Maternal Separation Induces Sex-Specific Differences in Sensitivity to Traumatic Stress

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with a high economic burden. Two risk factors for increasing the chances of developing PTSD are sex (being female) and early life stress. These risk factors suggest that early life stress-induced changes and sex differences in emotional circuits and neuroendocrinological systems lead to susceptibility to traumatic stress. Exploring mechanisms via which stress leads to specific effects can be accomplished in animal models, but reliable animal models that allow for an examination of how early life stress interacts with sex to increase susceptibility to traumatic stress is lacking. To address this, we examined the effects of early life stress [using the maternal separation (MS) model] and late adolescence/early adult traumatic stress [using the single prolonged stress (SPS) model] on startle reactivity, anxiety-like behavior in the open field (OF), and basal corticosterone levels in male and female rats. Female rats exposed to MS and SPS (MS/SPS) showed enhanced startle reactivity relative to MS/control female rats. Enhanced startle reactivity was not observed in MS/SPS male rats. Instead, non-maternally separated male rats that were exposed to SPS showed enhanced startle reactivity relative to controls. Female rats had enhanced locomotor activity in the OF and higher basal corticosterone levels in comparison to males, but measures in the OF and basal corticosterone were not affected by MS or SPS. Overall the results suggest that the combined MS and SPS models can be used to explore how changes in maternal care during infancy lead to sex differences in sensitivity to the effects of traumatic stress as adolescents and adults.

Download Full-text

Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22041899 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1899 ◽

Cited By ~ 1

Author(s):

Hae Jeong Park ◽

Sang A. Kim ◽

Won Sub Kang ◽

Jong Woo Kim

Keyword(s):

Gut Microbiota ◽

Relative Abundance ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Female Rats ◽

Rrna Gene ◽

Dependent Manner ◽

Male And Female Rats

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

Download Full-text

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

Brain Sciences ◽

10.3390/brainsci10070447 ◽

2020 ◽

Vol 10 (7) ◽

pp. 447 ◽

Cited By ~ 2

Author(s):

Héctor González-Pardo ◽

Jorge L. Arias ◽

Eneritz Gómez-Lázaro ◽

Isabel López Taboada ◽

Nélida M. Conejo

Keyword(s):

Sex Differences ◽

Prefrontal Cortex ◽

Mitochondrial Function ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Female Rats ◽

Dopamine Turnover ◽

Mitochondrial Energy Metabolism ◽

Brain Mitochondrial Function

Sex differences have been reported in the susceptibility to early life stress and its neurobiological correlates in humans and experimental animals. However, most of the current research with animal models of early stress has been performed mainly in males. In the present study, prolonged maternal separation (MS) paradigm was applied as an animal model to resemble the effects of adverse early experiences in male and female rats. Regional brain mitochondrial function, monoaminergic activity, and neuroinflammation were evaluated as adults. Mitochondrial energy metabolism was greatly decreased in MS females as compared with MS males in the prefrontal cortex, dorsal hippocampus, and the nucleus accumbens shell. In addition, MS males had lower serotonin levels and increased serotonin turnover in the prefrontal cortex and the hippocampus. However, MS females showed increased dopamine turnover in the prefrontal cortex and increased norepinephrine turnover in the striatum, but decreased dopamine turnover in the hippocampus. Sex differences were also found for pro-inflammatory cytokine levels, with increased levels of TNF-α and IL-6 in the prefrontal cortex and hippocampus of MS males, and increased IL-6 levels in the striatum of MS females. These results evidence the complex sex- and brain region-specific long-term consequences of early life stress.

Download Full-text

Postnatal treatment with metyrapone attenuates the effects of diet-induced obesity in female rats exposed to early-life stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00308.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. E98-E108 ◽

Cited By ~ 13

Author(s):

Margaret O. Murphy ◽

Joseph B. Herald ◽

Caleb T. Wills ◽

Stanley G. Unfried ◽

Dianne M. Cohn ◽

...

Keyword(s):

Metabolic Disease ◽

Glucose Intolerance ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Female Rats ◽

Male Rats ◽

Female Rat ◽

Diet Induced Obesity ◽

Postnatal Treatment

Experimental studies in rodents have shown that females are more susceptible to exhibiting fat expansion and metabolic disease compared with males in several models of fetal programming. This study tested the hypothesis that female rat pups exposed to maternal separation (MatSep), a model of early-life stress, display an exacerbated response to diet-induced obesity compared with male rats. Also, we tested whether the postnatal treatment with metyrapone (MTP), a corticosterone synthase inhibitor, would attenuate this phenotype. MatSep was performed in WKY offspring by separation from the dam (3 h/day, postnatal days 2–14). Upon weaning, male and female rats were placed on a normal (ND; 18% kcal fat) or high-fat diet (HFD; 60% kcal fat). Nondisturbed littermates served as controls. In male rats, no diet-induced differences in body weight (BW), glucose tolerance, and fat tissue weight and morphology were found between MatSep and control male rats. However, female MatSep rats displayed increased BW gain, fat pad weights, and glucose intolerance compared with control rats ( P < 0.05). Also, HFD increased plasma corticosterone (196 ± 51 vs. 79 ± 18 pg/ml, P < 0.05) and leptin levels (1.8 ± 0.4 vs. 1.3 ± 0.1 ng/ml, P < 0.05) in female MatSep compared with control rats, whereas insulin and adiponectin levels were similar between groups. Female control and MatSep offspring were treated with MTP (50 µg/g ip) 30 min before the daily separation. MTP treatment significantly attenuated diet-induced obesity risk factors, including elevated adiposity, hyperleptinemia, and glucose intolerance. These findings show that exposure to stress hormones during early life could be a key event to enhance diet-induced obesity and metabolic disease in female rats. Thus, pharmacological and/or behavioral inflection of the stress levels is a potential therapeutic approach for prevention of early life stress-enhanced obesity and metabolic disease.

Download Full-text

Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats

Developmental Neuroscience ◽

10.1159/000512221 ◽

2020 ◽

pp. 1-10

Author(s):

Maryam Mahmoodkhani ◽

Maedeh Ghasemi ◽

Leila Derafshpour ◽

Mohammad Amini ◽

Nasrin Mehranfard

Keyword(s):

Anxiety Disorders ◽

Glutamate Receptors ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Central Area ◽

Early Life Stress ◽

Brain Regions ◽

Male Rats ◽

Lower Percentage

Introduction: Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABAA receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. Methods: The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. Results: MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABAA receptor and calcineurin levels, with reduced expression of GABAA receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. Conclusions: Together, our study suggests that GABAA receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

Download Full-text

Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress

Psychopharmacology ◽

10.1007/s00213-021-05955-z ◽

2021 ◽

Author(s):

Cristian Bis-Humbert ◽

M. Julia García-Fuster

Keyword(s):

Risk Factors ◽

Negative Affect ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Maternal Deprivation ◽

Female Rats ◽

Suitable Model ◽

The Impact ◽

Early Drug

Abstract Rationale The combination of several risk factors (sex, a prior underlying psychiatric condition, or early drug initiation) could induce the emergence of negative affect during cocaine abstinence and increase the risk of developing addiction. However, most prior preclinical studies have been centered in male rodents, traditionally excluding females from these analyses. Objectives To ascertain the behavioral and neurochemical consequences of adolescent cocaine exposure when the combination of several risk factors is present (female, early-life stress). Methods Whole litters of Sprague–Dawley rats were exposed to maternal deprivation for 24 h on postnatal day (PND) 9. Cocaine was administered in adolescence (15 mg/kg/day, i.p., PND 33–39). Negative affect was assessed by several behavioral tests (forced swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal cell fate markers were evaluated by western blot (FADD, Bax, cytochrome c) or immunohistochemistry (Ki-67; cell proliferation). Results Maternal deprivation is a suitable model of psychiatric vulnerability in which to study the impact of adolescent cocaine in female rats. While adolescent cocaine did not alter affective-like behavior during adolescence, a pro-depressive–like state emerged during adulthood, exclusively in rats re-exposed to cocaine during abstinence. FADD regulation by cocaine in early-life stressed female rats might contribute to certain hippocampal neuroadaptations with some significance to the observed induced negative affect. Conclusions Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress, highlighting the risk of early drug initiation during adolescence for the emergence of negative reinforcement during abstinence likely driving cocaine addiction vulnerability, also in female rats.

Download Full-text

Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2020-0539 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Maryam Mahmoodkhani ◽

Maedeh Ghasemi ◽

Leila Derafshpour ◽

Mohammad Amini ◽

Nasrin Mehranfard

Keyword(s):

Prefrontal Cortex ◽

Young Adult ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

D2 Receptor ◽

Early Life Stress ◽

Adolescent And Young Adult ◽

Male Rats ◽

Gsk 3Β

Abstract Objectives Dopamine neurotransmission is implicated in multiple neuropsychiatric disorders, most strikingly in Parkinson’s disease, bipolar disorder, attention-deficit hyperactivity disorder and schizophrenia. In addition to canonical pathway, D2-receptor (D2R) exerts some of its biological actions through regulating the activity of Akt and GSK3, which in turn were found to be altered in several psychiatric illnesses. The present study examined the impacts of maternal separation, an early-life stress model which has been associated with disturbed neurodevelopment and appearance of many psychiatric disorders, on developmental changes in dopamine concentration and the expression of D2Rs, Akt and GSK-3β in the medial prefrontal cortex (PFC; a key target of stress) in adolescent and young adult male rats. Methods Maternal separation was performed 3 h per day from postnatal days 2 to 11. The PFC protein and dopamine contents were determined using western blotting analysis and Eliza, respectively. Results Results indicated long-term increases in the prefrontal dopamine levels in stressed adolescent and young adult male rats, accompanied by significant downregulation of D2R as well as upregulation of p-Akt and GSK-3β contents in stressed adolescence compared to controls, with all protein levels that returned to control values in stressed adult rats. Conclusions Our findings suggest that early-life stress differentially modulates prefrontal D2R/Akt/GSK-3β levels during development. Since adolescence period is susceptible to the onset of specific mental illnesses, disruption of noncanonical components of D2R signaling during this critical period may have an important role in programming neurobehavioral phenotypes in adulthood and manipulations influencing Akt/GSK-3β pathway may improve the expression of specific dopamine-related behaviors and the effects of dopaminergic drugs.

Download Full-text

Early life stress by repeated maternal separation induces long-term neuroinflammatory response in glial cells of male rats

Stress ◽

10.1080/10253890.2019.1604666 ◽

2019 ◽

Vol 22 (5) ◽

pp. 563-570 ◽

Cited By ~ 15

Author(s):

María Banqueri ◽

Marta Méndez ◽

Eneritz Gómez-Lázaro ◽

Jorge L. Arias

Keyword(s):

Glial Cells ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Male Rats ◽

Neuroinflammatory Response

Download Full-text

Got Milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats

10.1101/2022.01.03.474857 ◽

2022 ◽

Author(s):

Holly DeRosa ◽

Hieu Tran ◽

Amanda C Kentner

Keyword(s):

Animal Models ◽

Immune Activation ◽

Maternal Care ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Female Rats ◽

Maternal Immune Activation ◽

Adolescent Offspring ◽

And Behavior

The neonatal environment requires a high level of maternal demand in terms of both breastfeeding and other forms of maternal care. Previous studies have underscored the importance of these maternal factors on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we show that lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 immediately elevated milk corticosterone concentrations, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Sustained inflammatory-induced changes to the nutritional quality of milk were also evidenced by its composition of microbial communities associated with inefficient energy and lipid metabolism. Nutritional deficits in early development have been associated with metabolic dysfunction later in life. Indeed, MIA-associated changes in the nutritional profile of milk were reflected by increased adolescent offspring bodyweights. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day that followed the inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating and mechanical allodynia in MIA offspring. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

Download Full-text

A severe form of maternal separation in rat consisting of nineteen-day 6-hour daily separation at unpredictable times minimally affects behavior across lifespan and possibly confers protection against some maladaptive outcomes

10.1101/2021.06.07.447289 ◽

2021 ◽

Author(s):

Tatyana Budylin Behring ◽

Margaret H Kyle ◽

Maha Hussain ◽

Jack Zhang ◽

Alessia Manganaro ◽

...

Keyword(s):

Life Stress ◽

Maternal Separation ◽

Forced Swim Test ◽

Coping Behavior ◽

Early Life Stress ◽

Severe Form ◽

Female Rats ◽

Male Rats ◽

Protective Effects ◽

Multiple Species

Maternal separation (MS), a type of early life stress, has been associated with adverse socioemotional and behavioral outcomes throughout the lifespan across multiple species. Comprehensive longitudinal biobehavioral characterization of MS in rats is sparse and conflicting, warranting more studies. We conducted an MS paradigm involving 6-hour daily separation at unpredictable start times from P2 to P21. We hypothesized this severe form of MS would lead to developmentally emerging maladaptive biobehavioral consequences from juvenile through adult periods compared to Controls (C), especially in social behaviors. We tested: (1) own dam odor preference shortly after weaning; (2) juvenile and adult anxiety-like, sociability, and play behaviors using the light-dark test, three-chambered social interaction test, and video-coded juvenile play behavior; and (3) adult coping behaviors and neuroendocrine response using the forced swim test and blood corticosterone responses. Our results were mostly diametrically opposed to our initial hypothesis and show MS can, under certain circumstances, be protective against maladaptive biobehavioral outcomes. Recently weaned MS male rats had a stronger preference for their dam's odor. Juvenile MS females spent more time in rough-and-tumble play than C female rats. No differences in sociability were found in the juvenile or adult periods. MS promoted a decrease in anxiety-like behavior that persisted from juvenile to adult periods. Finally, MS led to deficits in coping behavior in male adults, but basal and reactive corticosterone levels were unaltered by MS. More studies are needed to validate our surprising findings and probe the neural mechanisms underlying these protective effects.

Download Full-text