Depression as a risk factor for Alzheimer's disease: Genes, steroids, cytokines and neurogenesis - What do we need to know?

Depression (MDD) is prodromal to, and a component of, Alzheimer's disease (AD): it may also be a trigger for incipient AD. MDD is not a unitary disorder, so there may be particular subtypes of early life MDD that pose independent high risks for later AD, though the identification of these subtypes is problematical. There may either be a common pathological event underlying both MDD and AD, or MDD may sensitize the brain to a second event ('hit') that precipitates AD. MDD may also accelerate brain ageing, including altered DNA methylation, increased cortisol but decreasing DHEA and thus the risk for AD. So far, genes predicting AD (e.g. APOEε4) are not risk factors for MDD, and those implicated in MDD (e.g. SLC6A4) are not risks for AD, so a common genetic predisposition looks unlikely. There is as yet no strong indication that an epigenetic event occurs during some forms of MDD that predisposes to later AD, though the evidence is limited. Glucocorticoids (GCs) are disturbed in some cases of MDD and in AD. GCs have marked degenerative actions on the hippocampus, a site of early ß-amyloid deposition, and rare genetic variants of GC-regulating enzymes (e.g. 11ß-HSD) predispose to AD. GCs also inhibit hippocampal neurogenesis and plasticity, and thus episodic memory, a core symptom of AD. Disordered GCs in MDD may inhibit neurogenesis, but the contribution of diminished neurogenesis to the onset or progression of AD is still debated. GCs and cytokines also reduce BDNF, implicated in both MDD and AD and hippocampal neurogenesis, reinforcing the notion that those cases of MDD with disordered GCs may be a risk for AD. Cytokines, including IL1ß, IL6 and TNFα, are increased in the blood in some cases of MDD. They also reduce hippocampal neurogenesis, and increased cytokines are a known risk for later AD. Inflammatory changes occur in both MDD and AD (e.g. raised CRP, TNFα). Both cytokines and GCs can have pro-inflammatory actions in the brain. Inflammation (e.g. microglial activation) may be a common link, but this has not been systematically investigated. We lack substantial, rigorous and comprehensive follow-up studies to better identify possible subtypes of MDD that may represent a major predictor for later AD. This would enable specific interventions during critical episodes of these subtypes of MDD that should reduce this substantial risk.

Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis.

Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate. Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected.

Testosterone administration does not affect men's rejections of low ultimatum game offers or aggressive mood.

Correlative evidence suggests that testosterone promotes dominance and aggression. However, causal evidence is scarce and offers mixed results. To investigate this relationship, we administered testosterone for 48h to 41 healthy young adult men in a within-subjects, double-blind placebo-controlled balanced crossover design. Subjects played the role of responders in an ultimatum game, where rejecting a low offer is costly, but serves to destroy the proposer's profit. Such action can hence be interpreted as non-physical aggression in response to social provocation. In addition, subjects completed a self-assessed mood questionnaire. As expected, self-reported aggressiveness was a key predictor of ultimatum game rejections. However, while testosterone affected subjective ratings of feeling energetic and interested, our evidence strongly suggests that testosterone had no effect on ultimatum game rejections or on aggressive mood. Our findings illustrate the importance of using causal interventions to assess correlative evidence.

Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms.

Major depressive disorder (MD) is a debilitating public mental health problem with severe societal and personal costs attached. Around one in six people will suffer from this complex disorder at some point in their lives, which has shown considerable etiological and clinical heterogeneity. Overall there remain no validated biomarkers in the youth population at large that can aid the detection of at-risk groups for depression in general and for boys and young men in particular. Using repeated measurements of two well-known correlates of MD (self-reported current depressive symptoms and early-morning cortisol), we undertook a population-based investigation to ascertain subtypes of adolescents that represent separate longitudinal phenotypes. Subsequently, we tested for differential risks for MD and other mental illnesses and cognitive differences between subtypes. Through the use of latent class analysis, we revealed a high-risk subtype (17% of the sample) demarcated by both high depressive symptoms and elevated cortisol levels. Membership of this class of individuals was associated with increased levels of impaired autobiographical memory recall in both sexes and the greatest likelihood of experiencing MD in boys only. These previously unidentified findings demonstrate at the population level a class of adolescents with a common physiological biomarker specifically for MD in boys and for a mnemonic vulnerability in both sexes. We suggest that the biobehavioral combination of high depressive symptoms and elevated morning cortisol is particularly hazardous for adolescent boys.

Childhood adversity subtypes and depressive symptoms in early and late adolescence.

Within a longitudinal study of 1,005 adolescents, we investigated how exposure to childhood psychosocial adversities was associated with the emergence of depressive symptoms between 14 and 17 years of age. The cohort was classified into four empirically determined adversity subtypes for two age periods in childhood (0-5 and 6-11 years). One subtype reflects normative/optimal family environments (n = 692, 69%), while the other three subtypes reflect differential suboptimal family environments (aberrant parenting: n = 71, 7%; discordant: n = 185, 18%; and hazardous: n = 57, 6%). Parent-rated child temperament at 14 years and adolescent self-reported recent negative life events in early and late adolescence were included in models implementing path analysis. There were gender-differentiated associations between childhood adversity subtypes and adolescent depressive symptoms. The discordant and hazardous subtypes were associated with elevated depressive symptoms in both genders but the aberrant parenting subtype only so in girls. Across adolescence the associations between early childhood adversity and depressive symptoms diminished for boys but remained for girls. Emotional temperament was also associated with depressive symptoms in both genders, while proximal negative life events related to depressive symptoms in girls only. There may be neurodevelopmental factors that emerge in adolescence that reduce depressogenic symptoms in boys but increase such formation in girls.

Functional polymorphism in the brain-derived neurotrophic factor gene interacts with stressful life events but not childhood maltreatment in the etiology of depression.

BACKGROUND: We test the hypothesis that the functional Val66Met polymorphism of BDNF interacts with recent life events to produce onset of new depressive episodes. We also explore the possibility that the Met allele of this polymorphism interacts with childhood maltreatment to increase the risk of chronic depression. METHODS: In a risk-enriched combined sample of unrelated women, childhood maltreatment and current life events were measured with the Childhood Experience of Care and Abuse, and Life Events and Difficulties Schedule interviews. Chronic episodes of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry interview. RESULTS: Met alleles of BDNF moderated the relationship between recent life events and adult onsets of depression in a significant gene-environment interaction (interaction risk difference 0.216, 95% CI 0.090-0.342; P =.0008). BDNF did not significantly influence the effect of childhood maltreatment on chronic depression in the present sample. CONCLUSIONS: The Met allele of BDNF increases the risk of a new depressive episode following a severe life event. The BDNF and the serotonin transporter gene length polymorphism (5-HTTLPR) and BDNF may contribute to depression through distinct mechanisms involving interactions with childhood and adulthood adversity respectively, which may, in combination, be responsible for a substantial proportion of depression burden in the general population.

Serotonin transporter length polymorphism, childhood maltreatment, and chronic depression: a specific gene-environment interaction.

BACKGROUND: Key questions about the interaction between the serotonin transporter length polymorphism (5-HTTLPR) and stress in the etiology of depression remain unresolved. We test the hypotheses that the interaction is restricted to childhood maltreatment (as opposed to stressful events in adulthood), and leads to chronic depressive episodes (as opposed to any onset of depression), using gold-standard assessments of childhood maltreatment, severe life events, chronic depression, and new depressive onsets. METHOD: In a risk-enriched sample of 273 unrelated women, childhood maltreatment was retrospectively assessed with the Childhood Experience of Care and Abuse (CECA) interview and 5-HTTLPR was genotyped. A subset of 220 women was followed prospectively for 12 months with life events assessed with the Life Events and Difficulties (LEDS) interview. Any chronic episode of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview. RESULTS: The short alleles of 5-HTTLPR moderated the relationship between childhood maltreatment and chronic depression in adulthood, reflected in a significant gene-environment interaction (RD = 0.226, 95% CI: 0.076-0.376, P = .0032). 5-HTTLPR did not moderate the effects of either childhood maltreatment or severe life events on new depressive onsets. CONCLUSIONS: The short variant of the serotonin transporter gene specifically sensitizes to the effect of early-life experience of abuse or neglect on whether an adult depressive episode takes a chronic course. This interaction may be responsible for a substantial proportion of cases of chronic depression in the general population.

Depressive symptoms during adolescence: comparison between epidemiological and high risk sampling.

PURPOSE: Both epidemiological (unselected) and high risk (screening on known risk criteria) samplings have been used to investigate the course of affective disorders. Selecting individuals on multiple risk criteria may create a sample not comparable to individuals with similar risk criteria within the general population. This study compared depressive symptoms across the two sampling methods to test this possibility. METHODS: The high risk Cambridge Hormones and Moods Project (CHAMP) screened and recruited adolescents aged 12 to 16. A total of 905 (710 high risk) individuals participated and were reassessed at three follow-ups. The ROOTS epidemiological sample consisted of 1,208 14-year-olds reassessed at 15.5 and 17 years. The risk profile for CHAMP was recreated in the ROOTS study. Both samples completed the Moods and Feelings Questionnaire, a self-report measure of current depressive symptoms. RESULTS: Comparing individuals with the same high risk profiles across the CHAMP and ROOTS studies revealed no significant differences in mean depression scores. Combining the samples revealed that for females, mean depression scores were maintained from 12 to 15 years then declined by 17 years. For males, scores declined from 12 throughout adolescence. High risk status led to consistently higher levels of depressive symptoms in female adolescents but result in little change within male adolescents. CONCLUSIONS: The high risk design recruited adolescents with a depression symptoms profile comparable to the general population for both sexes. High risk status may alter the trajectory of depressive symptoms in female adolescents only. Males may be less sensitive to recent adversity.

Profiles of family-focused adverse experiences through childhood and early adolescence: the ROOTS project a community investigation of adolescent mental health.

BACKGROUND: Adverse family experiences in early life are associated with subsequent psychopathology. This study adds to the growing body of work exploring the nature and associations between adverse experiences over the childhood years. METHODS: Primary carers of 1143 randomly recruited 14-year olds in Cambridgeshire and Suffolk, UK were interviewed using the Cambridge Early Experiences Interview (CAMEEI) to assess family-focused adversities. Adversities were recorded retrospectively in three time periods (early and later childhood and early adolescence). Latent Class Analysis (LCA) grouped individuals into adversity classes for each time period and longitudinally. Adolescents were interviewed to generate lifetime DSM-IV diagnoses using the K-SADS-PL. The associations between adversity class and diagnoses were explored. RESULTS: LCA generated a 4-class model for each time period and longitudinally. In early childhood 69% were allocated to a low adversity class; a moderate adversity class (19%) showed elevated rates of family loss, mild or moderate family discord, financial difficulties, maternal psychiatric illness and higher risk for paternal atypical parenting; a severe class (6%) experienced higher rates on all indicators and almost exclusively accounted for incidents of child abuse; a fourth class, characterised by atypical parenting from both parents, accounted for the remaining 7%. Class membership was fairly stable (~ 55%) over time with escape from any adversity by 14 years being uncommon. Compared to those in the low class, the odds ratio for reported psychopathology in adolescents in the severe class ranged from 8 for disruptive behaviour disorders through to 4.8 for depressions and 2.0 for anxiety disorders. Only in the low adversity class did significantly more females than males report psychopathology. CONCLUSIONS: Family adversities in the early years occur as multiple rather than single experiences. Although some children escape adversity, for many this negative family environment persists over the first 15 years of life. Different profiles of family risk may be associated with specific mental disorders in young people. Sex differences in psychopathologies may be most pronounced in those exposed to low levels of family adversities.

The efficacy of a nanosynthetic bone graft substitute as a bone graft extender in rabbit posterolateral fusion.

BACKGROUND CONTEXT: Synthetic bone graft substitutes are commonly used in spinal fusion surgery. Preclinical data in a model of spinal fusion to support their efficacy is an important component in clinical adoption to understand how these materials provide a biological and mechanical role in spinal fusion. PURPOSE: To evaluate the in vivo response of a nanosynthetic silicated calcium phosphate putty (OstP) combined with autograft compared to autograft alone or a collagen-biphasic calcium phosphate putty (MasP) combined with autograft in a rabbit spinal fusion model. STUDY DESIGN: Efficacy of a nanosynthetic silicated calcium phosphate putty as an extender to autograft was studied in an experimental animal model of posterolateral spinal fusion at 6, 9, 12 and 26 weeks, compared to a predicate device. METHODS: Skeletally mature female New Zealand White rabbits (70) underwent single level bilateral posterolateral intertransverse process lumbar fusion, using either autograft alone (AG), a nanosynthetic silicated calcium phosphate putty (OstP) combined with autograft (1:1), or a collagen-biphasic calcium phosphate putty (MasP) combined with autograft (1:1). Iliac crest autograft was harvested for each group, and a total of 2 cc of graft material was implanted in the posterolateral gutters per side. Fusion success was assessed at all time points by manual palpation, radiographic assessment, micro-CT and at 12 weeks only using non-destructive range of motion testing. Tissue response, bone formation and graft resorption were assessed by decalcified paraffin histology and by histomorphometry of PMMA embedded sections. RESULTS: Assessment of fusion by manual palpation at the 12 week endpoint showed 7 out of 8 (87.5%) bilateral fusions in the OstP extender group, 4 out of 8 (50%) fusions in the MasP extender group, and 6 out of 8 (75%) fusions in the autograft alone group. Similar trends were observed with fusion scores of radiographic and micro-CT data. Histology showed a normal healing response in all groups, and increased bone formation in the OstP extender group at all timepoints compared to the MasP extender group. New bone formed directly on the OstP granule surface within the fusion mass while this was not a feature of the Collagen-Biphasic CaP material. After 26 weeks the OstP extender group exhibited 100% fusions (5 out of 5) by all measures, whereas the MasP extender group resulted in bilateral fusions in 3 out of 5 (60%), assessed by manual palpation, and fusion of only 20 and 0% by radiograph and micro-CT scoring, respectively. Histology at 26 weeks showed consistent bridging of bone between the transverse processes in the Ost P extender group, but this was not observed in the MasP extender group. CONCLUSIONS: The nanosynthetic bone graft substituted studied here, used as an extender to autograft, showed a progression to fusion between 6 and 12 weeks that was similar to that observed with autograft alone, and showed excellent fusion outcomes, bone formation and graft resorption at 26 weeks. CLINICAL SIGNIFICANCE: This preclinical study showed that the novel nanosynthetic silicated CaP putty, when combined with autograft, achieved equivalent fusion outcomes to autograft. The development of synthetic bone grafts that demonstrate efficacy in such models can eliminate the need for excessive autograft harvest and results from this preclinical study supports their effective use in spinal fusion surgery.

Polymorphisms in BDNF (Val66Met) and 5-HTTLPR, morning cortisol and subsequent depression in at-risk adolescents.

BACKGROUND: There is increasing evidence for genetic effects on the hypothalamic-pituitary axis system. More than one gene is likely to moderate corticoid-mediated activity. AIMS: To investigate whether the brain-derived neurotrophic factor (BDNF) polymorphism (rs6265, Val66Met) is associated with morning waking salivary cortisol and moderates the corticoid-mediated risk for subsequent depressive episode onset independently of the known effects of 5-HTTLPR (the serotonin transporter gene promoter). METHOD: High-risk adolescents (n = 401) were genotyped for Val66Met BDNF and 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 h of waking. There were 365 (91%) remaining participants reassessed at 12 months for episodes of psychiatric disorder in the follow-up period. Of these, 357 (89%) had complete data for multivariate modelling. RESULTS: There were 41 (11.2%) individuals who reported a new episode of clinical depression over the follow-up period. Increased risk for subsequent depression was found in carriers of the Val66Val genotype in BDNF with higher morning waking cortisol. This remained present when the known interaction between carriers of a short allele of 5-HTTLPR with higher morning salivary cortisol was taken into account. CONCLUSIONS: Both BDNF and 5-HTTLPR genes show evidence of modifying the risk of a subsequent new depressive episode associated with elevated morning salivary cortisol. In adolescents morning salivary cortisol levels may constitute a biomarker for some forms of unipolar depression.

Serotonin transporter genotype, morning cortisol and subsequent depression in adolescents.

BACKGROUND: The short (s) allele of the serotonin transporter gene promoter (5-HTTLPR) may be associated with exposure to social adversities and the subsequent onset of depressive illness in adulthood. AIMS: To test in adolescents at high risk for depression whether the short 's' allele is associated with levels of morning cortisol and the subsequent onset of a depressive episode. METHOD: High-risk adolescents (n = 403) were genotyped for 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 h of waking from 393 (97.5%) individuals and 367 (91%) underwent a mental state reassessment at 12 months. RESULTS: Multilevel analysis revealed higher levels of salivary cortisol in short allele carriers (s/s>s/l>l/l). A subsequent episode of depression was increased in those with higher cortisol and the 's' allele, and independently by depressive symptoms at entry, in both genders. CONCLUSIONS: The short allele of 5-HTTLPR may moderate the association between morning cortisol and the subsequent onset of a depressive episode.

Unusual presentation and urinary tract obstruction due to disseminated intra-abdominal eumycetomas caused by Curvularia species in a dog.

Intra-abdominal eumycetomas are rare in dogs and usually attributed to contamination of surgical wounds post-operatively. This is the first report of extensively disseminated intra-abdominal eumycetomas due to Curvularia resulting in urinary tract obstruction and associated chronic recurrent urinary tract infections in a Labrador retriever. Identification of the fungal genus was performed on samples obtained from culture of eumycetomic fungal grains that had been collected sterilely at necropsy.

Brain-derived neurotropic factor and neurogenesis in the adult rat dentate gyrus: interactions with corticosterone.

Flattening the diurnal corticosterone rhythm prevented the stimulating action of L-NAME (a nitric oxide synthase, NOS, inhibitor) on progenitor cell proliferation in the dentate gyrus in Lister-Hooded adult male rats. The increased expression of brain-derived neurotrophic factor (BDNF) and trkB mRNA in the dentate gyrus which otherwise occurred after L-NAME was also prevented by clamping the corticoid rhythm in adrenalectomized rats, but was restored by daily additional injections of corticosterone (which replicates the diurnal rhythm). Unilateral infusions of BDNF into the lateral ventricle increased proliferation in the dentate gyrus on the side of the infusion, but this was not observed following implantation of subcutaneous corticosterone, which flattened the diurnal corticosterone rhythm. 5HT1A mRNA in the dentate gyrus was increased on both sides of the brain by unilateral BDNF infusions, but this was also prevented by subcutaneous corticosterone pellets. These results show that the diurnal rhythm of corticosterone regulates the stimulating action of NOS inhibitors on BDNF as well as on neurogenesis in the dentate gyrus, and that BDNF becomes ineffective on both proliferation rates and 5HT1A expression in the absence of a rhythm in corticosterone. This, together with our previous findings, suggests that corticoid rhythms permit both serotonin and NO access to BDNF, and the latter to regulate progenitor cell activity.

Testosterone, Cortisol and Financial Risk-Taking.

Both testosterone and cortisol have major actions on financial decision-making closely related to their primary biological functions, reproductive success and response to stress, respectively. Financial risk-taking represents a particular example of strategic decisions made in the context of choice under conditions of uncertainty. Such decisions have multiple components, and this article considers how much we know of how either hormone affects risk-appetite, reward value, information processing and estimation of the costs and benefits of potential success or failure, both personal and social. It also considers how far we can map these actions on neural mechanisms underlying risk appetite and decision-making, with particular reference to areas of the brain concerned in either cognitive or emotional functions.

Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents.

BACKGROUND: We have previously reported higher and more variable salivary morning cortisol in 13-year-old adolescents whose mothers were depressed in the postnatal period, compared with control group adolescents whose mothers did not develop postnatal depression (PND). This observation suggested a biological mechanism by which intrafamilial risk for depressive disorder may be transmitted. In the current article, we examined whether the cortisol disturbances observed at 13 years could predict depressive symptomatology in adolescents at 16 years of age. METHODS: We measured self-reported depressive symptoms in 16-year-old adolescents who had (n = 48) or had not (n = 39) been exposed to postnatal maternal depression and examined their prediction by morning and evening cortisol indices obtained via 10 days of salivary collections at 13 years. RESULTS: Elevated morning cortisol secretion at 13 years, and particularly the maximum level recorded over 10 days of collection, predicted elevated depressive symptoms at 16 years over and above 13-year depressive symptom levels and other possible confounding factors. Morning cortisol secretion mediated an association between maternal PND and symptomatology in 16-year-old offspring. CONCLUSIONS: Alterations in steroid secretion observed in association with maternal PND may provide a mechanism by which risk for depression is transmitted from mother to offspring.

Interactions between nitric oxide and corticosterone in the regulation of progenitor cell proliferation in the dentate gyrus of the adult rat.

It is well established that L-NAME, a generic NOS inhibitor, stimulates neurogenesis in the dentate gyrus of the adult rat and corticosterone reduces it. These experiments explore the interaction between L-NAME and corticosterone. L-NAME (50 mg/kg), as expected, increased proliferation, but also lowered plasma corticosterone levels. However, the stimulating action of L-NAME depends on the presence of rhythmic changes in plasma corticosterone, as it is abolished in rats treated with a subcutaneous implant of corticosterone, which flattens the diurnal rhythm. Adrenalectomized rats implanted with corticosterone also failed to respond to L-NAME. Giving them a single daily injection of corticosterone (2 mg/kg) in an attempt to replicate the diurnal rhythm restored the sensitivity of the progenitor cells to L-NAME. The mechanism for this result remains to be investigated. Excess corticosterone given by daily injection (40/mg/kg) reduced proliferation but did not alter the response to L-NAME, even though this occurred from a lower baseline. nNOS was demonstrable only in the inner (proliferative) layer of the dentate gyrus in control rats, and did not alter following excess corticosterone treatment. iNOS was detectable at low levels in control rats, but was increased markedly following corticosterone. eNOS was evident throughout the dentate gyrus, and also increased after corticosterone (particularly in the hilus). Aminoguanidine (100 mg/kg/day; an iNOS antagonist) significantly increased proliferation in corticosterone-treated rats (40 mg/kg/day) but not in controls without additional corticosterone, confirming that iNOS plays a role in corticosterone-regulated neurogenesis. Corticosterone may thus act on progenitor cells in part at least through increased nitric oxide (NO) formation. The effects of reduced NO on neurogenesis may rely on a dual mechanism: corresponding reductions in plasma corticosterone and increased induction of iNOS (and/or eNOS) within the dentate gyrus. The possibility that NO acts downstream of glucocorticoids in the dentate gyrus is suggested.

Stimulation of neurogenesis in the hippocampus of the adult rat by fluoxetine requires rhythmic change in corticosterone.

BACKGROUND: Fluoxetine stimulates proliferation of progenitor cells in the dentate gyrus of the adult hippocampus. There are suggestions that this action may underlie the therapeutic effects of such drugs in depression. Glucocorticoids also regulate neurogenesis, and there are multiple interactions between serotonin and corticoids. Diurnal cortisol rhythms are dysregulated in depression. We explored the role of diurnal variations in corticosterone on the ability of fluoxetine to alter neurogenesis in the dentate gyrus. METHODS: We manipulated plasma corticosterone by implanting corticosterone pellets or giving daily corticosterone injections to corticosterone-clamped adrenalectomized or intact rats that received fluoxetine or vehicle treatment. Proliferation of progenitor cells in the dentate gyrus was measured using BrdU or Ki-67. RESULTS: Our results strongly suggest that a diurnal rhythm in corticosterone is necessary for fluoxetine to stimulate neurogenesis in the adult dentate gyrus in the male rat. Preliminary data suggest this may be related to the 5-HT1A receptor. CONCLUSIONS: If altered neurogenesis in the dentate gyrus is part of the therapeutic response to antidepressants such as fluoxetine, the results we report suggest that concurrent manipulation of the HPA axis might improve sensitivity to selective serotonin reuptake inhibitors in some treatment-resistant patients.

Serotonin modulates the suppressive effects of corticosterone on proliferating progenitor cells in the dentate gyrus of the hippocampus in the adult rat.

This series of experiments explores the interaction between corticosterone and serotonin (5-HT) in the regulation of cell proliferation in the dentate gyrus of the adult rat. Intracerebroventricular 5,7-DHT (5,7-dihydroxytryptamine) (either 200 or 300 microg) resulted in highly significant depletion of 5-HT as measured by high performance liquid chromatography in the frontal cortex but had no effect on the number of proliferating cells in the dentate gyrus by measuring 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 cytochemistry. Treatment with PCPA (p-chlorophenylalanine: a tryptophan hydroxylase inhibitor: 300 mg/kg initially followed by 100 mg/kg/day) resulted in reduced proliferation as measured by Ki-67 after 3 days treatment, but not by BrdU uptake, and not after 14 days treatment by either method. In addition, injection of corticosterone (10-40 mg/kg/day) for 8 days significantly reduced proliferation in the dentate gyrus, as expected, measured by both BrdU uptake and Ki-67 immunostaining. Adrenalectomized (ADX) rats with a replacement subcutaneous pellet of corticosterone showed reduced proliferation when given additional corticosterone (10 mg/kg/day for 8 days), but this was prevented by 5-HT depletion (i.c.v. 5,7-DHT). Finally, a dose-response study showed that progressive doses of corticosterone (0-40 mg/kg/day) in ADX rats resulted in diminished suppression of proliferation in 5-HT-depleted compared with 5-HT-intact rats. These results strongly suggest that 5-HT regulates the sensitivity of proliferating cells in the dentate gyrus to corticosterone.