Sex Steroids and Brain-Derived Neurotrophic Factor Interactions in the Nervous System: A Comprehensive Review of Scientific Data

1. Introduction

Sex steroid hormones, i.e., androgens, estrogens and progesterone, are well-known for their role in stimulating the reproductive organs and the development of secondary sexual characteristics in female and male [1]. They share similar structures and can reach the brain across the blood-brain barrier, when released from peripheral steroidogenic organs [2], or be synthesized de novo within the brain [3] whereby they regulate neuronal functions. The synthesis of neuroactive steroids occurs primarily in neurons, but also in microglia and astrocytes, and requires the translocation of cholesterol across the mitochondrial membrane through a molecular complex formed by the translocator protein 18 kDa, the steroidogenic acute regulatory protein, the voltage-dependent anion channel protein and the adenine nucleotide transporter protein. Cholesterol is converted to pregnenolone by enzymatic activity in the mitochondria, and pregnenolone diffuses into the cytosol where it is further metabolized by different enzymes into different neuroactive steroids (see Figure 1). [4,5].

In addition to sexual dimorphism, present in several neural circuits, sex steroids generally play a neuroprotective role and impact differently on the brain’s function [6]. Two main effects of the steroid hormones on the brain are described to produce sexual dimorphism in vertebrates: the first is organizational, associated with changes during sensitive phases of development, such as prenatal and/or perinatal sexual differentiation, and adolescence; and the second referring to activational effects associated with sexually dimorphic phenotypic changes during puberty and throughout adulthood [7]. Furthermore, experimental studies show that learning responses are influenced differently by sex steroids in males and females through various mechanisms underlying neuroplasticity, i.e., learning-induced and hormone-driven brain region- and cell type-specific cellular activity and morphology [8]. Exposure of undifferentiated neural stem cells to different sex steroids results in phenotypic changes with alteration in functional and behavioral responses [9,10].

The brain-derived neurotrophic factor (BDNF) is a conserved neurotrophin that participates in multiple processes related to brain development and functioning, i.e., neuronal cell migration and differentiation, axonal growth and synaptogenesis. The actions of sex steroids overlap with those of BDNF in various neural plasticity processes, however, the mechanisms underlaying such interactions are not fully elucidated [11,12,13,14]. Further, a possible time- and region- specificity for sex steroid effects on BDNF activity adds an extra complexity to this topic [15,16].

The presence of estrogen responsive element (ERE) in BDNF gene sequence started the investigations on the participation of sex hormones in the development and organization of the nervous system. The interaction between estrogen and BDNF was initially evidenced by the co-localization of BDNF and TrkB mRNAs in estrogen-sensitive neurons of the developing cerebral cortex [17]. Next, Singh, Meyer, and Simpkins [18] pointed out that estrogens were more effective in maintaining BDNF levels in the hippocampus than in the cortex of female rats. Which supports the thesis that steroids regulation of BDNF expression is influenced by the neurosteroids availability.

Estrogens activation and translocation of the nuclear estrogen receptors (ERs) to cell nuclei can directly regulate the expression of BDNF via its ERE sequence. This can be called as the ‘genomic mechanism’. Additionally, membrane-associated steroid receptors can activate extra nuclear-initiated kinase signaling and modify intracellular mechanisms amplifying steroids’ effect on gene expression [19,20]. For instance, estrogens activation of G-protein coupled membrane ER activates the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways and, as the kinases downstream MAPK and protein kinase (PKA) pathways increase ER phosphorylation, this potentiate estrogens signal [21].

BDNF signaling via tyrosine kinase (Trk) B receptors within neurons membrane elicits various intracellular signaling pathways including MAPK/ extracellular signal-regulated protein kinase (ERK), phospholipase Cγ (PLCγ) and PI3K pathways that induce the synthesis of proteins that regulate neuronal survival and synaptic maintenance [22]. This implies that BDNF function in synaptic plasticity is partially shared with that of estrogen.

In spite of a great number of studies have addressed the estrogen’s influence on BDNF activity, the regulation of BDNF by androgen and progesterone is also seen to participate in neuroplasticity processes in females and males. Progesterone exerts its effects on BDNF through genomic and non-genomic mechanisms. While the induction of BDNF expression requires the nuclear PR, the release of BDNF can be mediated by activation of a distinct membrane-associated PR. Additionally, some membrane-associated PRs may lead to the activation of ERK1/2 which may exert an inhibitory influence on BDNF expression [23].

In light of the above mentioned, in this literature review we collected experimental evidence available up to February 2022 on interactions between sex steroids (estrogens, testosterone, progesterone) and BDNF from studies in vitro, in vivo and ex vivo, and provided a qualitative synthesis of the mechanisms by which sex steroids participate in neuroplasticity via BDNF modulation.

2. Estrogen and BDNF Interactions

Sex steroids hormones regulate BDNF activity in many neuronal circuits and at different phases of the lifespan. They act on brain tissues at different stages of development, specifically during the perinatal sensitive period, and the adolescence to organize sexual differentiation, and to produce sex-specific behaviors throughout the whole life [1]. The scientific data supporting sex steroids interactions with BDNF in neural tissues are going to be discussed in the following subheadings, and a brief summary of findings is displayed in Table 1, Table 2 and Table 3.

A conserved co-regulation of genes such as ER, BDNF and TrkB through different species indicates that the genes have closely associated functions and are part of a same pathway [24,25]. The patterns of these genes expression in developmental estrogen targets neurons were the first evidences that BDNF expression is related to neurons sensitivity to estrogen [17]. In line, Singh et al. [18] showed that ovariectomy (OVX) results in reduction in BDNF levels in cortical tissue. Associations between reductions in ER and BDNF levels have been reported by several studies.

From another perspective, activation of ERs were seen to increase BDNF levels and synaptogenesis in the cerebellum of neonatal mice [26], the pre-frontal cortex of rats [27], and in zebrafish [28]. Such regulatory role of ERs over BDNF result in positive cognitive outcomes [26,27,28]. Indeed, estrogens directly regulate the expression of BDNF in neural cells [29,30,31,32,33,34,35,36,37,38,39]. Additionally, ER can regulate BDNF expression and function via transactivation of TrkB receptors [40,41,42,43,44,45]. In addition to EREs, activation of TrkB receptors also potentiate estrogen’s effects via ERα phosphorylation downstream TrkB/MAPK/ERK pathway. Meanwhile, the activity of the PI3K/AKT pathway constitutively inhibits basal transcription at EREs and inhibits TrkB-dependent transcriptional activation at EREs [46]. This grants an homeostatic equilibrium to an estrogens regulation on BDNF function. For instance, disruption in estrogens regulation of BDNF expression leads to an elevation in TrkB phosphorylation [47,48,49,50].

The functional interaction between estradiol and BDNF participates in activity-dependent dendritogenesis. Murphy, Cole, and Segal [51] detected a short-term decrease in BDNF concentrations in hippocampal neurons treated with estradiol in which BDNF declined up to 24 hr and recovered within 48 hr. This affected the activity-dependent formation of dendritic spines in GABAergic hippocampal neurons.

Zhu et al. [52] investigated whether estradiol regulates BDNF expression in the hypothalamus during the estrous cycle in rats. BDNF expression transiently increase in the ventromedial nucleus of hypothalamus following the estradiol peak. Balasubramanian et al. [53] added that a chronic exposition of the amygdala to estradiol leads to a decrease in BDNF expression levels and behavioral implications. Alternatively, Cavus and Duman [54] had reported that BDNF levels decrease in the dentate gyrus and the medial prefrontal cortex, when estradiol levels are highest during estrus. And that acute estradiol treatment decreased hippocampal BDNF expression in acutely OVX rats, with no effect in chronically OVX rats. The findings indicate that the effect of cells exposition to estradiol on BDNF expression shall be influenced by time and intensity and involve selective mechanisms according to the neuronal population.

Nuclear ER (α and β) are present in cells from multiple brain regions, e.g., hippocampus, hypothalamus, amygdala, and prelimbic cortex [55,56,57,58,59,60,61,62,63]. Activation of estrogen-related receptor γ also regulate BDNF expression in dopaminergic neurons [64]. The study by Wu et al., [65] reported that neither OVX nor estradiol treatment altered BDNF expression in the hippocampus of BDNF Val66Met heterozygote mice. OVX reduced the expression of BDNF only in the hippocampus of wild-type mice and the estradiol-induced BDNF increase was resumed to the dorsal hippocampus of wild type OVX mice. The control of BDNF function requires the processing of the pro-apoptosis pro-BDNF isoform into the mature BDNF. The Val66Met polymorphism negatively affects BDNF expression and processing into secretory pathways, altering the released pro-BDNF/BDNF [66,67]. It might be so that Val66Met heterozygote mice already presented altered hippocampal levels of BDNF in a way that these levels were not substantially changed by OVX or estradiol treatments.

The enzymatic activity of aromatase plays a relevant role in the regulation of BDNF expression by estrogens [68,69]. Aromatase is a membrane-bound enzyme, located in the endoplasmic reticulum in estrogen-producing cells, which catalyzes the desaturation (aromatization) of the ring A of C19 androgens and converts them to C18 estrogens. Dittrich et al. [70] demonstrated that estradiol-induced BDNF expression in the forebrain song control nucleus of male juvenile zebra finches is decreased by the selective aromatase inhibitor fadrozole.

In line, aging importantly effects estrogens regulation on BDNF. Data from Jezierski and Sohrabji [71,72] study reports that estrogen increases the expression of TrkB receptor in the brain of young, but not in older animals. Data also identified that aging impairs estrogens regulation on pro-apoptotic p75 neurotrophic receptor expression, favouring its increase and influencing on neuronal apoptosis. It is possible that the ERE in BDNF gene becomes less sensitive to estrogen with age, and this leads to a loss in BDNF regulation of TrkB receptors. Moreno-Piovano et al. [73] comparison of mouse with short-term vs. long-term OVX concluded that estradiol effect on BDNF expression decays in time. A possible negative feedback of ER expression to long-term exposure to estrogens might contribute to the loss of estrogens effect on BDNF regulation.

From a physiological perspective, exercise was shown to improve estradiol regulation on BDNF expression [74]; and to restore hippocampal levels of BDNF in OVX animals. These preliminary studies report that rats with a 14-day free-wheel access, or running on a treadmill at low-intensity for 30 min during 20 days; or else, combining 3 days of resistance training and 3 days of running for 8 weeks displayed of improvements in the sex steroids regulation on BDNF expression in their hippocampi [75,76,77,78].

3. Progesterone and BDNF Regulation

The early experiments of Gibbs et al., [79,80] pointed that the levels of BDNF fluctuate across the estrous cycle, and increase in response to acute hormones replacement. Murphy et al. [51,81] identified that estradiol transiently reduces BDNF and GABA synthesis in hippocampal cells and, consequently, reduces inhibitory GABAergic connections and leads to a brief enhancement in neuronal activity, after which, BDNF returns to normal levels and the inhibitory tone is restored. They detected that progesterone was able to blocks the increase in CREB phosphorylation and prevent estradiol-induced increase in cell activity and spine density. In line, Aguirre et al., [82] showed that progesterone reverses estradiol-induced increase in ER and BDNF levels, and eliminates estradiol effect against glutamatergic excitotoxicity in hippocampal cultures. It seems that progesterone inhibition on CREB activity has a negative influence on estradiol effects on BDNF in GABAergic neurons. Additionally, Franklin & Perrot-Sinal, [83] reported that young adult female rats treated with estradiol have higher hippocampal BDNF levels than those treated with estradiol and progesterone combination.

Table 2. Data summary of interactions between Progesterone and BDNF.

	Title	Aim/experiment	Main Findings
1	Treatment with estrogen and progesterone affects relative levels of brain-derived neurotrophic factor mRNA and protein in different regions of the adult rat brain DOI: 10.1016/S0006-8993(99)01880-6	To examine the acute effects of estrogen and PROG on levels of BDNF expression and protein in different brain regions in adult mice.	Estrogen or estrogen + PROG increase BDNF expression and protein levels in the pyriform cortex of mice. Increases in BDNF expression in the hippocampus accompanied a decrease in BDNF protein.
2	Progesterone prevents estrogen-induced dendritic spine formation in cultured hippocampal neurons DOI: 10.1159/000054580	To examine PROG effects on estrogen- induced formation of dendritic spines in hippocampal cell cultures.	PROG does not affect the estrogen-induced downregulation of BDNF, but it did block the effect of estrogen on CREB phosphorylation.
3	Progesterone counteracts estrogen-induced increases in neurotrophins in the aged female rat brain DOI: 10.1097/00001756-200412030-00021	To test estrogen and estrogen + PROG effects on neurotrophin levels in cognitive brain regions in aged OVX mice.	Estrogen treatment increased BDNF, NGF, and NT3 levels in the mice entorhinal cortex, and PROG abated these effects dropping BDNF levels to aged OVX non-treated mice.
4	Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord DOI:10.1016/j.neuroscience.2004.02.024	To demonstrate that BDNF increases with PROG treatment, in ventral horn motoneurons from spinal cord injured mice.	Spinal cord injury reduces BDNF expression levels by 50% in spinal motoneurons. PROG enhances BDNF in the motoneurons of lesioned spinal cord mice.
5	Progesterone treatment of spinal cord injury: Effects on Receptors, Neurotrophins, and Myelination DOI: 10.1385/JMN:28:1:3	To examine the cellular mechanisms involved in PROG neuroprotection in spinal cord injured rats.	PROG increases BDNF expression and protein in motoneurons in injured rats. These increases correlated with an increased TrkB and the phosphorylated CREB in motoneurons.
6	Progesterone increases Brain-Derived Neurotrophic Factor Expression and Protects Against Glutamate Toxicity in a Mitogen-Activated Protein Kinase- and Phosphoinositide-3 Kinase-Dependent Manner in Cerebral Cortical Explants Paramjit DOI: 10.1002/jnr.21370	To examine frontal and cingulate cerebral cortex explants from mice treated with PROG in vitro.	PROG induces a 75% increase in BDNF expression in explants of the cerebral cortex, with a nearly identical effect on BDNF protein levels.
7	Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons DOI:10.1016/j.expneurol.2006.08.019	To examined steroid and BDNF expression and protein in the spinal cord, and in muscle atrophy in wobbler rodent.	BDNF expression was in in neuros of steroid-naïve Wobbler mice compared to controls. PROG treatment increased BDNF expression in Wobblers compared to untreated, but not to controls.
8	Progesterone pre-treatment enhances serotonin-stimulated BDNF gene expression in rat C6 glioma cells through production of 5α-reduced neurosteroids DOI:10.1007/s12031-007-9034-6	To investigate the rule of neurotransmitters on glial cell metabolism and function in rat glioma cells in vitro.	BDNF expression levels in both non- treated and PROG-pre-treated glioma cells were similarly elevated by serotonin treatment with a concentration-dependent effect of serotonin on BDNF gene expression.
9	The differences in neuroprotective efficacy of progesterone and medroxyprogesterone acetate correlate with their effects on brain-derived neurotrophic factor expression DOI: 10.1210/en.2008-1247	To determine which type of PROG receptor mediates the neuroprotective effect of PROG on BDNF.	PROG induces increase in the BDNF protein levels in cerebral cortical explants in a concentration-dependent manner. PROG regulates BDNF expression through the classical PROG receptor.
10	Progesterone, BDNF and Neuroprotection in the Injured CNS DOI:10.1080/00207450903116430	To investigate the neuroprotective mechanism of PROG and BDNF.	PROG had no effect on BDNF expression in granule neurons. No neuroprotective role for PROG on BDNF was observed.
11	Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β. DOI:10.1111/j.1471-4159.2010.07038.x	To examine PROG and estrogen treatment in cultured hippocampal slices on levels of ERα and ERβ, and BDNF.	Estrogen elevated ERβ expression and protein levels, did not modify ERα expression, but increased ERα protein levels, and increased BDNF expression levels in hippocampal cells. PROG reversed the estrogen-elicited increases in ERβ, ERα protein, and BDNF expression levels.
12	Progesterone treatment alters neurotrophin/proneurotrophin balance and receptor expression in rats with traumatic brain injury. DOI:10.3233/RNN-2011-0628	To characterize the expression of BDNF isoforms following PROG treatment for traumatic brain injury .	PROG reduces levels of pro-BDNF and TrkB post- brain injury. Mature BDNF was decreased at 24 and 72 h.
13	Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. DOI: 10.1210/en.2011-2177	To study PROG-induced BDNF release and the extracellular signal-regulated kinase 5.	PROG and the membrane-impermeable PROG both induced BDNF release from glial cells and primary astrocytes, which lack the classical nuclear/intracellular PROG receptor but express a membrane-associated PROG receptors.
14	Progesterone effects on neuronal brain-derived neurotrophic factor and glial cells during progression of Wobbler mouse neurodegeneration. DOI:10.1016/j.neuroscience.2011.11.034	To compared PROG regulation of BDNF in motoneurons and oligodendrocytes of Wobbler mice.	PROG upregulated the low levels of BDNF expression in the grey matter regions at the symptomatic stage of disease, and increased BDNF expression in the late stage Wobblers. BDNF protein was normal in steroid-naive symptomatic Wobblers.
15	Progesterone attenuates several hippocampal abnormalities of the wobbler mouse. DOI: 10.1111/jne.12004	To examine the hippocampus of Wobbler mice and their changes in response to PROG treatment.	Wobblers mice display a decreased BDNF expression. PROG did not change the normal parameters in control mice and attenuated hippocampal abnormalities in Wobblers.
16	Progesterone in the treatment of neonatal arterial ischemic stroke and acute seizures: Role of BDNF/TrkB signaling. DOI:10.1016/j.neuropharm.2016.03.052	To examine the effects of PROG on BDNF-TrkB signaling and inflammation following neonatal arterial ischemic stroke in mice.	PROG suppresses the expression of BDNF in seizure mice at day 1, but at day 3, BDNF expression is comparable to controls. PROG treatment first inhibited TrkB expression at day 1 then increased TrkB receptor expression at days 3.
17	Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus. DOI: 10.1016/j.neulet.2019.134384	To study the effect of PROG on post-traumatic epileptogenesis survival-related pathways.	PROG treated animals reduced the duration of seizures and enhanced the amount of BDNF in the ipsilateral hippocampus.
18	Progesterone’s Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABAA Activity in the Hippocampus and Cortex. DOI:10.3389/fendo.2020.552805	To evaluate PROG effect on the hippocampal and cortical levels of BDNF in mice.	PROG increased BDNF levels in the hippocampus, but not in the cortex, of male mice.

Table 2. Data summary of interactions between Progesterone and BDNF.

	Title	Aim/experiment	Main Findings
1	Treatment with estrogen and progesterone affects relative levels of brain-derived neurotrophic factor mRNA and protein in different regions of the adult rat brain DOI: 10.1016/S0006-8993(99)01880-6	To examine the acute effects of estrogen and PROG on levels of BDNF expression and protein in different brain regions in adult mice.	Estrogen or estrogen + PROG increase BDNF expression and protein levels in the pyriform cortex of mice. Increases in BDNF expression in the hippocampus accompanied a decrease in BDNF protein.
2	Progesterone prevents estrogen-induced dendritic spine formation in cultured hippocampal neurons DOI: 10.1159/000054580	To examine PROG effects on estrogen- induced formation of dendritic spines in hippocampal cell cultures.	PROG does not affect the estrogen-induced downregulation of BDNF, but it did block the effect of estrogen on CREB phosphorylation.
3	Progesterone counteracts estrogen-induced increases in neurotrophins in the aged female rat brain DOI: 10.1097/00001756-200412030-00021	To test estrogen and estrogen + PROG effects on neurotrophin levels in cognitive brain regions in aged OVX mice.	Estrogen treatment increased BDNF, NGF, and NT3 levels in the mice entorhinal cortex, and PROG abated these effects dropping BDNF levels to aged OVX non-treated mice.
4	Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord DOI:10.1016/j.neuroscience.2004.02.024	To demonstrate that BDNF increases with PROG treatment, in ventral horn motoneurons from spinal cord injured mice.	Spinal cord injury reduces BDNF expression levels by 50% in spinal motoneurons. PROG enhances BDNF in the motoneurons of lesioned spinal cord mice.
5	Progesterone treatment of spinal cord injury: Effects on Receptors, Neurotrophins, and Myelination DOI: 10.1385/JMN:28:1:3	To examine the cellular mechanisms involved in PROG neuroprotection in spinal cord injured rats.	PROG increases BDNF expression and protein in motoneurons in injured rats. These increases correlated with an increased TrkB and the phosphorylated CREB in motoneurons.
6	Progesterone increases Brain-Derived Neurotrophic Factor Expression and Protects Against Glutamate Toxicity in a Mitogen-Activated Protein Kinase- and Phosphoinositide-3 Kinase-Dependent Manner in Cerebral Cortical Explants Paramjit DOI: 10.1002/jnr.21370	To examine frontal and cingulate cerebral cortex explants from mice treated with PROG in vitro.	PROG induces a 75% increase in BDNF expression in explants of the cerebral cortex, with a nearly identical effect on BDNF protein levels.
7	Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons DOI:10.1016/j.expneurol.2006.08.019	To examined steroid and BDNF expression and protein in the spinal cord, and in muscle atrophy in wobbler rodent.	BDNF expression was in in neuros of steroid-naïve Wobbler mice compared to controls. PROG treatment increased BDNF expression in Wobblers compared to untreated, but not to controls.
8	Progesterone pre-treatment enhances serotonin-stimulated BDNF gene expression in rat C6 glioma cells through production of 5α-reduced neurosteroids DOI:10.1007/s12031-007-9034-6	To investigate the rule of neurotransmitters on glial cell metabolism and function in rat glioma cells in vitro.	BDNF expression levels in both non- treated and PROG-pre-treated glioma cells were similarly elevated by serotonin treatment with a concentration-dependent effect of serotonin on BDNF gene expression.
9	The differences in neuroprotective efficacy of progesterone and medroxyprogesterone acetate correlate with their effects on brain-derived neurotrophic factor expression DOI: 10.1210/en.2008-1247	To determine which type of PROG receptor mediates the neuroprotective effect of PROG on BDNF.	PROG induces increase in the BDNF protein levels in cerebral cortical explants in a concentration-dependent manner. PROG regulates BDNF expression through the classical PROG receptor.
10	Progesterone, BDNF and Neuroprotection in the Injured CNS DOI:10.1080/00207450903116430	To investigate the neuroprotective mechanism of PROG and BDNF.	PROG had no effect on BDNF expression in granule neurons. No neuroprotective role for PROG on BDNF was observed.
11	Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β. DOI:10.1111/j.1471-4159.2010.07038.x	To examine PROG and estrogen treatment in cultured hippocampal slices on levels of ERα and ERβ, and BDNF.	Estrogen elevated ERβ expression and protein levels, did not modify ERα expression, but increased ERα protein levels, and increased BDNF expression levels in hippocampal cells. PROG reversed the estrogen-elicited increases in ERβ, ERα protein, and BDNF expression levels.
12	Progesterone treatment alters neurotrophin/proneurotrophin balance and receptor expression in rats with traumatic brain injury. DOI:10.3233/RNN-2011-0628	To characterize the expression of BDNF isoforms following PROG treatment for traumatic brain injury .	PROG reduces levels of pro-BDNF and TrkB post- brain injury. Mature BDNF was decreased at 24 and 72 h.
13	Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. DOI: 10.1210/en.2011-2177	To study PROG-induced BDNF release and the extracellular signal-regulated kinase 5.	PROG and the membrane-impermeable PROG both induced BDNF release from glial cells and primary astrocytes, which lack the classical nuclear/intracellular PROG receptor but express a membrane-associated PROG receptors.
14	Progesterone effects on neuronal brain-derived neurotrophic factor and glial cells during progression of Wobbler mouse neurodegeneration. DOI:10.1016/j.neuroscience.2011.11.034	To compared PROG regulation of BDNF in motoneurons and oligodendrocytes of Wobbler mice.	PROG upregulated the low levels of BDNF expression in the grey matter regions at the symptomatic stage of disease, and increased BDNF expression in the late stage Wobblers. BDNF protein was normal in steroid-naive symptomatic Wobblers.
15	Progesterone attenuates several hippocampal abnormalities of the wobbler mouse. DOI: 10.1111/jne.12004	To examine the hippocampus of Wobbler mice and their changes in response to PROG treatment.	Wobblers mice display a decreased BDNF expression. PROG did not change the normal parameters in control mice and attenuated hippocampal abnormalities in Wobblers.
16	Progesterone in the treatment of neonatal arterial ischemic stroke and acute seizures: Role of BDNF/TrkB signaling. DOI:10.1016/j.neuropharm.2016.03.052	To examine the effects of PROG on BDNF-TrkB signaling and inflammation following neonatal arterial ischemic stroke in mice.	PROG suppresses the expression of BDNF in seizure mice at day 1, but at day 3, BDNF expression is comparable to controls. PROG treatment first inhibited TrkB expression at day 1 then increased TrkB receptor expression at days 3.
17	Progesterone modulates post-traumatic epileptogenesis through regulation of BDNF-TrkB signaling and cell survival-related pathways in the rat hippocampus. DOI: 10.1016/j.neulet.2019.134384	To study the effect of PROG on post-traumatic epileptogenesis survival-related pathways.	PROG treated animals reduced the duration of seizures and enhanced the amount of BDNF in the ipsilateral hippocampus.
18	Progesterone’s Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABAA Activity in the Hippocampus and Cortex. DOI:10.3389/fendo.2020.552805	To evaluate PROG effect on the hippocampal and cortical levels of BDNF in mice.	PROG increased BDNF levels in the hippocampus, but not in the cortex, of male mice.

The modulatory effects of progesterone combination to estradiol on BDNF might be influenced by dosage. Bimonte-Nelson et al., [84] showed that aged female rats receiving estradiol at a 1.5 mg/60 day regime exhibited increases in cortical levels of BDNF, and this was null when the animals received also progesterone at a 200mg/60 day regime. Oppositely, Saland, Schoepfer, and Kabbaj [85] reported that rats under cyclic administration of estradiol and progesterone that received ketamine injection exhibited an increase in hippocampal BDNF levels that did not occur to those receiving only estradiol or progesterone.

The time of exposition might be important for the neuroprotective effects of progesterone regulation on BDNF. Coughlan et al., [86] did not find an effect for progesterone on BDNF expression in the brain of mice who received a single progesterone dose of 8 mg/kg at the onset of a stroke; and Cekic et al., [87] reported that the levels of BDNF and pro-BDNF and TrkB were reduced in the brain of rats treated with progesterone as 8mg/kg intraperitoneal injection at 1 hr, and subcutaneous injections at 6 and 24 h and every 24 h post-injury. Alternatively, Yousuf et al., [88] showed that stroke rats who received progesterone (8 or 16 mg/kg) injections at 2 h, 6 h and every 24 h until day 7 post-occlusion restored BDNF levels at 3 and 7 days post-stroke. Similarly, Atif et al., [89] mice with ischemic stroke that received 8 mg/kg progesterone injections at 1 h post-ligation, at 3 h post-ligation and every 24 h for 6 days showed a transient reduction in BDNF expression at day 1 that increased at day 3 through day 7. Finally, Ghadiri et al., [90] recently showed that male rats had an increase in hippocampal BDNF concentrations with a low-dose progesterone treatment; and that a high-dose progesterone treatment resulted in a BDNF levels decline to lower than those found in brain-injury rats. It is possible that a time gap evidenced in BDNF response to progesterone occurs due to demands on membrane-associate-PRs. And that a critical range in progesterone dosage dictates whether BDNF expression will be induced by progesterone receptors activation or inhibited by CREB inhibition.

Jodhka et al., [91] identified that progesterone regulation of BDNF expression in mice brain is mediated by the classical nuclear PR; Su et al., [92] showed that progesterone induces BDNF release in glial cells and astrocytes, which lack the classical nuclear PR, by activation of the membrane component 1 signalling (Pgrmc1). Nuclear steroid receptors stimulate gene expression by facilitating the assembly of basal transcription factors into a preinitiation complex that requires additional, and sometimes common, coactivators. Which means that activation of ERs might impair PR-dependent gene expression via sequester of the common coactivator of CREB (CREB binding protein) [93]. A competition between these nuclear receptors for a limited concentrations of common coactivators is an integrative mechanism by which sex steroids concur in the genomic regulation of BDNF.

Although the presence of ERs is more abundantly present across brain tissues, and the gene for BDNF contains an ERE sequence so that ERs activation more effectively regulate the neuroprotective effects of BDNF. Progesterone activation of non-nuclear receptors influences on BDNF expression and release in diverse neuronal and non-neuronal tissues, and has been identified to positively regulate BDNF expression in spinal cord motor neurons, striatal neuros, hippocampal and cortical neurons [94,95,96,97,98,99,100].

4. Androgens and BDNF Interactions

Several studies elucidate that testosterone is able to increase the expression levels of BDNF in the high vocal center (HVC) of female and male birds, whereby it mediates recruital and survival of newborn neurons Xu et al., [101], Louissaint et al., [102], Fusani et al., [103], Hartog et al., [104], Ottem et al., [105], Li et al., [106], Fanaei et al., [107] and Falk Dittrich et al., [108]. Throughout life, new neurons arise from the ventricular zone of the adult songbird brain and are recruited to the song control nucleus HVC, from which they extend projections to its target. This process of ongoing circuit integration is modulated by seasonal surges in systemic testosterone, and supported by BDNF [109,110]. However, while It is known that singing upregulates HVC’s BDNF expression, and BDNF mediates androgen-induced HVC neuronal recruitment, the expression of BDNF is found diminished in aromatase-inhibited birds [111]. It is important to point out that brain aromatase converts circulating testosterone to estradiol and thus the HVC is exposed to both androgenic and estrogenic stimulation. Considering a sexual dimorphism in BDNF expression in the canary HVC, with higher levels in the adult male than female and evidence of testosterone-induced increase in BDNF levels in adult female HVC, the indirect effect of testosterone on BDNF expression may occur either via its metabolite estradiol or via testosterone-induced increases in singing activity. Consonantly, Allen et al., [112] experiments in adolescent male rats and macaques added that neither gonadectomy nor testosterone replacement altered BDNF or TrkB expression levels in the hippocampal tissue of the animals. Together, these findings suggest that local changes in BDNF expression likely follow estradiol availability and, possibly, gonadectomy or testosterone replacement did not alter the hippocampal production of estradiol.

Table 3. Data summary of interactions between Testosterone and BDNF.

	Title	Experiment	Main Findings
1	Brain-derived neurotrophic factor regulates expression of androgen receptors in perineal motoneurons DOI: 10.1073/pnas.94.4.1521	To examine steroid receptor expression in motoneurons of the SNB in mice.	Axonal transport disruption downregulates AR expression in motoneurons and BDNF treatment reverses it.
2	Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch DOI: 10.1073/pnas.96.14.8241	To examine the expression of AR, BDNF, and TrkB in the HVC, neostriatum, and archistriatum in Zebra finches.	BDNF expression is increased in the HVC of male, but not female, zebra finches. Estrogen and aromatase inhibition induce a premature stimulation and an inhibition on the increase patterns of BDNF expression, respectively, in juvenile males.
3	BDNF mediates the effects of testosterone on the survival of new neurons in an adult brain DOI:10.1016/S0896-6273(00)80678-9	To examine BDNF responses to testosterone treatment in the HVC of male canaria.	Testosterone treatment increases BDNF levels in the HVC of adult canaria. BDNF antibody blocked the testosterone-induced increase in new neurons.
4	BDNF regulation of androgen receptor expression in axotomized SNB motoneurons of adult male rats DOI:10.1016/S0006-8993(99)02225-8	To examine BDNF effects on axotomy- induced loss of AR expression in SNB motoneurons in rats.	Delayed application of BDNF to axotomized SNB motoneurons restored AR expression the intact levels.
5	Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons DOI: 10.1523/jneurosci.21-12-04366.2001	To exploit motoneuron cell death in the SNB of mice and androgens effect.	Blockage of TrkB activity prevented the androgenic sparing of SNB motoneurons. This did not reduce SNB motoneuron number.
6	Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain DOI: 10.1016/S0896-6273(02)00722-5	To investigated testosterone-related angiogenesis and neuronal recruitment in adult songbird neostriatum.	HVC endothelial cells produce BDNF in a testosterone-dependent manner.
7	Aromatase inhibition affects testosterone-induced masculinization of song and the neural song system in female canaries DOI: 10.1002/neu.10141	To investigated the role of estrogen in controlling the development of the song structure (HVC) in female canaries.	Aromatase inhibition of testosterone-induced song motor development correlate with inhibition of BDNF in HVC of adult female canaries and alters the song pattern.
8	Brain-Derived Neurotrophic Factor and Androgen Interact in the Maintenance of Dendritic Morphology in a Sexually Dimorphic Rat Spinal Nucleus DOI: 10.1210/en.2003-0853	To test BDNF and testosterone effects on dendritic morphology in motoneurons of the SNB in rats.	Testosterone or BDNF failed to support dendritic length or distribution. Treatment with testosterone plus BDNF restores dendritic morphology to the level of controls.
9	Androgen regulates trkB immunolabeling in spinal motoneurons DOI: 10.1002/jnr.21122	To examine gonadal hormones regulation of BDNF systems in rodents spinal motoneurons.	TrkB receptors regulation is androgen sensitive in motoneurons on the SNB. Castration- induced changes in SNB motoneurons are prevented by testosterone replacement.
10	Androgen-dependent regulation of brain-derived neurotrophic factor and tyrosine kinase B in the sexually dimorphic SNB DOI: 10.1210/en.2007-0308	To investigate the androgens regulation of BDNF protein in SNB motoneurons.	SNB motoneurons and the non-androgen-responsive motoneurons of the adjacent retrodorsolateral nucleus express BDNF and trkB. Testosterone regulates BDNF protein in SNB, but not in the retrodorsolateral nucleus dendrites.
11	Differential expression and regulation of brain-derived neurotrophic factor mRNA isoforms in androgen-sensitive motoneurons of the rat lumbar spinal cord. DOI:10.1016/j.mce.2010.07.001	To examine the specific BDNF transcripts regulated by androgens in the SNB motoneurons of male rats.	BDNF isoforms containing exon VI were decreased in SNB motoneurons in an androgen-dependent manner, but unaffected in retrodorsolateral motoneurons.
12	Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature. DOI: 10.1210/en.2009-1036	To examine androgens regulation of BDNF in quadriceps and SNB motoneurons, and their corresponding target musculature in male rats.	Castration reduced BDNF protein in the quadriceps and SNB motoneurons, and their target musculature, and this was prevented with testosterone replacement.
13	Modulatory Effects of Sex Steroid Hormones on Brain-Derived Neurotrophic Factor-Tyrosine Kinase B Expression during Adolescent Development in C57Bl/6 Mice. DOI:10.1111/j.1365-2826.2012.02277.x	To examine sex steroid hormones and neurotrophic signalling during adolescent development in a mouse model.	Castration and testosterone or DHT replacement had a receptor-dependent effect on BDNF-TrkB signalling in the forebrain and hippocampal regions of the adolescent animals. Females changes in BDNF-TrkB signalling do not correspond with changes in serum estrogen.
14	Androgen action at the target musculature regulates brain-derived neurotrophic factor protein in the SNB. DOI: 10.1002/dneu.22083	To examine if testosterone regulates BDNF in SNB motoneurons of male rats by acting locally at the bulbocavernosus muscle.	Testosterone directly to the bulbocavernosus muscle maintains BDNF levels in SNB motoneurons intact, after castration. AR blockage decreases BDNF, compared with animals treated with intramuscular testosterone.
15	Regulatory mechanisms of testosterone-stimulated song in the sensorimotor nucleus HVC of female songbirds. DOI:10.1186/s12868-014-0128-0	To examine the effects of testosterone on the anatomy and the song control nucleus HVC of female European robins.	Testosterone induced differentiation, angiogenesis and neuron projection morphogenesis. BDNF functions as a common mediator of the testosterone effects in HVC.
16	Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. DOI:10.1016/j.brainres.2014.02.028	To evaluate the effects of testosterone on BDNF and neurogenesis in a castrated male rat model of focal cerebral ischemia.	Testosterone increased BDNF levels and neurogenesis after focal cerebral ischemia.
17	The effect of adolescent testosterone on hippocampal BDNF and TrkB mRNA expression: Relationship with cell proliferation. DOI:10.1186/s12868-015-0142-x	To examine the molecular mechanism underlying testosterone actions on postnatal neurogenesis and BDNF/TrkB levels in rhesus macaque and rat.	Gonadectomy or steroids replacement did not alter BDNF or TrkB expression levels in young adult male rat or rhesus macaque hippocampus. There was a positive correlation between cell proliferation and TrkB expression, only when steroids are present.
18	Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice. DOI:10.1080/15287394.2016.1193113	To study the protective role of testosterone on cognitive performance in an Alzheimer disease animal model.	The expression of BDNF and cyclic-AMP response element binding protein (CREB)/CREB levels were elevated in testosterone treated animals.
19	Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. DOI: 10.1038/SREP21322	To investigate the testosterone contribution to the rapid antidepressant-like effects of ketamine.	Testosterone treatment responsiveness was associated with higher hippocampal BDNF levels in female rats.
20	TrkB is necessary for male copulatory behavior in the Syrian Hamster (Mesocricetus auratus). DOI:10.1016/j.yhbeh.2017.10.016	To examine how TrkB and BDNF mediate testosterone effects on the medial preoptic nucleus in Hamsters.	Testosterone treatment increased BDNF expression levels and conversely lowered the expression of TrkB receptors in the medial preoptic area of animals.
21	Prenatal Androgenization Induces Anxiety-Like Behavior in Female Rats, Associated with Reduction of Inhibitory Interneurons and Increased BDNF in Hippocampus and Cortex. DOI:10.1155/2019/3426092	To evaluated the influence of maternal hyperandrogenemia on offspring levels of BDNF in the hippocampus and cerebral cortex.	BDNF expression was increased in the hippocampus and cerebral cortex of Prenatal hyperandrogenization offspring in comparison with the controls.
22	Deficiency in Androgen Receptor Aggravates the Depressive-Like Behaviors in Chronic Mild Stress Model of Depression. DOI: 10.3390/cells8091021	To exploit how AR and stress influence the onset of the major depressive disorder.	Loss of AR affects depressive-like behaviours by modulate BDNF expression.
23	Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice. DOI:10.1016/j.yhbeh.2019.03.005	To examine how adolescent androgens influence psychosis-like behaviour in the adulthood and the BDNF rule, in mice.	Testosterone and DHT treatment reduce the expression of dopamine transporter in the medial prefrontal cortex of mice. These effects are absent in BDNF heterozygous mice.
24	Dose-dependent effects of testosterone on spatial learning strategies and brain-derived neurotrophic factor in male rats. DOI:10.1016/j.psyneuen.2020.104850	To investigate the effect of different doses of testosterone on spatial learning strategies in male rats.	Low testosterone dose increased total BDNF in the striatum, and high dose increased total BDNF in the hippocampus.

Table 3. Data summary of interactions between Testosterone and BDNF.

	Title	Experiment	Main Findings
1	Brain-derived neurotrophic factor regulates expression of androgen receptors in perineal motoneurons DOI: 10.1073/pnas.94.4.1521	To examine steroid receptor expression in motoneurons of the SNB in mice.	Axonal transport disruption downregulates AR expression in motoneurons and BDNF treatment reverses it.
2	Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch DOI: 10.1073/pnas.96.14.8241	To examine the expression of AR, BDNF, and TrkB in the HVC, neostriatum, and archistriatum in Zebra finches.	BDNF expression is increased in the HVC of male, but not female, zebra finches. Estrogen and aromatase inhibition induce a premature stimulation and an inhibition on the increase patterns of BDNF expression, respectively, in juvenile males.
3	BDNF mediates the effects of testosterone on the survival of new neurons in an adult brain DOI:10.1016/S0896-6273(00)80678-9	To examine BDNF responses to testosterone treatment in the HVC of male canaria.	Testosterone treatment increases BDNF levels in the HVC of adult canaria. BDNF antibody blocked the testosterone-induced increase in new neurons.
4	BDNF regulation of androgen receptor expression in axotomized SNB motoneurons of adult male rats DOI:10.1016/S0006-8993(99)02225-8	To examine BDNF effects on axotomy- induced loss of AR expression in SNB motoneurons in rats.	Delayed application of BDNF to axotomized SNB motoneurons restored AR expression the intact levels.
5	Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons DOI: 10.1523/jneurosci.21-12-04366.2001	To exploit motoneuron cell death in the SNB of mice and androgens effect.	Blockage of TrkB activity prevented the androgenic sparing of SNB motoneurons. This did not reduce SNB motoneuron number.
6	Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain DOI: 10.1016/S0896-6273(02)00722-5	To investigated testosterone-related angiogenesis and neuronal recruitment in adult songbird neostriatum.	HVC endothelial cells produce BDNF in a testosterone-dependent manner.
7	Aromatase inhibition affects testosterone-induced masculinization of song and the neural song system in female canaries DOI: 10.1002/neu.10141	To investigated the role of estrogen in controlling the development of the song structure (HVC) in female canaries.	Aromatase inhibition of testosterone-induced song motor development correlate with inhibition of BDNF in HVC of adult female canaries and alters the song pattern.
8	Brain-Derived Neurotrophic Factor and Androgen Interact in the Maintenance of Dendritic Morphology in a Sexually Dimorphic Rat Spinal Nucleus DOI: 10.1210/en.2003-0853	To test BDNF and testosterone effects on dendritic morphology in motoneurons of the SNB in rats.	Testosterone or BDNF failed to support dendritic length or distribution. Treatment with testosterone plus BDNF restores dendritic morphology to the level of controls.
9	Androgen regulates trkB immunolabeling in spinal motoneurons DOI: 10.1002/jnr.21122	To examine gonadal hormones regulation of BDNF systems in rodents spinal motoneurons.	TrkB receptors regulation is androgen sensitive in motoneurons on the SNB. Castration- induced changes in SNB motoneurons are prevented by testosterone replacement.
10	Androgen-dependent regulation of brain-derived neurotrophic factor and tyrosine kinase B in the sexually dimorphic SNB DOI: 10.1210/en.2007-0308	To investigate the androgens regulation of BDNF protein in SNB motoneurons.	SNB motoneurons and the non-androgen-responsive motoneurons of the adjacent retrodorsolateral nucleus express BDNF and trkB. Testosterone regulates BDNF protein in SNB, but not in the retrodorsolateral nucleus dendrites.
11	Differential expression and regulation of brain-derived neurotrophic factor mRNA isoforms in androgen-sensitive motoneurons of the rat lumbar spinal cord. DOI:10.1016/j.mce.2010.07.001	To examine the specific BDNF transcripts regulated by androgens in the SNB motoneurons of male rats.	BDNF isoforms containing exon VI were decreased in SNB motoneurons in an androgen-dependent manner, but unaffected in retrodorsolateral motoneurons.
12	Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature. DOI: 10.1210/en.2009-1036	To examine androgens regulation of BDNF in quadriceps and SNB motoneurons, and their corresponding target musculature in male rats.	Castration reduced BDNF protein in the quadriceps and SNB motoneurons, and their target musculature, and this was prevented with testosterone replacement.
13	Modulatory Effects of Sex Steroid Hormones on Brain-Derived Neurotrophic Factor-Tyrosine Kinase B Expression during Adolescent Development in C57Bl/6 Mice. DOI:10.1111/j.1365-2826.2012.02277.x	To examine sex steroid hormones and neurotrophic signalling during adolescent development in a mouse model.	Castration and testosterone or DHT replacement had a receptor-dependent effect on BDNF-TrkB signalling in the forebrain and hippocampal regions of the adolescent animals. Females changes in BDNF-TrkB signalling do not correspond with changes in serum estrogen.
14	Androgen action at the target musculature regulates brain-derived neurotrophic factor protein in the SNB. DOI: 10.1002/dneu.22083	To examine if testosterone regulates BDNF in SNB motoneurons of male rats by acting locally at the bulbocavernosus muscle.	Testosterone directly to the bulbocavernosus muscle maintains BDNF levels in SNB motoneurons intact, after castration. AR blockage decreases BDNF, compared with animals treated with intramuscular testosterone.
15	Regulatory mechanisms of testosterone-stimulated song in the sensorimotor nucleus HVC of female songbirds. DOI:10.1186/s12868-014-0128-0	To examine the effects of testosterone on the anatomy and the song control nucleus HVC of female European robins.	Testosterone induced differentiation, angiogenesis and neuron projection morphogenesis. BDNF functions as a common mediator of the testosterone effects in HVC.
16	Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. DOI:10.1016/j.brainres.2014.02.028	To evaluate the effects of testosterone on BDNF and neurogenesis in a castrated male rat model of focal cerebral ischemia.	Testosterone increased BDNF levels and neurogenesis after focal cerebral ischemia.
17	The effect of adolescent testosterone on hippocampal BDNF and TrkB mRNA expression: Relationship with cell proliferation. DOI:10.1186/s12868-015-0142-x	To examine the molecular mechanism underlying testosterone actions on postnatal neurogenesis and BDNF/TrkB levels in rhesus macaque and rat.	Gonadectomy or steroids replacement did not alter BDNF or TrkB expression levels in young adult male rat or rhesus macaque hippocampus. There was a positive correlation between cell proliferation and TrkB expression, only when steroids are present.
18	Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice. DOI:10.1080/15287394.2016.1193113	To study the protective role of testosterone on cognitive performance in an Alzheimer disease animal model.	The expression of BDNF and cyclic-AMP response element binding protein (CREB)/CREB levels were elevated in testosterone treated animals.
19	Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. DOI: 10.1038/SREP21322	To investigate the testosterone contribution to the rapid antidepressant-like effects of ketamine.	Testosterone treatment responsiveness was associated with higher hippocampal BDNF levels in female rats.
20	TrkB is necessary for male copulatory behavior in the Syrian Hamster (Mesocricetus auratus). DOI:10.1016/j.yhbeh.2017.10.016	To examine how TrkB and BDNF mediate testosterone effects on the medial preoptic nucleus in Hamsters.	Testosterone treatment increased BDNF expression levels and conversely lowered the expression of TrkB receptors in the medial preoptic area of animals.
21	Prenatal Androgenization Induces Anxiety-Like Behavior in Female Rats, Associated with Reduction of Inhibitory Interneurons and Increased BDNF in Hippocampus and Cortex. DOI:10.1155/2019/3426092	To evaluated the influence of maternal hyperandrogenemia on offspring levels of BDNF in the hippocampus and cerebral cortex.	BDNF expression was increased in the hippocampus and cerebral cortex of Prenatal hyperandrogenization offspring in comparison with the controls.
22	Deficiency in Androgen Receptor Aggravates the Depressive-Like Behaviors in Chronic Mild Stress Model of Depression. DOI: 10.3390/cells8091021	To exploit how AR and stress influence the onset of the major depressive disorder.	Loss of AR affects depressive-like behaviours by modulate BDNF expression.
23	Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice. DOI:10.1016/j.yhbeh.2019.03.005	To examine how adolescent androgens influence psychosis-like behaviour in the adulthood and the BDNF rule, in mice.	Testosterone and DHT treatment reduce the expression of dopamine transporter in the medial prefrontal cortex of mice. These effects are absent in BDNF heterozygous mice.
24	Dose-dependent effects of testosterone on spatial learning strategies and brain-derived neurotrophic factor in male rats. DOI:10.1016/j.psyneuen.2020.104850	To investigate the effect of different doses of testosterone on spatial learning strategies in male rats.	Low testosterone dose increased total BDNF in the striatum, and high dose increased total BDNF in the hippocampus.

Interaction between BDNF and testosterone seems to be necessary to maintain dendritic morphology in SNB motoneurons. Testosterone can regulate the expression of AR and TrKB in spinal motoneurons [113], and BDNF signaling through TrkB is able to regulate the expression of androgen receptors (AR) [114,115,116,117]. Furthermore, BDNF expression is shown to be upregulated by testosterone signalling in AR expressing motoneurons of the vastus lateralis and the spinal nucleus of the bulbocavernosus and their corresponding muscles [118,119]. Together these findings suggest a mechanistic interaction between BDNF and testosterone whereby testosterone improves BDNF signaling and, consequently its expression, which in turn improves testosterone sensitivity via AR regulation. In the experiment by Yang, Verhovshek, and Sengelaub [120], treatment of castrated male rats with testosterone or BDNF alone was not sufficient to promote dendritic length and distribution in SNB motoneurons; whereas, combined treatment with testosterone and BDNF was able to restore the SNB dendritic morphology. Additionally, Zhang et al., [121] data indicate that different doses of testosterone may differently affect BDNF expression levels within the brain. In their experiment, young adult rats that received a low dose of testosterone (0.125 mg) showed increased BDNF concentrations in the striatum, and those who received a high dose (0.500 mg) had increased BDNF in their hippocampus.

The study by Hill et al., [122] reported a region-specific and time-dependent sex differences in BDNF-TrkB expression and signaling during adolescence. They described that serum testosterone levels increase in males mice from week 3 to 12, peaking at week 8 and then declining, and brain BDNF expression levels were increasing in a positive correlation with serum testosterone, peaking from weeks 7 to 10. A tendency for TrkB expression to decrease when BDNF levels were increasing was noted and castration did not affect BDNF expression in the mice brains. In females, BDNF expression did not change from week 3 to 12, however, TrkB activity was seen to increase from week 4, peaked at week 6, and then declined. OVX resulted in an increase in BDNF expression levels, that was not affected by estrogen replacement, and a decrease in TrkB activity in these adolescent mice. In Brague et al., [123] experiment, testosterone also increased the expression of BDNF while reduced TrkB levels in the hypothalamus of male Syrian hamster. Recently, the study by Rankov Petrovic et al., [124] revealed that the adult female offspring from testosterone-treated pregnant female rats had increased BDNF levels in the hippocampus and cortex.

5. Summary and Conclusion

Sex steroids play an essential role in neuronal circuits formation and maintenance via regulation of BDNF expression in neuronal proliferation, differentiation and homeostasis at important areas of the brain i.e., cortex, hippocampus, hypothalamus and upper areas of the midbrain, and cerebellum [18,26,29,41,51,58]. This occurs from the developmental stages throughout life.

Estrogens regulation of BDNF either via classical nuclear receptors or via activation of membrane-associated ERs by second messenger signalling pathways [125,126] is essential to neuronal function and is suggestibly a main regulator of TrkB expression. Whereas, excessive concentrations of BDNF reportedly downregulate TrkB expression levels [127]. Further, BDNF autocrine and paracrine signal transduction regulates its own expression within neighbour cells [128], and this enhances ERs activity, which in turn, increases BDNF mRNA transcription in a synergistic manner [17,32,36,40,47,48,50,56,129]. That implies that the estrogen/ER system is able to regulate the BDNF/TrkB system; while, the inhibitory effect of TrkB/PI3K/AKT pathway on ERE transcription indicates that BDNF signal is important to limit and control BDNF expression [46,47,48,50]. Furthermore, the time- and region- specific influence found for sex steroids on BDNF function likely depend on the presence and concentrations of estrogens [30,101,102,103,104,105,106,109,113,118,119,120,121,124,130].

A neuroprotective effect for the estrogens regulation of BDNF is consistently seen in individuals with various pathological conditions such as stress, hypertension, ischemic brain injury, Parkinson’s and Alzheimer’s diseases [27,28,31,33,42,59,74,75,76,77,78,83,86,89,107,110].

Although much less research is present on interactions between progesterone and BDNF. A direct regulation of BDNF expression was evidenced in cortical cells expressing the classical nuclear PR [75,91]. In addition, progesterone is able to increase BDNF synthesis and enhance neuroprotective cell responses by different ways [52,79,80,91,92,93,94,95,96,97,98,131]. For example, progesterone enhances anti-inflammatory processes and tissue recovery from neural injury [87,88,89,132,133,134,135].

Figure 2. Schematic illustration of direct (complete arrow) and indirect (dot arrow) interactions between sex steroids and BDNF systems via activation of nuclear receptors in neuronal cells within the brain. Created with BioRender.com.

Figure 2. Schematic illustration of direct (complete arrow) and indirect (dot arrow) interactions between sex steroids and BDNF systems via activation of nuclear receptors in neuronal cells within the brain. Created with BioRender.com.

Testosterone does not regulate BDNF gene directly, but rather via activation of ARs which translocate to the nucleus and start gene expression at androgen responsive elements sequences of androgen-responsive genes upstream BDNF [108,114,115,136]. This regulation appears to be influenced by local factors. For instance, the findings of Zhang et al., [121] report that a low-dose of testosterone increase BDNF levels in the striatum while a high-dose testosterone increase BDNF levels in the hippocampus of male rats. Interestingly, the BDNF/TrkB system positively regulates the expression of AR in neurons, potentiating testosterone regulation on BDNF [120].

Regarding progesterone, studies report various effects of interactions between progesterone and estradiol combination on BDNF expression [43,45,81,84,85,94,95,99]. It is possible that their competitive activation of nuclear receptors might deplete co-activators, or their signaling through membrane-associated receptors result in a gain or a loss of effect on BDNF regulation. Further studies on the mechanistic interactions between sex steroids in the regulation of gene expression would be necessary to elucidate of progesterone and estradiol.

Sex steroids regulate the expression of BDNF either directly via nuclear receptors or by altering intracellular pathways that affect genomic regulation of BDNF. This in times can represent concurrent mechanisms.