Molly J Dickens

Ph.D Jodi L Pawluski
email: j.pawluski@univ-rennes1.fr

The HPA axis during the Perinatal Period: implications for Perinatal Depression (minireview)

Keywords: Pregnancy, depression, anxiety, postpartum depression, stress, cortisol, motherhood

The transition to motherhood is characterized by some of the most pronounced endocrine changes a women will experience in her lifetime. Unfortunately matrescence is also a time in a woman's life when she is most susceptible to mental illness such as perinatal depression. A growing body of research has aimed to determine how key endocrine systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, are involved in the dysregulation of perinatal mental health. However, very little research has consistently linked perinatal changes in the HPA axis with maternal mental illness. Therefore the aims of this mini review are to 1) clearly summarize the normative changes in the HPA axis that occur during pregnancy and the postpartum period;

2) summarize what we know about the HPA axis in perinatal depression, and 3) propose key areas for future research. Understanding physiological biomarkers that can predict which women are at risk for perinatal mood disorders will lead to better tools for treating and ultimately preventing these debilitating disorders; improving the health of mother, child and family.

Introduction

The perinatal period is marked by arguably the most pronounced endocrine changes a women will experience in her lifetime. These physiological changes in the mother are essential for pregnancy, birth, lactation, as well as child development and survival. Unfortunately the perinatal period is also a time when a woman is most susceptible to mental illness [START_REF] Munk-Olsen | Risks and predictors of readmission for a mental disorder during the postpartum period[END_REF][START_REF] Pawluski | The Neurobiology of Postpartum Anxiety and Depression[END_REF]. A growing body of research has aimed to discover how key endocrine systems are involved in the dysregulation of perinatal mental health [START_REF] Bloch | Endocrine factors in the etiology of postpartum depression[END_REF][START_REF] Gregoire | Transdermal oestrogen for treatment of severe postnatal depression[END_REF]. Because of its role in stress and the effects of stress in the development of mental illness [START_REF] Mcewen | Glucocorticoids, depression, and mood disorders: structural remodeling in the brain[END_REF] the hypothalamic-pituitary-adrenal (HPA) axis has been acknowledged as a key player in perinatal mental illnesses [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF]. However, very little research has consistently contributed changes in the HPA axis during pregnancy and/or the postpartum period with perinatal mental illnesses such as postpartum depression (arguably the most well studied maternal mental illness) [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF][START_REF] Orta | The association between maternal cortisol and depression during pregnancy, a systematic review[END_REF][START_REF] Guintivano | Predictors of Postpartum Depression: A Comprehensive Review of the Last Decade of Evidence[END_REF]. Therefore, the aims of this mini review are to 1) clearly summarize the normative changes in the HPA axis that occur during pregnancy, parturition and the postpartum period; 2) summarize what we know about the HPA axis in perinatal depression and, where possible, anxiety, from clinical research and animal models; and 3) propose key areas for future research. We have very little knowledge of the physiological basis of maternal mental illnesses yet the tragic consequences are clear -suicide is the leading cause of death in pregnant and postpartum women [START_REF] Gagliardi | Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations[END_REF]. Given the role that the HPA axis plays in mental illness outside of the perinatal period we hope this review will provide information for areas of future research on perinatal mental illnesses.

In writing this mini review we relied on recent studies and reviews in the area, as well as essential foundational studies related to HPA regulation and mental health, and HPA regulation during pregnancy and the postpartum period.

HPA and the Perinatal Period

The HPA axis is characterized by a cascade of hormones that regulates glucocorticoids (predominantly cortisol in humans, corticosterone in rodents, and for purposes of this review, we will be referring to cortisol). Often the HPA axis is associated with cortisol release in response to stress but its regulation also has important basic homeostatic functionalities beyond responding to acute stressors (e.g. metabolism, immune system regulation) [START_REF] Sapolsky | How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions[END_REF]. The hormone cascade is initiated in the corticotrophs of the paraventricular nucleus (PVN) of the hypothalamus, which release corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP), hormones that then stimulate the anterior pituitary gland to release adrenocorticotropin releasing hormone (ACTH) which stimulates the adrenal cortex to release cortisol [START_REF] Sapolsky | How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions[END_REF]. Increased cortisol concentrations exert negative feedback on all levels of the HPA axis via glucocorticoid receptors (GR) to ensure a relatively rapid return of cortisol to baseline concentrations [START_REF] Sapolsky | How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions[END_REF][START_REF] Dallman | Chronic stress and energy balance: role of the hypothalamo-pituitaryadrenal axis[END_REF].

Stimulation and maintenance of the HPA axis and cortisol signaling at the level of the adrenals relies on a number of factors and input from the brain to the circulation. Brain regions, such as the hippocampus, amygdala, and prefrontal cortex, for example, regulate the response to, and recovery from, an acute stress and play a role in daily functions such as cognition [START_REF] Herman | Neurocircuitry of stress: central control of the hypothalamo-pituitaryadrenocortical axis[END_REF][START_REF] Dedovic | The brain and the stress axis: the neural correlates of cortisol regulation in response to stress[END_REF]. In the bloodstream, corticosteroid binding globulin (CBG) regulates the bioavailability of cortisol to bind receptors [START_REF] Hammond | Determinants of steroid hormone bioavailability[END_REF]. Throughout the body, the presence (or absence) of these mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) impact the response and relative responsiveness to cortisol. In addition, MRs and GRs have different affinities for cortisol with MRs having 10x the affinity for cortisol when compared to GRs [START_REF] Kloet | Brain corticosteroid receptor balance in health and disease[END_REF]. For cells that express both of these receptor types (not all do), GRs only bind cortisol when cortisol levels reach stressinduced concentrations. At the cellular level, the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) converts glucocorticoids to an inactive form and, with CBG, determines the bioavailability of cortisol to bind the different receptor types [START_REF] Stewart | 11β-Hydroxysteroid Dehydrogenase[END_REF][START_REF] Whorwood | Tissue localization of 11βhydroxysteroid dehydrogenase and its relationship to the glucocorticoid receptor[END_REF][START_REF] Bolton | Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin[END_REF]. Pregnancy, birth, and lactation significantly change the way the HPA axis and circulating cortisol functions. Many important basic and new functionalities of the HPA hormones overlap such that increased cortisol concentrations (and to some degree, placental CRH (pCRH) that we will describe below) are responsible for critical stages of a healthy pregnancy. These stages include (but are not limited to) preparing the fetus for the outside world (maturation of systems thermoregulation, glucose metabolism, lung development, etc) (19-21), parturition [START_REF] Li | Roles of glucocorticoids in human parturition: a controversial fact?[END_REF], labor [START_REF] Talbert | Maternal and fetal serum levels of total cortisol and cortisone, unbound cortisol, and corticosteroid-binding globulin in vaginal delivery and cesarean section[END_REF], and activation of mammary glands and milk synthesis [START_REF] Casey | The role of glucocorticoids in secretory activation and milk secretion, a historical perspective[END_REF]. Perhaps due to these increased functionalities, basal cortisol concentrations rise throughout pregnancy. The steepest increase in cortisol levels occurs in the final weeks of pregnancy, reaching 2-5 times non-pregnant concentrations, but with great variability between individuals (as reviewed in [START_REF] Lindsay | The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment[END_REF]). The diurnal rhythm of the HPA axis appears to be blunted during this time [START_REF] Atkinson | The hypothalamic-pituitary-adrenal axis in rat pregnancy and lactation: circadian variation and interrelationship of plasma adrenocorticotropin and corticosterone[END_REF] as is the HPA response to acute stress in pregnancy [START_REF] Neumann | Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes[END_REF] and lactation [START_REF] Lightman | Alterations in hypothalamic-pituitary responsiveness during lactation[END_REF][START_REF] Slattery | No stress please! Mechanisms of stress hyporesponsiveness of the maternal brain[END_REF].

The predominant factor responsible for the elevated basal cortisol concentrations in human pregnancy is not the HPA axis, but it is the placenta. During pregnancy, the placenta increasingly exerts its role as an endocrine gland. In addition to secreting estrogens and progesterone, the placenta releases its own version of CRH (placental CRH, pCRH) which is identical in structure and bioactivity to hypothalamic CRH (30) but due to its size likely does not cross the blood brain barrier [START_REF] Martins | Unidirectional specific and modulated brain to blood transport of corticotropin-releasing hormone[END_REF]. Placental CRH is responsible for the elevation in circulating cortisol concentrations [START_REF] King | Placental corticotrophin-releasing hormone, local effects and fetomaternal endocrinology[END_REF]. Importantly, pCRH, and subsequent increases in cortisol concentrations, do not follow the classic negative feedback system seen with hypothalamic CRH.

Instead, cortisol stimulates the human placenta to produce pCRH [START_REF] Robinson | Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta[END_REF][START_REF] Jones | Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta[END_REF] and, pCRH, in turn, continues to stimulate cortisol production which results in a positive feedback loop (Figure 1B). CBG levels also increase during pregnancy and decrease in the weeks and days prior to delivery [START_REF] Scott | The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels[END_REF]. The rise in CBG levels during gestation is not enough to decrease (or 'normalize') free cortisol concentrations; possibly due to the high affinity of CBG for rising progesterone levels [START_REF] Demey-Ponsart | Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy[END_REF].

Another marked difference between hypothalamic CRH and pCRH is that circulating pCRH is bound to a binding protein, CRH-BP. CRH-BP can modify the bioactivity of pCRH throughout pregnancy. This is especially true in the last few weeks of pregnancy when CRH-BP levels fall by nearly 50% and free circulating pCRH levels rise [START_REF] Mclean | Corticotropin-releasing Hormone in Human Pregnancy and Parturition[END_REF]. With changes in CRH-BP, pCRH concentrations increase exponentially across pregnancy (likely due to the positive feedback loop with cortisol), and a decreased response to cortisol negative feedback occurs along the HPA axis [START_REF] Smith | The nonsuppressibility of plasma cortisol persists after pregnancy[END_REF]. Thus, circulating cortisol concentrations continue to increase throughout pregnancy. Cortisol concentrations at the end of a healthy pregnancy reach concentrations only seen in non-pregnant individuals with severe HPA dysregulation, such as Cushing's Disease [START_REF] Magiakou | The hypothalamic-pituitary-adrenal axis and the female reproductive system[END_REF].

Even though pCRH is the factor responsible for circulating levels of maternal cortisol, the HPA axis during pregnancy still maintains a role in the maintenance of maternal HPA pulsatility (both circadian and ultradian rhythms) [START_REF] Stirrat | Pulsatility of glucocorticoid hormones in pregnancy: Changes with gestation and obesity[END_REF]. Since CRH in the brain is at nearly undetectable levels, AVP from the PVN is likely responsible for this prenatal HPA pulsatility [START_REF] Magiakou | The hypothalamic-pituitary-adrenal axis and the female reproductive system[END_REF].

Although concentrations of cortisol during pregnancy reach levels well beyond what is

normally seen in a healthy, non-pregnant, individual, it has been suggested that maternal cortisol can't be too high. Exposure to optimal and adaptive circulating cortisol concentrations facilitate growth and development of the fetus and supports the maintenance of pregnancy. To protect the fetus from cortisol levels outside of an optimal range placental 11β-HSD metabolizes maternal cortisol [START_REF] Edwards | Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension?[END_REF]. In addition, during pregnancy and into the postpartum period the responsiveness of the HPA axis to stress is blunted, and this reduced HPA axis response may act to further protect the mother and neonate (41)(as reviewed in ( 42)). From the data available, it remains unclear what neuroendocrine mechanisms in the human maternal brain underlie the changes in HPA reactivity across the perinatal period. Specifically, how the perinatal changes in concentrations of cortisol and placental CRH (pCRH) affect the regulatory regions of the HPA axis and the ability of the maternal HPA axis to respond to stress remains to be determined. For example, the down regulation of hypothalamic CRH from the PVN during gestation, as described above, may be due to strong negative feedback of the elevated circulating cortisol concentrations. As it is unlikely that pCRH crosses the blood brain barrier from the circulation [START_REF] Martins | Unidirectional specific and modulated brain to blood transport of corticotropin-releasing hormone[END_REF], therefore the blunted HPA response to stress may be due to elevated concentrations of cortisol reaching the brain and changes in GR density in the hippocampus. However, any alterations at the level of the PVN, prefrontal cortical areas, or additional brain regions via pregnancy-related cortisol concentrations or lack of CRH release have not been well defined in humans.

During parturition there is a marked increase in cortisol, particularly during a vaginal delivery as compared to C-section [START_REF] Talbert | Maternal and fetal serum levels of total cortisol and cortisone, unbound cortisol, and corticosteroid-binding globulin in vaginal delivery and cesarean section[END_REF][START_REF] Pawluski | Prenatal SSRI exposure alters neonatal corticosteroid binding globulin, infant cortisol levels, and emerging HPA function[END_REF][START_REF] Isherwood | Effects of delivery on fetal unbound cortisol concentration[END_REF]. This increase in cortisol at delivery is a response to the intensity of labor and is likely essential for preparing the neonate for the outside world.

Then, with the delivery of the placenta, the source of pCRH is removed. Plasma CRH levels return to normal, pre-pregnancy, concentrations within 15 hours of delivery [START_REF] Campbell | Plasma corticotropinreleasing hormone concentrations during pregnancy and parturition[END_REF]. Cortisol also dramatically decreases in the days and weeks postpartum [START_REF] Kirschbaum | Salivary cortisol in psychobiological research: an overview[END_REF] contributing to a dramatic shift in HPA axis regulation [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF].

It is interesting to note that glucocorticoid levels differ with maternal experience in both humans and rodent models. For example, multiparous women show a smaller magnitude of change in circulating cortisol levels postpartum compared to primiparous women [START_REF] Grajeda | Stress during labor and delivery is associated with delayed onset of lactation among urban Guatemalan women[END_REF] and biparous female rats have less pronounced changes in corticosterone and CBG levels compared to age-matched primiparous females [START_REF] Pawluski | Reproductive experience alters corticosterone and CBG levels in the rat dam[END_REF]. Others report that parity and feeding type (lactation vs bottle feeding) play a role in cortisol levels and HPA function postpartum such that breastfeeding multiparous mothers show reduced cortisol levels and reduced cortisol responsiveness to psychology stress compared to non-breastfeeding multiparous mothers [START_REF] Tu | Diurnal salivary cortisol levels in postpartum mothers as a function of infant feeding choice and parity[END_REF][START_REF] Tu | Multiparity reveals the blunting effect of breastfeeding on physiological reactivity to psychological stress[END_REF]. In this study, feeding type did not affect cortisol levels of primiparous mothers [START_REF] Tu | Diurnal salivary cortisol levels in postpartum mothers as a function of infant feeding choice and parity[END_REF][START_REF] Tu | Multiparity reveals the blunting effect of breastfeeding on physiological reactivity to psychological stress[END_REF]. This suggests that maternal experience may act to further alter the maternal HPA axis. This is perhaps not surprising given that glucocorticoids play an important role in the initiation and maintenance of maternal care-giving behaviors, particularly in primiparous mothers. For example, Fleming et al (1997) report that first-time mothers with elevated cortisol concentrations are more attracted to their own infant's body odor [START_REF] Fleming | Cortisol, hedonics, and maternal responsiveness in human mothers[END_REF]. In rodents, corticosterone is important for the pup retrieval, maternal memory, and maintenance of maternal care [START_REF] Graham | The effects of adrenalectomy and corticosterone replacement on maternal memory in postpartum rats[END_REF][START_REF] Rees | The effects of adrenalectomy and corticosterone replacement on induction of maternal behavior in the virgin female rat[END_REF][START_REF] Rees | The effects of adrenalectomy and corticosterone replacement on maternal behavior in the postpartum rat[END_REF]. Thus maternal experience alone may be an important regulator of the HPA axis during the postpartum period and, perhaps, during pregnancy.

HPA and Perinatal Mood Disorders

As Pariante and Lightman (2008) point out in their review focused on the HPA axis and major depression: "Considering its role at the interface between stress and brain functioning, it is perhaps not surprising that the HPA axis has been found abnormal in psychiatric disorders, and in particular in major depression." [START_REF] Pariante | The HPA axis in major depression: classical theories and new developments[END_REF]. But to truly understand how the HPA axis appropriately responds to stress and initiates, adapts, and maintains homeostasis, several factors must be considered. In the brain the response to stress is modulated by the distribution and localization of the two types of receptors, MR and GR, and their affinity for glucocorticoids, the release pattern of glucocorticoids (circadian and ultradian), circulating CBG, 11β-HSD concentrations and activity, and alterations in transcriptional regulators [START_REF] Joels | The stressed brain of humans and rodents[END_REF]. These factors determine how quickly neurons will respond to cortisol. There are a wide range of potential mechanisms -genetic, epigenetic, inflammatory, microbial, biochemical -regulating the HPA axis that may result in individual vulnerability to depression or anxiety [START_REF] Haim | A survey of neuroimmune changes in pregnant and postpartum female rats[END_REF][START_REF] Rackers | Emerging literature in the Microbiota-Brain Axis and Perinatal Mood and Anxiety Disorders[END_REF][START_REF] Foster | Stress & the gut-brain axis: Regulation by the microbiome[END_REF][START_REF] Barnes | Genetic Contributions of Inflammation to Depression[END_REF][START_REF] Ebner | Individual differences in stress susceptibility and stress inhibitory mechanisms[END_REF].

The important thing to point out is that a majority of studies to date that link the HPA axis with major depression (and those included in the review above) have been conducted in young male humans and rodents. The female brain is grossly understudied. This sex/gender bias in the literature is especially problematic given the differences between males and females, particularly with regards to gonadal steroid effects on the HPA axis [START_REF] Oyola | Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity[END_REF], HPA responsiveness and female vulnerability to stress-related mental health concerns [START_REF] Bangasser | Sex differences in stress responses: a critical role for corticotropin-releasing factor[END_REF].

Even without a detailed knowledge of the HPA axis in pregnancy and the postpartum period we do know that the dysregulation of the HPA axis is often implicated in mental illness in men and women; a recent meta-analysis shows that women with major depression or an anxiety disorder have blunted cortisol stress responses [START_REF] Zorn | Cortisol stress reactivity across psychiatric disorders: A systematic review and meta-analysis[END_REF], and increased cortisol awakening response (CAR) is often predictive to increased vulnerability of depression [START_REF] Dedovic | The brain and the stress axis: the neural correlates of cortisol regulation in response to stress[END_REF][START_REF] Hardeveld | Increased cortisol awakening response was associated with time to recurrence of major depressive disorder[END_REF]. The maternal brain, which is exposed to extreme changes in steroid hormones and HPA axis functionality, is even less understood but potentially far more complex and prone to dysregulation. Thus, dysregulation of the HPA axis seems a likely candidate for the onset of perinatal depression and anxiety. When talking about rates of maternal mental illness rates it should be noted that psychiatric admissions for women during the early postpartum period are higher than at any other time in a woman's life and that suicide is the leading cause of death in pregnant and postpartum women [START_REF] Gagliardi | Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations[END_REF][START_REF] Rackers | Emerging literature in the Microbiota-Brain Axis and Perinatal Mood and Anxiety Disorders[END_REF]. The perinatal period is also a time when a significant number of women suffer from elevated depression and/or anxiety. Up to 15% of women in industrialized countries will suffer from perinatal depression (PND) [START_REF] Horowitz | A longitudinal study of maternal postpartum depression symptoms[END_REF][START_REF] Strat | Prevalence and correlates of major depressive episode in pregnant and postpartum women in the United States[END_REF][START_REF] Fisher | Pregnancy, child birth and the postpartum period. Mental health aspects of women's reproductive health; a global review of the literature[END_REF] and rates of PND can be 2 to 3 times higher in developing countries [START_REF] Fisher | Prevalence, nature, severity and correlates of postpartum depressive symptoms in Vietnam[END_REF]. Four to twenty percent of women will experience mood disorders during pregnancy, the postpartum, or throughout the perinatal period [START_REF] Bennett | Prevalence of depression during pregnancy: systematic review[END_REF][START_REF] Ajinkya | Depression during pregnancy: Prevalence and obstetric risk factors among pregnant women attending a tertiary care hospital in Navi Mumbai[END_REF].

Anxiety disorders during the perinatal period are nearly as prevalent as PND [START_REF] Horowitz | A longitudinal study of maternal postpartum depression symptoms[END_REF][START_REF] Fleming | Postpartum Adjustment in First-Time Mothers: Relations between Mood, Maternal Attitudes and Mother-Infant Interactions[END_REF], however much less research has focused on the endocrinology of perinatal anxiety in women. For the purposes of this mini review, we focus on the HPA axis in PND.

The symptom profile of PND includes persistent factors such as sad mood, restlessness/agitation, and impaired concentration as well as a major depressive episode during pregnancy or the recent postpartum [START_REF] Association | Diagnostic and statistical manual of mental disorders[END_REF], resembling that of a major depressive disorder experienced at other times in life. PND is diverse, with up to 5 distinct subtypes being evident such as severe anxious depression, moderate anxious depression, and anxious anhedonia based on the type of symptoms, time of onset and severity [START_REF]Postpartum Depression: Action Towards C, Treatment C. Heterogeneity of postpartum depression: a latent class analysis[END_REF]. Thus, the profile of PND can be markedly different from woman to woman and the etiology, detection and treatment can vary widely. PND is often predicted by a prepartum history of either depression or anxiety, a number of psychosocial risk factors including abuse/trauma, family history of psychiatric illness, and discontinuing antidepressant medication during gestation [START_REF] Guintivano | Predictors of Postpartum Depression: A Comprehensive Review of the Last Decade of Evidence[END_REF][START_REF] Florio | Is Postpartum Depression a Distinct Disorder?[END_REF]. If left untreated PND can have detrimental effects on the mother leading to increased risk of substance abuse, poor nutrition, marital conflict, further episodes of depression and, in extreme cases, suicide [START_REF] Stewart | Postpartum Depression[END_REF][START_REF] Almond | Postnatal depression: a global public health perspective[END_REF]. Poor maternal mental health is also associated with a host of negative outcomes in children such as preterm birth, decreased cognitive ability, increased risk of psychiatric illness and altered social behaviors [START_REF] Almond | Postnatal depression: a global public health perspective[END_REF][START_REF] Glover | Prenatal stress and the programming of the HPA axis[END_REF][START_REF] Oberlander | Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence[END_REF].

Despite its prevalence and pervasive costs for the mother, child and family, our understanding of the biological bases of perinatal mood disorders is limited [START_REF] El | In search of neural endophenotypes of postpartum psychopathology and disrupted maternal caregiving[END_REF]. As mentioned previously, the HPA axis may be a key player in PND as it is strongly implicated in depression at other times in life, and its significant plasticity during the perinatal period may increase a mother's vulnerability to mental illness. But what do we really know about the HPA and PND?

In 2006 Krammer et al proposed that depression during pregnancy could be characterized by high levels of cortisol but depression during the postpartum period would be characterized by low levels of cortisol. They further hypothesized that depression during pregnancy would be more melancholic and depression during the postpartum period would be more atypical [START_REF] Kammerer | The HPA axis and perinatal depression: a hypothesis[END_REF].

This was an interesting idea that mapped on to the inherent physiological changes that occur in the HPA axis in pregnancy and the postpartum, as discussed above. Now, 12 years later, recent reviews of the studies that have taken place over the past 20 years investigating how the HPA axis may be linked to PND have shown that 1) often no relationship exists between cortisol and depressive symptoms during the perinatal period in women, 2) of the studies that do show a relationship between the HPA and PND it appears that indeed depression in pregnancy is characterized by very different HPA profiles from those of depression during the postpartum period [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF][START_REF] Orta | The association between maternal cortisol and depression during pregnancy, a systematic review[END_REF]. During pregnancy a recent systematic review on antepartum depression and cortisol levels shows that of the studies reporting an association between maternal depressive symptoms and cortisol, elevated cortisol concentrations during the 2 nd and 3 rd trimester are most often associated with antepartum depressive symptoms [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF][START_REF] Orta | The association between maternal cortisol and depression during pregnancy, a systematic review[END_REF]. Others report that maternal morning cortisol levels are reduced in pregnant women with major depression as diagnosed by a clinician [START_REF] Szpunar | A systematic review of cortisol, thyroid-stimulating hormone, and prolactin in peripartum women with major depression[END_REF]. In line with this, O'Connor et al (2014) note that pregnant women with major depression have significantly lower cortisol levels at waking but overall elevated average cortisol levels compared to controls [START_REF] O'connor | Diurnal cortisol patterns and psychiatric symptoms in pregnancy: short-term longitudinal study[END_REF]. Interestingly CBG, which is responsible for free cortisol levels in serum [START_REF] Bolton | Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin[END_REF], and has also be implicated in depression [START_REF] Ktiouet | Decrease in transcortin binding activity in depression[END_REF] but less well studied with regards to PND. Recent research has shown that both total serum levels of cortisol and CBG are negatively associate with depression symptoms in late pregnant women such that elevated levels of total cortisol or CBG are related to lower scores of depression during late pregnancy [START_REF] Pawluski | Prenatal SSRI exposure alters neonatal corticosteroid binding globulin, infant cortisol levels, and emerging HPA function[END_REF].

During the postpartum period there is a fall in cortisol and CRH in the days and weeks after birth. This decrease in cortisol and CRH may be linked to the onset of postpartum depression. Of the studies that do show a relationship between changes in the HPA axis and postpartum depression it is lower cortisol levels that are evident in women with postpartum depression (up to one year postpartum) [START_REF] Seth | Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review[END_REF][START_REF] Szpunar | A systematic review of cortisol, thyroid-stimulating hormone, and prolactin in peripartum women with major depression[END_REF][START_REF] Groer | Immune, health and endocrine characteristics of depressed postpartum mothers[END_REF][START_REF] Parry | Hormonal basis of mood and postpartum disorders[END_REF]. Recently [START_REF] Glynn | New insights into the role of perinatal HPA-axis dysregulation in postpartum depression[END_REF] proposed that prenatal HPA axis dysregulation may be predictive of postpartum depression with elevated or accelerated pCRH trajectories during gestation being associated with an exaggerated postpartum drop in cortisol leading to postpartum depression [START_REF] Glynn | New insights into the role of perinatal HPA-axis dysregulation in postpartum depression[END_REF][START_REF] Glynn | Evaluation of the association between placental corticotrophinreleasing hormone and postpartum depressive symptoms[END_REF]. Antepartum and postpartum depression are often in continuum and a recent study has shown that pregnant women with consistently elevated salivary cortisol levels have increased ante-and post-natal self-reported mood symptoms [START_REF] Laurent | Course of ante-and postnatal depressive symptoms related to mothers' HPA axis regulation[END_REF]. This points to the value of longitudinal research in determining the link between the HPA axis and maternal mood. Although these findings show that HPA axis dysregulation is linked to PND, more research is needed to determine how depression during pregnancy and/or the postpartum period is related to different factors of the HPA axis.

Furthermore, this future research needs to take into account the severity of depression, depression subtype and time point during pregnancy or postpartum.

One way to understand how the HPA axis is dysregulated is to assess how effective treatments alter its output via cortisol concentrations or HPA responsiveness. Although limited, some research shows that mothers with a high risk of developing depression who attend cognitive behavior therapy (CBT) classes have lower salivary cortisol levels and display lessened stress reactivity after a few sessions of CBT compared to non-treated high risk mothers [START_REF] Urizar | Impact of a prenatal cognitive-behavioral stress management intervention on salivary cortisol levels in low-income mothers and their infants[END_REF][START_REF] Richter | Effects of an early intervention on perceived stress and diurnal cortisol in pregnant women with elevated stress, anxiety, and depressive symptomatology[END_REF].

Others have shown that yoga or a support group can reduce depression, anxiety and anger in pregnant women as well as significantly reduce salivary cortisol levels [START_REF] Field | Yoga and social support reduce prenatal depression, anxiety and cortisol[END_REF]. SSRIs are often the first-line of treatment for PND [START_REF] Pawluski | The Neurobiology of Postpartum Anxiety and Depression[END_REF][START_REF] Charlton | Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: a population-based study in six European regions[END_REF][START_REF] Oberlander | Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data[END_REF] and even though SSRIs can alter the HPA axis in some individuals with depression [START_REF] Schule | Hypothalamic-pituitary-adrenocortical system dysregulation and new treatment strategies in depression[END_REF][START_REF] Ising | Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression -a potential biomarker?[END_REF] and animal models are pointing to a role of SSRIs in attenuating the stress response during the postpartum period [START_REF] Pawluski | Chronic fluoxetine treatment and maternal adversity differentially alter neurobehavioral outcomes in the rat dam[END_REF], clinical research has not clearly shown an effect of SSRIs on the HPA axis in women during the perinatal period [START_REF] Pawluski | Prenatal SSRI exposure alters neonatal corticosteroid binding globulin, infant cortisol levels, and emerging HPA function[END_REF].

Although there are significant differences between pregnancy and the postpartum period in humans and rodent models, rodents, and other animal models, can be valuable tools to manipulate and understand the contribution of the HPA axis to perinatal depression. A growing body of rodent research is showing that stress, or activation of the HPA axis prior to, or during, gestation can be a valuable model of postpartum depression. This activation of the maternal HPA axis prior to parturition can alter the HPA axis postpartum by decreasing basal corticosterone (similarly to what is seen in women with postpartum depression) and lead to increased depressive-and anxiety-like behavior in the rat dam postpartum [START_REF] Pawluski | Chronic fluoxetine treatment and maternal adversity differentially alter neurobehavioral outcomes in the rat dam[END_REF][START_REF] Hillerer | From stress to postpartum mood and anxiety disorders: how chronic peripartum stress can impair maternal adaptations[END_REF][START_REF] Hillerer | Exposure to chronic pregnancy stress reverses peripartum-associated adaptations: implications for postpartum anxiety and mood disorders[END_REF](100)(101)(102)(103). More recent research has shown that dysregulation of the HPA axis at the level of CRH neurons in the PVN (specifically the loss of K+/Cl-co-transporter) is sufficient to induce postpartum behavioral profiles modelling postpartum depression suggesting a potential target for future treatments (104).

As with research on the link between HPA activation and depression during pregnancy in women, rodent models are not clear on how activation of the HPA axis during gestation affects depressive-like behavior in the pregnant female. We do know that repeated stress during gestation can lead to decreased basal and stress-induced corticosterone levels in late pregnancy and decreased GR density in the CA3 region of the hippocampus (105,106). How these changes link to depressive-or anxiety-like behaviors in rodents during pregnancy remain to be determined.

Future directions

There is much more research that is needed in order to understand the link between the HPA axis and maternal mental illness. First, the mechanisms underlying HPA axis regulation and dysregulation in the human brain during pregnancy and postpartum are relatively unknown.

Much of what we know about the perinatal period at the neural level comes from rodent models (e.g. ( 42)). However, there are marked differences between gestation in humans and rodents (namely the rodent placenta does not produce pCRH and therefore does not exert effects on the perinatal HPA axis). In addition, we still have much to learn about the basic sex differences in the regulatory pathways feeding into the HPA axis (see review in [START_REF] Bangasser | Sex differences in stress responses: a critical role for corticotropin-releasing factor[END_REF]107), but evidence is mounting that the hormone fluctuations of the estrous/menstrual cycle may underlie female vulnerability to mental illness. Given that the perinatal period exposes females to even more extremes in hormone fluctuations, the connection between the HPA axis during the perinatal period and maternal mental illness should be an important target for future research.

Since our ability to study the human brain is limited one theoretical approach that may be valuable in understanding the relationship between the HPA axis, stress, hormone fluctuations and maternal mental illness is The Reactive Scope Model. This model expands the Allostasis Model for stress, and considers the delicate balance of maintaining homeostasis in the face of adaptive change (108). Pregnancy itself is not a disease state, yet it makes the body more vulnerable to a range of pathologies, from mood disorders to hypertension (109), diabetes (110), or cardiovascular disease (109). In the Reactive Scope Model, the range between Predictive/Reactive Homeostasis (adaptive -normal, non-pathological state) and Homeostatic Overload (maladaptive -pathological) becomes smaller when the physiological mechanisms maintaining homeostatic balance increasingly compensate for pressure on the system -elephants maintaining the balance on a seesaw rather than mice maintaining the balance. As the range between adaptive and maladaptive gets closer together, the likelihood of the body to 'tip' into pathology increases, the vulnerability increases. The third and "fourth" trimester (the first days and months into postpartum) represent a unique homeostatic state in a woman's body -in balance yet pushed to an extreme. Considering the HPA axis specifically, when additional predispositions are added that make the threshold even smaller, any activation beyond the normal functioning system such as an acute stress from any number of sources -a difficult birth, challenges with breastfeeding, adjusting to new motherhood -may push the maternal HPA axis into a state of overload and dysregulation. Applying this model allows researchers, clinicians, women, and their care team to consider the benefits of more "holistic" approaches to decrease the likelihood of her activating the stress pathways. Perhaps this is the underlying reason for the growing evidence that mindfulness, labor support and postpartum support have a positive effect on maternal mental health (111-114).

Clinical studies often rely on peripheral biomarkers of the HPA axis, of which cortisol is the most popular due to its detectability in saliva, hair or urine. However, AVP and CRH (during pregnancy) can also be detected from serum samples and it may be that the relationship of these factors to each other, or their change across time, is more important than the change in any one factor at any given time point. Previous research suggests that the progesterone to estradiol ratio across parturition is important for maternal attachment (115) and thus it may be that the AVP-Cortisol ratio or Cortisol-CRH ratio may be a better indicator of PND. That being said, it could also be the change over time of one, or a few, of these HPA biomarkers is a better indicator of PND. For these type of studies to be performed serum or plasma samples would have to be collected regularly and the relationship of these factors with their binding globulins would need to be accounted for.

Functional studies of the HPA axis prior to pregnancy may also be valuable in detecting how the HPA axis during pregnancy or the postpartum period may increase the susceptibility to the development perinatal depression or anxiety. Although there is limited research in this area, promising work by [START_REF] Bloch | Cortisol response to ovine corticotropin-releasing hormone in a model of pregnancy and parturition in euthymic women with and without a history of postpartum depression[END_REF] shows that women with a history of postpartum depression (PPD) have enhanced sensitivity at the level of the pituitary-adrenal axis to CRH stimulation tests (116). Thus, HPA stimulation tests may be valuable tools to investigate the risk of dysregulation of the HPA axis and how it relates to perinatal mental illness.

It should also be noted that the variability amongst individuals, the interplay between systems, and how homeostasis is maintained during pregnancy from the endocrine pathways to the level of cellular signaling is far too complex (and grossly understudied) for simple solutions to a growing health concern: 1 in 5 women will have a mental illness during the perinatal period! We need more resources dedicated for research on maternal mental illness to effectively treat and prevent the effects of these illnesses on mother, child and family.

Conclusions

The first recorded accounts of postpartum depression occurred in the 11 th or 13 th century where it was stated that "if the womb is too moist, the brain is filled with water, and the moisture running over the eyes, compels them to involuntarily shed tears" (117). Although we have moved forward in our understanding of perinatal depression, we still are in our infancy as to how a mother's physiology may be involved in her mental health during the perinatal period.

Figure 1 .

 1 Figure 1. Schematic representation summarizing the key components of the hypothalamic-

MJD is employed by Bloomlife: Smart Pregnancy Wearable. JLP has received consultant fees and lecture fees from Binc-Geneva (http://binc-geneva.org/).


Amira Rjiba
email: amira.rjiba@univ-rennes1.fr

Tahar Aifa

Mohamed Ghanmi

Ahref Boulares

Ahref Boulares

Tahar Aïfa

Achref Boulares

Geophysical data from Kalaa Khesba and Kalaat Senam grabens, Central Tunisian Atlas and their geodynamic implications

Keywords: Kalaa Khesba, Kalaat Senam, seismic, gravity, thrust

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The region of Kalaat Senam is located in the northwestern Tunisia, in which the geological evolution is strongly marked by the whole behavior of the north African Alpine Chain (Maghrebides) and the western Mediterranean (Fig. 1). Indeed, the central part of the country is marked by the existence of several NW-SE and WNW-ESE grabens (Burollet, 1991). Atlasic troughs are associated with strikeslips and evolve most often in pull-apart (Chihi, 1995). The study of Kalaat Senan area was performed within the framework of structural and geophysical analyses regarding the emplacement of troughs and associated structures. In fact, the major ultimate objective is to inspect the different interpretations and hypotheses considering the existence of geological conditions leading to the presence of hydrocarbons using geophysical techniques (2D seismic and gravimetric data). As a matter of fact, these methods allowed to (i) specify the deep structure of troughs, (ii) identify the major subsurface structures, and (iii) check the geometry borders of grabens.

lithostratigraphy

The lithostratigraphic formations of the Kalaat Senam area extend and outcrop from the Triassic to the Quaternary. In a manner that some formations, such as those of the Jurassic and the Paleocene series, outcrop only outside the region. While those of the Lower Cretaceous have a weak occurrence. Moreover several specific geological formations show variations in facies and possibly in thicknesses. The Triassic formations are presented in the shape of a chaotic lithological mixture, often largely taken up by the folding in a manner that it is impossible to develop a clear stratigraphic sequence. The Cretaceous series outcrop widely in the northern Tunisia and along the Tunisian Atlas. Indeed, in the Kalaat Senam region, the Cretaceous formations will be described through their facies: Aptian-Albian (Hamaima, Serdj with limestones which appearing at the top of diapirs of Bou El Hanèche, Dj. Jerissa and Dj. Slata (Lehotsky and Bujnowsky, 1995) and M'Cherga Formations), Albo-Cenomanian (Fahdene Formation), Cenomanian-Turonian (Bahloul Formation), Turonian-Campanian (Aleg Formation), Campanian-Maastrichtian (Abiod Formation). In the Upper Maastrichtian-Paleocene, the El Haria Formation corresponds to a series of dark gray clays or blackish ones. Consequently, they turn out to be easily identifiable in the field due to the color and morphology which are distinguished from the massive carbonate of Abiod and Metlaoui. In the Lower Eocene, a set of mainly carbonated series encompassing in its basal part a phosphate term of terminal Paleocene-Ypresian age constitutes the Chouabine Formation. In its middle part, the Eocene is represented by dominant carbonate alternations. Its upper part is represented by a carbonated term with nummulites of Ypresian-Lutetian age corresponding to the El Gueria Formation.

At the Late Paleocene-Lower Ypresian, the Chouabine Formation lies on top of the El Haria Formation. In fact, it is represented by an alternation sequence of phosphorite marls, marls and carbonates. The Miocene Formation is characterized by an alternation of sandstones, conglomerates and marls, and variegated marls rich of gypsum alternating with silts and sandstones. The continental Mio-Pliocene Formations are composed of conglomerates with sub-angular elements that are cemented by sandstones, alternating with a set of sandstones and clays.

Geophysical data

The geophysical data represents the 2D seismic data which result from the database of ETAP. The seismic survey profiles were realized by ETAP in the graben of Kalaat Senam in 1970 (P1), 1981 (P2), 2011 (P3), 1945 (P4), 1967 (P5), and 1969 (P6). The oil wells, considered in this study, are among six from W1 to W6 (Fig. 2). The seismic lines were established further to several seismic surveys, with different parameters of acquisition and processing stages. Their processing allowed us to improve the seismic sections for a better interpretation. The acquisition of gravimetric data was made using a CG3 gravity-meter within the framework of the Tunisian gravimetric Atlas. A general gravity overview was first conducted using a Worden gravitymeter in the Kalaat Senam-Kalaa Khesba area. A correlation between the density of Nettleton and the measured densities gave a regional density of 2.4 g.cm -3 .

Results and interpretation

The interpretation of the seismic lines, i.e. isochron, isovelocity and isobath maps allows to obtain a succession of tectonic events which succeeded one another between the Triassic and the Present day. Compressive phases of NW-SE direction appear to be responsible for block tilting and the creation of anticlinal and synclinal structures affected by many normal, reverse faults or strike-slips. The extension of the NE-SW direction guided the formation of structures in grabens, half-grabens and vast synclines. The seismic profiles show that the NW of Tunisia is characterized by lateral and deep variations of facies, unconformities, sedimentary gaps, and folded and faulted structures. This results in complex structures deduced from the superimposition of the compression phase during the Miocene. The interpretation of the gravimetric data (Bouguer, regional and residual anomaly maps, etc.) were made to better follow the behavior of the various accidents in the region and to follow their depths and dips (Spector and Grant, 1970;Thompson, 1982;Reid et al., 1990Reid et al., , 2003;;FitzGerald et al., 2004;Chen et al., 2014). These maps, based on several applied treatments (derivatives, Euler deconvolution, upward continuations, etc.), led to the definition of the lineaments related to the Atlasic tectonic regime (Figs. 3,4). The variation of anomalies on the maps indicates the depths of each structure. Within the Kalaa Khesba graben a negative anomaly at shallow depth, as well as a generally NW-SE fault direction bordering this graben, were identified. This anomaly reflects the existence of low density series compared to the basement density. At subsurface, well data located in the centre of the trough ensured the presence of Triassic material. Indeed, the gravimetric response in terms of anomaly presents the association of Triassic evaporites resulting in series of low density.

Conclusion

The study area belongs to an extended NW-SE domain that occupies a privileged place in the NW Paleogeography of Tunisia. Geological data analysis as well as the tectonic events of the Tunisian grabens of the central Atlas region that have been proposed (Ben Ayed, 1986;Chihi, 1995;Dlala, 2001), showed that the tackled series were presented from the Triassic to the Quaternary and helped us to explain the grabens border structure (Caire, 1971;Burollet and Rouvier, 1971;Ben Ayed, 1986;Chihi, 1995;Gabtni et al., 2016). The results were supported by seismic and gravimetric data interpretation. From seismic reflection, they show that (i) the horizons sequence within the grabens, (ii) the main faults orientations that have contributed to its current configuration, (iii) the activation of the bordering faults of the grabens as well as the large fault supporting fault branches leading to a flower structure. From gravimetry, they show (i) the faults activation and their movements, as well as (ii) the mobilization and raise of the Triassic material. Within the trough, a negative anomaly that reflects the existence of low density series, and an NW-SE fault direction bordering this graben were evidenced.

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Fig. 1 :

 1 Fig. 1: Simplified geological map of the study area extracted from the map of Tunisia at 1/50,000, projected on a WGS84 UTM Z32 N system. 1. Quaternary, 2. Mio-Pliocene, 3. Upper Miocene, 4. Oligocene, 5. Ypresian-Lutetian, 6. Coniacian-Maastrichtian, 7. Turonian, 8. Cenomanian, 9. Early Cretaceous, 10. Triassic.

Fig. 2 :

 2 Fig. 2: Map showing locations of seismic lines in the NW study area of Tunisia. W1-W6: oil wells.

Fig. 3 :

 3 Fig. 3: Bouguer anomaly map of Kalaa Khesba and Kalaat Senam computed using a density of 2.4 g.cm -3

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