Developmental and adult stress: effects of steroids and neurosteroids

Figures & data

Table 1. Chemical Names, Common Names, and Abbreviations for Neuroactive Derivatives of Sex Steroids and Glucocorticoids.

Chemical name	Common name	Abbreviation
Pregn-4-ene-3,20-dione	Progesterone, Pregnenedione	P4
17β- estradiol	Estradiol	E2
17β- hydroxy-4-androsten-3-one	Testosterone	T
11β, 21-dihydroxy-4-pregnene- 3,20-dione	Corticosterone, 17-Deoxycortisol	CORT
3α‐Hydroxy‐5α‐pregnan‐20‐one	Allopregnanolone	ALLO
3β‐Hydroxypregn‐5-en‐20‐one	Pregnenolone	P5
3α, 21‐Dihydroxy‐5α‐pregnan‐20‐ one	Tetrahydrodeoxycorticosterone	THDOC
5α-androstan‐3α, 17 β ‐diol	Androstanediol	3α-diol
5α-pregnane‐3, 20-dione	5α-Dihydroprogesterone	5α-DHP
21-hydroxy-5α-pregnan-20-one	5α-Dihydrodeoxycorticosterone	DHDOC
21-Hydroxy-4- pregnene-3,20- dione	Deoxycorticosterone, 11-Deoxycorticosterone, 21-hydroxyprogesterone	DOC
3-hydroxyestra-1,3,5 (10)-trien- 17-one	Estrone	E1
17α-hydroxyprogesterone	17-Hydroxyprogesterone	17-OH Progesterone

Figure 1. Subcellular Compartments for Steroid/Neurosteroid Synthesis. Diagram showing that steroid/neurosteroid synthesis occurs in the mitochondria and endoplasmic reticulum.

Cholesterol enters the mitochondria facilitated by StAR and TSPO protein where it is cleaved into pregnenolone by enzyme P450scc. Pregnenolone is converted to progesterone (P4) by 3β- HSD. In the endoplasmic reticulum, progesterone is converted to testosterone by a two-step pathway. 17-hydroxy progesterone and androstenedione catalyzed by P450c17 and 17β-HSD respectively. T is reduced to 5α-DHT and then 3α-diol. P450 aromatase enzyme (P450 aro) reduces androstenedione and T into estrone and estradiol respectively. In the cytoplasm, progesterone is also catalyzed into 5α-DHP and then into allopregnanolone by 5α-reductase and 3α-HSD). Estrone is reversibly converted to estradiol by 17β- HSD. Progesterone is converted into DOC by 21-hydroxylase which undergoes two subsequent reduction steps by 5α-reductase and 3α-HSD to form THDOC. DOC can also be converted into corticosterone by 11β-hydroxylase. Enzymes are denoted in red, steroids and neurosteroids in blue boxes. The arrows and directional arrows indicate irreversible and reversible reactions respectively. Abbreviations; StAR; steroidogenic acute regulatory protein; TSPO, translocator protein; p450scc, P450 side chain cleavage; P4, progesterone; HSD, hydroxysteroid dehydrogenase; 17-OH progesterone, 17-hydroxyprogesterone; 5α- DHT, 5α- dihydrotestosterone; 5α- DHP, 5α- dihydroprogestrone; DOC, deoxycorticosterone; THDOC, tetrahydrodeoxycorticosterone

Figure 2. Chemical Structures of Neurosteroid Synthesis. Neurosteroids are closely related structurally, which allows many to serve as ligands for the same receptors. Neurosteroids binding to GABAa receptors and endocannabinoid receptors are surrounded by red and blue boxes respectively. Abbreviations: HSD, hydroxysteroid dehydrogenase; P450 scc, P450 side chain cleavage enzyme; P450 aro, P450 aromatase; DOC, deoxycorticosterone; DHDOC, dihydrodeoxycorticosterone; THDOC, tetrahydrodeoxycorticosterone; 5α-DHP, 5α- dihydroprogesterone; 17-OH progesterone, 17-hydroxyprogesterone; 5α-DHT, 5α- dihydrotestosterone.

Figure 3. Diagram Illustrating Some of the Effects of Developmental Stress on Steroid and Neurosteroid Levels, Neuronal Morphology, Glial Expression, and PNN Integrity. Note: Stress influences various aspects of brain function that extend beyond the factors mentioned in the diagram. P4, Progesterone; E2, Estradiol; T, Testosterone; ALLO, Allopregnanolone; CORT, Corticosterone; DHP, Dihydroprogesterone; DHT, Dihydrotestosterone; DOC, Deoxycorticosterone; THDOC, Tetrahydrodeoxycorticosterone; BLA, Basolateral amygdala; PFC, prefrontal cortex; HIP, hippocampus; dHIP, dorsal hippocampus; vHIP, ventral hippocampus; Iba1, ionized calcium binding adaptor molecule 1; GFAP, Glial fibrillary acidic protein; PNN, Perineuronal nets; PV, Parvalbumin; CSPG, Chondroitin sulfate proteoglycan. ♂: male ♀: female.

Table 2. Impact of Stress on Sex Steroid, Glucocorticoid, and Neurosteroid Levels.

Time of Stress	Stressor	Species/Sex	Brain Region	Sex Steroid/Glucocorticoid/Neurosteroid	Change in Levels	Associated Behavioral Changes	Reference
Early Life	LBN	Rats/Male and Female	N/A (serum levels)	E2	Increased in males	Shorter latency to engage in reproductive behavior	Eck et al., 2020, 2022
	MS	Mice/Male	N/A (serum levels)	T	Decreased	Decreased aggressive behavior	Miyaso et al., 2021; Tsuda et al., 2011
	MSEW	Mice/Female (Diestrus)	vHIP	P4, ALLO	Increased P4, Decreased ALLO	Increased avoidance	Laham et al., 2022
	Restraint- Late Gestation	Rats/Male and Female	mPFC, HIP	P4 to 5α-reduced metabolites (DHP, ALLO), 3α-diol, DHT	Decreased Conversion to 5α-reduced metabolites. Decreased 3α-diol, DHT in males	Impaired object recognition, Increased avoidance, reduced social interaction	Paris & Frye, 2011b; Walf & Frye, 2012
	LPS – Late Gestation	Rats/Female	HIP, PFC	ALLO	Decreased	Impaired object recognition	Paris et al., 2011
Adulthood	SI	Mice/Male, Rats/Male	mPFC, nACC, HIP, OB	ALLO, THDOC, 5α- reductase P5, P4, ALLO, THDOC, DHP	Decreased	Increased avoidance and aggression	Bortolato et al., 2011; Serra et al., 2005, 2000; Dong et al., 2001; Pinna et al., 2004
	Swim, CO2	Rats/Male and Female	FC, AMY, Brainstem, HYPO, serum	ALLO, DOC, P4, THDOC	Increased (More in Females) Decreased ALLO in serum	Disrupted prepulse inhibition	Sze et al., 2018; Reddy & Rogawski, 2002; Vallée et al., 2000; Barbaccia et al., 1996; Purdy et al., 1991; Pallarès et al., 2015
	CUS	Mice/Female	N/A (serum measures)	T, E2	Decreased	Not reported	Gao et al., 2020
	Restraint, Shock, Swim	Rats/Male	N/A (serum measures)	T	Decreased	Greater latency to engage in reproductive behavior	Retana-Márquez et al., 2003;

*Compared to unstressed controls.

LBN, limited bedding and nesting; MS, maternal separation, MSEW, maternal separation and early weaning; SI, social isolation; DHP, dihydroprogesterone; DHT, dihydrotestosterone; DOC, deoxycorticosterone; DHDOC, dihydrodeoxycorticosterone; THDOC, tetrahydrodeoxycorticosterone; T, testosterone; E2, estradiol; ALLO, allopregnanolone; P4, progesterone; P5, pregnenolone; PFC, prefrontal cortex; HIP, hippocampus; ACC, anterior cingulate cortex; OB, olfactory bulb; FC, frontal cortex; AMY, amygdala; HYPO, hypothalamus.

Table 3. Impact of Stress on Neurons: Involvement of Steroids and Neurosteroids.

Time of Stress	Stressor	Species/Sex	Brain Region	Sex Steroid/Glucocorticoid/Neurosteroid	Affected Neuron Type or Area	Effect on Neurons	Reference
Early Life	MS, MS + SI	Rats/Male and Female; Mice/Male and Female	HIP, PFC	CORT	Immature neurons of dentate gyrus; PV + Interneurons	Reduced number of new neurons and PV+ neurons, as well as suppressed maturation of PV+ neurons	Mirescu et al., 2004; Katahira et al., 2018
	Multiple stressors	Rats/Male and Female	dHIP, mPFC, HYPO	DHP, P4, E2	Pyramidal cells	Decrease in spine density in dHIPP, no differences in spine density noted in mPFC and HYPO	Paris & Frye, 2011a
Adulthood	Shock	Rats/Male and Female	HIP	E2	CA1 pyramidal cells	Increased Dendritic Spine Density	Shors et al., 1999; Shors et al., 2001
	Restraint, multiple acute stressors	Rats/Male and Female	HIP	E2 (in females), Glucocorticoids	Pyramidal cells	Decreased dendritic spine density, apical dendritic length and complexity	Hokenson et al., 2021; Watanabe et al., 1992; Luine et al., 1994
	Restraint, SI	Rats/Male and Female	HIP, AMY	CORT, E2	PV + interneurons of CA1, CA3, and dentate gyrus; BLA pyramidal cells	Chronic stress induced decrease in number; Increase in spine density; Increase in dendritic length at intermediate branches	Filipović et al., 2013; Kraus et al., 2022; Mitra et al., 2005; Shansky et al., 2010

* Compared to unstressed controls.

MS, maternal separation; SI, social isolation; CORT, corticosterone; E2, estradiol; P4, progesterone; DHP, dihydroprogesterone; PV, parvalbumin; BLA, basolateral amygdala; HIP, hippocampus, PFC, prefrontal cortex; AMY, amygdala; HYPO, hypothalamus.

Table 4. Impact of Stress on Perineuronal Nets: Involvement of Steroids and Neurosteroids?.

Time of Stressor	Stressor	Species/Sex	Brain Region	PNN Change	Associated Behavioral Changes	Reference
Early Life	MSEW	Mice/Male and Female; Rats/Male and Female	HIP, BLA, PFC	Increased PNN Intensity; Increased PNN CSPGs; Affects PNN Composition (increased C4S+/WFA + cells in ventral CA1)	Increased avoidance	Murthy et al., 2019; Dimatelis et al., 2013; Laham et al., 2022
	MS, SI	Rats/Male and Female	PFC	Reduced PV + PNN structural integrity, PV + PNN reduced number in females	Increased locomotion, increased risk assessment in females	Gildawie et al., 2021
	LBN	Rats/Male and Female	BLA	Increased PNN density around PV + cells	Increased fear	Guadagno et al., 2020
	LBN	Rats/Male	BLA	Reduced PNN intensity	Increased threat response	Santiago et al., 2018
Adulthood	Social Defeat	Rats/Male and Female	HIP	Increased PNN number around PV + cells	Reduced object location memory and maintenance of LTP	Riga et al., 2017
	SI	Mice/Male	HIP, RC, PFC	Reduced PNN number; Reduction in PNN number in PFC	N/A	Klimczak et al., 2021; Ueno et al., 2018
	CMS	Rats/Male	PFC	Reduced PNN number	Depressive-like behavior	Yu et al., 2020
	Chronic CORT	Mice/Male and Female	HIP	Increased PNN Intensity	Increased avoidance, reduced working memory	Alaiyed et al., 2020

*Compared to unstressed controls.

MSEW; Maternal separation and early weaning; MS, maternal separation; SI; social isolation; LBN; limited bedding and nesting; CMS, chronic mild stress; PNN, perineuronal nets; CSPG, chondroitin sulfate proteoglycan; C4S, chondroitin-4-sulfate; WFA, wisteria floribunda agglutinin; LTP, long-term potentiation; PFC, prefrontal cortex; HIP, hippocampus; BLA, basolateral amygdala; RC, retrosplenial cortex.

Table 5. Impact of Stress on Microglia and Astrocytes: Involvement of Steroids and Neurosteroids?

Time of Stressor	Stressor	Species/Sex	Brain Region	Changes in Microglia/Astrocytes	Reference
Early Life	MS	Rats/Male and Female; Mice/Male and Female	HIP; SSCx; Medulla; PFC; nACC, dorsal striatum	Increased activated microglia, decreased astrocyte density and number of processes; Increased motility of microglial processes in SSCx; Increased size of microglial soma and decreased arborization in medulla; Decreased astrocytes	Roque et al., 2016; Takatsuru et al., 2015; Baldy et al., 2018; Delpech et al., 2016: Giridharan et al., 2019, Réus et al., 2017, 2019; Banqueri et al., 2019
	MS and FR	Rats/Male and Female	PFC	Increased Iba1, hyper- ramified microglia	Ganguly et al., 2018
	MS and LPS	Rats/Male	HIP	Increased microglial activation, decreased astrocytes	Saavedra et al., 2017
	MS and SI	Rats/Male and Female	PFC	Decreased GFAP mRNA	Yamawaki et al., 2018
	LBN	Mice/Male and Female	HIP, entCx	Increased astrocyte coverage at P9, and a decrease noted at 10 months	Abbink et al., 2020
Adulthood	CUS	Mice/Male; Rat/Male and Female	HIP; PFC	Increased activated astrocytes in HIP; atrophy of astrocyte processes; Decreased GFAP mRNA levels in PFC; decreased astrocytes in HIP	Bian et al., 2012; Li et al., 2013; Liu et al., 2009, 2011; Lou et al., 2018; Tynan et al., 2013
	Restraint	Gerbil/ Male; Rat/Male and Female	HIP	Hypertrophied and activated microglia; Increase in microglia density, number	Park et al., 2011; Tynan et al., 2010
	Restraint and Swim	Mice/Male and Female	Thalamus, HYPO, HIP, Substantia nigra, central gray	Increased microglial activation	Sugama et al., 2007
	Shock	Rats/Male and Female	HIP	Increased microglia, no change in astrocytes; reduced microglial phagocytic activity	Frank et al., 2007; Fonken et al., 2018
	Social stress	Mice/Male	AMY, HIPP, PFC	Increased de-ramified microglia	Wohleb et al., 2011
	Psychosocial stress	Tree shrew/Male	HIP	Decreased astrocytes and soma volume	Czéh et al., 2006
	SI	Rats/Male	nACC, PFC	Increased microglia	Schiavone et al., 2009

*Compared to unstressed controls.

MS, maternal separation; MSEW, maternal separation and early weaning; FR, food restriction; LPS, lipopolysaccharide; SI, social isolation; LBN, limited bedding and nesting; CUS, chronic unpredictable stress; iba1; ionized calcium binding adaptor molecule-1; GFAP, Glial fibrillary acidic protein; PFC, prefrontal cortex; HIP, hippocampus; SSCx, somatosensory cortex; nACC, nucleus accumbens; entCx, entrorhinal cortex; HYPO, hypothalamus; AMY, amygdala.

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