Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood–brain barrier (BBB). Triozan^TM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + Triozan^TM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.     

Semax,synthetic ACTH(4–10) analogue,attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats

Selective serotonin reuptake inhibitors (SSRI) are commonly used to treat depression during pregnancy. SSRIs cross the placenta and may influence the maturation of the foetal brain. Clinical and preclinical findings suggest long-term consequences of SSRI perinatal exposure for the offspring. The mechanisms of SSRI effects on developing brain remain largely unknown and there are no directional approaches for prevention of the consequences of maternal SSRI treatment during pregnancy. The heptapeptide Semax (MEHFPGP) is a synthetic analogue of ACTH(4–10) which exerts marked nootropic and neuroprotective activities. The aim of the present study was to investigate the long-term effects of neonatal exposure to the SSRI fluvoxamine (FA) in white rats. Additionally, the study examined the potential for Semax to prevent the negative consequences of neonatal FA exposure. Rat pups received FA or vehicle injections on postnatal days 1–14, a time period equivalent to 27–40 weeks of human foetal age. After FA treatment, rats were administered with Semax or vehicle on postnatal days 15–28. During the 2nd month of life, the rats underwent behavioural testing, and monoamine levels in brain structures were measured. It was shown that neonatal FA exposure leads to the impaired emotional response to stress and novelty and delayed acquisition of food-motivated maze task in adolescent and young adult rats. Furthermore, FA exposure induced alterations in the monoamine levels in brains of 1- and 2- month-old rats. Semax administration reduced the anxiety-like behaviour, improved learning abilities and normalized the levels of brain biogenic amines impaired by the FA exposure. The results demonstrate that early-life FA exposure in rat pups produces long-term disturbances in their anxiety-related behaviour, learning abilities, and brain monoamines content. Semax exerts a favourable effect on behaviour and biogenic amine system of rats exposed to the antidepressant. Thus, peptide Semax can prevent behavioural deficits caused by altered 5-HT levels during development.     

Exposure to extrinsic stressors,social defeat or bisphenol A,eliminates sex differences in DNA methyltransferase expression in the amygdala

Chemical and psychological stressors can exert long lasting changes in brain function and behaviour. Changes in DNA methylation have been shown to be an important mechanism mediating long lasting changes in neural function and behaviour, especially for anxiety‐like or stress responses. In the present study, we examined the effects of either a social or chemical stressor on DNA methyltransferase (DNMT) gene expression in the amygdala, an important brain region modulating stress responses and anxiety. In adult California mice (Peromyscus californicus) that were naïve to social defeat, females had higher levels of Dnmt1 expression in punch samples of the central amygdala (CeA) than males. In addition, mice that underwent social defeat stress showed reduced Dnmt1 and Dnmt3a expression in the CeA of females but not males. A second study using more anatomically specific punch samples replicated these effects for Dnmt1. Perinatal exposure (spanning from periconception through lactation) to bisphenol A or ethinyl oestradiol (oestrogens in birth control pills) also abolished sex differences in Dnmt1 expression in the CeA but not the basolateral amygdala. These findings identify a robust sex difference in Dnmt1 expression in the CeA that is sensitive to both psychological and chemical stressors. Future studies should aim to examine the impact of psychological and chemical stressors on DNA methylation in the CeA and also investigate whether Dnmt1 may have an underappreciated role in plasticity in behaviour.     

Plasticity of the parental brain: a case for neurogenesis

Profound behavioural changes occur in the mother at parturition, together with extensive remodelling of neural circuits. These changes include neurochemical, morphological and functional plasticity. The continuous generation of new neurones in the hippocampus and the olfactory system is an additional form of neuroplasticity that contributes to motherhood. This review describes the reciprocal relationships between hippocampal and olfactory neurogenesis and parental behaviour. Studies in rodents demonstrate that parturition and interactions with the young affect both cell proliferation and survival in a different manner across neurogenic zones. Species in which an individual recognition of the offspring is formed, such as sheep, show a down-regulation of neurogenesis during the perinatal period. This would function to decrease cell competition, favouring the selection of newborn neurones involved in olfactory recognition of the young. Also, in biparental species, increases in olfactory neurogenesis occur in the father in response to pup exposure during the early postpartum period. Oestradiol, corticosterone and prolactin changes associated with parturition are the main physiological factors involved in the regulation of neurogenesis that have been determined so far. In the father, prolactin mediates an enhancement of olfactory neurogenesis. Contradictory evidence indicates a functional link between neurogenesis and parenting behaviour. Mice receiving focal irradiation of the olfactory neurogenic subventricular zone show few disturbances in the expression of maternal behaviour, whereas a reduction of both hippocampal and olfactory neurogenesis as a result of the infusion of an anti-mitotic agent induces behavioural deficits. Disrupting prolactin signalling abolished increased paternal neurogenesis and offspring recognition by the father, and rescuing this neurogenesis restored recognition behaviour. More studies that selectively suppress the changes of neurogenesis are needed to confirm the role of new neurones in regulating parenting behaviour.     

Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress‐reactive Wistar Kyoto rats

Early‐life stress (ELS) can alter neurodevelopment in variable ways, ranging from producing deleterious outcomes to stress resilience. While most ELS studies focus on its harmful effects, recent work by our laboratory and others shows that ELS elicits positive effects in certain individuals. We exposed Wistar Kyoto (WKY) rats, known for a stress reactive, anxiety/depression‐like phenotype, to maternal separation (MS), a model of ELS. MS exposure elicited anxiolytic and antidepressant behavioral effects as well as improved cardiovascular function in adult WKY offspring. This study interrogates an epigenetic mechanism (DNA methylation) that may confer the adaptive effects of MS in WKY offspring. We quantified global genome methylation levels in limbic brain regions of adult WKYs exposed to daily 180‐min MS or neonatal handling from postnatal day 1–14. MS exposure triggered dramatic DNA hypermethylation specifically in the hippocampus. Next‐generation sequencing methylome profiling revealed reduced methylation at intragenic sites within two key nodes of insulin signaling pathways: the insulin receptor and one of its major downstream targets, mitogen‐activated protein kinase kinase kinase 5 (Map3k5). We then tested the hypothesis that enhancing DNA methylation in WKY rats would elicit adaptive changes akin to the effects of MS. Dietary methyl donor supplementation improved WKY rats’ anxiety/depression‐like behaviors and also improved cardiovascular measures, similar to previous observations following MS. Overall, these data suggest a potential molecular mechanism that mediates a predicted adaptive response, whereby ELS induces DNA methylation changes in the brain that may contribute to successful stress coping and adaptive physiological changes in adulthood.     

Ovarian hormones induce de novo DNA methyltransferase expression in the Siberian hamster suprachiasmatic nucleus

The present study investigated neuroanatomically localised changes in de novo DNA methyltransferase expression in the female Siberian hamster (Phodopus sungorus). The objectives were to identify the neuroendocrine substrates that exhibit rhythmic Dnmt3a and Dnmt3b expression across the oestrous cycle and also examine the role of ovarian steroids. Hypothalamic Dnmt3a expression was observed to significantly increase during the transition from pro‐oestrous to oestrous. A single bolus injection of diethylstilbestrol and progesterone was sufficient to increase Dnmt3a cell numbers and Dnmt3b immunoreactive intensity in the suprachiasmatic nucleus. In vitro analyses using an embryonic rodent cell line revealed that diethylstilbestrol was sufficient to induce Dnmt3b expression. Up‐regulating DNA methylation in vitro reduced the expression of vasoactive intestinal polypeptide, Vip, and the circadian clock gene, Bmal1. Together, these data indicate that ovarian steroids drive de novo DNA methyltransferase expression in the mammalian suprachiasmatic nucleus and increased methylation may regulate genes involved in the circadian timing of oestrous: Vip and Bmal1. Overall, epigenetically mediated neuroendocrine reproductive events may reflect an evolutionarily ancient process involved in the timing of female fertility.     

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.     

The involvement of oxytocin in the effects of chronic social defeat stress on emotional behaviours in adult female mandarin voles

Chronic social defeat stress (CSDS) can induce anxiety and depression in male rodents, but the prevalence of anxiety and depression is much higher in females, and effects of CSDS on adult females and its underlying mechanism remain unclear. Oxytocin is a stress‐buffering hormone in the brain that modulates the physiological effects of stress. Strikingly, research regarding the effect of oxytocin on emotional changes caused by CSDS is still lacking in females. Thus, we focused on the involvement of the oxytocin system in changes in emotional regulation induced by CSDS in female voles. Seventy‐day‐old female mandarin voles (Microtus mandarinus) were exposed to aggressive adult females for 14 days, and the effects of CSDS on emotion and regulation of oxytocin system were characterized. In addition, we injected vehicle, oxytocin and oxytocin receptor antagonist into the nucleus accumbens (Nacc) of female voles to investigate the involvement of Nacc oxytocin in the effect of CSDS on emotion. Herein, we reported that CSDS increased anxiety and depression‐like behaviour and the circulating level of corticosterone, but decreased the number of oxytocin projections and the protein and mRNA expression levels of oxytocin receptor in the Nacc. Injection of oxytocin into the Nacc reversed the effects of CSDS on anxiety‐like and depressive‐like behaviour, whereas combined injections of oxytocin and oxytocin receptor antagonist eliminated these effects. In conclusion, CSDS increases the levels of anxiety and depression possibly via a reduction in oxytocin projections and the oxytocin receptor level in the Nacc. Nacc oxytocin may be involved in the effects of CSDS on emotional behaviours.     

Perinatal citalopram does not prevent the effect of prenatal stress on anxiety,depressive‐like behaviour and serotonergic transmission in adult rat offspring

It is still not clear whether the selective serotonin reuptake inhibitors frequently prescribed to depressed pregnant women improve the behavioural outcome in their children. The current study investigated whether administration of citalopram to pregnant rats could prevent anxiety and depressive‐like behaviour induced by gestational stress in their offspring, and restore the expression of serotonin 1A autoreceptors in GABAergic interneurons in the medial prefrontal cortex and dorsal raphe nuclei in males, and of corticotropin‐releasing factor type 2 receptors in GABAergic interneurons in the dorsal raphe nuclei in females. Activation of these receptors modulates serotonergic transmission to target areas and is reduced in a sex‐dependent manner by prenatal stress. Citalopram (10 mg/kg/day), administered orally from day 7 of gestation until 21 days postpartum, prevented the increase in anxiety in stressed mothers but did not reduce anxiety and depressive‐like behaviour in their offspring and even induced depressive‐like behaviour in the offspring of control mothers. Citalopram failed to restore the reduction in the expression of serotonin 1A autoreceptors in the prefrontal cortex of males and in corticotropin‐releasing factor type 2 receptors in the dorsal raphe nuclei of females induced by prenatal stress. Prenatal citalopram did not prevent the behavioural changes or reduction in serotonergic transmission to target areas induced by prenatal stress. It had adverse behavioural effects in the offspring of control rats, which, together with the lack of any change in prenatally‐stressed rats, may be due to inhibition of the foetal serotonin transporter thereby preventing normal development of the serotonin system.     

Fatherhood reduces the survival of adult‐generated cells and affects various types of behavior in the prairie vole (Microtus ochrogaster )

Motherhood has profound effects on physiology, neuronal plasticity, and behavior. We conducted a series of experiments to test the hypothesis that fatherhood, similarly to motherhood, affects brain plasticity (such as cell proliferation and survival) and various behaviors in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult males were housed with their same‐sex cage mate (control), single‐housed (isolation), or housed with a receptive female to mate and produce offspring (father) for 6 weeks. Fatherhood significantly reduced cell survival (assessed by bromodeoxyuridine labeling), but not cell proliferation (assessed by Ki67‐labeling), in the amygdala, dentate gyrus of the hippocampus, and ventromedial hypothalamus, suggesting that fatherhood affects brain plasticity. In Experiment 2, neither acute (20 min) nor chronic (20 min daily for 10 consecutive days) pup exposure altered cell proliferation or survival in the brain, but chronic pup exposure increased circulating corticosterone levels. These data suggest that reduced cell survival in the brain of prairie vole fathers was unlikely to be due to the level of pup exposure and display of paternal behavior, and may not be mediated by circulating corticosterone. The effects of fatherhood on various behaviors (including anxiety‐like, depression‐like, and social behaviors) were examined in Experiment 3. The data indicated that fatherhood increased anxiety‐ and depression‐like behaviors as well as altered aggression and social recognition memory in male prairie voles. These results warrant further investigation of a possible link between brain plasticity and behavioral changes observed due to fatherhood.     

Prenatal Social Stress in the Rat Programmes Neuroendocrine and Behavioural Responses to Stress in the Adult Offspring: Sex‐Specific Effects

Stress exposure during pregnancy can ‘programme’ adult behaviour and hypothalamic‐pituitary‐adrenal (HPA) axis stress responsiveness. In the present study, we utilised an ethologically relevant social stressor to model the type of stress that pregnant women may experience. We investigated the effects of social defeat by a resident lactating rat over 5 days during the last week of pregnancy on the pregnant intruder rat HPA axis, and on HPA responsivity to stress and anxiety‐related behaviour in the adult offspring of the socially‐defeated intruder rats. HPA axis responses after social defeat were attenuated in the pregnant rats compared to virgin females. In the adult offspring, systemic interleukin (IL)‐1β or restraint increased adrenocorticotrophic hormone and corticosterone secretion in male and female control rats; however, in prenatally stressed (PNS) offspring, HPA responses were greatly enhanced and peak hormone responses to IL‐1β were greater in females versus males. Male PNS rats displayed increased anxiety behaviour on the elevated plus maze; however, despite marked changes in anxiety behaviour across the oestrous cycle, there were no differences between female control and PNS rats. Investigation of possible mechanisms showed mineralocorticoid mRNA levels were reduced in the hippocampus of male and female PNS offspring, whereas glucocorticoid receptor mRNA expression was modestly reduced in the CA2 hippocampal subfield in female PNS rats only. Corticotropin‐releasing hormone mRNA and glucocorticoid receptor mRNA expression in the central amygdala was greater in PNS males and females compared to controls. The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper‐reactivity to stress in PNS offspring.     

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice

Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12‐ to18‐month‐old (APA) and 4‐month‐old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety‐related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.     

Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes

The hypothalamus and hippocampus are sensitive to early exposure to endocrine disrupting chemicals (EDCs). Two EDCs that have raised particular concerns are bisphenol A (BPA), a widely prevalent chemical in many common household items, and genistein (GEN), a phyto‐oestrogen present in soy and other plants. We hypothesised that early exposure to BPA or GEN may lead to permanent effects on gene expression profiles for both coding RNAs (mRNAs) and microRNAs (miRs), which can affect the translation of mRNAs. Such EDC‐induced biomolecular changes may affect behavioural and metabolic patterns. California mice (Peromyscus californicus) male and female offspring were developmentally exposed via the maternal diet to BPA (5 mg kg^‐1 feed weight low dose [LD] and 50 mg kg^‐1 feed weight upper dose [UD]), GEN (250 mg kg^‐1 feed weight) or a phyto‐oestrogen‐free diet (AIN) control. Behavioural and metabolic tests were performed at 180 days of age. A quantitative polymerase chain reacttion analysis was performed for candidate mRNAs and miRs in the hypothalamus and hippocampus. LD BPA and GEN exposed California mice offspring showed socio‐communication impairments. Hypothalamic Avp, Esr1, Kiss1 and Lepr were increased in LD BPA offspring. miR‐153 was elevated but miR‐181a was reduced in LD BPA offspring. miR‐9 and miR‐153 were increased in the hippocampi of LD BPA offspring, whereas GEN decreased hippocampal miR‐7a and miR‐153 expression. Correlation analyses revealed neural expression of miR‐153 and miR‐181a was associated with socio‐communication deficits in LD BPA individuals. The findings reveal a cause for concern such that developmental exposure of BPA or GEN in California mice (and potentially by translation in humans) can lead to long standing neurobehavioural consequences.     

Regulators of glucocorticoid receptor function in an animal model of depression and obesity

Obesity is a disease that often co‐occurs with depression and there is some evidence to indicate that chronic stress in the perinatal period, in association with overactive glucocorticoids, can cause permanent changes that increase the risk of the development of both depression and obesity later in life. However, the mechanism responsible for the overly potent action of glucocorticoids in both depression and obesity is not known. The present study aimed to determine the expression of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) and the factors that affect GR function (FKBP51, Bag‐1 and HSP70) in a prenatal stress animal model of depression, a model of obesity and a model of both depression and obesity. Prenatal stress but not high‐fat diet (HFD) was found to decrease the GR concentration in the frontal cortex. The level of the Bag‐1M (46 kDa) isoform was also decreased in this structure but only in prenatal‐stressed animals that did not show depression‐like behaviour in the Porsolt test and were fed the standard diet. In the model of depression employed in the present study, decreases in MR expression and GR co‐chaperone (FKBP51) levels in the hippocampus were also observed and HFD intensified the prenatal stress‐induced changes in MR expression. The results obtained indicated that prenatal stress affected the expression of GRs, MRs and their co‐chaperones in the brain, although its effects were different in the frontal cortex and hippocampus. The decrease in MR density in the hippocampus and increased plasma insulin level appeared to be the most significant changes observed in the model of the co‐occurrence of depression and obesity, which could limit the neuroprotective effects associated with the activation of MR and be a marker of peripheral insulin resistance, respectively.     

Prolonged prenatal exposure to low-level ozone affects aggressive behaviour as well as NGF and BDNF levels in the central nervous system of CD-1 mice

The long-term effects on isolation-induced aggressive behaviour and central NGF and BDNF levels of gestational exposures to ozone (O(3)) were evaluated in adult CD-1 mice. Females were exposed to O(3), at the dose of 0.0, 0.3 or 0.6 ppm from 30 days prior the formation of breeding pairs until gestational day 17. Litters were fostered at birth to untreated dams and, at adulthood, male offspring underwent five successive daily encounters (15 min each) with a standard opponent of the same strain, sex, weight and age. The encounters on day 1, 3 and 5 were videotaped and agonistic and non-agonistic behavioural items finely scored. O(3)-exposed mice showed a significant increase in freezing and defensive postures, a decrease in nose-sniffing behaviour and reduced progressively the aggressive behavioural profile displayed on day 1. Reduced NGF levels in the hippocampus and increased BDNF in the striatum were also found upon O(3) exposure.     

Chernobyl exposure as stressor during pregnancy and behaviour in adolescent offspring

Objective: Research in animals has shown that exposure to stressors during pregnancy is associated with offspring behavioural disorders. We aimed to study the effect of in utero exposure to the Chernobyl disaster in 1986, and maternal anxiety presumably associated with that exposure, on behaviour disorder observed at age 14. Method: Exposed (n = 232) and non‐exposed Finnish twins (n = 572) were compared. A semi‐structured interview was used to assess lifetime symptoms of depression, generalized anxiety disorder, attention deficit hyperactivity disorder, conduct disorder and oppositional defiant disorder symptoms. Results: Adolescents who were exposed from the second trimester in pregnancy onwards, had a 2.32‐fold risk (95% CI: 1.13–4.72) of having lifetime depression symptoms, an increased risk of fulfilling DSM‐III‐R criteria of a major depressive disorder (OR = 2.48, 95% CI: 1.06–5.7), and a 2.01‐fold risk (95% CI: 1.14–3.52) of having attention deficit hyperactivity disorder symptoms. Conclusion: Perturbations in fetal brain development during the second trimester may be associated with the increased prevalence of depressive and attention deficit hyperactivity disorder symptoms.     

Longitudinal studies examining the impact of prenatal and subsequent episodes of maternal depression on offspring antisocial behaviour

Maternal depression is associated with adverse child outcomes including antisocial behaviour (ASB). Prospective longitudinal studies have focused on the timing and cumulative exposure to maternal depression to further delineate the association and mechanisms of effect. The objective of this systematic review was to synthesise and evaluate the findings of longitudinal studies of maternal depression and offspring antisocial behaviour. Three databases were searched (Psychinfo, Web of Science, and Medline). Twenty of 5936 studies met inclusion criteria. Study quality was assessed using the Critical Appraisal Skills Programme criteria [Critical Appraisal Skills Programme (2017) CASP (cohort observation checklist). https://casp-uk.net/wpcontent/uploads/2018/01/CASP-Cohort-Study-Checklist.pdf]. Results of individual studies were highly varied, using diverse analytical approaches and not all studies explored the independent effects of different episodes. Only three studies examined hypothesised mechanisms. Prenatal, postnatal, and later episodes of depression were all predictive of antisocial outcomes. One particular time period of depression exposure did not emerge as more predictive of offspring ASB than another. However, measures of maternal depression after the perinatal period were limited and typically included a one-off assessment of mothers’ depressive symptoms that was concurrent to the assessment of offspring ASB. When cumulative exposure to maternal depression and specific timing effects were measured within the same study it was cumulative exposure that conferred the greatest risk for offspring ASB—particularly when this exposure began during the perinatal period. Findings are discussed in terms of limitations in the literature and highlight the need for future research to examine the biological and environmental mechanisms that underpin associations between maternal depression and offspring antisocial behaviour during different stages of development.

     

Sex mediates dopamine and adrenergic receptor expression in adult rats exposed prenatally to cocaine

The extent of catecholaminergic receptor and respective behavioral alterations associated with prenatal cocaine exposure varies according to exogenous factors such as the amount, frequency, and route of maternal exposure, as well as endogenous factors such as specific brain regions under consideration and sex of the species. The goal of the current study was to use autoradiography to delineate possible moderators of dopaminergic and adrenergic receptor expression in adult rat offspring exposed to cocaine in utero. The current study demonstrated sex-dependent D1 receptor, alpha2, and noradrenergic transporter binding alterations in prelimbic, hippocampus, and anterior cingulate regions of adult rat brains exposed to cocaine during gestational days 8-21. Of further interest was the lack of alterations in the nucleus accumbens for nearly all receptors/transporters investigated, as well as the lack of alterations in D3 receptor binding in nearly all of the regions investigated (nucleus accumbens, prelimbic region, hippocampus, and cingulate gyrus). Thus, the current investigation demonstrated persistent receptor and transporter alterations that extend well into adulthood as a result of cocaine exposure in utero. Furthermore, the demonstration that sex played a mediating role in prenatal cocaine-induced, aberrant receptor/transporter expression is of primary importance for future studies that seek to control for sex in either design or analysis.     

Foraging Activity is Reduced in a Mouse Model of Depression

Depression interferes with the human ability to make decisions. Multiple criteria have been adopted for the diagnosis of depression in humans, but no clear indicators are available in animal models to reflect the depressive mood, involving higher cognitive functions. The act of foraging is a species-specific behaviour which is believed to involve the decision-making and higher cognitive functions. We previously established a method to detect the foraging behaviour of rodents, in which our results demonstrated that NMDA and dopamine receptors were involved. Conversely, increased NMDA receptors and reduced dopamine have been reported in depression model rodents. However, we hypothesise that foraging activities may also be impaired in depression. To test the theory, we successfully established a mouse model of depression using the chronic unpredictable mild stress (CUMS) paradigm. Most interestingly, the food foraging activity of mice after CUMS was significantly reduced. In addition, the treatment of anti-depressant fluoxetine reversed most depressive symptoms and reduced glial fibrillary associated protein (GFAP) expression in the hippocampus, but was less effective in the reduction of foraging activities. However, clozapine reversed all symptoms of CUMS-exposed mice including reduction of GFAP expression in the hippocampus and impaired foraging activity. Our findings of GFAP expression as a marker to validate the CUMS protocol provide further validation of our hypothesis, that the reduced food foraging is probably a new behavioural finding of depression in which the serotoninergic system could not be singly involved. Our study suggests that NMDA receptors, serotoninergic and dopaminergic systems are differentially involved in these food foraging behaviours. Our data suggest that the foraging test in rodents can be a useful tool to assess the ability of decision-making in depression.