Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2-9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3',4'-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Traumatic brain injury promotes neurogenesis at the cost of astrogliogenesis in the adult hippocampus of male mice.

Traumatic brain injury (TBI) can result in long-lasting changes in hippocampal function. The changes induced by TBI on the hippocampus contribute to cognitive deficits. The adult hippocampus harbors neural stem cells (NSCs) that generate neurons (neurogenesis), and astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, it is not known how TBI may affect hippocampal astrogliogenesis. Using a controlled cortical impact model of TBI in male mice, single cell RNA sequencing and spatial transcriptomics, we assessed how TBI affected hippocampal NSCs and the neuronal and astroglial lineages derived from them. We observe an increase in NSC-derived neuronal cells and a concomitant decrease in NSC-derived astrocytic cells, together with changes in gene expression and cell dysplasia within the dentate gyrus. Here, we show that TBI modifies NSC fate to promote neurogenesis at the cost of astrogliogenesis and identify specific cell populations as possible targets to counteract TBI-induced cellular changes in the adult hippocampus.

Maternal stress in the postpartum period is associated with altered human milk fatty acid composition.

BACKGROUND & AIMS: Maternal stress in the postpartum period affects not only the mother, but also her newborn child who is at increased risk for a wide range of disorders later in life. The mechanisms underlying transmission of maternal stress to the child remain elusive. Human milk (HM) is a potential candidate and is an important source of fatty acid (FA), which are crucial for child (neuro)development. This study aims to investigate whether maternal psychological and biological stress influences HM FA composition over the first month postpartum. METHODS: The Amsterdam Mother's Milk study is a prospective cohort study. We included lactating women who delivered at term with a large range of stress levels: a high stress (HS) group, women whose child was hospitalized for a minimum of 2 days (n=23) and a control (CTL) group, women who gave birth to a healthy child (n=73). HM was collected three times a day at postpartum days 10, 17 and 24. Perceived psychological stress was measured using multiple validated questionnaires, while biological stress measures were based on cortisol in hair, saliva and HM. HM FAs were analyzed by gas-chromatography and compared between groups. RESULTS: Maternal perceived stress scores were significantly higher in the HS group (p < 0.01), whereas cortisol measurements did not differ between groups. The absolute concentrations of total FA in HM (p=0.023), including the total amount of poly unsaturated fatty acids (PUFAs) (p=0.022) and omega-6 PUFAs (p=0.018), were lower in the HS group compared to the CTL group. Relative values of FAs did not differ between groups. CONCLUSION: Maternal stress in the first month postpartum was associated with overall lower levels of FA in HM. This possibly indicates a route of transmission of maternal stress signals to the infant. Future research should investigate if these stress-induced changes in HM FAs have consequences for child development.

Psychiatric characteristics of older persons with medically unexplained symptoms: A comparison with older patients suffering from medically explained symptoms.

BACKGROUND: Empirical studies on the clinical characteristics of older persons with medically unexplained symptoms are limited to uncontrolled pilot studies. Therefore, we aim to examine the psychiatric characteristics of older patients with medically unexplained symptoms (MUS) compared to older patients with medically explained symptoms (MES), also across healthcare settings. METHODS: A case-control study including 118 older patients with MUS and 154 older patients with MES. To include patients with various developmental and severity stages, patients with MUS were recruited in the community (n = 12), primary care (n = 77), and specialized healthcare (n = 29). Psychopathology was assessed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (Mini-International Neuropsychiatric Interview) and by dimensional measures (e.g., psychological distress, hypochondriasis, and depressive symptoms). RESULTS: A total of 69/118 (58.5%) patients with MUS met the criteria for a somatoform disorder according to DSM-IV-TR criteria, with the highest proportion among patients recruited in specialized healthcare settings (p = 0.008). Patients with MUS had a higher level of psychological distress and hypochondriasis compared to patients with MES. Although psychiatric disorders (beyond somatoform disorders) were more frequently found among patients with MUS compared to patients with MES (42.4 vs. 24.8%, p = 0.008), this difference disappeared when adjusted for age, sex, and level of education (odds ratio = 1.7 [95% confidence interval: 1.0-3.0], p = 0.070). CONCLUSIONS: Although psychological distress is significantly higher among older patients with MUS compared to those with MES, psychiatric comorbidity rates hardly differ between both patient groups. Therefore, treatment of MUS in later life should primarily focus on reducing psychological distress, irrespective of the healthcare setting patients are treated in.

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

Insult-induced aberrant hippocampal neurogenesis: Functional consequences and possible therapeutic strategies.

Adult hippocampal neurogenesis plays a critical role in a wide spectrum of hippocampus-dependent functions. Brain pathologies that involve the hippocampus like epilepsy, stroke, and traumatic brain injury, are commonly associated with cognitive impairments and mood disorders. These insults can affect neural stem cells and the subsequent neurogenic cascade in the hippocampus, resulting in the induction of aberrant neurogenesis, which is thought to compromise hippocampal network function, thereby hampering hippocampus-dependent behavior. We here summarize recent preclinical literature on hippocampal insult-induced changes in neurogenesis and based on that, we propose that normalizing aberrant neurogenesis post-insult may help to prevent or rescue behavioral deficits which could help develop novel therapeutic strategies.

Prefrontal alterations in GABAergic and glutamatergic gene expression in relation to depression and suicide.

People that committed suicide were reported to have enhanced levels of gene transcripts for synaptic proteins in their prefrontal cortex (PFC). Given the close association of suicide with major depressive disorder (MDD), we here assessed whether these changes are related to suicide or rather to depression per se. We used quantitative PCR to determine mRNA levels of 32 genes encoding for proteins directly involved in glutamatergic or GABAergic synaptic transmission in postmortem samples of the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). Seventy-two brain samples from 3 groups of subjects were derived from the Stanley Medical Research Institute (SMRI): i) patients with MDD who committed suicide (MDD-S), ii) MDD patients who died of non-suicidal causes (MDD-NS) and iii) age-matched, non-psychiatric control subjects. In the ACC, a significantly enhanced expression of genes related to glutamatergic or GABAergic synaptic transmission was found only in MDD-S patients, whereas in MDD-NS patients, decreased levels for these transcripts were found. Moreover, in the DLPFC, expression of these genes was decreased in MDD-S, relative to MDD-NS patients, whereas both groups showed increased expression compared to control subjects. In conclusion, our findings indicate that MDD is associated with increases in GABA and glutamate related genes in the DLPFC (irrespective of suicide), while in the ACC, the increase in GABA and glutamate related genes may relate to suicide, rather than to MDD per se.

Ghrelin and hypothalamic NPY/AgRP expression in mice are affected by chronic early-life stress exposure in a sex-specific manner.

Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin's receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders.

[Approaching psychological problems like a general practitioner]. / Psychische problemen benaderen als een huisarts.

An important cause of the high prescription levels of psychotropic medication for psychological symptoms is that these symptoms are assessed according to the same model as applied for physical symptoms, the disease model. This has led to a one-sided medical approach to psychological symptoms. A person-centred approach offers an alternative; the positive aspects of the disease-centred approach are retained and attention for the patient and his/her context become the central focal point for the general practitioner. Important elements of the person-centred approach are empathy, a good doctor-patient relationship, a shared approach to problem definition and understanding of the patient's problem, development of a therapeutic alliance, and a focus on the patient's hopes and expectations. If additional primary care-based treatment by mental health practice nurses is indicated, this model could be suitable since it is based on patients' strengths and focuses on personal growth rather than reduction of symptoms.

Early-life stress diminishes the increase in neurogenesis after exercise in adult female mice.

Exposure to early-life stress (ES) has long-lasting consequences for later cognition and hippocampal plasticity, including adult hippocampal neurogenesis (AHN), i.e., the generation of new neurons from stem/progenitor cells in the adult hippocampal dentate gyrus. We had previously demonstrated a sex-specific vulnerability to ES exposure; female mice exposed to ES from P2-P9 exhibited only very mild cognitive changes and no reductions in AHN as adult, whereas ES-exposed male mice showed impaired cognition closely associated with reductions in AHN. Given the apparent resilience of AHN to ES in females, we here questioned whether ES has also altered the capacity to respond to positive stimuli for neurogenesis. We therefore investigated whether exercise, known for its strong pro-neurogenic effects, can still stimulate AHN in adult female mice that had been earlier exposed to ES. We confirm a strong pro-neurogenic effect of exercise in the dorsal hippocampus of 8-month-old control female mice, but this positive neurogenic response is less apparent in female ES mice. These data provide novel insights in the lasting consequences of ES on hippocampal plasticity in females and also indicate that ES might lastingly reduce the responsiveness of the hippocampal stem cell pool, to exercise, in female mice.

Health assessment instruments for people with intellectual disabilities-A systematic review.

BACKGROUND: People with intellectual disabilities (ID) experience health disparities and are less likely to undergo recommended age- and gender-specific screening and health promotion. New diagnoses are frequently missed. Assessments with the aid of health assessment instruments are a way to address these problems. AIM: The aim of this review is to find the available health assessment instruments for people with ID used in primary care and evaluate their quality. METHODS: We conducted an electronic literature search of papers published between January 2000 and May 2016. After a two-phase selection process (kappa: 0.81 and 0.77) we collected data from the 29 included peer-reviewed articles on the following four domains; development, clinimetric properties (i.e. validity, reliability, feasibility, acceptability), content (i.e. ID-related health problems, prevention and health promotion topics) and effectiveness of the instruments. RESULTS/CONCLUSIONS: We distinguished 20 different health assessment instruments. Limited information was found on the development of the instruments as well as on their clinimetric properties. The content of the instruments was rather diverse. The included papers agreed that health assessment instruments are effective. However, only three instruments evaluated effectiveness in a randomised controlled trial. Patients with ID, carers and general practitioners (GPs) generally appreciated the health assessment instruments. IMPLICATION: Two instruments, "Stay well and healthy -Health risk appraisal (SWH-HRA)"and the "Comprehensive Health Assessment Programme (CHAP)", appeared to have the highest quality. These instruments can be used to construct a health assessment instrument for people with ID that meets scientific standards.

Exposure to chronic early-life stress lastingly alters the adipose tissue, the leptin system and changes the vulnerability to western-style diet later in life in mice.

Early-life stress (ES) increases the vulnerability to develop psychopathologies and cognitive decline in adulthood. Interestingly, this is often comorbid with metabolic disorders, such as obesity. However, it is unclear whether ES leads to lasting metabolic changes and to what extent this is associated with the ES-induced cognitive impairments. Here, we used an established chronic ES mouse model (from postnatal day (P) 2 to P9) to investigate the short- and long-term effects of ES exposure on parameters of the adipose tissue and the leptin system (i.e. circulating levels and gene expression of leptin and its receptor) in both sexes. Immediately following ES, the offspring exhibited reductions in white adipose tissue (WAT) mass, plasma leptin levels and in leptin mRNA expression in WAT. Furthermore, ES exposure led to increased brown adipose tissue and browning of WAT, which was evident by a drastic increase in uncoupling protein 1 mRNA expression in the inguinal WAT at P9. Notably, the ES-induced reductions in WAT mass, plasma leptin and leptin expression in WAT were sustained into adulthood and were accompanied by changes in body fat distribution, such as a higher ratio between mesenteric WAT and other WATs. Interestingly, while ES exposure increased leptin receptor mRNA expression in the choroid plexus, it was unaltered in the hippocampus. This suggests an adaptation to maintain central leptin homeostasis following ES exposure. In addition, chronic ES exposure resulted in the well-established cognitive impairment in object recognition performance during adulthood, which correlated positively with reductions in WAT mass observed in male, but not in female mice. Finally, to assess if ES leads to a different metabolic phenotype in a moderate obesogenic environment, we measured body fat accumulation of control and ES-exposed mice in response to a moderate western-style diet (WSD) that was provided during adulthood. ES-exposed mice subjected to WSD exhibit a higher increase in adiposity when compared to controls, suggesting that ES exposure might result in a higher vulnerability to develop obesity in a moderate obesogenic environment. To conclude, chronic ES exposure alters parameters of the adipose tissue, leads to central adaptations in leptin regulation and results in higher fat accumulations when exposed to a WSD challenge later in life. A better understanding of these metabolic effects induced by ES might open up new avenues for therapeutic (e.g. nutritional) interventions.

Effects of early-life stress on cognitive function and hippocampal structure in female rodents.

We tested the effect of early-life stress (ELS) - 24h maternal deprivation (MD) at postnatal day (PND) 3 - on cognitive performance and hippocampal structure in 12-17-week-old female rats. Behavioral performance was examined in: the Elevated Plus Maze, as an index for general anxiety; the rodent Iowa gambling test, probing reward-based decision making; and the object recognition and object-in-location task, to assess non-stressful contextual memory performance. We further determined hippocampal dentate gyrus (DG) volume and cell density as well as adult proliferation and neurogenesis rates. Half of the rats was treated with the glucocorticoid receptor antagonist mifepristone during a critical pre-pubertal developmental window (PNDs 26-28), in an attempt to ameliorate the potentially adverse behavioral consequences of ELS. Neither MD nor treatment with the glucocorticoid antagonist affected behavioral performance of the females in any of the tasks. Also, DG structure, proliferation and neurogenesis were not different between the groups. Lack of structural differences and a behavioral phenotype in non-stressful hippocampus dependent learning tasks fits with the lack of phenotype generally reported after ELS in female but less so in male rodents. As evident from an extensive literature review, female and male animals appear to respond more similarly to early-life adversity when tested in anxiety-related tasks. This agrees with recent findings in humans suggesting that females may be relatively resilient to the structural/hippocampal effects of childhood maltreatment, but not to the anxiety and mood-related psychopathology for which childhood maltreatment is considered a risk factor.

Context as a drug: some consequences of placebo research for primary care.

OBJECTIVE: On the basis of emerging research evidence, this review aims to discuss the importance of the context surrounding the doctor-patient encounter for the success of treatment. DESIGN AND SETTING: Discussion paper based on placebo-nocebo and pain studies conducted in the western world. MAIN OUTCOME MEASURES: Literature-based theory about impact of communication elements on seriousness of symptoms in clinical practice. RESULTS: The therapeutic outcome seems to be impacted by rituals around a clinical encounter and by the doctor patient communication and relation. A warm, friendly and empathic attitude is crucial in the first contact with the practice and during the consultation as it influences the patient's perceived outcome. It is important to raise positive expectations when discussing the prognosis, conducting treatment and prescribing medications as the effect may be reduced if the physician expresses doubt about the effectiveness of the medication. Additionally, overly focus on side effects in the doctor-patient conversation about proposed treatments seems to influence the magnitude of perceived side effects in the patient. Thus, shared decision-making might be a desirable tool for ensuring better expectations in the patient and successful symptom relief. CONCLUSIONS: The context of the doctor-patient interplay matters. Placebo-nocebo research provides strong evidence for this link. The therapeutic context induces biomedical processes in the patient's brain that may enhance or reduce the effects of chosen interventions. The context thus works as a drug, with real effects and side effects. KEY POINTS Increased awareness of the context drug may help GPs alleviate symptoms and better motivate patients for treatment. Treatment is affected by multiple types of context, as also confirmed by placebo-nocebo research. The therapeutic context influences the biomedical processes, which may enhance or reduce intervention effects on symptoms. The impact of context should be considered in daily general practice as it may serve as a drug, with real effects and side effects.

Big Five personality traits and medically unexplained symptoms in later life.

BACKGROUND: Personality dysfunction has been postulated as the most clinically salient problem of persons suffering from medically unexplained symptoms (MUS) but empirical studies are scarce. This study aims to compare the personality profile of older patients suffering from MUS with two comparison groups and a control group. METHODS: Ninety-six older patients with MUS were compared with 153 frequent attenders in primary care suffering from medically explained symptoms (MES), 255 patients with a past-month depressive disorder (DSM-IV-TR), and a control group of 125 older persons. The Big Five personality domains (NEO-Five-Factor Inventory) were compared between groups by multiple ANCOVAs adjusted for age, sex, education, partner status and cognitive functioning. Linear regression analyses were applied to examine the association between health anxiety (Whitley Index) and somatization (Brief Symptom Inventory). RESULTS: The four groups differed with respect to neuroticism (P<0.001), extraversion (P<0.001), and agreeableness (P=0.045). Post hoc analyses, showed that MUS patients compared to controls scored higher on neuroticism and agreeableness, and compared to depressed patients lower on neuroticism and higher on extraversion as well agreeableness. Interestingly, MUS and MES patients had a similar personality profile. Health anxiety and somatization were associated with a higher level of neuroticism and a lower level of extraversion and conscientiousness, irrespective whether the physical symptom was explained or not. CONCLUSIONS: Older patients with MUS have a specific personality profile, comparable to MES patients. Health anxiety and somatization may be better indicators of psychopathology than whether a physical symptom is medically explained or not.

[Depression prevention in primary care is not worthwhile]. / Depressiepreventie in de eerste lijn is niet zinvol.

An increasing number of prevention programmes are being introduced in primary and secondary care. Patients seldom doubt the usefulness of these programmes, but doctors more frequently do. Primary care programmes for prevention of depression require a high level of effort, but are not very effective: the incidence of new depressive episodes is relatively low, and there is a high percentage of drop-outs from intervention programmes. We need to look critically at the ever increasing expansion of screening and prevention activities in the general practitioner's (GP's) practice, because the fuller the GP's agenda the less time there is for the patient's personal story.

Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide.

There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.

Effects of long-term methylphenidate treatment in adolescent and adult rats on hippocampal shape, functional connectivity and adult neurogenesis.

Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post-mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.

Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients.

Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis that stimulates glucocorticoid (GC) release from the adrenal. These hormones exert numerous effects in the body and brain and bind to a.o. glucocorticoid receptors (GR) expressed in the limbic system, including the hippocampus and amygdala. Hyperactivity of the HPA axis and disturbed stress feedback are common features in major depression. GR protein is present in the human hypothalamus and hippocampus, but little is known-neither in healthy subjects nor in depressed patients-about GR expression in the amygdala, a brain structure involved in fear and anxiety. Since chronic stress in rodents affects GR expression in the amygdala, altered GR protein level in depressed versus healthy controls can be expected. To test this, we investigated GR-α protein expression in the post-mortem human amygdala and assessed changes in ten major or bipolar depressed patients and eight non-depressed controls. Abundant GR immunoreactivity was observed in the human amygdala, both in neurons and astrocytes, with a similar pattern in its different anatomical subnuclei. In major depression, GR protein level as well as the percentage of GR-containing astrocytes was significantly higher than in bipolar depressed patients or in control subjects. Taken together, the prominent expression of GR protein in the human amygdala indicates that this region can form an important target for corticosteroids and stress, while the increased GR expression in major, but not bipolar, depression suggests possible involvement in the etiology of major depression.

All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation.

Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-α (RAR-α) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus-pituitary-adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all-trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback. RA was applied to rats chronically through intracerebroventricular injection. A 19-day RA exposure induced potent HPA axis activation and typical depression-like behavior. Dexamethasone failed to suppress basal corticosterone (CORT) secretion, which is indicative of a disturbed GR negative feedback. In the hypothalamic paraventricular nucleus, increased CRH⁺ and c-fos⁺ cells were found while a negative R-2⁺/ER⁺ correlation was present between the number of RAR-α⁺ and GR⁺ cells. This was paralleled by increased RAR-α and decreased GR protein expression in the hypothalamus. Additional in vitro studies confirmed that RA abolished GR-mediated glucocorticoid-induced suppression of CRH expression, indicating a negative cross-talk between RAR-α and GR signaling pathways. Finally, the above changes could be rapidly normalized by treatment with GR antagonist mifepristone. We conclude that in addition to the 'classic' RAR-α-mediated transcriptional control of CRH expression, disturbances in GR negative feedback constitute a novel pathway that underlies RA-induced HPA axis hyperactivity. The rapid normalization by mifepristone may be of potential clinical interest in this respect.