Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD.

Stress affects the brain and alters its neuroarchitecture and function; these changes can be severe and lead to psychiatric disorders. Recent evidence suggests that astrocytes and microglia play an essential role in the stress response by contributing to the maintenance of cerebral homeostasis. These cells respond rapidly to all stimuli that reach the brain, including stressors. Here, we used a recently validated rodent model of post-traumatic stress disorder in which rats can be categorized as resilient or vulnerable after acute inescapable footshock stress. We then investigated the functional, molecular, and morphological determinants of stress resilience and vulnerability in the prefrontal cortex, focusing on glial and neuronal cells. In addition, we examined the effects of a single subanesthetic dose of ketamine, a fast-acting antidepressant recently approved for the treatment of resistant depression and proposed for other stress-related psychiatric disorders. The present results suggest a prompt glial cell response and activation of the NF-κB pathway after acute stress, leading to an increase in specific cytokines such as IL-18 and TNF-α. This response persists in vulnerable individuals and is accompanied by a significant change in the levels of critical glial proteins such as S100B, CD11b, and CX43, brain trophic factors such as BDNF and FGF2, and proteins related to dendritic arborization and synaptic architecture such as MAP2 and PSD95. Administration of ketamine 24 h after the acute stress event rescued many of the changes observed in vulnerable rats, possibly contributing to support brain homeostasis. Overall, our results suggest that pivotal events, including reactive astrogliosis, changes in brain trophic factors, and neuronal damage are critical determinants of vulnerability to acute traumatic stress and confirm the therapeutic effect of acute ketamine against the development of stress-related psychiatric disorders.

How effective are mood stabilizers in treating bipolar patients comorbid with cPTSD? Results from an observational study.

BACKGROUND: Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients. RESULTS: Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD. CONCLUSIONS: The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments.

Exploring the Interplay between Complex Post-Traumatic Stress Disorder and Obsessive-Compulsive Disorder Severity: Implications for Clinical Practice.

Background and Objectives: Traumatic events adversely affect the clinical course of obsessive-compulsive disorder (OCD). Our study explores the correlation between prolonged interpersonal trauma and the severity of symptoms related to OCD and anxiety disorders. Materials and Methods: The study follows a cross-sectional and observational design, employing the International Trauma Questionnaire (ITQ) to examine areas linked to interpersonal trauma, the Hamilton Anxiety Rating Scale (HAM-A), and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess anxious and obsessive-compulsive symptoms, respectively. Descriptive analysis, analysis of variance (ANOVA), and logistic regression analyses were conducted. Results: We recruited 107 OCD-diagnosed patients, categorizing them into subgroups based on the presence or absence of complex post-traumatic stress disorder (cPTSD). The ANOVA revealed statistically significant differences between the two groups in the onset age of OCD (p = 0.083), psychiatric familial history (p = 0.023), HAM-A, and Y-BOCS (p < 0.0001). Logistic regression indicated a statistically significant association between the presence of cPTSD and Y-BOCS scores (p < 0.0001). Conclusions: The coexistence of cPTSD in OCD exacerbates obsessive-compulsive symptoms and increases the burden of anxiety. Further advancements in this field are crucial for mitigating the impact of early trauma on the trajectory of OCD and associated anxious symptoms.

Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Unraveling the Complexity: Exploring the Intersection of Panic Disorder, Dissociation, and Complex Post-Traumatic Stress Disorder.

BACKGROUND: Patients with panic disorder (PD) may experience increased vulnerability to dissociative and anxious phenomena in the presence of repeated traumatic events, and these may be risk factors for the development of complex post-traumatic stress disorder (cPTSD). The present study aims to find out whether the presence of cPTSD exacerbates anxiety symptoms in patients suffering from panic disorder and whether this is specifically associated with the occurrence of dissociative symptoms. METHODS: One-hundred-and-seventy-three patients diagnosed with PD were recruited and divided into two groups based on the presence (or absence) of cPTSD using the International Trauma Questionnaire (ITQ) scale. Dissociative and anxious symptoms were assessed using the Cambridge Depersonalization Scale (CDS) and Hamilton Anxiety Scale (HAM-A), respectively. RESULTS: Significant differences in re-experienced PTSD (p < 0.001), PTSD avoidance (p < 0.001), PTSD hyperarousal (p < 0.001), and DSO dysregulation (p < 0.001) were found between the cPTSD-positive and cPTSD-negative groups. A statistically significant association between the presence of cPTSD and total scores on the HAM-A (p < 0.001) and CDS (p < 0.001) scales was found using regression analysis. CONCLUSIONS: This study highlights the potential link between dissociative symptoms and a more severe clinical course of anxiety-related conditions in patients with PD. Early intervention programs and prevention strategies are needed.

The Impact of Complex PTSD on Suicide Risk in Patients with Bipolar Disorder: A Cross-Sectional Study.

BACKGROUND: Patients with bipolar disorder (BD) are more likely than the general population to experience traumatic events, particularly during childhood, and these may predict and be a risk factor for the development of complex PTSD (cPTSD). The presence of multiple traumas plays a relevant role from a psychopathological point of view, but little is known about the effect this may have on suicide attempts in patients with BD. METHODS: A cross-sectional study was conducted comparing socio-demographic and clinical characteristics, recruiting 344 patients diagnosed with BD I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire (ITQ). Suicide attempts were assessed directly during the clinical interview and from the patient's medical record. RESULTS: The results emerging from the study indicate that cPTSD can be considered a risk factor for suicide attempts in patients with BD. Furthermore, evidence is provided to support the idea that cPTSD is highly prevalent in patients with BD and is related to a higher psychopathological burden. CONCLUSIONS: The results recommend an urgent and comprehensive assessment of suicidal risk in patients with comorbidity of both bipolar disorder and cPTSD. There is a crucial demand for early intervention initiatives and proactive prevention strategies to address the intricate intersection of these mental health challenges.

Changes at glutamate tripartite synapses in the prefrontal cortex of a new animal model of resilience/vulnerability to acute stress.

Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser9 were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II-III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.

Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic.

COVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19? Evidence accumulated so far indicates that the pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism or in response to cytokine storm), all affecting the brain. It is reasonable to hypothesize that all these events may initiate or worsen psychiatric and cognitive disorders. Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by astrocytes which are the homeostatic cell par excellence. Astrocytes undergo complex morphological, biochemical, and functional remodeling aimed at mobilizing the regenerative potential of the central nervous system. If the brain is not directly damaged, resolution of systemic pathology usually results in restoration of the physiological homeostatic status of neuroglial cells. The completeness and dynamics of this process in pathological conditions remain largely unknown. In a subset of patients, glial cells could fail to recover after infection thus promoting the onset and progression of COVID-19-related neuropsychiatric diseases. There is evidence from post-mortem examinations of the brains of COVID-19 patients of alterations in both astrocytes and microglia. In conclusion, COVID-19 activates a huge reactive response of glial cells, that physiologically act as the main controller of the inflammatory, protective and regenerative events. However, in some patients the restoration of glial physiological state does not occur, thus compromising glial function and ultimately resulting in homeostatic failure underlying a set of specific neuropsychiatric symptoms related to COVID-19.

Palmitoylethanolamide and White Matter Lesions: Evidence for Therapeutic Implications.

Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.

Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis.

A combination of anticancer drugs and chemosensitizing agents has been approached as a promising strategy to potentiate chemotherapy and reduce toxicity in aggressive and chemoresistant cancers, like hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pancreatic ductal adenocarcinoma (PDAC). In the present study, the ability of caryophyllane sesquiterpenes to potentiate sorafenib efficacy was studied in HCC, CCA, and PDAC cell models, focusing on the modulation of STAT3 signaling and ABC transporters; tolerability studies in normal cells were also performed. Results showed that the combination of sorafenib and caryophyllane sesquiterpenes synergized the anticancer drug, especially in pancreatic Bx-PC3 adenocarcinoma cells; a similar trend, although with lower efficacy, was found for the standard ABC transporter inhibitors. Synergistic effects were associated with a modulation of MDR1 (or Pgp) and MRP transporters, both at gene and protein level; moreover, activation of STAT3 cascade and cell migration appeared significantly affected, suggesting that the STAT3/ABC-transporters axis finely regulated efficacy and chemoresistance to sorafenib, thus appearing as a suitable target to overcome drawbacks of sorafenib-based chemotherapy in hepato-biliary-pancreatic cancers. Present findings strengthen the interest in caryophyllane sesquiterpenes as chemosensitizing and chemopreventive agents and contribute to clarifying drug resistance mechanisms in HCC, CCA, and PDAC cancers and to developing possible novel therapeutic strategies.

Co-Ultramicronized Palmitoylethanolamide/Luteolin Restores Oligodendrocyte Homeostasis via Peroxisome Proliferator-Activated Receptor-α in an In Vitro Model of Alzheimer's Disease.

Oligodendrocytes are cells fundamental for brain functions as they form the myelin sheath and feed axons. They perform these critical functions thanks to the cooperation with other glial cells, mainly astrocytes. The astrocyte/oligodendrocyte crosstalk needs numerous mediators and receptors, such as peroxisome proliferator-activated receptors (PPARs). PPAR agonists promote oligodendrocyte precursor cells (OPCs) maturation in myelinating oligodendrocytes. In the Alzheimer's disease brain, deposition of beta-amyloid (Aß) has been linked to several alterations, including astrogliosis and changes in OPCs maturation. However, very little is known about the molecular mechanisms. Here, we investigated for the first time the maturation of OPCs co-cultured with astrocytes in an in vitro model of Aß1-42 toxicity. We also tested the potential beneficial effect of the anti-inflammatory and neuroprotective composite palmitoylethanolamide and luteolin (co-ultra PEALut), which is known to engage the isoform alfa of the PPARs. Our results show that Aß1-42 triggers astrocyte reactivity and inflammation and reduces the levels of growth factors important for OPCs maturation. Oligodendrocytes indeed show low cell surface area and few arborizations. Co-ultra PEALut counteracts the Aß1-42-induced inflammation and astrocyte reactivity preserving the morphology of co-cultured oligodendrocytes through a mechanism that in some cases involves PPAR-α. This is the first evidence of the negative effects exerted by Aß1-42 on astrocyte/oligodendrocyte crosstalk and discloses a never-explored co-ultra PEALut ability in restoring oligodendrocyte homeostasis.

Effects of Ultramicronized Palmitoylethanolamide on Mitochondrial Bioenergetics, Cerebral Metabolism, and Glutamatergic Transmission: An Integrated Approach in a Triple Transgenic Mouse Model of Alzheimer's Disease.

The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months via a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by in vivo microdialysis in the ventral HIPP (vHIPP). We demonstrated that chronic um-PEA treatment ameliorates the decrease in the complex-I respiration rate and the FoF1-ATPase (complex V) activity, as well as ATP content depletion in the cortical mitochondria. Otherwise, the impairment in mitochondrial bioenergetics and the release of glutamate after depolarization was not ameliorated by um-PEA treatment in the HIPP of both young and adult 3 × Tg-AD mice. Moreover, progressive age- and pathology-related changes were observed in the cortical and hippocampal metabolism that closely mimic the alterations observed in the human AD brain; these metabolic alterations were not affected by chronic um-PEA treatment. These findings confirm that the HIPP is the most affected area by AD-like pathology and demonstrate that um-PEA counteracts mitochondrial dysfunctions and helps rescue brain energy metabolism in the FC, but not in the HIPP.

Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex.

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

Neuroglia in Psychiatric Disorders.

In the twentieth century, neuropsychiatric disorders have been perceived solely from a neurone-centric point of view, which considers neurones as the key cellular elements of pathological processes. This dogma has been challenged thanks to the better comprehension of the brain functioning, which, even if far from being complete, has revealed the complexity of interactions that exist between neurones and neuroglia. Glial cells represent a highly heterogeneous population of cells of neural (astroglia and oligodendroglia) and non-neural (microglia) origin populating the central nervous system. The variety of glia reflects the innumerable functions that glial cells perform to support functions of the nervous system. Aberrant execution of glial functions contributes to the development of neuropsychiatric pathologies. Arguably, all types of glial cells are implicated in the neuropathology; however, astrocytes have received particular attention in recent years because of their pleiotropic functions that make them decisive in maintaining cerebral homeostasis. This chapter describes the multiple roles of astrocytes in the healthy central nervous system and discusses the diversity of astroglial responses in neuropsychiatric disorders suggesting that targeting astrocytes may represent an effective therapeutic strategy.

Astrocytes: The Housekeepers and Guardians of the CNS.

Astroglia are a diverse group of cells in the central nervous system. They are of the ectodermal, neuroepithelial origin and vary in morphology and function, yet, they can be collectively defined as cells having principle function to maintain homeostasis of the central nervous system at all levels of organisation, including homeostasis of ions, pH and neurotransmitters; supplying neurones with metabolic substrates; supporting oligodendrocytes and axons; regulating synaptogenesis, neurogenesis, and formation and maintenance of the blood-brain barrier; contributing to operation of the glymphatic system; and regulation of systemic homeostasis being central chemosensors for oxygen, CO2 and Na+. Their basic physiological features show a lack of electrical excitability (inapt to produce action potentials), but display instead a rather active excitability based on variations in cytosolic concentrations of Ca2+ and Na+. It is expression of neurotransmitter receptors, pumps and transporters at their plasmalemma, along with transports on the endoplasmic reticulum and mitochondria that exquisitely regulate the cytosolic levels of these ions, the fluctuation of which underlies most, if not all, astroglial homeostatic functions.

Principles of Astrogliopathology.

The role of astrocytes in the nervous system pathology was early on embraced by neuroscientists at end of the nineteenth and the beginning of the twentieth century, only to be pushed aside by neurone-centric dogmas during most of the twentieth century. However, the last decade of the twentieth century and the twenty-first century have brought the astroglial "renaissance", which has put astroglial cells as key players in pathophysiology of most if not all disorders of the nervous system and has regarded astroglia as a fertile ground for therapeutic intervention.Astrocytic contribution to neuropathology can be primary, whereby cell-autonomous changes, such as mutations in gene encoding for glial fibrillary acidic protein, can drive the pathologic progression, in this example, Alexander disease. They can also be secondary, when astrocytes respond to a variety of insults to the nervous tissue. Regardless of their origin, being cell-autonomous or not, changes in astroglia that occur in pathology, that is, astrogliopathology, can be contemporary and arbitrary classified into four forms: (i) reactive astrogliosis, (ii) astrocytic atrophy with loss of function, (iii) pathological remodelling of astrocytes and (iv) astrodegeneration morphologically manifested as clasmatodendrosis. Inevitably, as with any other classification, this classification of astrogliopathology awaits its revision that shall be rooted in new discoveries and concepts.

Astroglial Serotonin Receptors as the Central Target of Classic Antidepressants.

Major depressive disorder (MDD) presents multiple clinical phenotypes and has complex underlying pathological mechanisms. Existing theories cannot completely explain the pathophysiological mechanism(s) of MDD, while the pharmacology of current antidepressants is far from being fully understood. Astrocytes, the homeostatic and defensive cells of the central nervous system, contribute to shaping behaviors, and regulating mood and emotions. A detailed introduction on the role of astrocytes in depressive disorders is thus required, to which this chapter is dedicated. We also focus on the interactions between classic antidepressants and serotonin receptors, overview the role of astrocytes in the pharmacological mechanisms of various antidepressants, and present astrocytes as targets for the treatment of bipolar disorder. We provide a foundation of knowledge on the role of astrocytes in depressive disorders and astroglial 5-HT2B receptors as targets for selective serotonin reuptake inhibitors in vivo and in vitro.

Targeting the Oxytocinergic System: A Possible Pharmacological Strategy for the Treatment of Inflammation Occurring in Different Chronic Diseases.

Unresolved inflammation represents a central feature of different human pathologies including neuropsychiatric, cardiovascular, and metabolic diseases. The epidemiologic relevance of such disorders justifies the increasing interest in further understanding the mechanisms underpinning the inflammatory process occurring in such chronic diseases to provide potential novel pharmacological approaches. The most common and effective therapies for controlling inflammation are glucocorticoids; however, a variety of other molecules have been demonstrated to have an anti-inflammatory potential, including neuropeptides. In recent years, the oxytocinergic system has seen an explosion of scientific studies, demonstrating its potential to contribute to a variety of physiological processes including inflammation. Therefore, the aim of the present review was to understand the role of oxytocin in the modulation of inflammation occurring in different chronic diseases. The criterion we used to select the diseases was based on the emerging literature showing a putative involvement of the oxytocinergic system in inflammatory processes in a variety of pathologies including neurological, gastrointestinal and cardiovascular disorders, diabetes and obesity. The evidence reviewed here supports a beneficial role of oxytocin in the control of both peripheral and central inflammatory response happening in the aforementioned pathologies. Although future studies are necessary to elucidate the mechanistic details underlying such regulation, this review supports the idea that the modulation of the endogenous oxytocinergic system might represent a new potential pharmacological approach for the treatment of inflammation.