The parental brain, perinatal mental illness, and treatment: A review of key structural and functional changes.

The transition to parenthood is perhaps the only time in adult life when the brain changes to such a significant degree in such a short period, particularly in birthing parents. It is also a time when there is an increased risk of developing a mental illness, which may be due, in part, to the increased neuroplasticity. Thus, we must develop interventions and treatments that support parents and promote parental brain health. This review will highlight key findings from current research on how human brain structure and function are modified with 1) the transition to parenthood, 2) parenting stress and perinatal mental illness, and 3) treatments aimed at promoting perinatal mental health. The focus will be on birthing parents and mothers, but brain changes in non-birthing parents will also be discussed. Improvements in our understanding of the parental brain, in health and with illness, will promote the well-being of generations to come.

Maternal probiotic Lactocaseibacillus rhamnosus HN001 treatment alters postpartum anxiety, cortical monoamines, and the gut microbiome.

Peripartum mood and anxiety disorders (PMADs) affect 15-20% of peripartum women and are well known to disrupt infant caregiving. A recent study in humans reported that anxiety and depressive symptoms were alleviated by peripartum treatment with the probiotic, Lactocaseibacillus rhamnosus HN001. The current study determined the effects of chronic Lactocaseibacillus rhamnosus HN001 (HN001) treatment on postpartum affective and caregiving behaviors in a laboratory rodent model. Female rats were given probiotic overnight in their drinking water, or untreated water, from the first day of pregnancy through postpartum day 10. To determine whether the HN001 effects were influenced by a background of stress, half the females underwent chronic variable pregnancy stress and the other half remained undisturbed. The results revealed that, even without pregnancy stress, HN001 reduced postpartum anxiety-related behavior, increased variability in behavioral fragmentation when dams interacted with pups, increased time away from pups, and decreased prefrontal cortex norepinephrine (NE), dopamine (DA) and serotonin (5-HT). Probiotic plus stress consistently reduced the latency to float in the forced swim test, increased DA and 5-HT turnovers in the prefrontal cortex, increased hippocampal NE, and reduced hypothalamic DA. Fecal microbe alpha and beta diversities were lower postpartum than prepartum, which was prevented by the probiotic treatment and/or stress. Across the entire sample lower postpartum anxiety behavior was associated with lower fecal Bacteroides dorei. This study reveals novel information about how L. rhamnosus HN001 influences postpartum behavior and microbiota-gut-brain physiology in female laboratory rats, with implications for probiotic supplement use by pregnant and postpartum women.

Gestational stress and perinatal SSRIs differentially impact the maternal and neonatal microbiome-gut-brain axis.

Selective serotonin reuptake inhibitors (SSRIs) are the most popular antidepressant medications used to manage perinatal mood disturbances, yet our understanding of how they affect the microbiome-gut-brain axis of the mother and offspring is limited. The purpose of this study was to determine how peripartum SSRI treatment may prevent the effects of gestational stress on plasticity in the maternal hippocampus, plasticity in the neonatal brain and related changes in gut microbiota. To do this Sprague-Dawley female rats were left untreated or subjected to unpredictable stress during pregnancy. Half of the females were supplemented daily with fluoxetine. On postpartum day 2 brains were collected for measurement of plasticity (neurogenesis and microglia content) in the maternal hippocampus and in the neonatal brain. Glucocorticoid receptor density was also investigated in the maternal hippocampus. Microbiota composition was analyzed in fecal samples of dams during and after pregnancy, and colon tissue samples from offspring on postnatal day 2. Main findings show there are significant changes to the maternal microbiome-gut-brain axis that may be fundamental to mediating plasticity in the maternal hippocampus. In addition, there is significant impact of gestational stress on neonatal gut microbiota and brain microglia density, while the effects of SSRIs are limited. This is the first study to explore the impact of gestational stress and SSRIs on the microbiome-gut-brain axis in the mother and neonate. Findings from this study will help inform pathways to intervention strategies including stress reduction techniques and/or microbiota targeted nutritional approaches directed towards improving maternal gut health and outcomes for mother and neonate.

It's Time to Rebrand "Mommy Brain".

This Viewpoint discusses the concept of "mommy brain" and why it needs to change.

Less can be more: Fine tuning the maternal brain.

PAWLUSKI, J.L., Hoekzema, E., Leuner, B., and Lonstein, J.S. Less can be more: Fine tuning the maternal brain. NEUROSCI BIOBEHAV REV (129) XXX-XXX, 2022. Plasticity in the female brain across the lifespan has recently become a growing field of scientific inquiry. This has led to the understanding that the transition to motherhood is marked by some of the most significant changes in brain plasticity in the adult female brain. Perhaps unexpectedly, plasticity occurring in the maternal brain often involves a decrease in brain volume, neurogenesis and glial cell density that presumably optimizes caregiving and other postpartum behaviors. This review summarizes what we know of the 'fine-tuning' of the female brain that accompanies motherhood and highlights the implications of these changes for maternal neurobehavioral health. The first part of the review summarizes structural and functional brain changes in humans during pregnancy and postpartum period with the remainder of the review focusing on neural and glial plasticity during the peripartum period in animal models. The aim of this review is to provide a clear understanding of when 'less is more' in maternal brain plasticity and where future research can focus to improve our understanding of the unique brain plasticity occurring during matrescence.

Neurobiology of peripartum mental illness.

At least one in seven pregnant or recently postpartum women will experience a mental illness such as an anxiety disorder, depressive disorder, or substance use disorder. These mental illnesses have detrimental effects on the health of the mother, child, and family, but little is known about the hypothalamic and other neural correlates of maternal mental health concerns. The transition to parenthood alone is a time of remarkable neural plasticity, so it is perhaps not surprising that current research is showing that maternal mental illness has unique neural profiles. Furthermore, the neural systems affected by peripartum mental illness overlap and interact with the systems involved in maternal caregiving behaviors, and mother-infant interactions are, therefore, highly susceptible to disruption. This review discusses what we know about the unique neural changes occurring during peripartum mental illness and the role of the hypothalamus in these illnesses. With an improved understanding of the neural correlates of maternal mental health and disease, we will be better equipped to predict risk, develop effective treatments, and ultimately prevent suffering for millions of parents during this critical time in life.

The brain oxytocin and corticotropin-releasing factor systems in grieving mothers: What we know and what we need to learn.

The bond between a mother and her child is the strongest bond in nature. Consequently, the loss of a child is one of the most stressful and traumatic life events that causes Prolonged Grief Disorder in up to 94 % of bereaved parents. While both parents are affected, mothers are of higher risk to develop mental health complications; yet, very little research has been done to understand the impact of the loss of a child, stillbirth and pregnancy loss on key neurobiological systems. The emotional impact of losing a child, e.g., Prolonged Grief Disorder, is likely accompanied by dysregulations in neural systems important for mental health. Among those are the neuropeptides contributing to attachment and stress processing. In this review, we present evidence for the involvement of the brain oxytocin (OXT) and corticotropin-releasing factor (CRF) systems, which both play a role in maternal behavior and the stress response, in the neurobiology of grief in mothers from a behavioral and molecular point of view. We will draw conclusions from reviewing relevant animal and human studies. However, the paucity of research on the tragic end to an integral bond in a female's life calls for the need and responsibility to conduct further studies on mothers experiencing the loss of a child both in the clinic and in appropriate animal models.

Fos expression in the medial preoptic area and nucleus accumbens of female Japanese quail (Coturnix japonica) after maternal induction and interaction with chicks.

The neural system underlying maternal caregiving has often been studied using laboratory rodents and a few other mammalian species. This research shows that the medial preoptic area (mPOA) integrates sensory cues from the young that, along with hormonal and other environmental signals, control maternal acceptance of neonates. The mPOA then activates the mesolimbic system to drive maternal motivation and caregiving activities. How components of this neural system respond to maternal experience and exposure to young in non-mammals has rarely been examined. To gain more insight into this question, virgin female Japanese quail (Coturnix japonica) were induced to be maternal through four days of continuous exposure to chicks (Maternal), or were not exposed to chicks (Non-Maternal). Chicks were removed overnight from the Maternal group and half the females from each group were then exposed to chicks for 90 minutes (Exposed), or not exposed to chicks (Non-Exposed), before euthanasia. The number of Fos-immunoreactive (Fos-ir) cells was examined as a marker of neuronal activation. As expected, repeated exposure to chicks induced caregiving behavior in the Maternal females, which persisted after the overnight separation, suggesting the formation of a maternal memory. In contrast, Non-Maternal females were aggressive and rejected the chicks when exposed to them. Exposed females, whether or not they were given prior experience with chicks (i.e., regardless if they accepted or rejected chicks during the exposure before euthanasia), had more Fos-ir cells in the mPOA compared to Non-Exposed females. In the nucleus accumbens (NAC), the number of Fos-ir cells was high in all Maternal females whether or not they were Exposed to chicks again before euthanasia. In the lateral bed nucleus of the stria terminalis, a site involved in general stress responding, groups did not differ in the number of Fos-ir cells. These data indicate a conserved role for the mPOA and NAC in maternal caregiving across vertebrates, with the mPOA acutely responding to the salience rather than valence of offspring cues, and the NAC showing longer-term changes in activity after a positive maternal experience even without a recent exposure to young.

Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models.

The developmental impact of selective serotonin reuptake inhibitor (SSRI) and other antidepressant treatments during gestation and postpartum on anxiety and depression behaviors in offspring is unclear. This review focuses on how perinatal exposure to SSRI and other antidepressant may have long term consequences for these affective behaviors during early childhood and beyond. Outcomes vary and consideration is given to methodological factors related to how early SSRI exposure affects developments studied in rodent models such as: a) between pre- and early post-natal SSRI exposure, b) sex, c) experimental models of gestational maternal stress and d) impact of non-SSRI antidepressant medications. We will also review how multiple contextual factors (maternal caregiving and gene x environment interactions) may contribute to the effects of perinatal SSRI exposure and maternal mental illness on affective behaviors in children.

Sex matters in neuroscience and neuropsychopharmacology.

Prevalence and symptoms of most psychiatric and neurological disorders differ in men and women and there is substantial evidence that their neurobiological basis and treatment also differ by sex. This special issue sought to bring together a series of empirical papers and targeted reviews to highlight the diverse impact of sex in neuroscience and neuropsychopharmacology. This special issue emphasizes the diverse impact of sex in neuroscience and neuropsychopharmacology, including 9 review papers and 17 research articles highlighting investigation in different species (zebrafish, mice, rats, and humans). Each contribution covers scientific topics that overlap with genetics, endocrinology, cognition, behavioral neuroscience, neurology, and pharmacology. Investigating the extent to which sex differences can impact the brain and behavior is key to moving forward in neuroscience research.

Audiogenic seizure as a model of sudden death in epilepsy: A comparative study between four inbred mouse strains from early life to adulthood.

OBJECTIVE: Mouse models of sudden unexpected death in epileptic patients (SUDEP) using audiogenic seizures (AGS) are valuable because death can occur following a sound-induced seizure in the absence of any pharmacologic or electric component. However, only a few strains of mice are AGS prone, and the vast majority of studies involve DBA/2 or DBA/1 inbred strains. With the goal of characterizing the variation of AGS susceptibility with age, and of offering a larger panel of mice available for AGS studies, we performed a comparative study of the variability in AGS responses. METHODS: The variation of AGS with age was determined in two classically used inbred strains of mice, DBA/2 and DBA/1, and two additional strains, BALB/c and 129/SvTer. As AGS-stimulated tonic seizures can be lethal or nonlethal, even in the same inbred strain, in a second experiment, we addressed whether there is an innate capacity to reproduce the same response after a tonic AGS, referred to as "determinism," in the DBA/2J, DBA/1J, and 129/SvTer mouse strains. RESULTS: Results show that the 129/SvTer mouse is a more versatile model of SUDEP due to its wider age range of susceptibility compared to the DBA/2J and DBA/1J mouse strains. In addition, we show that determinism is not consistently evident in DBA/2J and 129/SvTer strains after AGS. Hence, one cannot be certain that a lethal AGS will always be lethal in successive testing after resuscitation and vice versa in these two mouse strains. SIGNIFICANCE: These studies highlight the phenotypic variability of AGS in different mouse strains, show the value of an additional mouse strain, 129/SvTer, for studies using AGS, and thus provide valuable information for future studies of AGS and SUDEP.

Effect of sertraline on central serotonin and hippocampal plasticity in pregnant and non-pregnant rats.

One of the most frequently prescribed selective serotonin reuptake inhibitor medications (SSRIs) for peripartum mood and anxiety disorders is sertraline (Zoloft®). Sertraline can help alleviate mood and anxiety symptoms in many women but it is not known how sertraline, or SSRIs in general, affect the neurobiology of the brain particularly when pregnant. The aim of this study was to investigate how sertraline affects plasticity in the hippocampus, a brain area integral in depression and SSRI efficacy (particularly in males), during late pregnancy and whether these effects differ from the effects of sertraline in non-pregnant females. To do this pregnant and age-matched non-pregnant female Sprague-Dawley rats were used. For the last half of pregnancy (10 days), and at matched points in non-pregnant females, rats were given sertraline (2.5 mg/kg/day or 10 mg/kg/day) or vehicle (0 mg/kg/day). Brains were used to investigate effects on the serotonergic system in the hippocampus and prefrontal cortex and measures of neuroplasticity in the hippocampus. Results show that pregnant females have significantly higher serum levels of sertraline compared to non-pregnant females but that rates of serotonin turnover in the hippocampus and PFC are similar between pregnant and non-pregnant females. Sertraline increased synaptophysin density in the dentate gyrus and CA3 and was associated with a decrease in cell proliferation in the dentate gyrus of non-pregnant, but not pregnant, females. During late pregnancy the hippocampus showed significant reductions in neurogenesis and increases in synaptophysin density. This research highlights the need to consider the unique effect of reproductive state on the neuropharmacology of SSRIs.

Moving Forward From COVID-19: Bridging Knowledge Gaps in Maternal Health With a New Conceptual Model.

As the world faces the health crisis of a global pandemic-with healthcare protocols in overhaul, and patients and care teams experiencing unprecedented levels of stress and unpredictability-we predict that current knowledge gaps in maternal health will inevitably have a lasting impact on the health of women giving birth now and in the near future. Since we are decades away from closing the knowledge gaps we need filled today, we recommend shifting thinking toward a comprehensive conceptual model that merges knowledge of stress physiology, neurobiology, and pregnancy physiology. The model we present here, the Maternal Reactive Scope Model, is an expansion of the Reactive Scope Model built upon the concept of Homeostasis and Allostasis. The model provides a framework to consider pathways and interactions across physiological systems to attribute a physiological basis for considering stress exposure and bridge research gaps on mechanisms to measure or target for treatment. Our intention is to provide an adaptable, heuristic framework for discussion of research considerations and new healthcare models that aim to provide the best care for new mothers during and after the COVID-19 pandemic.

Glyphosate and glyphosate-based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome.

Glyphosate is found in a large array of non-selective herbicides such as Roundup® (Monsanto, Creve Coeur, MO, USA) and is by far the most widely used herbicide. Recent work in rodent models suggests that glyphosate-based herbicides during development can affect neuronal communication and result in altered behaviours, albeit through undefined mechanisms of action. To our knowledge, no study has investigated the effects glyphosate or its formulation in herbicide on maternal behaviour and physiology. In the present study, relatively low doses of glyphosate (5 mg kg-1  d-1 ), Roundup® (5 mg kg-1  d-1 glyphosate equivalent), or vehicle were administered by ingestion to Sprague-Dawley rats from gestational day (GD) 10 to postpartum day (PD)22. The treatments significantly altered licking behaviour toward pups between PD2 and PD6. We also show in the dams at PD22 that Roundup exposure affected the maturation of doublecortin-immunoreactive new neurones in the dorsal dentate gyrus of the hippocampus of the mother. In addition, the expression of synaptophysin was up-regulated by glyphosate in the dorsal and ventral dentate gyrus and CA3 regions of the hippocampus, and down-regulated in the cingulate gyrus. Although a direct effect of glyphosate alone or its formulation on the central nervous system is currently not clear, we show that gut microbiota is significantly altered by the exposure to the pesticides, with significant alteration of the phyla Bacteroidetes and Firmicutes. This is the first study to provide evidence that glyphosate alone or in formulation (Roundup) differentially affects maternal behaviour and modulates neuroplasticity and gut microbiota in the mother.

Serotonin and motherhood: From molecules to mood.

Emerging research points to a valuable role of the monoamine neurotransmitter, serotonin, in the display of maternal behaviors and reproduction-associated plasticity in the maternal brain. Serotonin is also implicated in the pathophysiology of numerous affective disorders and likely plays an important role in the pathophysiology of maternal mental illness. Therefore, the main goals of this review are to detail: (1) how the serotonin system of the female brain changes across pregnancy and postpartum; (2) the role of the central serotonergic system in maternal caregiving and maternal aggression; and (3) how the serotonin system and selective serotonin reuptake inhibitor medications (SSRIs) are involved in the treatment of maternal mental illness. Although there is much work to be done, studying the central serotonin system's multifaceted role in the maternal brain is vital to our understanding of the processes governing matrescence and the maintenance of motherhood.