Neurodevelopment has a "sensitive period" during which the brain is highly sensitive to experience. In this study, we used maternal separation (MS) models of male Long-Evans rats to examine whether sensitivity to stress changes after postnatal day (PND) 10, when dendritic spine density begins to increase rapidly in the CA (Cornu Ammonis)1 region of the hippocampus. We assigned littermates to three groups: early maternal separation group (EMS: MS during PND 1-9), late maternal separation group (LMS: MS during PND 10-20), and control group. During adulthood (PND 56-75, which strictly corresponds to young adulthood), LMS showed increased depression-like behaviors and decreased dendritic spine density in the CA1 hippocampal region; however, EMS did not show any such changes. Accordingly, littermates at PND 10-20 have a greater vulnerability to MS than those at PND 1-9. These findings suggest that dendritic spine formation in the hippocampus is an important factor in determining sensitivity to MS.

This study aimed to investigate the impact of early childhood chronic stress on the development of the brain extracellular matrix (ECM) and how alterations in the ECM following early-life adversity (ELA) affect auditory learning and cognitive flexibility. ELA was induced through a combination of maternal separation and neonatal isolation in male Sprague-Dawley rats, and the success of the ELA model was assessed behaviorally and biochemically. A cortex-dependent go/no-go task with two phases was used to determine the impact of ELA on auditory learning and cognitive flexibility. The effects of the ECM on cognition were tested via the enzymatic removal of the ECM. The molecular structure of the adult ECM was examined via immunohistochemistry. ELA impaired initial auditory learning but did not significantly affect cognitive flexibility. Hyase injection into the auditory cortex (ACx) restored initial learning. ELA rats display a reduced perineural net (PNN) and parvalbumin + cell density. Our findings reveal that ELA induces significant alterations in the ECM within the ACx, accompanied by impaired initial auditory learning. Although PNN density is already lower in ELA rats, degrading the ECM facilitates the repair of auditory learning. A reduced PNN number in ELA rats fails to enhance learning unless supplemented with Hyase injection.

Amounting findings on maternal separation and early disturbed caregiving suggest that this type of early experience negatively influences socioemotional development and may be associated with behavioral and mental health problems in later life. Concerning previously published studies, we have assessed if maternal separation and disrupted caregiving before adoption in infancy could be related to heightened levels of dissociative symptoms and behavioral problems in middle childhood. We involved 30 children (sample S1) who had experienced maternal separation after birth and short-term institutional or foster care prior to adoption before 16.7 months of age. Based on the parents' reports, they had not experienced any other significant adversities by the time of evaluation. These children were compared to a control group of children who have lived with their biological mothers in complete families (sample S2; N = 25). Although the findings are correlational and not causal, they indicate that specific adverse experiences, maternal separation after birth, and relatively short disruptive caregiving prior to successful adoption in infancy could be associated with significantly heightened levels of dissociative symptoms and behavioral problems in school-aged children. Our data also contribute to the literature on child socioemotional development and the etiology of dissociative disorders.

Maternal separation as an early life stress can lead to long-lasting deleterious effects on cognitive and behavioral functions, and the mood state. On the other hand, Psilocybe cubensis (as one of the most well-known magic mushrooms) may be beneficial in the improvement or the treatment of neuropsychiatric disorders. In the present study, we aimed to investigate the effect of P. cubensis extract (PCE) on depressive-like and anxiety-like behaviors, and locomotor activity in mice exposed to early maternal separation. Also, we assessed the expression and methylation level of Slc6a4 and Nr3c1 in the hippocampus. Maternal separation was done in postnatal days (PNDs) 2-18. PCE was intraperitoneally injected at the dose of 20 mg/kg at PND 60, and our tests were done at days 1, 3, and 10, of administration. The results showed that maternal separation significantly induced depressive-like behavior in the forced swim test and anxiety-like behavior in the open field test (OFT). Also, maternal separation decreased locomotor activity in the OFT. In addition, maternal separation decreased the expression and increased the methylation level of both Slc6a4 and Nr3c1 in the hippocampus. However, PCE significantly reversed all these effects. In conclusion, it seems that P. cubensis affects serotonergic signaling via altering Slc6a4 expression and methylation level in the hippocampus of mice. The effect of P. cubensis on Nr3c1 expression and methylation level may also lead to alter the function of the hypothalamus-pituitary-adrenal axis and the stress response in mice exposed to maternal separation.

The perinatal period encompasses a critical window for neurodevelopment that renders the brain highly responsive to experience. Trauma, such as intimate partner violence (IPV) and early life stress/neglect, during this period negatively affects physical and mental health outcomes, including increasing ones risk for chronic pain. Although epigenetic programming likely contributes, the mechanisms that drive the relationship between perinatal trauma and adverse health outcomes, are not fully understood. Therefore, we explored the relationship between perinatal trauma (in utero exposure to IPV and/or early life neglect) and socio-emotional functioning, nociceptive sensitivity, and transcriptomic changes within the prefrontal cortex (PFC) and hypothalamus in dams and their adolescent offspring. Rat dams were randomly assigned to an IPV (i.e., combined mild traumatic brain injury and strangulation) or sham procedure during pregnancy. Following birth, offspring were subsequently assigned the early life neglect or control paradigm. In adolescence, offspring received a plantar incision or sham injury. Perinatal trauma altered nociception and emotional functioning in a sex-dependent manner when combined with the surgical procedure. We identified transcriptomic changes related to DNA transcription and expression within the PFC and hypothalamus of the dams. Examination of the offspring transcriptome highlighted impairment in immune regulation, dysfunction in stress-reactivity, as well as microglia activation. We also identified altered expression of genes associated with chronic pain. This demonstrates that perinatal trauma modifies offspring behaviour, including nociceptive sensitivity. We provide insight into the mechanisms that contribute to the chronification of pain, thereby informing future research targeted at the generation of prevention and therapeutic strategies. PERSPECTIVE: Perinatal trauma impaired cognitive, socio-emotional, and pain processing in offspring, while also inducing changes in gene expression, in both mothers and offspring. The findings highlight possible mechanisms responsible for intergenerational transmission of risk for chronic pain and provide targets for therapeutics which could potentially reverse perinatal-trauma induced epigenetic change.

Exposure to stressful life events is associated with a high risk of developing psychiatric disorders with a wide variety of symptoms. Cognitive symptoms in stress-related psychiatric disorders can be particularly challenging to understand, both for those experiencing them and for health care providers. To gain insights, it is important to capture stress-induced structural, epigenomic, transcriptomic, and proteomic changes in relevant brain regions such as the amygdala, hippocampus, locus coeruleus, and prefrontal cortex that result in long-lasting alterations in brain function. In this review, we will emphasize a subset of stress molecular mechanisms that alter neuroplasticity, neurogenesis, and balance between excitatory and inhibitory neurons. Then, we discuss how to identify genetic risk factors that may accelerate stress-driven or stress-induced cognitive impairment. Despite the development of new technologies such as single-cell resolution sequencing, our understanding of the molecular effects of stress in the brain remains to be deepened. A better understanding of the diversity of stress effects in different brain regions and cell types is a prerequisite to open new avenues for mechanism-informed prevention and treatment of stress-related cognitive symptoms.

The early postnatal period is a critical neurodevelopmental stage characterized by rapid neural maturation and is adversely affected by early-life stressors. This study explored the behavioural, physiological, and epigenetic consequences of early-life stress in a population of homeless rescue kittens. This longitudinal study included 50 kittens rescued and placed into foster care by the Prince Edward Island Humane Society. They underwent behavioural testing at 8, 10, and 12 weeks of age. Hair cortisol concentration was measured at 8 weeks and served as a physiological marker of the previous 3 months' cumulative stress response, which, for these kittens, included the late gestation period. A blood sample for relative telomere length measurement was taken at 10-12 weeks to estimate epigenetic changes as young kittens. Data were analyzed with respect to age and performance in all repeated measures tests, status as a stray or a surrender, and the presence of the dam in their foster homes. As expected, the performance of kittens in all tests changed over the 5 weeks of testing. Kittens separated from their mothers exhibited significantly higher hair cortisol concentrations (p = 0.02) and elongated relative telomere lengths (p = 0.04). No correlation was found between hair cortisol concentration and relative telomere lengths (p = 0.99). These results support the need for further study on the effects of epigenetics and early-life stress, both in kittens and across species.

Rodents are highly dependent on maternal care after birth. Disturbing mother and pup interactions leads to detrimental alternations for the rat and the mother. Maternal separation (MS) is an accepted model for investigating disruption of mother and pup relationship. In addition to other detrimental effects, MS is a model known to induce permanent changes in learning and memory. Methylphenidate has been effective in memory enhancement in individuals suffering from memory deficits, attention-deficit hyperactive disorder (ADHD), as well as healthy subjects for better performance in exams.

In this research, a 21-day separation for 3 h was implemented, and the effects of MS on spatial and passive avoidance learning, and memory were evaluated in the mid-adolescence period of rats, in both males and females. Also, a drug intervention of a high therapeutic dose of 5 mg per kg was used in a five-day period in different control and MS groups. Morris water maze was utilized for spatial learning and memory analysis, and a shuttle box paradigm was used for passive avoidance learning and memory.

Through our behavioral tests, we have shown that MS can alter spatial learning and memory in males. On the other hand, females are protected from the detrimental effects of MS on spatial learning and memory. Furthermore, passive avoidance learning was not different among groups, be it male or female. However, in the case of memory evaluation in the passive avoidance test, the male did not exhibit a significant difference in step-through latency. However, maternally separated females had poor performance in the memory phase with shorter step-through latencies.

Methylphenidate compensated for the deleterious effects of MS on learning and spatial memory for the male group and passive avoidance memory in the female group at the behavioral level.

Depression and cardiovascular diseases are two of the world's major health problems. Escitalopram (ESC) is widely used because of its safety in relation to other drugs in that class; however, it can affect the cardiovascular system. The present study evaluated the cardiovascular parameters of depressive-like male rats and the cardiovascular effects of ESC treatment on that condition. The EMS protocol consisted of separating the litter from the dam for 3 h over 13 days. Animals were anesthetized with tribromoethanol (250 mg/kg, intraperitoneally) and the catheters were inserted into the femoral and into the femoral vein. Depressive-like rats showed an increase in the pressor response to phenylephrine (Emax:depressive = 50.36 ± 2.997 mmHg; non-depressive = 39.51 ± 3.328 mmHg; p < 0.05) and a reduction in the EC50 (depressive = 0.6203 ± 0.03005 μg/kg; non-depressive = 0.7320 ± 0.03519 μg/kg; p < 0.05) with no change in the other cardiovascular parameters. After treatment with ESC, a reduction of intrinsic heart rate was observed in the depressive-like rats (control: 342 ± 6 bpm; ESC: 316 ± 5 bpm; p < 0.05). In addition, ESC treatment increased the bradycardic (control: -97.81 ± 8.3 bpm; ESC: -137.1 ± 12.31 bpm; p = 0.0236; t = 2.502) during the baroreflex response, caused by an increase in cardiac parasympathetic modulation in the heart, in depressive-like rats (p < 0.001). The findings suggest that depressive-like rats showed cardiovascular changes, and that ESC treatment was able to reverse these changes, suggesting that ESC has a good safety profile for depressive patients with cardiovascular disease due to increased parasympathetic modulation.

Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined.

Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2-12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes.

Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype.

Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood.

Rodent pups use a variety of ultrasonic vocalizations (USVs) to facilitate maternal care. Importantly, infant USV repertoires are dependent on both the age and early life experiences of the pups. We have shown that an adverse rearing environment modeled with the maternal separation (MS) paradigm alters caregiving behavior but little is known about how pup USVs differentially elicit maternal attention. In the present study, maternal approach towards a vocalizing pup over a non-vocalizing pup was tested in a Y-maze apparatus at two developmental time points over the course of MS. At postnatal day (P)10, MS dams engaged in longer interaction times with vocalizing pups compared to non-vocalizing pup, and this effect was strongest in male pups. As expected at P20, dams did not show a preference for either the vocalizing or non-vocalizing pups regardless of rearing environment; however, MS dams spent a greater amount of time in the center of the apparatus as compared to control dams, which can be interpreted as a measure of uncertainty or indecision. These effects of MS on dam USV sensitivity are important considering the sex specific effects of MS exposure across all developmental stages. Our novel findings support the hypothesis that sex-specific pup-dam interactions may drive later life outcomes following adversity.

Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience.

Chronic pain is highly prevalent and burdensome, affecting millions of people worldwide. Although it emerges at any point in life, it often manifests in adolescence. Given that adolescence is a unique developmental period, additional strains associated with persistent and often idiopathic pain lead to significant long-term consequences. While there is no singular cause for the chronification of pain, epigenetic modifications that lead to neural reorganization may underpin central sensitization and subsequent manifestation of pain hypersensitivity. Epigenetic processes are particularly active during the prenatal and early postnatal years. We demonstrate how exposure to various traumas, such as intimate partner violence while in utero or adverse childhood experiences, can significantly influence epigenetic regulation within the brain and in turn modify pain-related processes. We provide compelling evidence that the burden of chronic pain is likely initiated early in life, often being transmitted from mother to offspring. We also highlight two promising prophylactic strategies, oxytocin administration and probiotic use, that have the potential to attenuate the epigenetic consequences of early adversity. Overall, we advance understanding of the causal relationship between trauma and adolescent chronic pain by highlighting epigenetic mechanisms that underlie this transmission of risk, ultimately informing how to prevent this rising epidemic.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 μg/μl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function.

Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones.

MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol.

The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.

Environmental enrichment (EE) is a paradigm that offers the animal a plethora of stimuli, including physical, cognitive, sensory, and social enrichment. Exposure to EE can modulate both anxiety responses and plasma corticosterone. In this study, our objective was to explore how chronic unpredictable stress (CUS) impacts anxiety-related behaviors in male Swiss mice raised in EE conditions. Additionally, we investigated corticosterone and adrenocorticotropic hormone (ACTH) levels to assess the involvement of the hypothalamic-pituitary-adrenal (HPA) axis in mediating these responses. Mice were housed under either EE or standard housing conditions for 21 days. Afterward, they were exposed to 11 days of CUS while still reared in their distinct housing conditions, with half of the mice receiving daily pretreatment with the vehicle and the other half receiving daily metyrapone (MET) injections, an inhibitor of steroid synthesis, 30 mins before CUS exposure. Blood samples were obtained to assess plasma corticosterone and ACTH levels. The 11-day CUS protocol induced anxiety-like phenotype and elevated ACTH levels in EE mice. Chronic MET pretreatment prevented anxiety-like behavior in the EE-CUS groups, by mechanisms involving increased plasma corticosterone levels and decreased ACTH. These results suggest a role of the HPA axis in the mechanism underlying the anxiogenic phenotype induced by CUS in EE mice and shed light on the complex interplay between environmental factors, stress, and the HPA axis in anxiety regulation.

The occurrence of major depressive disorder is widespread and can be observed in individuals belonging to all societies. It has been suggested that changes in the NO pathway and heightened oxidative stress may play a role in developing this condition. Anethole is a diterpene aromatic compound found in the Umbelliferae, Apiaceae, and Schisandraceae families. It has potential pharmacological effects like antioxidant, anxiolytic, analgesic, anti-inflammatory, antidiabetic, gastroprotective, anticancer, estrogenic, and antimicrobial activities. This study aimed to investigate the potential antidepressant properties of Anethole in a mouse model experiencing maternal separation stress while also examining its impact on oxidative stress and nitrite levels. The research involved the participation of 40 male NMRI mice, separated into five distinct groups to conduct the study. The control group was administered 1 ml/kg of normal saline, while the MS groups were given normal saline and Anethole at 10, 50, and 100 mg/kg doses. The study comprised various behavioural tests, including the open field test (OFT), forced swimming test (FST), and splash test, to assess the effects of Anethole on the mice. In addition to the behavioural tests, measurements were taken to evaluate the total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrite levels in the hippocampus of the mice. According to the findings, maternal separation stress (MS) led to depressive-like conduct in mice, including a rise in immobility duration during the FST and a reduction in the duration of grooming behaviour in the splash test. Additionally, the results indicated that MS correlated with an increase in the levels of MDA and nitrite and a reduction in the TAC in the hippocampus. However, the administration of Anethole resulted in an increase in grooming activity time during the splash test and a decrease in immobility time during the FST. Anethole also exhibited antioxidant characteristics, as demonstrated by its ability to lower MDA and nitrite levels while increasing the TAC in the hippocampus. The results suggest that Anethole may have an antidepressant-like impact on mice separated from their mothers, likely partly due to its antioxidant properties in the hippocampus.

Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.

Early-life adversity covers a range of physical, social and environmental stressors. Acute viral infections in early life are a major source of such adversity and have been associated with a broad spectrum of later-life effects outside the immune system or "off-target". These include an altered hypothalamus-pituitary-adrenal (HPA) axis and metabolic reactions. Here, we used a murine post-natal day 14 (PND 14) Influenza A (H1N1) infection model and applied a semi-holistic approach including phenotypic measurements, gene expression arrays and diffusion neuroimaging techniques to investigate HPA axis dysregulation, energy metabolism and brain connectivity. By PND 56 the H1N1 infection had been resolved, and there was no residual gene expression signature of immune cell infiltration into the liver, adrenal gland or brain tissues examined nor of immune-related signalling. A resolved early-life H1N1 infection had sex-specific effects. We observed retarded growth of males and altered pre-stress (baseline) blood glucose and corticosterone levels at PND42 after the infection was resolved. Cerebral MRI scans identified reduced connectivity in the cortex, midbrain and cerebellum that were accompanied by tissue-specific gene expression signatures. Gene set enrichment analysis confirmed that these were tissue-specific changes with few common pathways. Early-life infection independently affected each of the systems and this was independent of HPA axis or immune perturbations.

Premature infants are exposed to numerous stressors in neonatal intensive care unit (NICU) during a crucial period for brain development; this period exerts long-term influences on cognitive and behavioral development.

To evaluate the effect of NICU-related stress on neonatal rat pups and explore the effect of Chinese medicine treatment (CMT).

Sixty male rat pups were randomly assigned to three groups: the control group, the NICU group (NICU-related stress), and the CMT group (NICU-related stress plus CMT). All stressors and interventions were administered from 0 to 7 days after birth. Body weight, serum corticosterone levels, and behavior in the open field (OF) test, elevated plus maze (EPM) test, sucrose preference test, and Morris water maze (MWM) test were recorded, and blood samples were collected at five different time points (T0, T1, T2, T3, and T4).

The body weights of rats in the CMT and control groups were heavier than those in the NICU group in both early life and adulthood (P < 0.05). Serum corticosterone levels significantly differed with time (except T0 vs. T1 and T3 vs. T4) but did not significantly differ among the three groups (F = 0.441, P = 0.894). Regardless of age, spatial memory and anxiety-like and depression-like behavior did not differ among the three groups.

NICU-related stress exerted a long-term effect on rat growth and development but did not affect spatial memory, anxiety-like behavior, depression-like behavior, or serum corticosterone levels. CMT alleviated the impact of NICU-related stress on rats and promoted the growth and development of neonatal rats.

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.

Autism spectrum disorder (ASD) represents an inheritable neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Numerous studies have underscored the significant roles played by genetic and environmental factors in the etiology of ASD, and these factors are known to perpetuate behavioral impairments across generations.

The primary objective of this study was to assess the behavioral and cognitive attributes in the second filial (F2) generation of male and female rats, with a particular focus on those whose parents had been exposed to valproic acid (VPA) during embryonic development.

In this study, a cohort of 32 male and 32 female rats from the second filial (F2) generation, referred to as Mother.ASD, Father.ASD, or Both.ASD, was examined. These designations indicate whether the mother, father, or both parents had experienced embryonic exposure to valproic acid (600 mg/kg, i.p.). During adolescence, the F2 pups underwent behavioral and cognitive assessments, including open field testing, marble burying, social interaction evaluations, and Morris water maze tasks.

Our data revealed that while both the Mother.ASD and Father.ASD groups, regardless of sex, exhibited elevated anxiety-like behavior in the open field test. Only the Mother.ASD group displayed repetitive behaviors and deficits in social memory. Additionally, spatial memory impairments were observed in both sexes. These findings highlight the transmission of autistic-like behaviors in the offspring of Mother.ASD rats from both sexes. Nevertheless, future research endeavors should be more targeted in identifying the specific genes responsible for this transmission.

In summary, our findings underscore the transmission of autistic-like behaviors, including anxiety-like behavior, repetitive actions, impairments in social interactions, and deficits in memory, to the offspring of the Mother.ASD group, irrespective of their sex.

Imidacloprid (IMI), a widely used pesticide in agriculture and a potential food contaminant, poses significant health concerns. This study sought to comprehensively evaluate its neurotoxic effects while investigating the potential protective role of alpha-lipoic acid (ALA), a naturally occurring dietary antioxidant renowned for its capacity to combat oxidative stress, support cardiovascular health, and maintain optimal nerve function. In this study, 28 rats were divided evenly into four groups and administered oral treatments of corn oil, IMI, IMI + ALA, and ALA, respectively. The results of the study indicated that rats exposed to IMI exhibited significant neurobehavioral impairments, decreased levels of antioxidant enzymes and acetylcholinesterase activity, reduced expression of HO-1 and Nrf2, and increased levels of pro-inflammatory cytokines like IL-6 and TNF-α in their hippocampal tissues. Furthermore, histopathological analysis of the brain tissues, specifically cortex and hippocampus, from the IMI-treated group revealed varying degrees of neuronal degeneration. In contrast, rats co-administered ALA alongside IMI showed noticeable improvements in all the assessed toxicological parameters. This study underscores the vital significance of ALA as a potential therapeutic adjunct in mitigating the adverse neurobehavioral consequences of insecticide exposure. By harnessing the Nrf2/HO-1 pathway, ALA demonstrates its ability to shield against IMI-induced neurotoxicity, offering a promising avenue for enhancing public health and safety. As a result, our findings advocate for the incorporation of ALA as a daily dietary supplement to fortify resilience against oxidative stress-related neurobehavioral deficits linked to pesticide exposure, thereby advancing our understanding of neuroprotection strategies in the face of environmental challenges.

Early life stress (ELS) affects neurogenesis and spatial learning, and increases neuroinflammation after a pediatric mild traumatic brain injury (mTBI). Previous studies have shown that ELS has minimal effects in juveniles but shows age-dependent effects in adults. Hence, we aimed to evaluate the effects of ELS in adult male rats after an mTBI. Maternal separation for 180 min per day (MS180) during the first 21 post-natal (P) days was used as the ELS model. At P110, the rats were subjected to a mild controlled cortical impact injury (2.6 mm) or sham surgery. Spatial learning was evaluated in the Morris water maze (MWM) 14 days after surgery and both microglial activation and neurogenesis were quantified. The results indicate that MS180 + mTBI, but not control (CONT) + mTBI, rats show deficiencies in the acquisition of spatial learning. mTBI led to comparable increases in microglial activation in both the hilus and cortical regions for both groups. However, MS180 + mTBI rats exhibited a greater increase in microglial activation in the ipsilateral CA1 hippocampus subfield compared with CONT + mTBI. Interestingly, for the contralateral CA1 region, this effect was observed exclusively in MS180 + mTBI. ELS and mTBI independently caused a decrease in hippocampal neurogenesis and this effect was not increased further in MS180 + mTBI rats. The findings demonstrate that ELS and mTBI synergistically affect cognitive performance and neuroinflammation, thus supporting the hypothesis that increased inflammation resulting from the combination of ELS and mTBI could underlie the observed effects on learning.

The enduring influence of early life stress (ELS) on brain and cognitive development has been widely acknowledged, yet the precise mechanisms underlying this association remain elusive. We hypothesize that ELS might disrupt the genome-wide influence on brain morphology and connectivity development, consequently exerting a detrimental impact on children's cognitive ability. We analyzed the multimodal data of DNA genotypes, brain imaging (structural and diffusion MRI), and neurocognitive battery (NIH Toolbox) of 4276 children (ages 9-10 years, European ancestry) from the Adolescent Brain Cognitive Development (ABCD) study. The genome-wide influence on cognitive function was estimated using the polygenic score (GPS). By using brain morphometry and tractography, we identified the brain correlates of the cognition GPSs. Statistical analyses revealed relationships for the gene-brain-cognition pathway. The brain structural variance significantly mediated the genetic influence on cognition (indirect effect = 0.016, PFDR < 0.001). Of note, this gene-brain relationship was significantly modulated by abuse, resulting in diminished cognitive capacity (Index of Moderated Mediation = -0.007; 95 % CI = -0.012 ∼ -0.002). Our results support a novel gene-brain-cognition model likely elucidating the long-lasting negative impact of ELS on children's cognitive development.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus-pituitary-adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny.

Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed.

The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior.

It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.

Wild orangutans (Pongo spp.) rescued from human-wildlife conflict must be adequately rehabilitated before being returned to the wild. It is essential that released orangutans are able to cope with stressful challenges such as food scarcity, navigating unfamiliar environments, and regaining independence from human support. Although practical skills are taught to orangutans in rehabilitation centres, post-release survival rates are low. Psychological resilience, or the ability to 'bounce back' from stress, may be a key missing piece of the puzzle. However, there is very little knowledge about species-appropriate interventions which could help captive orangutans increase resilience to stress. This scoping review summarises and critically analyses existing human and non-human animal resilience literature and provides suggestions for the development of interventions for orangutans in rehabilitation. Three scientific databases were searched in 2021 and 2023, resulting in 63 human studies and 266 non-human animal studies. The first section brings together human resilience interventions, identifying common themes and assessing the applicability of human interventions to orangutans in rehabilitation. The second section groups animal interventions into categories of direct stress, separation stress, environmental conditions, social stress, and exercise. In each category, interventions are critically analysed to evaluate their potential for orangutans in rehabilitation. The results show that mild and manageable forms of intervention have the greatest potential benefit with the least amount of risk. The study concludes by emphasising the need for further investigation and experimentation, to develop appropriate interventions and measure their effect on the post-release survival rate of orangutans.

The opioid epidemic has resulted in a drastic increase in gestational exposure to opioids. Opioid-dependent pregnant women are typically prescribed medications for opioid use disorders ("MOUD"; e.g., buprenorphine [BUP]) to mitigate the harmful effects of abused opioids. However, the consequences of exposure to synthetic opioids, particularly BUP, during gestation on fetal neurodevelopment and long-term outcomes are poorly understood. Further, despite the known adverse effects of opioids on maternal care, many preclinical and clinical studies investigating the effects of gestational opioid exposure on offspring outcomes fail to report on maternal care behaviors. Considering that offspring outcomes are heavily dependent upon the quality of maternal care, it is important to evaluate the effects of gestational opioid exposure in the context of the mother-infant dyad. This review compares offspring outcomes after prenatal opioid exposure and after reduced maternal care and integrates this information to potentially identify common underlying mechanisms. We explore whether adverse outcomes after gestational BUP exposure are due to direct effects of opioids in utero, deficits in maternal care, or a combination of both factors. Finally, suggestions for improving preclinical models of prenatal opioid exposure are provided to promote more translational studies that can help to improve clinical outcomes for opioid-dependent mothers.

Mood disorders, including depressive and bipolar disorders, are the group of psychiatric disorders with the highest prevalence and disease burden. However, their pathophysiology remains poorly understood. Animal models are an extremely useful tool for the investigation of molecular mechanisms underlying these disorders. For psychiatric symptom assessment in animals, a meaningful behavioral phenotype is needed. Social behaviors constitute naturally occurring complex behaviors in rodents and can therefore serve as such a phenotype, contributing to insights into disorder related molecular changes. In this narrative review, we give a fundamental overview of social behaviors in laboratory rodents, as well as their underlying neuronal mechanisms and their assessment. Relevant behavioral and molecular changes in models for mood disorders are presented and an outlook on promising future directions is given.

Maternal morphine exposure has negative consequences for learning and memory in the offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal Separation (MS) can cause behavioral and neuropsychiatric problems later in life. It seems that adolescents are more susceptible to the effects of early life stress; evidence for the combinatory effects of oral chronic maternal morphine exposure and MS in the CA1 area of the hippocampus in the male adolescent offspring is not found. Therefore, this study aimed to evaluate the effects of chronic maternal morphine consumption (21 days before and after mating, and gestation), and MS (180 min/day from postnatal day (PND) 1-21) on the synaptic plasticity of male offspring in mid-adolescence. Control, MS, Vehicle (V), Morphine, V + MS, and Morphine + MS groups were tested for in vivo field potential recording from the CA1 area of the hippocampus. The current results demonstrated that chronic maternal morphine exposure impaired the induction of early long-term potentiation (LTP). MS impaired average fEPSPs, induction of early-LTP and maintenance. Chronic maternal morphine exposure in combination with MS impaired the induction of early LTP but didn't deteriorate maintenance and the average field excitatory post-synaptic potentials (fEPSPs) measured in two hours. Prepulse facilitation ratios remained undisturbed and I/O curves showed decreased fEPSP slopes at high stimulus intensities in combinatory group. We concluded that chronic maternal morphine exposure in combination with MS negatively affects synaptic plasticity in the CA1 area in male adolescent offspring.

Those with a negative experience of psychosocial stress during the early stage of life not only have a high susceptibility of the psychiatric disorder in all phases of their life span, but they also demonstrate more severe symptoms and poorer response to treatment compared to those without a history of early-life stress. The interventions targeted to early-life stress may improve the effectiveness of treating and preventing psychiatric disorders. Brain regions associated with mood and cognition develop rapidly and own heightened plasticity during adolescence. So, manipulating nonpharmacological interventions in fewer side effects and higher acceptance during adolescence, which is a probable window of opportunity, may ameliorate or even reverse the constantly deteriorating impact of early-life stress. The present article reviews animal and people studies about adolescent nonpharmacological interventions for early-life stress. We aim to discuss whether those adolescent nonpharmacological interventions can promote individuals' psychological health who expose to early-life stress.

Adolescent chronic pain is a growing public health epidemic. Our understanding of its etiology is limited; however, several factors can increase susceptibility, often developing in response to an acute pain trigger such as a surgical procedure or mild traumatic brain injury (mTBI), or an adverse childhood experience (ACE). Additionally, the prevalence and manifestation of chronic pain is sexually dimorphic, with double the rates in females than males. Despite this, the majority of pre-clinical pain research focuses on males, leaving a gap in mechanistic understanding for females. Given that emerging evidence has linked the gut microbiome and the brain-gut-immune axis to various pain disorders, we aimed to investigate sex-dependent changes in taxonomic and functional gut microbiome features following an ACE and acute injury as chronic pain triggers. Male and female Sprague Dawley rat pups were randomly assigned to either a maternal separation (MS) or no stress paradigm, then further into a sham, mTBI, or surgery condition. Chronically, the von Frey test was used to measure mechanical nociception, and fecal samples were collected for 16S rRNA sequencing. Animals in the surgery group had an increase in pain sensitivity when compared to mTBI and sham groups, and this was complemented by changes to the gut microbiome. In addition, significant sex differences were identified in gut microbiome composition, which were exacerbated in response to MS. Overall, we provide preliminary evidence for sex differences and ACE-induced changes in bacterial composition that, when combined, may be contributing to heterogeneity in pain outcomes.

Chronic low back pain is difficult to treat and despite increased spending on health services, clinical outcomes for people with low back pain have not improved. Innovative, large scale initiatives seem necessary to stem the cost of low back pain. Psychological health contributes to the development and persistence of chronic low back pain and psychological interventions are important in the management of low back pain. Given the contribution of psychological health to low back pain development and management, it raises the question; can we support psychological health in later life by bolstering emotional development in early life, and reduce the burden of this common condition? Positive early life experiences, including those induced by extended paid parental leave, could bolster emotional development and support the psychological health necessary to manage low back pain in later life. We present the current state of evidence demonstrating the potential value of increasing support for parent-child relationships in early life to reduce the burden of low back pain in future generations. The current evidence is limited to cross-sectional associations, but strong preclinical data clearly shows the potential negative impacts of maternal separation on rodent pup health that compels consideration in human populations. PERSPECTIVE: The benefits stemming from enhanced child development include stable emotional foundations, possibly improving psychological health and low back pain management in the future. This perspective raises questions for future studies - within the context of low back pain, what ingredients bolster stable psychological health? And are these ingredients influenced by parental leave?

Neurological conditions, including cognitive impairment and Alzheimer's disease (AD), impose a huge burden on society, affecting millions of people globally. In addition to genetic factors, recent studies indicate that environmental and experiential factors may contribute to the pathogenesis of these diseases. Early life adversity (ELA) has a profound impact on brain function and health later in life. In rodent models, exposure to ELA results in specific cognitive deficits and aggravated AD pathology. Extensive concerns have been raised regarding the higher risk of developing cognitive impairments in people with a history of ELA. In this review, we scrutinize findings from human and animal studies focusing on the connection of ELA with cognitive impairment and AD. These discoveries suggest that ELA, especially at early postnatal stages, increases susceptibility to cognitive impairment and AD later in life. In terms of mechanisms, ELA could lead to dysregulation of the hypothalamus-pituitary-adrenal axis, altered gut microbiome, persistent inflammation, oligodendrocyte dysfunction, hypomyelination, and aberrant adult hippocampal neurogenesis. Crosstalks among these events may synergistically contribute to cognitive impairment later in life. Additionally, we discuss several interventions that may alleviate adverse consequences of ELA. Further investigation into this crucial area will help improve ELA management and reduce the burden of related neurological conditions.

More than 80% of depressed patients struggle with learning new tasks, remembering positive events, or concentrating on a single topic. These neurocognitive deficits accompanying depression may be linked to functional and structural changes in the prefrontal cortex and hippocampus. However, their mechanisms are not yet completely understood. We conducted a narrative review of articles regarding animal studies to assess the state of knowledge. First, we argue the contribution of changes in neurotransmitters and hormone levels in the pathomechanism of cognitive dysfunction in animal depression models. Then, we used numerous neuroinflammation studies to explore its possible implication in cognitive decline. Encouragingly, we also observed a positive correlation between increased oxidative stress and a depressive-like state with concomitant memory deficits. Finally, we discuss the undeniable role of neurotrophin deficits in developing cognitive decline in animal models of depression. This review reveals the complexity of depression-related memory impairments and highlights the potential clinical importance of gathered findings for developing more reliable animal models and designing novel antidepressants with procognitive properties.

One of the characteristic features of adolescence is risk-taking behavioural traits. Uncontrolled risk-taking without proper assessment may have harmful impact on mental health later in life. Therefore, it is essential to identify it early for the preventable health problems. In the present study, we have designed a novel paradigm, viz. Risky Decision-taking Task (RDTT), to evaluate the spontaneous risk-taking behavioural repertoire in adolescent rodents. The task was designed based on both risk and cognitive factors. To validate and compare the risk-taking tendency, we have used early maternal separation and isolation (MS) stress model, as it is known to increase anxiety and curiosity-like behaviour at adolescence. We have used Sprague-Dawley rats of both sexes. Rats were exposed to MS stress for 10 days daily for six hours during stress hyporesponsive period (SHRP) from postnatal day 4 to 13. These rats were subjected to RDTT during adolescence. This task is a reward-based task where the latency to collect reward in the presence or absence of a risk factor is assessed. It consists of habituation, training to find the location of small and large rewards, reward preference for small and large reward and testing period under risky situation. Rats were trained individually to retrieve the valuation-based rewards under the risky, but innate aversive environments. The results from RDTT showed that as compared to controls, MS rats from both sexes showed reduced latency to collect large reward in the presence of a risk element and a reduced risk-index which is indicative of a higher risk-taking tendency in these rats. In addition, MS rats showed a trend towards anxiety-like behaviour as compared to controls in the Light-Dark Test. These results together show decreased risk latency for the large reward and reduced risk assessment in MS rats which is suggestive of more risk-taking tendency in these rats. Thus, we propose that RDTT paradigm can be used to evaluate the spontaneous risk-taking behavioural repertoire based on innate, spontaneous aversion and cognitive factors in rats.

In the study, we examined the effects of ketamine and extremely low-frequency electromagnetic fields (ELF-EMF) on depression-like behavior, learning and memory, expression of GFAP, caspase-3, p53, BDNF, and NMDA receptor in animals subjected to chronic unpredictable stress (CUS).

After applying 21 days of chronic unpredictable stress, male rats received intraperitoneal (IP) of ketamine (5 mg/kg) and then were exposed to ELF-EMF (10-Hz, 10-mT exposure conditions) for 3 days (3 h per day) and behavioral assessments were performed 24 h after the treatments. Instantly after the last behavioral test, the brain was extracted for Nissl staining, immunohistochemistry, and real-time PCR analyses. Immunohistochemistry (IHC) was conducted to assess the effect of ketamine and ELF-EMF on the expression of astrocyte marker (glial fibrillary acidic protein, GFAP) in the CA1 area of the hippocampus and medial prefrontal cortex (mPFC). Also, real-time PCR analyses were used to investigate the impacts of the combination of ketamine and ELF-EMF on the expression of caspase3, p53, BDNF, and NMDA receptors in the hippocampus in rats submitted to the CUS procedure. Results were considered statistically significant when p < .05.

Our results revealed that the combination of ketamine and ELF-EMF increased depression-like behavior, increased degenerated neurons and decreased the number of GFAP (+) cells in the CA1 area and mPFC, incremented the expression of caspase-3, and reduced the expression of BDNF in the hippocampus but showed no effect on the expression of p53 and NMDA-R.

These results reveal that combining ketamine and ELF-EMF has adverse effects on animals under chronic unpredictable stress (CUS).

A variety of stressful experiences can influence the ability to form and subsequently inhibit fear memory. While nonsocial stress can impact fear learning and memory throughout the lifespan, psychosocial stressors that involve negative social experiences or changes to the social environment have a disproportionately high impact during adolescence. Here, we review converging lines of evidence that suggest that development of prefrontal cortical circuitry necessary for both social experiences and fear learning is altered by stress exposure in a way that impacts both social and fear behaviors throughout the lifespan. Further, we suggest that psychosocial stress, through its impact on the prefrontal cortex, may be especially detrimental during early developmental periods characterized by higher sociability. This article is part of the Special Issue on 'Fear, Anxiety and PTSD'.

To explore the relationship between leucine in cerebrospinal fluid (CSF) and cognitive dysfunction in rats with early life stress (ELS) induced mental illness, and pathophysiological mechanism involved.

The maternal separation (MS), an animal paradigm used widely as a preclinical model of ELS which is one of the important risk factors for mental disorders. Behavioral experiments including open-field test, sucrose preference, object recognition and Morris water maze tests, Nissl staining, transmission electron microscopy and WES were employed in the present study.

The behavioral results showed that MS rats were more prone to cognitive impairment and depression-and-anxiety-like behaviors than controls, including spatial self-exploration ability, memory ability, and spatial learning and memory function. Nissl staining analysis indicated that the number of neurons in the CA1 and CA3 regions of the hippocampus significantly decreased and the arrangement of nerve cells was abnormal. The leucine levels were decreased in the CSF of MS rats and highly correlated with the number of hippocampal neurons, and yet leucine supplementation improved the degree of MS-induced cognitive impairment. Furthermore, there were autophagosomes in the hippocampus of the low-leucine diet rats of the control and MS group but not in the high-leucine diet MS group by transmission electron microscopy. The protein expression of Beclin-1 in the hippocampus was significantly increased in the MS normal diet group and MS low-leucine diet group, yet decreased in the MS high-leucine diet group compared with the MS low-leucine diet group. Meanwhile, the Bcl-2/Bax ratio was significantly decreased in the control low-leucine diet group, MS normal diet group and MS low-leucine diet group. Ultimately, in vitro experiments suggested that leucine deficiency could activate neuronal autophagy including enhanced LC3II/LC3I and mRFP-GFP-LC3, which was consistent with the in vivo results, and the cell apoptosis rate and lactate dehydrogenase (LDH) cytotoxicity were also increased with leucine deficiency, while the above effects could be partly reversed by autophagy inhibitor treatment.

MS model caused adult male rats to be susceptible to cognitive dysfunction, which may regulate autophagy in hippocampal neurons through leucine metabolism in CSF.

Propranolol is a β-adrenergic antagonist used in the management of hypertension, cardiac arrhythmia, and angina pectoris. There is some evidence that propranolol may benefit individuals with behavioural and psychological symptoms of dementia (BPSD). A total of three case series, one randomized controlled trial and one case report were identified (from a literature search of three major databases: PubMed, Ovid, and Cochrane collaboration) that assessed the use of propranolol for the management of BPSD. From these studies, it appears that propranolol improves BPSD, including agitation and aggression. Propranolol is also well tolerated with no significant bradycardia or hypotension noted in these studies. Current data on the use of propranolol for the management of BPSD are limited in comparison to other pharmacological agents (atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, and cannabinoids) and treatment modalities (repetitive transcranial magnetic stimulation and electroconvulsive therapy). The efficacy and safety of these treatments among individuals with BPSD has been evaluated in multiple controlled studies. In clinical practice, the routine use of propranolol among people with BPSD cannot be recommended at this time given the limited data. However, propranolol can be trialled among individuals with BPSD when symptoms have not responded adequately to other medications. Propranolol may also be used prior to embarking on trials of repetitive transcranial magnetic stimulation and electroconvulsive therapy among people with BPSD given the greater acceptance of this medication in the general population.

The elevated plus maze (EPM) and the marble burying (MB) tests are common behavioral tests used for behavioral phenotyping in mouse models for neurodevelopmental disorders. However, the behavioral effects of maternal separation (MS), a standard paradigm for early life stress in animals, in both the EPM and MB tests remain incompletely known.

This study aimed to investigate the behavioral effects of prolonged MS in the offspring of mice using the EPM and MB tests.

Male BALB/c mice were isolated from their mothers for 4 h each day during the first 30 days after birth. On day 50 postnatal, groups of separated and non-separated mice (n = 18/each group) were subjected to the EPM and MB tests for comparative behavioral evaluations. In addition, the locomotor activity of mice was evaluated using the actophotometer test.

The findings of the EPM test revealed that separated mice exhibited anxiolytic-like behaviors, as evidenced by a significant increase in the latency to closed arms and the time spent in the open arms compared with non-separated mice. Separated mice also showed compulsive burying activity in the MB test, as determined by a significant increase in the number of buried marbles. The results of the actophotometer test did not show any significant change in locomotor activity.

Prolonged MS caused the adult offspring of mice to exhibit a decrease in anxiety state and increased compulsive burying activity, which were not associated with a change in locomotor activity. Further investigations with validated tests are needed to support these findings.

Two-thirds of individuals experience adversity during childhood such as neglect, abuse or highly-stressful events. Early-life adversity (ELA) increases the life-long risk of developing mood and substance use disorders. Reward-related deficits has emerged as a key endophenotype of such psychiatric disorders. Animal models are invaluable for studying how ELA leads to reward deficits. However, the existing literature is heterogenous with difficult to reconcile findings. To create an overview, we conducted a systematic review containing multiple meta-analyses regarding the effects of ELA on reward processes overall and on specific aspects of reward processing in animal models. A comprehensive search identified 120 studies. Most studies omitted key details resulting in unclear risk of bias. Overall meta-analysis showed that ELA significantly reduced reward behaviors (SMD: -0.42 [-0.60; -0.24]). The magnitude of ELA effects significantly increased with longer exposure. When reward domains were analyzed separately, ELA only significantly dampened reward responsiveness (SMD: -0.525[-0.786; -0.264]) and social reward processing (SMD: -0.374 [-0.663; -0.084]), suggesting that ELA might lead to deficits in specific reward domains.

Depression and coronary heart diseases are the common comorbid disorder affecting humans globally. The present study evaluated the effectiveness of rosmarinic acid (RA) against myocardial infarction (MI) in comorbid depression induced by maternal separation in rats. Maternal stress is one of the childhood crises that may be a potential risk factor for coronary heart disease in later part of life. As per protocol, 70-80% of pups were separated daily for 3 h between postnatal day 1 (PND1) and postnatal day 21 (PND21). Forced-swim test, sucrose preference test, and electrocardiography were performed during the experiment. Body weight was measured on PND0, PND35, and PND55. Orally rosmarinic acid (25 mg/kg and 50 mg/kg) and fluoxetine (10 mg/kg) was done from PND35 to PND55. On PND53 and PND54, isoproterenol (100 mg/kg, subcutaneously) was administered to induce myocardial infarction. On PND55, blood was collected and animals sacrificed, and plasma corticosterone, brain-derived neurotrophic factor, cardiac biomarkers, interleukine-10, and anti-oxidant parameters were measured. Rosmarinic acid and fluoxetine ameliorated the maternal separation-induced increase in immobility period, anhedonia, body weight, ST elevation, corticosterone, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). At the same time, both drugs elevated the tissue levels of BDNF, IL-10, glutathione, and superoxide dismutase activity. This study provides the first experimental evidence that maternal stress is an independent risk factor of cardiac abnormalities in rats. Moreover, maternal stress synergistically increases the severity of cardiac abnormalities induced by isoproterenol. Interestingly, fluoxetine and rosmarinic acid effectively ameliorated behavioral anomalies and myocardial infarction in maternally separated rats. Schematic representation of possible molecular mechanism of action of rosmarinic acid against MS-induced myocardial infarction. RA, rosmarinic acid; MS, maternal separation; PND, postnatal days; ISO, isoproterenol; BDNF, brain-derived neurotrophic factor; GSH, glutathione; SOD, superoxide dismutase; IL-10, interleukin-10; MI, myocardial infarction.