RESUMEN

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.

Asunto(s)

Astrocitos , Lesiones Traumáticas del Encéfalo , Hipocampo , Células-Madre Neurales , Neurogénesis , Animales , Masculino , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Hipocampo/patología , Hipocampo/citología , Astrocitos/metabolismo , Ratones , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neuronas/metabolismo , Ratones Endogámicos C57BL , Giro Dentado/patología , Modelos Animales de Enfermedad , Diferenciación Celular , Transcriptoma

RESUMEN

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.

RESUMEN

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.

Asunto(s)

Ácidos Grasos , Leche Humana , Humanos , Lactante , Recién Nacido , Femenino , Leche Humana/química , Ácidos Grasos/análisis , Lactancia , Estudios Prospectivos , Hidrocortisona/análisis , Periodo Posparto , Ácidos Grasos Insaturados/análisis , Lactancia Materna

RESUMEN

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.

Asunto(s)

Envejecimiento/metabolismo , Encéfalo/metabolismo , Ritmo Circadiano , Glucocorticoides/metabolismo , Hipocampo/citología , Células-Madre Neurales/metabolismo , Animales , Encéfalo/citología , Proliferación Celular , Masculino , Ratones , Neurogénesis , Receptores de Glucocorticoides/metabolismo

RESUMEN

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.

Asunto(s)

Hipocampo/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Animales , Lesiones Traumáticas del Encéfalo/fisiopatología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Epilepsia/fisiopatología , Hipocampo/patología , Humanos , Trastornos del Humor/fisiopatología , Células-Madre Neurales/patología , Neuronas/patología , Accidente Cerebrovascular/fisiopatología

RESUMEN

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.

Asunto(s)

Depresión , Expresión Génica/fisiología , Ácido Glutámico/metabolismo , Corteza Prefrontal/metabolismo , Suicidio , Ácido gamma-Aminobutírico/metabolismo , Adulto , Depresión/metabolismo , Depresión/patología , Depresión/psicología , Femenino , Estudios de Seguimiento , Ácido Glutámico/genética , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , ARN Mensajero/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Transducción de Señal/genética , Transmisión Sináptica/genética , Adulto Joven , Ácido gamma-Aminobutírico/genética

RESUMEN

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.

Asunto(s)

Proteína Relacionada con Agouti/metabolismo , Ghrelina/metabolismo , Neuropéptido Y/metabolismo , Tejido Adiposo/metabolismo , Proteína Relacionada con Agouti/farmacología , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/metabolismo , Conducta Alimentaria/efectos de los fármacos , Femenino , Ghrelina/genética , Ghrelina/farmacología , Hipotálamo/metabolismo , Insulina/genética , Insulina/metabolismo , Insulina/farmacología , Leptina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptido Y/farmacología , Obesidad/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Factores Sexuales , Estrés Psicológico/fisiopatología

RESUMEN

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.

Asunto(s)

Hipocampo/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Condicionamiento Físico Animal/fisiología , Estrés Psicológico , Factores de Edad , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Femenino , Hipocampo/patología , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Estrés Psicológico/patología , Estrés Psicológico/fisiopatología , Estrés Psicológico/rehabilitación

RESUMEN

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.

Asunto(s)

Tejido Adiposo/metabolismo , Dieta Occidental , Leptina/metabolismo , Obesidad/metabolismo , Estrés Psicológico/metabolismo , Animales , Modelos Animales de Enfermedad , Conducta Alimentaria/fisiología , Leptina/sangre , Leptina/genética , Ratones , Obesidad/sangre , Obesidad/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo

RESUMEN

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.

Asunto(s)

Cognición , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Privación Materna , Estrés Psicológico/patología , Animales , Animales Recién Nacidos , Ansiedad/etiología , Ansiedad/patología , Ansiedad/fisiopatología , Ansiedad/prevención & control , Cognición/efectos de los fármacos , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Juego de Azar/etiología , Juego de Azar/patología , Juego de Azar/fisiopatología , Juego de Azar/prevención & control , Hipocampo/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Memoria/efectos de los fármacos , Memoria/fisiología , Mifepristona/farmacología , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Distribución Aleatoria , Ratas Wistar , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Maduración Sexual , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatología , Insuficiencia del Tratamiento

RESUMEN

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.

Asunto(s)

Sistema de Transporte de Aminoácidos X-AG/metabolismo , Depresión/patología , Depresión/psicología , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Corteza Prefrontal/metabolismo , Suicidio , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Cambios Post Mortem , Escalas de Valoración Psiquiátrica

RESUMEN

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.

Asunto(s)

Estimulantes del Sistema Nervioso Central/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/patología , Metilfenidato/toxicidad , Neurogénesis/efectos de los fármacos , Administración Oral , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Envejecimiento/fisiología , Envejecimiento/psicología , Animales , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno Depresivo/inducido químicamente , Trastorno Depresivo/patología , Trastorno Depresivo/fisiopatología , Hipocampo/crecimiento & desarrollo , Hipocampo/fisiología , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neurogénesis/fisiología , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Descanso

RESUMEN

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.

Asunto(s)

Amígdala del Cerebelo/metabolismo , Trastornos del Humor/patología , Receptores de Glucocorticoides/metabolismo , Anciano , Anciano de 80 o más Años , Amígdala del Cerebelo/patología , Análisis de Varianza , Estudios de Casos y Controles , Recuento de Células , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neuroglía/metabolismo , Neuronas/metabolismo , Caracteres Sexuales , Estadísticas no Paramétricas

RESUMEN

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.

Asunto(s)

Conducta Animal/efectos de los fármacos , Corticosterona/metabolismo , Depresión/metabolismo , Retroalimentación Fisiológica/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Receptores de Glucocorticoides/efectos de los fármacos , Tretinoina/farmacología , Animales , Hormona Liberadora de Corticotropina/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Depresión/inducido químicamente , Dexametasona/farmacología , Glucocorticoides/farmacología , Antagonistas de Hormonas/farmacología , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Mifepristona/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Transducción de Señal , Tretinoina/efectos adversos

Asunto(s)

Encéfalo/fisiopatología , Depresión/etiología , Neurogénesis/fisiología , Estrés Psicológico/fisiopatología , Depresión/complicaciones , Humanos , Estrés Psicológico/complicaciones

RESUMEN

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.

Asunto(s)

Hipocampo/citología , Motivación/genética , Neurogénesis/genética , Neuronas/fisiología , Receptores de Glucocorticoides/deficiencia , Animales , Movimiento Celular/genética , Condicionamiento Clásico/fisiología , Corticosterona/metabolismo , Dendritas/metabolismo , Dendritas/ultraestructura , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Miedo , Vectores Genéticos/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Técnicas In Vitro , Trastornos de la Memoria/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Neuronas/ultraestructura , Terminales Presinápticos/metabolismo , ARN Interferente Pequeño/metabolismo , Radioinmunoensayo

Asunto(s)

Antineoplásicos/toxicidad , Aprendizaje por Asociación/efectos de los fármacos , Hipocampo/fisiopatología , Neurogénesis/efectos de los fármacos , Ritmo Teta/efectos de los fármacos , Animales , Masculino

RESUMEN

We have characterized the expression of doublecortin-like (DCL), a microtubule-associated protein involved in embryonic neurogenesis that is highly homologous to doublecortin (DCX), in the adult mouse brain. To this end, we developed a DCL-specific antibody and used this to compare DCL expression with DCX. In the neurogenic regions of the adult brain like the subventricular zone (SVZ), the rostral migratory stream (RMS), the olfactory bulb (OB), and the hippocampus, DCL colocalizes with DCX in immature neuronal cell populations. In contrast to DCX, we also found high DCL expression in three other brain regions with suspected neurogenesis or neuronal plasticity. First, the radial glia-like, hypothalamic tanycytes show high DCL expression that partly colocalizes with the neural stem cell marker vimentin. Second, DCL expression is found in cells of the suprachiasmatic nucleus (SCN), which lacks expression of the adult neuron marker NeuN. Third, a novel region exhibiting DCL expression is part of the olfactory tubercle where DCL is found in the neuropil of the islands of Calleja (ICj). Our findings define DCL as a novel marker for specific aspects of adult neurogenesis, which partly overlap with DCX. In addition, we propose unique roles for DCL in adult neurogenesis and we suggest high levels of neuronal plasticity in tanycytes, SCN, and ICj.

Asunto(s)

Encéfalo/metabolismo , Proteínas Asociadas a Microtúbulos/biosíntesis , Neurogénesis/fisiología , Neuronas/metabolismo , Neuropéptidos/biosíntesis , Proteínas Serina-Treonina Quinasas/biosíntesis , Animales , Encéfalo/citología , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Quinasas Similares a Doblecortina , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Ratones , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neuronas/citología

RESUMEN

Early life is a period of unique sensitivity during which experience can confer enduring effects on brain structure and function. During early perinatal life the quality of the surrounding environment and experiences, in particular the parent-child relationship, is associated with emotional and cognitive development later in life. For instance, adverse early-life experience is correlated with an increased vulnerability to develop psychopathologies and aging-related cognitive decline. These are thought to be mediated by acute and long-lasting effects on the, at that time still developing, stress-neuroendocrine and cognitive systems. Adult hippocampal neurogenesis is involved in learning and memory while both regulation of the stress response as well as early-life stress is known to permanently reduce neurogenesis, and to be implicated in these functional deficits. In order to increase our understanding of the influence of the perinatal environment on the long-lasting programming of neurogenesis, we here discuss immediate and lasting effects of various adverse early-life experiences on hippocampal neurogenesis and the associated behavioral alterations. Considering the persistence of these effects, the underlying molecular mechanisms, with focus on the potential epigenetic mechanisms will be discussed as well. Finally, special attention will be paid to the prominent sex differences in early-life stress-induced alterations in neurogenesis.

Asunto(s)

Hipocampo/fisiopatología , Privación Materna , Neurogénesis/fisiología , Estrés Psicológico/fisiopatología , Animales , Conducta Animal/fisiología , Plasticidad Neuronal/fisiología

RESUMEN

Hyperactivity of the Hypthalamus-Pituitary-Adrenal (HPA)-axis is common in major depression and evident from e.g., a frequently exaggerated response to combined application of dexamethasone and CRH in this disorder. HPA-axis activity and hence the secretion of glucocorticoids (GC), the endpoint of the HPA-axis, depends to some extent on GC binding to glucocorticoid receptors (GR) that are abundantly expressed in the hippocampus. To assess whether differences in hippocampal GR expression occur in association with depression, we investigated GR-alpha protein immunoreactivity (ir) in postmortem hippocampal tissue of an elderly cohort of 9 well-characterized depressed patients and 9 control subjects that were pair-wise matched for age, sex, CSF-pH and postmortem delay. Abundant nuclear GR-ir was observed in neurons of the hippocampal Ammon's horn (CA) and dentate gyrus (DG) subregions. GR-ir in the DG correlated positively with age in the depressed but not the control group. Although no significant differences were found in GR-ir between the depressed and control groups, a significant increase in GR-ir was present in depressed females compared to depressed males. Whether this sex difference in hippocampal GR-ir in depression relates to the increased incidence of depression in females awaits further study. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Asunto(s)

Envejecimiento , Depresión/patología , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Regulación de la Expresión Génica/fisiología , Glucocorticoides/metabolismo , Hipocampo/patología , Humanos , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Factores Sexuales