cell membranes in neurons in many brains regions, while the more recently described G-protein-linked estrogen receptor (GPER) is found on membranes of both neurons and glia (Korol and Pisani 2015; Waters et al. 2015; Torres-Revereron et al. 2020). Chronic effects of steroids are mediated mainly through nuclear receptors and genomic mechanisms, while binding to membrane receptors mediates the rapid effects through the activation of numerous signaling pathways. Recent studies indicate that interaction between nuclear and membrane receptors may also mediate some steroid effects (Arevalo et al. 2015; Kramár et al. 2013; Luine and Frankfurt 2012). As a membrane receptor, GPER also activates signaling pathways. Which receptors are involved in mediating spine dynamics in neurons and whether the different receptors have an additive effect on steroid-mediated spinogenesis remain to be determined.
Although some differences in effects have been reported, agonists for both ERα and ERβ alter spine density (Murakami et al. 2006; Phan et al. 2011). Studies in OVX mice showed that propyl pyrazole triol (PPT), an ERα agonist, increased dendritic spine density in the stratum radiatum and lacunosum-moleculare of CA1 within 1 h, whereas diarylpropionitrile (DPN), an ERβ agonist, decreased spine density in the lacunosum-moleculare of CA1 (Phan et al. 2011). In the PFC, agonists of the GPER, but not ERα/β receptors, rapidly increased spine density, and the opposite selectivity was found in CA1 (Ye et al. 2019).
Dendritic spine plasticity implies cycling of immature spines to mature spines that make synaptic contact (Ziv and Smith 1996) and changes that existing spines may undergo after exposure to different stimuli (Kasai et al. 2010b; Koleske 2013; Sehgal et al. 2013). This process requires mobilization of many proteins, particularly actin and associated proteins (Penzes and Rafalovich 2012; Hokenson et al. 2021; Koleske 2013). The cycling between filamentous and globular actin is an essential part of spine plasticity and requires interaction with other proteins, including several actin-binding proteins such as cofilin and profilin, which regulate actin polymerization (Basu and Lamprecht 2018; Borovac et al. 2018).
Since spine plasticity is dependent on mobilization of actin and synaptic proteins, it is notable that these proteins have also been shown to be altered by gonadal steroids. Estradiol inactivates cofilin, which is responsible for the disassembly of actin (Kramár et al. 2009). In addition, OVX decreased spine density in the CA1 region of mice in which the expression of cofilin was increased and profilin, which promotes actin polymerization, decreased (Lan et al. 2021). These results may explain how estradiol promotes filamentous actin and spine assembly (Kramár et al. 2009). Estrogen also increases other proteins that are found in the synapses, such as PSD95 and spinophilin (Tang et al. 2004; Maclusky et al. 2005; Lee et al. 2004). Estrogen-induced increases in dendritic spine density have been demonstrated to involve the activation of multiple cell signaling pathways, such as ERK, mTOR (Tuscher et al. 2016), CREB, and PI3, that promote the assembly of actin and protein synthesis and other proteins involved in spine dynamics (Sheppard et al. 2019; Frankfurt and Luine 2015; Fortress et al. 2013; Luine and Frankfurt 2013; Bethea and Reddy 2010; Hansberg-Pastor et al. 2015). Overall, it appears that estrogen acting via multiple pathways influences the assembly of actin and synaptic proteins, which, in turn, increases the number or the maturity of existing spines (Fig. 8.3).
The mechanisms by which androgens influence dendritic spines have been less well studied than estrogens, but the presence of both nuclear and membrane receptors on neurons has also been described for androgens (Atwi et al. 2016; Chen et al. 2022). Studies to date show that androgens exert similar effects to estrogens in terms of altering cytoskeletal and other proteins in dendritic spines. For example, orchiectomy decreases spine density, actin polymerization, and post-synaptic density thickness in adult male mice (Zhao et al. 2018). In addition, Chen et al. (2022) demonstrated that, in cultured hippocampal neurons from male mice, T promoted the maturation of immature spines and increased synaptic markers PSD 95 and synapsin.
Taken together, the data suggest that steroids can alter dendritic spine density by binding with steroid receptors on neurons and then initiating a series of intracellular events that promote the proteins, which increase the number of dendritic spines. Although most of the studies described here are related to rapid membrane-mediated effects of gonadal steroids, it is interesting to note that both types of receptors appear to mediate similar effects on synaptic proteins. Using antagonists to both nuclear and membrane estrogen receptors, Xing et al. (2018) found that receptor antagonists to ERα, Erβ, and GPER administered to mice decreased PSD-95, spinophilin, spine density, and synaptic density. These results suggest that both genomic and non-genomic receptors play a role in estrogen-induced reorganization of the actin cytoskeleton. There is some evidence for cross talk between the genomic and membrane estrogen receptors, especially given that binding of estrogens to nuclear ERα and ERβ in some circumstances results in alterations in rapid signaling pathways (Kramár et al. 2013; Arevalo et al. 2015; Luine and Frankfurt 2012).
8.4 Dendritic Spine Plasticity and Gonadal Steroids: Potential Clinical Importance
There are clear sex differences in the incidence of some neuropsychiatric diseases (Bangasser and Cuarenta 2021; Seney et al. 2022; Bangasser and Valentino 2014; Schulte Holthausen and Habel 2018; Vegeto et al. 2020). Alzheimer’s disease is more prevalent in women, and Parkinson’s disease occurs more often in men (Vegeto et al. 2020). Psychiatric disorders such as major depressive disorder and anxiety are more prevalent in women (Bangasser and Cuarenta 2021; Seney et al. 2022; Bangasser and Valentino 2014). Personality disorders, such as paranoid, schizotypal, and narcissistic disorders, are diagnosed more often in men, and borderline histrionic disorders are more common in women (Schulte Holthausen and Habel 2018).
Thus, it is interesting to speculate on the possible clinical importance of gonadal steroid interactions with spines in neural and psychiatric diseases because this information may provide insights into the etiologies and possible treatments for these conditions.
8.4.1 Sex Differences in the Brain
Results of preclinical, clinical, and anatomical studies provide some basis for the sex differences in neuropsychiatric disease. There are reports of sex differences in neural structure in rats (McEwen and Milner 2017; Brandt et al. 2020; Scharfman and Maclusky 2017; Yagi and Galea 2019; Marrocco and McEwen 2016). Nevertheless, sex differences in spine density reports are inconclusive. Female rats in proestrus were found to have greater spine density in CA1 than male rats (Woolley et al. 1990; Shors et al. 2001), and male rats have more thorny excrescences in hippocampal CA3 neurons than female rats (Gould et al. 1990a). However, in other studies no sex differences in spine density were seen in CA1 or the mPFC (Bowman et al. 2015; Gould et al. 1990a). The latter two studies did not consider the estrous stage of the females, and this may account for the different findings among studies. Thus, while sex differences in brain structure exist, data regarding spine density differences are limited and further research is required to determine possible relationship(s) to clinically observed sex differences in diseases.
What about sex differences in brain structure in humans? Imaging studies have shown that men have larger brains, more cortical surface area, and more white matter (except for the corpus callosum) than women, and women have denser gray matter than men (Salminen et al. 2022). Male brains have been shown to have greater ipsilateral connectivity, while female brains have greater commissural connectivity (Ingalhalikar et al. 2014). In the hippocampus, there are sex differences in the size of different hippocampal subregions (Van Eijk et al. 2020). These studies are not conclusive, and it should be noted that there is controversy regarding how real these differences are after being corrected for men’s larger brain sizes, sample sizes, and general differences in analysis (for reviews see Hines (2020), Salminen et al. (2022), and Hoggetts and Hausman (2023)).
Therefore, it appears that sex differences in the brain are more subtle than straightforward sexual dimorphisms and may be the result of ongoing developmental exposure during critical periods in the lifespan. One must consider that hormone-induced effects on neurons in adults are the result of multiple effects of hormones at different life stages. These include organizational exposure to gonadal steroids during development and activational exposure starting with adolescence, which may be further influenced by environmental factors (Fig. 8.4), rendering it challenging to correlate levels of steroid hormones with disease (McEwen and Milner 2017). Finally, there is a great deal of variability in preclinical studies with respect to time from gonadectomy to steroid replacement, dose used, length of steroid administration, and age of the animals during the experiment and animal strain, all of which could impact the results. Sex differences in response to stress (see below) are an example of the interaction of factors that may occur when sex differences in disease are manifested. Thus, neural networks seem more important for function than individual differences. Neural networks are connected by spines and synapses, which make them important to study. In the next section, we will review the intersection between spine pathology and gonadal steroids in a few examples to address potential mechanisms that may underlie the sex differences observed clinically.
8.5 Dendritic Spine Plasticity, Gonadal Steroids, and Neuropsychiatric Disorders
8.5.1 Depression
Depression-related alterations in neural plasticity have been studied extensively in animal models subjected to stress because stressed animals exhibit depression-like disturbances, such as anhedonia and alterations in dendritic spines and synapses in the hippocampus and PFC (Leuner and Shors 2013; Yang et al. 2020; Licznerski and Duman 2013). Therefore, stress-induced plasticity in rodents is thought to model what occurs in the human brain with depression.
The brain regions involved in mediating stress-induced responses include the PFC, hippocampus, and amygdala, which have extensive interconnections. Chronic restraint stress has been shown to decrease dendritic spine density in the hippocampus and PFC and increase it in the amygdala (Qiao et al. 2016). Most studies have only been done in male animals, and unfortunately, there are little data from female animals. However, 21 days of chronic restraint stress causes retraction of apical dendrites in the CA3 region of the hippocampus in male, but not female, rats (Galea et al. 1997). In a mouse model in which animals were stressed for 1 h for 6 days using different stressors, only OVX female mice were susceptible to the stress (Iqbal and Ma 2020). These authors found that OVX female mice had significantly higher corticosterone levels, increased spine density on PFC neurons, increased immobility time of several behavioral tests, and decreased sucrose consumption, which is consistent with anhedonia, in comparison with intact males and sham-operated females. Interestingly, sex differences in behavioral responses to stress have been clearly demonstrated in rats. Chronic restraint stress, 6 h for 21 consecutive days, impairs male performance on several behavioral cognitive tasks and either enhances or has no effect on female cognitive function (Luine et al. 2017; Bowman et al. 2022). In terms of spine density, Shors et al. (2001) found that 24 h after 30 minutes of intermittent stress, spine density in CA1 pyramidal cells was increased in male but decreased in female rats. In the lateral hypothalamic area, there is a sex difference in spine density on putative orexin neurons, and males have less spines than females (Grafe et al. 2019). Following 5 days of 30-minute restraint stress, this sex difference was no longer present, meaning that stress decreased spine density in females only. Following a paradigm of 30 minutes of restraint stress for 5 days, male rats were able to habituate to the stress but female rats did not, and females had significantly higher levels of corticosterone compared to males (Grafe and Bhatnagar 2020). These different stress studies may yield inconsistent results because of the different stress paradigms and behavioral assessments used, but the results do suggest that neural networks related to depression are differentially affected during stress and these changes may help explain sex differences in the incidence of depression.
8.5.2 Schizophrenia
Spine density alterations have also been shown in other diseases (Khanal and Hotulainen 2021). Postmortem Golgi studies have found a decrease in spine density in the dorsolateral prefrontal cortex (DLPFC) and the superior temporal gyrus (Glausier and Lewis 2013; Penzes et al. 2011) of schizophrenic patients, which implies decreased connectivity in regions known to be critical to cognitive function. These authors speculate that dendritic spine plasticity/pruning may be altered during early development and adolescence in schizophrenic patients, time periods in which gonadal steroids influence dendritic spine turnover. Although direct comparisons to the PFC in rodents are difficult, a preclinical study in rats subjected to repeated variable perinatal stress demonstrated a sex difference in the pattern of dendritic development in the PFC (Markham et al. 2013). Dendritic connectivity in both sexes in layer III pyramidal cells of the PFC during adolescence was increased, but maximal growth occurred earlier in female rats and lasted later, into adulthood. Increased spine density was seen in both sexes before puberty, but only females showed pruning of spines in late adolescence. These preliminary results support potential network alterations during a period of gonadal hormone secretions that may explain the observed sex difference in schizophrenia.
8.5.3 Alzheimer’s Disease
The incidence of neurodegenerative diseases increases with aging. With aging, there are also decreases in spine density (Young et al. 2014; Dumitriu et al. 2010; Walker and Herskowitz 2021; Wallace et al. 2007; Luine et al. 2011). Whether the decreases in spine density in these regions are due to an overall decrease in neuronal number is unclear. However, these changes may be related to the increased incidence of neurodegenerative diseases that is seen with aging. Spine abnormalities, including decreases in number and alterations in spine subtype, have been reported for numerous neurodegenerative diseases that have a cognitive component, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease (for review, see Herms and Dosostkar (2016), and Walker and Herskowitz (2021)). The accumulation of extracellular proteins in Alzheimer’s disease appears to interfere with dendritic spines, leading to synaptic loss in both the hippocampus and cortex of patients with Alzheimer’s disease (Chidambaram et al. 2019). Given the importance of spine plasticity to the process of learning and memory, it is not surprising that in Alzheimer’s disease there are alterations in dendritic spine density (Walker and Herskowitz 2021). Interestingly, Walker and Hershowitz (2021) review the literature that demonstrates that patients with preclinical Alzheimer’s disease, who have some signs of the disease but have normal cognitive functions, have higher levels of dendritic spines and synaptic proteins in the hippocampus and PFC than patients who were known to have impaired cognition. This finding implies that dendritic spines may confer resilience to cognitive decline and that decreases in spine density are related to impaired cognition, which is consistent with previous animal studies (Luine and Frankfurt 2020c; Frankfurt and Luine 2015).
8.6 Conclusion
Gonadal steroids exert acute and chronic effects on dendritic spines in pyramidal neurons across the lifespan in both males and females. These effects are mediated by both genomic and non-genomic mechanisms, which influence the assembly of actin and synaptic proteins to promote spinogenesis. Although gonadal steroids have been shown to influence spine density in many brain areas, sex differences have not been adequately investigated, and therefore, it is a challenge to relate differences observed in neuropsychiatric disorders to the basic and clinical data on sex differences to date. This apparent discrepancy may be due to the multifactorial processes and timing during hormonal exposure. Given that there are also spine density changes reported for these disorders, it may become important to consider potential differences in treatment based on sex. However, local alterations in spine density under different conditions imply that alterations in the neural networks may be a critical underlying issue and should be further investigated in relation to potential sex differences.
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Frankfurt, M., Nassrallah, Z., Luine, V. (2023). Steroid Hormone Interaction with Dendritic Spines: Implications for Neuropsychiatric Disease. In: Rasia-Filho, A.A., Calcagnotto, M.E., von Bohlen und Halbach, O. (eds) Dendritic Spines. Advances in Neurobiology, vol 34. Springer, Cham. https://doi.org/10.1007/978-3-031-36159-3_8
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