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.

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.

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.

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.

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.

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment.

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX(+) cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX(+) cell number was significantly reduced. This was most profound for older (class II) DCX(+) cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX(+) cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.

Effects of educational interventions on primary dementia care: A systematic review.

OBJECTIVE: To determine the effects of educational interventions about dementia, directed at primary care providers (PCPs). DESIGN: We searched Medline, Embase, PsycInfo, Cinahl and the Cochrane library for relevant articles. Two researchers independently assessed the citations identified against the following inclusion criteria: educational intervention on dementia directed at PCPs and study designs being randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) or interrupted time series (ITS) analyses. Outcomes of interest were PCPs' knowledge and attitude on dementia, and quality of dementia care at PCP and patient level. RESULTS: Of 3953 citations identified, six articles representing five studies (four cluster RCTs and one CBA) were eligible, describing educational interventions directed at 1904 PCPs. Compliance to the interventions varied from 18 to 100%. Systematic review of the studies showed moderate positive results. Five articles reported at least some effects of the interventions. A small group workshop and a decision support system (DSS) increased dementia detection rates. An interactive 2-h seminar raised GPs' suspicion of dementia. Adherence to dementia guidelines only improved when an educational intervention was combined with the appointment of dementia care managers. This combined intervention also improved patients' and caregivers' quality of life. Effects on knowledge and attitudes were minor. CONCLUSION: Educational interventions for PCPs that require active participation improve detection of dementia. Educational interventions alone do not seem to increase adherence to dementia guidelines. To effectively change professionals' performance in primary dementia care, education probably needs to be combined with adequate reimbursement or other organizational incentives.

Discontinuation of long-term benzodiazepine use: 10-year follow-up.

BACKGROUND: Several interventions aiming at discontinuation of long-term benzodiazepine use have been proven effective in the short term. However, data on the persistence of discontinuation are lacking. OBJECTIVES: To assess 10-year follow-up status in patients who succeeded in stopping benzodiazepine use after a discontinuation letter from the patient's own GP. To identify determinants of successful discontinuation on the long term. METHODS: Follow-up data of patients who participated in a large prospective, controlled stepped care intervention programme among long-term benzodiazepine users in primary care. RESULTS: At 10-year follow-up, the percentage of benzodiazepine abstinence was 58.8%. Non-abstinent patients used lower doses of benzodiazepine. Being abstinent at 21 months after the intervention predicted abstinence at 10-year follow-up. CONCLUSIONS: Ten years after a minimal intervention to decrease long-term benzodiazepine use, the majority of patients who were able to discontinue benzodiazepine use initially, does not use benzodiazepines at 10-year follow-up. Patients who did not succeed in maintaining abstinence from benzodiazepines appear to use lower or average dosages.

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.

Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11beta-hydroxysteroid dehydrogenase type 2.

Prenatal stress (PS) produces persistent abnormalities in anxiety-related behaviors, stress responsivity, susceptibility to psychopathology and hippocampal changes in adult offspring. The hippocampus shows a remarkable degree of structural plasticity, notably in response to stress and glucocorticoids. We hypothesized that PS would differentially affect hippocampal neurogenesis in rats selectively bred for genetic differences in anxiety-related behaviors and stress responsivity. Pregnant dams of high anxiety-related behavior (HAB) and low anxiety-related behavior (LAB) strains were stressed between days 5 and 20 of pregnancy. The survival of newly generated hippocampal cells was found to be significantly lower in 43-day-old HAB than in LAB male offspring of unstressed pregnancies. PS further reduced newly generated cell numbers only in HAB rats, and this was paralleled by a reduction in doublecortin-positive cell numbers, indicative of reduced neurogenesis. As maternal plasma corticosterone levels during PS were similar in both strains, we examined placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which catalyses rapid inactivation of maternal corticosterone to inert 11-dehydrocorticosterone and thus serves as a physiological 'barrier' to maternal glucocorticoids. PS significantly increased placental 11beta-HSD2 activity in LAB, but not HAB, rats. We conclude that PS differentially affects the number of surviving newly generated cells and neurogenesis in HAB and LAB rats. The high sensitivity of hippocampal neurogenesis to PS in HAB rats is paralleled by a failure to increase placental 11beta-HSD2 activity after stress rather than by different maternal corticosterone responses. Hence, stress-induced placental 11beta-HSD2 expression may be critical in protecting the fetal brain from maternal stress-induced effects on adult neurogenesis.

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.

Mature astrocytes in the adult human neocortex express the early neuronal marker doublecortin.

Doublecortin (DCX) is a microtubule-associated protein expressed by migrating neuroblasts and is considered to be a reliable marker of neurogenesis. DCX has been used to study the relation between neurogenesis in adult human brain and neurological and neurodegenerative disease processes in the search for putative therapeutic strategies. Using autopsy and surgically resected tissue from a total of 60 patients, we present evidence that DCX is present in several cellular compartments of differentiated astrocytes in the adult human neocortex. One of these compartments consisted of peripheral processes forming punctate envelopes around mature neuronal cell bodies. Markers of glial activation, such as GFAP and HLA, were not associated with DCX immunoreactivity, however, the presence of cytoarchitectural alterations tended to correlate with reduced DCX staining of astrocytic somata. Interestingly, local Alzheimer pathology that showed no relation with cytoarchitectural abnormalities appeared to correlate negatively with the expression of DCX in the astrocytic somata. In combination with the literature our data support the view that DCX in the adult human neocortex may have a function in glia-to-neuron communication. Furthermore, our results indicate that in the adult human neocortex DCX is neither a reliable nor a selective marker of neurogenesis.

An in-home geriatric programme for vulnerable community-dwelling older people improves the detection of dementia in primary care.

BACKGROUND/OBJECTIVE: Dementia is under-diagnosed in primary care. This study investigated whether an in-home geriatric assessment and management programme could improve the identification of patients with dementia in primary care. METHODS: A secondary analysis was performed, using data of a randomised controlled trial that studied the effects of an in-home geriatric evaluation and management programme compared with usual care. In this trial, 151 vulnerable community-dwelling patients, aged 70 years and older, participated: 86 in the intervention group and 66 in de control group. The effect of the programme on the dementia detection rate was determined by comparing the number of new dementia diagnoses in both study arms at 6 months follow-up. RESULTS: Of all 151 participants, 38 (25%) had a registered dementia diagnosis at baseline. During follow-up, 23 of 113 patients without a registered dementia diagnosis at baseline were identified as suffering from dementia. The difference between the numbers of new dementia diagnoses in the intervention group (19 of 66 patients) and the control group (4 of 47 patients) was significant. (p = 0.02) CONCLUSION: An in-home geriatric assessment and management programme for vulnerable older patients improves the detection of dementia and can therefore contribute to overcoming of under-diagnosis of dementia.

Systemic corticosteroids for acute gout.

BACKGROUND: Gout is one of the most frequently occurring rheumatic diseases, worldwide. Given the well-known drawbacks of the regular treatments for acute gout (non-steroidal anti-inflammatory drugs (NSAIDs), colchicine), systemic corticosteroids might be safe alternatives. OBJECTIVES: To assess the efficacy and safety of systemic corticosteroids in the treatment of acute gout in comparison with placebo, NSAIDs, colchicine, other active drugs, other therapies, or no therapy. SEARCH STRATEGY: Searches were done in the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007); MEDLINE (1966 to 2007) through PubMed; EMBASE (1974 to 2007); Web of Science (1975 to 2007); LILACS (1986 to 2007); and databases of ongoing trials (up to April 2007). SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the use of systemic corticosteroids in the treatment of acute gout were included. DATA COLLECTION AND ANALYSIS: Two review authors decided independently which trials to include. The same review authors also collected the data in a standardised form and assessed the methodological quality of the trial using validated criteria. When possible, continuous and dichotomous data were summarised statistically. MAIN RESULTS: Three head to head trials involving 148 patients (74 systemic corticosteroids; 74 comparator drugs) were included. Placebo-controlled trials were not found. In the studies, different kinds of systemic corticosteroids and different kinds of control drugs were used, both administered in different routes. Intramuscular triamcinolone acetonide was compared respectively to oral indomethacine, and intramuscular adrenocorticotropic hormone (ACTH); oral prednisolone (together with a single intramuscular diclophenac injection) was compared to oral indomethacine (together with a single placebo injection). Outcome measurements varied: average number of days until total relief of signs, mean decrease of pain per unit of time in mm on a visual analogue scale (VAS) - during rest and activity. In the triamcinolone-indomethacine trial the clinical joint status was used as an additional outcome. Clinically relevant differences between the studied systemic corticosteroids and the comparator drugs were not found; important safety problems attributable to the used corticosteroids were not reported. The quality of the three studies was graded as very low to moderate. Statistical pooling of results was not possible. AUTHORS' CONCLUSIONS: There is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout. Patients with gout did not report serious adverse effects from systemic corticosteroids, when used short term.

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.