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Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 ("don't eat me signals") located on synapses. We extensively report on disease characteristics, such as cause of death, reason for euthanasia, and psychiatric state when deceased. When excluding MDD donors in a euthymic state, the trend of lower CD45 membrane expression on white matter microglia became significant, and the difference in gray matter microglia became larger. For Western blot analysis of CD47 and CD200, both means of the definitely depressed donor groups (MDD-D) increased. This underscores the utmost importance of reporting on patient and episode characteristics, such as severity, episode traits, (type of) suicidality, mode of decease, and state of illness at death in post-mortem- and biological psychiatric research. For psychiatric post-mortem research, we suggest using well-characterized donors (eg, after "psychological autopsy") selected by an experienced clinician.
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Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer's disease (AD). This phenomenon has been referred to as 'resilience'. The molecular and cellular underpinnings of resilience remain poorly understood. To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals and age-matched controls (n = 11-12 per group). 897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors. Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia. As changes in MT, mitochondria, heat shock proteins and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes. MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors. Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males. Taken together, these results show possible mechanisms involving MTs, mitochondrial processes and the UPR by which individuals might maintain cognition despite the presence of AD pathology.
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Enfermedad de Alzheimer , Perfilación de la Expresión Génica , Metalotioneína , Mitocondrias , Respuesta de Proteína Desplegada , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Metalotioneína/genética , Metalotioneína/metabolismo , Femenino , Masculino , Anciano , Respuesta de Proteína Desplegada/genética , Respuesta de Proteína Desplegada/fisiología , Mitocondrias/metabolismo , Mitocondrias/genética , Mitocondrias/patología , Anciano de 80 o más Años , Resiliencia PsicológicaRESUMEN
Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer's Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.
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Enfermedad de Alzheimer , Resiliencia Psicológica , Animales , Humanos , Enfermedad de Alzheimer/patología , Encéfalo/patología , CogniciónRESUMEN
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.
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Síndrome de Prader-Willi , Humanos , Ratones , Animales , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/psicología , Microglía , Proteínas Portadoras/genética , Fenotipo , Fagosomas , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
The human hypothalamus modulates mental health by balancing interactions between hormonal fluctuations and stress responses. Stress-induced progesterone release activates progesterone receptors (PR) in the human brain and triggers alterations in neuropeptides/neurotransmitters. As recent epidemiological studies have associated peripheral progesterone levels with suicide risks in humans, we mapped PR distribution in the human hypothalamus in relation to age and sex and characterized its (co-) expression in specific cell types. The infundibular nucleus (INF) appeared to be the primary hypothalamic structure via which progesterone modulates stress-related neural circuitry. An elevation of the number of pro-opiomelanocortin+ (POMC, an endogenous opioid precursor) neurons in the INF, which was due to a high proportion of POMC+ neurons that co-expressed PR, was related to suicide in patients with mood disorders (MD). MD donors who died of legal euthanasia were for the first time enrolled in a postmortem study to investigate the molecular signatures related to fatal suicidal ideations. They had a higher proportion of PR co-expressing POMC+ neurons than MD patients who died naturally. This indicates that the onset of endogenous opioid activation in MD with suicide tendency may be progesterone-associated. Our findings may have implications for users of progesterone-enriched contraceptives who also have MD and suicidal tendencies.
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Receptores de Progesterona , Suicidio , Humanos , Progesterona , Analgésicos Opioides , Proopiomelanocortina , HipotálamoRESUMEN
Bipolar disorder (BD) is worldwide a prevalent mental illness and a leading risk factor for suicide. Over the past three decades, it has been discovered that sex differences exist throughout the entire panorama of BD, but the etiologic regions and mechanisms that generate such differences remain poorly characterized. Available evidence indicates that the dorsolateral prefrontal cortex (DLPFC), a critical region that controls higher-order cognitive processing and mood, exhibits biological disparities between male and female patients with psychiatric disorders, which are highly correlated with the co-occurrence of psychotic symptoms. This review addresses the sex differences in BD concerning epidemiology, cognitive impairments, clinical manifestations, neuroimaging, and laboratory abnormalities. It also provides strong evidence linking DLPFC to the etiopathogenesis of these sex differences. We emphasize the importance of identifying gene signatures using human brain transcriptomics, which can depict sexually different variations, explain sex-biased symptomatic features, and provide novel targets for sex-specific therapeutics.
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Trastorno Bipolar , Humanos , Masculino , Femenino , Trastorno Bipolar/etiología , Corteza Prefontal Dorsolateral , Corteza Prefrontal , Caracteres Sexuales , Encéfalo/patologíaRESUMEN
Introduction: Pituitary adenylate cyclase-activating peptide (PACAP) is a stress-related neuropeptide that is produced in several brain areas. It acts by 3 receptors: PACAP type-1 (PAC1), vasoactive intestinal peptide (VIP) -1 and -2 (VPAC1 and 2). Data on polymorphisms in PACAP and PAC1 indicate a relationship of the PACAP system with schizophrenia (SCZ). Methods: The prefrontal cortex was chosen to measure PACAP-gene related expression changes, since this is a central structure in the symptoms of schizophrenia (SCZ). We investigated alterations in the expression of the PACAP-related genes by qPCR in the human dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of 35 SCZ patients and 34 matched controls in relation to SCZ, suicide, gender and medication. Results: The ACC revealed an upregulation in PACAP, PAC1, VPAC1 and VPAC2 in SCZ suicide (S) completers compared to controls. An increase in PACAP, VPAC1 and VPAC2 expression was also present in the ACC in SCZ-S compared to SCZ patients who died naturally (SCZ-N). In the DLPFC, an increase in PAC1 was found in SCZ-N patients compared to SCZ-S and controls. Moreover, an increase in all PACAP-related genes was present in SCZ-N male patients compared to SCZ-N females. Concluding, expression changes were found in PACAP-related genes in relation to SCZ, suicide and gender. In particular, there was a higher PACAP-related gene expression in SCZ patients in the ACC in relation to suicide and in DLPFC in relation to SCZ. Discussion: These findings suggest a potential link between PACAP and the pathophysiology of SCZ and suicide. Further research is needed to understand the functional significance and potential clinical applications of these changes.
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Evidence from animal experiments has shown that the hypothalamic paraventricular nucleus (PVN) plays a key role in regulating body weight and blood glucose levels. However, it is unclear whether neuron populations in the human PVN are involved in the development of type 2 diabetes mellitus (T2DM). To address this, we investigated the neuronal and glial populations in the PVN of 26 T2DM patients and 20 matched controls. Our findings revealed a significant reduction in oxytocin (Oxt) neuron density in the PVN of T2DM patients compared to controls, while other neuronal populations remained unchanged. This suggests that Oxt neurons may play a specific role in the pathophysiology of T2DM. Interestingly, the reduction in Oxt neurons was accompanied by a decreased melanocortinergic input in to the PVN as reflected by a reduction in alpha-MSH immunoreactivity. We also analysed two glial cell populations, as they are important for maintaining a healthy neural microenvironment. We found that microglial density, phagocytic capacity, and their proximity to neurons were not altered in T2DM patients, indicating that the loss of Oxt neurons is independent of changes in microglial immunity. However, we did observe a reduction in the number of astrocytes, which are crucial for providing trophic support to local neurons. Moreover, a specific subpopulation of astrocytes characterized by aquaporin 4 expression was overrepresented in T2DM patients. Since this subset of astrocytes is linked to the glymphatic system, their overrepresentation might point to alterations in the hypothalamic waste clearance system in T2DM. Our study shows selective loss of Oxt neurons in the PVN of T2DM individuals in association with astrocytic reduction and gliovascular remodelling. Therefore, hypothalamic Oxt neurons may represent a potential target for T2DM treatment modalities.
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Diabetes Mellitus Tipo 2 , Oxitocina , Humanos , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Neuronas/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismoRESUMEN
OBJECTIVE: Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. METHODS: In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). RESULTS: In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. INTERPRETATION: Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.
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Arginina Vasopresina , Narcolepsia , Humanos , Dopamina , Histamina , Hormona Liberadora de Corticotropina , Norepinefrina/metabolismo , Narcolepsia/genéticaRESUMEN
Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders remains unclear. The present study was designed to explore whether and how SIRT1 in the mouse bed nucleus of the stria terminalis (BNST), a key limbic hub region, regulates anxiety. In a chronic stress model to induce anxiety in male mice, we used site- and cell-type-specific in vivo and in vitro manipulations, protein analysis, electrophysiological and behavioral analysis, in vivo MiniScope calcium imaging and mass spectroscopy, to characterize possible mechanism underlying a novel anxiolytic role for SIRT1 in the BNST. Specifically, decreased SIRT1 in parallel with increased corticotropin-releasing factor (CRF) expression was found in the BNST of anxiety model mice, whereas pharmacological activation or local overexpression of SIRT1 in the BNST reversed chronic stress-induced anxiety-like behaviors, downregulated CRF upregulation, and normalized CRF neuronal hyperactivity. Mechanistically, SIRT1 enhanced glucocorticoid receptor (GR)-mediated CRF transcriptional repression through directly interacting with and deacetylating the GR co-chaperone FKBP5 to induce its dissociation from the GR, ultimately downregulating CRF. Together, this study unravels an important cellular and molecular mechanism highlighting an anxiolytic role for SIRT1 in the mouse BNST, which may open up new therapeutic avenues for treating stress-related anxiety disorders.
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The mood disorders major depressive disorder (MDD) and bipolar disorder (BD) are highly prevalent worldwide. Women are more vulnerable to these psychopathologies than men. The bed nucleus of the stria terminalis (BNST), the amygdala, and the hypothalamus are the crucial interconnected structures involved in the stress response. In mood disorders, stress systems in the brain are put into a higher gear. The BNST is implicated in mood, anxiety, and depression. The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is highly abundant in the central BNST (cBNST). In this study, we investigated alterations in PACAP in the cBNST of patients with mood disorders. Immunohistochemical (IHC) staining of PACAP and in situ hybridization (ISH) of PACAP mRNA were performed on the cBNST of post-mortem human brain samples. Quantitative IHC revealed elevated PACAP levels in the cBNST in both mood disorders, MDD and BD, but only in men, not in women. The PACAP ISH was negative, indicating that PACAP is not produced in the cBNST. The results support the possibility that PACAP innervation of the cBNST plays a role in mood disorder pathophysiology in men.
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Trastorno Depresivo Mayor , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Núcleos Septales , Femenino , Humanos , Masculino , Trastornos del Humor , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Núcleos Septales/metabolismo , Estrés PsicológicoRESUMEN
BACKGROUND: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. METHODS: PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). RESULTS: PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. CONCLUSION: The results support the possibility that PACAP plays a role in mood disorder pathophysiology.