Surgery for temporal lobe epilepsy (TLE) is a well-recognised therapy for drug resistant seizures which occur in more than 50 % of patients with TLE. Blood-brain barrier (BBB) dysfunction is commonly observed in resected brain tissue from patients with treatment resistant epilepsy however, no studies have documented the recovery of BBB function following surgery. We firstly prospectively performed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on seven patients scheduled for temporal lobe resections before and after resection. DCE-MRI revealed BBB dysfunction in frontal and temporal brain regions. At 6-24 months post-resection, there was a reduction in the percentage of brain volume with BBB dysfunction in 5/7 patients. We then retrospectively characterised resected brain tissue from 6 further TLE cases (total n = 13) by q-RT-PCR and immunohistochemistry which revealed region-specific changes in markers of BBB integrity and inflammation with changes in CLDN12 and TJP1/2 in the hippocampus and CSF1R pathway genes in cortical and hippocampal tissue. BBB dysfunction is a key component of the molecular disruption caused by seizures and in longstanding early onset chronic epilepsy that is refractory to treatment. Here, we demonstrate for the first time the rescue of BBB dysfunction by controlling seizures after surgery.

Blood vessels are critical to deliver oxygen and nutrients to tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier (BBB), which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and protects the neural tissue from toxins and pathogens, and alterations of this barrier are important components of the pathogenesis and progression of various neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the brain endothelial cells (ECs) that form the walls of the blood vessels. These properties are regulated by interactions between different vascular, perivascular, immune, and neural cells. Understanding how these cell populations interact to regulate barrier properties is essential for understanding how the brain functions in both health and disease contexts.

Toxoplasma gondii is an obligatory intracellular parasite responsible for causing toxoplasmosis. It is estimated that approximately one-third of the world's population has positive serology for toxoplasmosis. Acute T. gondii infection often results in subtle symptoms because of its nonspecific nature. Owing to immune pressure, parasites tend to encyst and persist in different tissues and organs, such as the brain, chronicling the infection. While most chronically infected individuals do not develop significant symptoms, the parasite can affect the central nervous system (CNS), leading to symptoms that range from dizziness to behavioral changes. To reach the CNS, parasites must overcome the blood-brain barrier, which is composed primarily of endothelial cells. While these cells are typically efficient at separating blood elements from the CNS, in T. gondii infection, they not only permit parasitic colonization of the CNS but also contribute to an inflammatory profile that may exacerbate previously established conditions at both the local CNS and systemic levels. An increasing body of research has demonstrated a potential link between the CNS, infection by T. gondii and the cellular or humoral response to infection, with the worsening of psychiatric conditions, such as schizophrenia. Therefore, continually advancing research aimed at understanding and mitigating the relationship between parasitic infection and schizophrenia is imperative.

Neurogranin (Ng) expression is a biomarker for Alzheimer's disease. A loss of brain Ng and an increase in CSF Ng positively correlate with cognitive decline. Ng is known to regulate neuronal calcium-calmodulin binding and synaptic plasticity, which are critical for learning/memory. Interestingly, we discovered that Ng is also expressed in mouse and human blood-brain barrier (BBB). However, the role of Ng expression in brain vasculature remains largely undefined. In this study, we investigated the role of Ng expression on neurovascular structure and function using Ng null mice and human cerebral microvascular endothelial (hCMEC/D3) cells. We performed brain clearing and immunolabeling of blood vessels from whole brains and brain slices. Deletion of Ng significantly decreases neurovascular density in mice. Using in vivo permeability assays, we found increased neurovascular permeability in Ng null mice. We also observed significant changes in the expression of tight junction proteins using western blot and immunofluorescent staining. To identify the molecular pathways involved, we carried out label-free proteomics on brain lysates from endothelial-specific Ng knockout mice. Ingenuity Pathway Analysis indicated that the AKT pathway is attenuated in the vasculature of endothelial-specific Ng knockout mice. To validate these in vivo findings, we pharmacologically manipulated AKT signaling in hCMEC/D3 cells and observed that inhibition of AKT activation causes increased permeability. Our results indicate that the loss of Ng expression alters neurovascular structure and permeability, potentially contributing to neurological dysfunction. Therefore, modulating Ng expression in the BBB may offer a novel therapeutic approach for Alzheimer's disease.

Schizophrenia spectrum disorder (SSD) is a chronic neuropsychiatric illness accompanied by significant brain structural and functional abnormalities and higher rate of cardio- and cerebrovascular comorbidities. We hypothesized that genetic and environmental risk factors that led to SSD act throughout the body and demonstrated the association between lower integrity of peripheral vascular endothelium and white matter (WM) microstructure.

Microvascular endothelial function was evaluated using brachial artery post-occlusive reactive hyperemia (PORH), in which endothelial responses are measured under reduced blood flow and after blood flow is restored. White matter microstructure was assessed by multi-shell diffusion tensor imaging in n = 48 healthy controls (HCs) and n = 46 SSD.

Patients showed significantly lower PORH (F1,90 = 5.31, P = .02) effect and lower whole-brain fractional anisotropy (FA) values by diffusion imaging (F1,84 = 7.46, P = .008) with a group × post-occlusion time interaction effect (F3,90 = 4.58, P = .02). The PORH and whole-brain FA were significantly correlated in the full sample (r = 0.28, P = .01) and in SSD (r = 0.4, P = .008) separately, but not HC (r = 0.18, P = .28).

This study demonstrated, for the first time, significantly lower integrity of vascular endothelium in participants with SSD and showed that it is associated with WM microstructural abnormalities. Together, these findings support the need for a more holistic, body-brain approach to study the pathophysiology of SSD.

Blood-brain barrier (BBB) dysfunction occurs in numerous central nervous system disorders. Unfortunately, a limited understanding of the mechanisms governing barrier function hinders the identification and assessment of BBB-targeted therapies. Previously, we found that non-muscle myosin light chain kinase (nmMLCK) negatively regulates the tight junction protein claudin-5 in brain microvascular endothelial cells (BMVECs) under inflammatory conditions. Here, we used complementary animal and primary cell co-culture models to further investigate nmMLCK and claudin-5 during neuroinflammation. We found that nmMLCK-knockout mice resisted experimental autoimmune encephalomyelitis (EAE), including paralysis, demyelination, neutrophil infiltration, and BBB dysfunction. However, transiently silencing claudin-5 culminated in a fulminant disease course. In parallel, we found that neutrophil-secreted factors triggered a biphasic loss in the barrier quality of wild-type BMVEC monolayers, plus pronounced neutrophil migration during the second phase. Conversely, nmMLCK-knockout monolayers resisted barrier dysfunction and neutrophil migration. Lastly, we found an inverse relationship between claudin-5 expression in BMVECs and neutrophil migration. Overall, our findings support a pathogenic role for nmMLCK in BMVECs during EAE that includes BBB dysfunction and neutrophil infiltration, reveal that claudin-5 contributes to the immune barrier properties of BMVECs, and underscore the harmful effects of claudin-5 loss during neuroinflammation.

Inflammation and synapse loss have been associated with deficits in social behavior and are involved in pathophysiology of many neuropsychiatric disorders. Synapse loss, characterized by reduction in dendritic spines can significantly disrupt synaptic connectivity and neural circuitry underlying social behavior. Chronic stress is known to induce loss of spines and dendrites in the prefrontal cortex (PFC), a brain region implicated in social behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of type I Interferon (IFN-I) signaling in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found increased expression of type I IFN receptor (IFNAR) in microglia following CUS. Conditional knockout of microglial IFNAR in adult mice rescued CUS-induced social behavior deficits and synapse loss. Bulk RNA sequencing data show that microglial IFNAR deletion attenuated CUS-mediated changes in the expression of genes such as Keratin 20 (Krt20), Claudin-5 (Cldn5) and Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) in the PFC. Cldn5 and Nr4a1 are known for their roles in synaptic plasticity. Krt20 is an intermediate filament protein responsible for the structural integrity of epithelial cells. The reduction in Krt20 following CUS presents a novel insight into the potential contribution of cytokeratin in stress-induced alterations in neuroplasticity. Overall, these results suggest that microglial IFNAR plays a critical role in regulating synaptic plasticity and social behavior deficits associated with chronic stress conditions.

The blood-brain barrier (BBB) plays a crucial role in maintaining the homeostasis of the central nervous system by regulating solute transport and preventing neurotoxic substances from infiltrating brain tissue. In schizophrenia, emerging evidence identifies BBB dysfunction as a key pathophysiological factor associated with neuroinflammation, tight junction abnormalities, and endothelial dysfunction. Recent advancements in neuroimaging techniques, such as arterial spin labeling (ASL), have provided valuable tools for investigating BBB permeability and its role in disease progression. This review synthesizes findings from postmortem studies, serum and cerebrospinal fluid biomarker analyses, and advanced neuroimaging research to elucidate BBB alterations in schizophrenia. It highlights the mechanistic roles of tight junction protein dysregulation, neurovascular unit dysfunction, and immune responses in disrupting BBB integrity. Furthermore, the review examines the bidirectional effects of antipsychotic medications on BBB, addressing both therapeutic opportunities and potential challenges. By emphasizing the pivotal role of BBB dysfunction in schizophrenia pathogenesis, this review underscores its translational potential. Through the integration of multidisciplinary evidence, it lays the foundation for innovative diagnostic approaches and therapeutic strategies, enhancing our understanding of schizophrenia's complex pathophysiology.

Neurological disorders impact global health by affecting both central and peripheral nervous systems. Understanding the neurogenic processes, i.e., neurogenesis and neuritogenesis, is of paramount importance in the context of nervous system development and regeneration as they hold promising therapeutic implications. Neurogenesis forms functional neurons from precursor cells, while neuritogenesis involves extending neurites for neuron connections. This review discusses how these processes are influenced by genetics, epigenetics, neurotrophic factors, environment, neuroinflammation, and neurotransmitters. It also covers gender-specific aspects of neurogenesis and neuritogenesis, their impact on brain plasticity, and susceptibility to neurological disorders. Alterations in these processes, under the influence of cytokines, growth factors, neurotransmitters, and aging, are linked to neurological disorders and potential therapeutic targets. Gender-specific effects of pharmacological interventions, like SSRIs, TCAs, atypical antipsychotics, and lithium, are explored in this review. Hormone-mediated effects of BDNF and PPAR-γ agonists, as well as variations in efficacy and tolerability of MAOIs, AEDs, NMDA receptor modulators, and ampakines, are detailed for accurate therapeutic design. The review also discusses nanotechnology's significant contribution to neural tissue regeneration for mending neurodegenerative disorders, enhancing neuronal connectivity, and stem cell differentiation. Gold nanoparticles support hippocampal neurogenesis, while other nanoparticles aid neuron growth and neurite outgrowth. Quantum dots and nanolayered double hydroxides assist neuroregeneration, which improves brain drug delivery. Gender-specific responses to nanomedicines designed to enhance neuroregeneration have not been extensively investigated. However, we have specified certain gender-related variables that should be taken into account during the development of nanomedicines in an aim to improve therapeutic efficacy. Further research on gender-specific responses to nanomedicines in neural processes could enhance personalized treatments for neurological disorders, paving the way for novel therapeutic approaches in neuroscience.

Schizophrenia (SZ), a complex psychiatric disorder of neurodevelopment, is characterised by a range of symptoms, including hallucinations, delusions, social isolation and cognitive deterioration. One of the hypotheses that underlie SZ is related to inflammatory events which could be partly responsible for symptoms. However, it is unknown how inflammatory molecules can contribute to cognitive decline in SZ. This review summarises and exposes the possible contribution of the imbalance between pro-inflammatory and anti-inflammatory interleukins like IL-1beta, IL-4 and TNFalfa among others on cognitive impairment. We discuss how this inflammatory imbalance affects microglia and astrocytes inducing the disruption of the blood-brain barrier (BBB) in SZ, which could impact the prefrontal cortex or associative areas involved in executive functions such as planning and working tasks. We also highlight that inflammatory molecules generated by intestinal microbiota alterations, due to dysfunctional microbial colonisers or the use of some anti-psychotics, could impact the central nervous system. Finally, the question arises as to whether it is possible to modulate or correct the inflammatory imbalance that characterises SZ, and if an immunomodulatory strategy can be incorporated into conventional clinical treatments, either alone or in complement, to be applied in specific phases, such as prodromal or in the first-episode psychosis.

Recent research has underscored the critical role of blood-brain barrier (BBB) integrity in psychiatric disorders, highlighting disruptions in tight junction (TJ) proteins, specifically claudin-5 and occludin. These proteins are pivotal in maintaining the BBB's selective permeability, which is essential forbrain homeostasis. Altered levels of the TJ proteins have been observed in various psychiatric conditions, suggesting potential as biomarkers for the pathophysiology of these disorders. This systematic review synthesizes existing research on the alterations of claudin-5 and occludin levels in the serum of individuals with psychiatric disorders, evaluating their correlation with BBB dysfunction and psychiatric pathophysiology.

In adherence to the PRISMA guidelines, a comprehensive search strategy was employed, utilizing databases such as PubMed, Google Scholar, Web of Science, and Scopus. The review encompassed studies published between 2000 and 2024 that measured serum claudin-5 and occludin levels of psychiatric patients. Thorough data extraction and synthesis were conducted.

Seventeen studies met the inclusion criteria. Key findings include indications for increased claudin-5 levels in Schizophrenia, Bipolar Disorder, Depression, and Specific learning disorder, and increased occludin levels in ADHD and Autism Spectrum Disorder patients. No significant differences were found in studies of patients with Alcohol Use and Insomnia Disorder.

The review underscores the potential association between altered serum levels of claudin-5 and occludin and psychiatric disorders, supporting their utility as biomarkers for BBB integrity and psychiatric pathophysiology. Further research is essential to elucidate the mechanisms linking TJ protein alterations with pathophysiology and, potentially, neuroprogression in psychiatric disorders, which could lead to novel diagnostic and therapeutic strategies.

Tight junctions are physical barriers that limit the paracellular diffusion of solutes and ions. The blood-retina barriers are cellular barriers composed of tight junctions established in retinal pigment epithelial (RPE) cells and retinal endothelial cells to maintain retinal homeostasis. Claudins are the major components of tight junctions, and their dysregulation leads to impaired blood-retina barrier integrity, resulting in retinal diseases with concomitant local inflammation. In this chapter, we introduce two important claudins, claudin-5 and -19, and briefly explain how decreased expression of these claudins is associated with the progress of diabetic retinopathy (DR) and age-related macular degeneration (AMD) by compromising the blood-retina barriers.

Depression is a highly prevalent psychological disorder characterized by persistent dysphoria, psychomotor retardation, insomnia, anhedonia, suicidal ideation, and a remarkable decrease in overall well-being. Despite the prevalence of accessible antidepressant therapies, many individuals do not achieve substantial improvement. Understanding the multifactorial pathophysiology and the heterogeneous nature of the disorder could lead the way toward better outcomes. Recent findings have elucidated the substantial impact of compromised blood-brain barrier (BBB) integrity on the manifestation of depression. BBB functions as an indispensable defense mechanism, tightly overseeing the transport of molecules from the periphery to preserve the integrity of the brain parenchyma. The dysfunction of the BBB has been implicated in a multitude of neurological disorders, and its disruption and consequent brain alterations could potentially serve as important factors in the pathogenesis and progression of depression. In this review, we extensively examine the pathophysiological relevance of the BBB and delve into the specific modifications of its components that underlie the complexities of depression. A particular focus has been placed on examining the effects of peripheral inflammation on the BBB in depression and elucidating the intricate interactions between the gut, BBB, and brain. Furthermore, this review encompasses significant updates on the assessment of BBB integrity and permeability, providing a comprehensive overview of the topic. Finally, we outline the therapeutic relevance and strategies based on BBB in depression, including COVID-19-associated BBB disruption and neuropsychiatric implications. Understanding the comprehensive pathogenic cascade of depression is crucial for shaping the trajectory of future research endeavors.

The development of the brain's vascular system is a predominantly prenatal process in mammalian species and is required for neurogenesis and further brain development. Our recent work on fetal pig has revealed that many neurodevelopmental processes start well before birth and proceed rapidly reaching near-mature status already around birth. Here, we analyzed the development of neocortical vasculature from embryonic day (E) 45 onward (gestation in pig lasts 114 days) using qualitative and quantitative image analyses and protein blots. In all cortical layers, vessel volume from total brain volume at E100 resembled that of a postnatal day (P) 30 piglet. Endothelial cells expressed the tight junction protein claudin-5 from E45 onward. GFAP+ and AQP4+ astrocytes, PDGFRβ+ pericytes, and α-SMA+ smooth muscle cells are detectable near vessels at E60 suggesting an early assembly of blood-brain barrier components. The vascular system in the visual cortex is advanced before birth with an almost mature pattern at E100. Findings were confirmed by blots that showed a steady increase of expression of tight junction and angiogenesis-related proteins (claudin-5, occludin, VE-cadherin, PECAM-1/CD31) from E65 onward until P90. The expression profile was similar in visual and somatosensory cortex. Together, we report a rapid maturation of the vascular system in pig cortex.

Cerebral small vessel disease (CSVD) is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease. A clear understanding of the underlying causes of CSVD remains elusive.

To explore the association between intercellular adhesion molecule-1 (ICAM-1) and blood-brain barrier (BBB) penetration in CSVD.

This study included patients admitted to Fuyang People's Hospital and Fuyang Community (Anhui, China) between December 2021 and March 2022. The study population comprised 142 patients, including 80 in the CSVD group and 62 in the control group. Depression was present in 53 out of 80 patients with CSVD. Multisequence magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI were applied in patients to determine the brain volume, cortical thickness, and cortical area of each brain region. Moreover, neuropsychological tests including the Hamilton depression scale, mini-mental state examination, and Montreal cognitive assessment basic scores were performed.

The multivariable analysis showed that age [P = 0.011; odds ratio (OR) = 0.930, 95% confidence interval (CI): 0.880-0.983] and ICAM-1 levels (P = 0.023; OR = 1.007, 95%CI: 1.001-1.013) were associated with CSVD. Two regions of interest (ROIs; ROI3 and ROI4) in the white matter showed significant (both P < 0.001; 95%CI: 0.419-0.837 and 0.366-0.878) differences between the two groups, whereas only ROI1 in the gray matter showed significant difference (P = 0.046; 95%CI: 0.007-0.680) between the two groups. ICAM-1 was significantly correlated (all P < 0.05) with cortical thickness in multiple brain regions in the CSVD group.

This study revealed that ICAM-1 levels were independently associated with CSVD. ICAM-1 may be associated with cortical thickness in the brain, predominantly in the white matter, and a significant increase in BBB permeability, proposing the involvement of ICAM-1 in BBB destruction.

Late-life depression (LLD) is a prevalent mental disorder among older adults. Previous studies revealed that many pathologic factors are associated with the onset and development of LLD. However, the precise mechanisms that cause LLD remain elusive. Aging induces chronic inflammatory changes mediated by alterations of immune responses. The chronic systemic inflammation termed "inflammaging" is linked to the etiology of aging-related disorders. Aged microglia induce senescence-associated secretory phenotype (SASP) and transition to M1-phenotype, cause neuroinflammation, and diminish neuroprotective effects. In addition, there is an age-dependent loss of blood-brain barrier (BBB) integrity. As the BBB breakdown can lead to invasion of immune cells into brain parenchyma, peripheral immunosenescence may cause microglial activation and neuroinflammation. Therefore, it is suggested that these mechanisms related to brain inflammaging may be involved in the pathogenesis of LLD. In this review, we described the role of brain inflammaging in LLD. Pharmacologic approaches to prevent brain inflammaging appears to be a promising strategy for treating LLD.

Tight junctions (TJs) are an important component of cellular connectivity. Claudin family proteins, as a constituent of TJs, determine their barrier properties, cell polarity and paracellular permeability. Claudin-12 is an atypical member of the claudin family, as it belongs to the group of non-classical claudins that lack a PDZ-binding domain. It has been shown that claudin-12 is involved in paracellular Ca2+ transients and it is present in normal and hyperplastic tissues in addition to neoplastic tissues. Dysregulation of claudin-12 expression has been reported in various cancers, suggesting that this protein may play an important role in cancer cell migration, invasion, and metastasis. Some studies have shown that claudin-12 gene functions as a tumor suppressor, but others have reported that overexpression of claudin-12 significantly increases the metastatic properties of various tumor cells. Investigating this dual role of claudin-12 is of utmost importance and should therefore be studied in detail. The aim of this review is to provide an overview of the information available to date on claudin-12, including its structure, expression in various tissues and substances that may affect it, with a final focus on its role in cancer.

Epilepsy in dogs and humans is associated with blood-brain barrier (BBB) dysfunction (BBBD), which may involve dysfunction of tight junction (TJ) proteins, matrix metalloproteases, and astrocytes. Imaging techniques to assess BBB integrity, to identify potential treatment strategies, have not yet been evaluated in veterinary medicine.

Some dogs with idiopathic epilepsy (IE) will exhibit BBBD. Identifying BBBD may improve antiepileptic treatment in the future.

Twenty-seven dogs with IE and 10 healthy controls.

Retrospective, prospective cohort study. Blood-brain barrier permeability (BBBP) scores were calculated for the whole brain and piriform lobe of all dogs by using dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) and subtraction enhancement analysis (SEA). Matrix metalloproteinase-9 (MMP9) activity in serum and cerebrospinal fluid (CSF) was measured and its expression in the piriform lobe was examined using immunofluorescent staining. Gene expression of TJ proteins and astrocytic transporters was analyzed in the piriform lobe.

The DCE-MRI analysis of the piriform lobe identified higher BBBP score in the IE group when compared with controls (34.5% vs 26.5%; P = .02). Activity and expression of MMP9 were increased in the serum, CSF, and piriform lobe of IE dogs as compared with controls. Gene expression of Kir4.1 and claudin-5 in the piriform lobe of IE dogs was significantly lower than in control dogs.

Our findings demonstrate BBBD in dogs with IE and were supported by increased MMP9 activity and downregulation of astrocytic potassium channels and some TJ proteins. Blood brain barrier dysfunction may be a novel antiepileptic therapy target.

Claudin-5 is one of the most essential tight junction proteins at the blood-brain barrier. A single nucleotide polymorphism rs10314 is located in the 3'-untranslated region of claudin-5 and has been shown to be a risk factor for schizophrenia. Here, we show that the pumilio RNA-binding protein, pumilio-1, is responsible for rs10314-mediated claudin-5 regulation. The RNA sequence surrounding rs10314 is highly homologous to the canonical pumilio-binding sequence and claudin-5 mRNA with rs10314 produces 25% less protein due to its inability to bind to pumilio-1. Pumilio-1 formed cytosolic granules under stress conditions and claudin-5 mRNA appeared to preferentially accumulate in these granules. Added to this, we observed granular pumilio-1 in endothelial cells in human brain tissues from patients with psychiatric disorders or epilepsy with increased/accumulated claudin-5 mRNA levels, suggesting translational claudin-5 suppression may occur in a brain-region specific manner. These findings identify a key regulator of claudin-5 translational processing and how its dysregulation may be associated with neurological and neuropsychiatric disorders.

Blood-brain barrier (BBB) dysfunction is a key feature in neuroimmunological and neurodegenerative diseases. In this study, we developed a microfluidic human BBB-on-a-chip to model barrier dysfunction and immune cell migration using immortalized TY10 brain endothelial cells, pericytes, and astrocytes. It was found that immortalized TY10 brain endothelial cells developed a microvascular structure under flow. Pericytes were localized on the basal side surrounding the TY10 microvascular structure, showing an in vivo-like structure. Barrier integrity increased under co-culture with pericytes. In addition, both ethylenediaminetetraacetic acid (EDTA) and anti-Claudin-5 (CLDN5) neutralizing antibody caused a decrease in the transendothelial electrical resistance (TEER). EDTA caused the leakage of 20 kDa dextran, suggesting different effects on the BBB based on the mechanism of action, whereas anti-CLDN5 antibody did not cause leakage. In the tri-culture model, human T cells migrated through endothelial vessels towards basal C-X-C motif chemokine ligand 12 (CXCL12). The live-imaging analysis confirmed the extravasation of fluorescence-labelled T cells in a CXCL12-concentration- and time-dependent manner. Our BBB model had an in vivo-like structure and successfully represented barrier dysfunction and transendothelial T cell migration. In addition, our study suggests that the inhibition of CLDN5 attenuates the BBB in humans. This platform has various potential uses in relation to the BBB in both drug discovery research and in elucidating the mechanisms of central nervous system diseases.

This review addresses the role of tight junction proteins at the blood-brain barrier (BBB). Their expression is described, and their role in physiological and pathological processes at the BBB is discussed. Based on this, new approaches are depicted for paracellular drug delivery and diagnostics in the treatment of cerebral diseases. Recent data provide convincing evidence that, in addition to its impairment in the course of diseases, the BBB could be involved in the aetiology of CNS disorders. Further progress will be expected based on new insights in tight junction protein structure and in their involvement in signalling pathways.

The blood-brain barrier (BBB) is a dynamic interface that regulates the exchange of molecules and cells between the brain parenchyma and the peripheral blood. The BBB is mainly composed of endothelial cells, astrocytes and pericytes. The integrity of this structure is essential for maintaining brain and spinal cord homeostasis and protection from injury or disease. However, in various neurological disorders, such as traumatic brain injury, Alzheimer's disease, and multiple sclerosis, the BBB can become compromised thus allowing passage of molecules and cells in and out of the central nervous system parenchyma. These agents, however, can serve as biomarkers of BBB permeability and neuronal damage, and provide valuable information for diagnosis, prognosis and treatment. Herein, we provide an overview of the BBB and changes due to aging, and summarize current knowledge on biomarkers of BBB disruption and neurodegeneration, including permeability, cellular, molecular and imaging biomarkers. We also discuss the challenges and opportunities for developing a biomarker toolkit that can reliably assess the BBB in physiologic and pathophysiologic states.

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.

The blood-brain barrier (BBB) and tight junction (TJ) proteins maintain the homeostasis of the central nervous system (CNS). The dysfunction of BBB allows peripheral T cells infiltration into CNS and contributes to the pathophysiology of multiple sclerosis (MS). Teriflunomide is an approved drug for the treatment of MS by suppressing lymphocytes proliferation. However, whether teriflunomide has a protective effect on BBB in MS is not understood. We found that teriflunomide restored the injured BBB in the EAE model. Furthermore, teriflunomide treatment over 6 months improved BBB permeability and reduced peripheral leakage of CNS proteins in MS patients. Teriflunomide increased human brain microvascular endothelial cell (HBMEC) viability and promoted BBB integrity in an in vitro cell model. The TJ protein claudin-1 was upregulated by teriflunomide and responsible for the protective effect on BBB. Furthermore, RNA sequencing revealed that the Wnt signaling pathway was affected by teriflunomide. The activation of Wnt signaling pathway increased claudin-1 expression and reduced BBB damage in cell model and EAE rats. Our study demonstrated that teriflunomide upregulated the expression of the tight junction protein claudin-1 in endothelial cells and promoted the integrity of BBB through Wnt signaling pathway.

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut-brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood-brain barrier and the blood-cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut-microbiota-brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut-brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders.

The eight biological hallmarks of health that we initially postulated (Cell. 2021 Jan 7;184(1):33-63) include features of spatial compartmentalization (integrity of barriers, containment of local perturbations), maintenance of homeostasis over time (recycling & turnover, integration of circuitries, rhythmic oscillations) and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, repair & regeneration). These hallmarks affect all eight somatic strata of the human body (molecules, organelles, cells, supracellular units, organs, organ systems, systemic circuitries and meta-organism). Here we postulate that mental and socioeconomic factors must be added to this 8×8 matrix as an additional hallmark of health ("psychosocial adaptation") and as an additional stratum ("psychosocial interactions"), hence building a 9×9 matrix. Potentially, perturbation of each of the somatic hallmarks and strata affects psychosocial factors and vice versa. Finally, we discuss the (patho)physiological bases of these interactions and their implications for mental health improvement.

The blood-brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Claudin-5 (CLDN-5) is a tetra-spanning protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL). Plasma levels of phosphorylated tau (pTau181), a biomarker of pathological tau, were elevated in patients with MCI or AD (2.86 and 4.20 pg/mL, respectively) compared with control subjects (1.81 pg/mL). In patients with MCI or AD, plasma levels of CLDN-5-but not pTau181-decreased with age, suggesting some age-dependent BBB changes in MCI and AD. These findings suggest that plasma CLDN-5 may a potential biochemical marker for the diagnosis of AD.

Schizophrenia (SCZ) is a complex neurodevelopmental disorder characterized by the manifestation of psychiatric symptoms in early adulthood. While many research avenues into the origins of SCZ during brain development have been explored, the contribution of endothelial/vascular dysfunction to the disease remains largely elusive. To model the neuropathology of SCZ during early critical periods of brain development, we utilized patient-derived induced pluripotent stem cells (iPSCs) to generate 3D cerebral organoids and define cell-specific signatures of disease. Single-cell RNA sequencing revealed that while SCZ organoids were similar in their macromolecular diversity to organoids generated from healthy controls (CTRL), SCZ organoids exhibited a higher percentage of endothelial cells when normalized to total cell numbers. Additionally, when compared to CTRL, differential gene expression analysis revealed a significant enrichment in genes that function in vessel formation, vascular regulation, and inflammatory response in SCZ endothelial cells. In line with these findings, data from 23 donors demonstrated that PECAM1+ microvascular vessel-like structures were increased in length and number in SCZ organoids in comparison to CTRL organoids. Furthermore, we report that patient-derived endothelial cells displayed higher paracellular permeability, implicating elevated vascular activity. Collectively, our data identified altered gene expression patterns, vessel-like structural changes, and enhanced permeability of endothelial cells in patient-derived models of SCZ. Hence, brain microvascular cells could play a role in the etiology of SCZ by modulating the permeability of the developing blood brain barrier (BBB).

Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood-brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis.Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands.This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond.

Studies from animal models and clinical trials of blood and cerebrospinal fluid have proposed that blood-brain barrier (BBB) dysfunction in depression (MDD). But there are no In vivo proves focused on BBB dysfunction in MDD patients. The present study aimed to identify whether there was abnormal BBB permeability, as well as the association with clinical status in MDD patients using dynamic contrast-enhanced magnetic resonance (DCE-MRI) imaging.

Patients with MDD and healthy adults were recruited and underwent DCE-MRI and structural MRI scans. The mean volume transfer constant (Ktrans) values were calculated for a quantitative assessment of BBB leakage. For each subject, the mean Ktrans values were calculated for the whole gray matter, white matter, and 90 brain regions of the anatomical automatic labeling template (AAL). The differences in Ktrans values between patients and controls and between treated and untreated patients were compared.

23 MDD patients (12 males and 11 females, mean age 28.09 years) and 18 healthy controls (HC, 8 males and 10 females, mean age 30.67 years) were recruited in the study. We found that the Ktrans values in the olfactory, caudate, and thalamus were higher in MDD patients compared to healthy controls (p<0.05). The Ktrans values in the orbital lobe, anterior cingulate gyrus, putamen, and thalamus in treated patients were lower than the patients never treated. There were positive correlations between HAMD total score with Ktrans values in whole brain WM, hippocampus and thalamus. The total HAMA score was positively correlated with the Ktrans of hippocampus.

These findings supported a link between blood-brain barrier leakage and depression and symptom severity. The results also suggested a role for non-invasive DCE-MRI in detecting blood-brain barrier dysfunction in depression patients.

Parenchymal accumulation of beta-amyloid (Aβ) characterizes Alzheimer's disease (AD). Aβ homeostasis is maintained by two ATP-binding cassette (ABC) transporters (ABCC1 and ABCB1) mediating efflux, and the receptor for advanced glycation end products (RAGE) mediating influx across the blood-brain barrier (BBB). Altered transporter levels and disruption of tight junctions (TJ) were linked to AD. However, Aβ transport and the activity of ABCC1, ABCB1 and RAGE as well as the functionality of TJ in AD are unclear.

ISMICAP, a BBB model involving microperfusion of capillaries, was used to assess BBB properties in acute cortical brain slices from Tg2576 mice compared to wild-type (WT) controls using two-photon microscopy. TJ integrity was tested by vascularly perfusing biocytin-tetramethylrhodamine (TMR) and quantifying its extravascular diffusion as well as the diffusion of FM1-43 from luminal to abluminal membranes of endothelial cells (ECs). To assess ABCC1 and ABCB1 activity, calcein-AM was perfused, which is converted to fluorescent calcein in ECs and gets actively extruded by both transporters. To probe which transporter is involved, probenecid or Elacridar were applied, individually or combined, to block ABCC1 and ABCB1, respectively. To assess RAGE activity, the binding of 5-FAM-tagged Aβ by ECs was quantified with or without applying FPS-ZM1, a RAGE antagonist.

In Tg2576 mouse brain, extravascular TMR was 1.8-fold that in WT mice, indicating increased paracellular leakage. FM1-43 staining of abluminal membranes in Tg2576 capillaries was 1.7-fold that in WT mice, indicating reduced TJ integrity in AD. While calcein was undetectable in WT mice, its accumulation was significant in Tg2576 mice, suggesting lower calcein extrusion in AD. Incubation with probenecid or Elacridar in WT mice resulted in a marked calcein accumulation, yet probenecid alone had no effect in Tg2576 mice, implying the absence of probenecid-sensitive ABC transporters. In WT mice, Aβ accumulated along the luminal membranes, which was undetectable after applying FPS-ZM1. In contrast, marginal Aβ fluorescence was observed in Tg2576 vessels, and FPS-ZM1 was without effect, suggesting reduced RAGE binding activity.

Disrupted TJ integrity, reduced ABCC1 functionality and decreased RAGE binding were identified as BBB alterations in Tg2576 mice, with the latter finding challenging the current concepts. Our results suggest to manage AD by including modulation of TJ proteins and Aβ-RAGE binding.

This research aimed to investigate serum Zonula occludens-1 (ZO-1) and Claudin-5 (CLDN5) levels to show whether or not their eventual changes in patients with insomnia disorder could have etiopathogenetic importance. There was no research investigating serum ZO-1 and CLDN5 concentrations in insomnia disorder.

This study included 60 insomnia disorder patients and 45 normal controls. None of the patients received drugs for insomnia. The patients completed Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI), and Polysomnography (PSG) to score the insomnia disorder symptoms. Venous blood samples were collected, and serum ZO-1 and claudin-5 levels were analyzed by enzyme-linked immunosorbent assay (ELISA).

Serum ZO-1 level was significantly higher without a significant difference between age, sex, and body mass index, whereas the difference in serum claudin-5 level between the two groups was not statistically significant. In addition, ZO-1 levels were positively correlated with ISI and PSQI and negatively with N1 and N1_perc. We also demonstrated a positive correlation between the levels of CLDN5 and HAMA, and a negative correlation with total sleep time (TST), N1 and N1_perc.

Our findings suggest an association between these intestinal and brain endothelial permeability markers and insomnia disorders. However, these remain modest and preliminary and need more extensive studies, including long-term follow-up populations and involving gut microbes, to further validate and explore the mechanisms involved.

Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood-retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/β-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs.

Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD.

We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions.

Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions.

This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.

Although there is convergent evidence for blood-brain barrier (BBB) dysfunction and peripheral inflammation in schizophrenia (SZ) and bipolar disorder (BD), it is unknown whether BBB deficits are intrinsic to brain microvascular endothelial cells (BMECs) or arise via effects of peripheral inflammatory cytokines. We examined BMEC function using stem cell-based models to identify cellular and molecular deficits associated with BBB dysfunction in SZ and BD. Induced pluripotent stem cells (iPSCs) from 4 SZ, 4 psychotic BD and 4 healthy control (HC) subjects were differentiated into BMEC-"like" cells. Gene expression and protein levels of tight junction proteins were assessed. Transendothelial electrical resistance (TEER) and permeability were assayed to evaluate BBB function. Cytokine levels were measured from conditioned media. BMECs derived from human iPSCs in SZ and BD did not show differences in BBB integrity or permeability compared to HC BMECs. Outlier analysis using TEER revealed a BBB-deficit (n = 3) and non-deficit (n = 5) group in SZ and BD lines. Stratification based on BBB function in SZ and BD patients identified a BBB-deficit subtype with reduced barrier function, tendency for increased permeability to smaller molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased matrix metallopeptidase 1 (MMP1) activity, which correlated with reduced CLDN5 and worse BBB function, and was improved by tumor necrosis factor α (TNFα) and MMP1 inhibition. These results show potential deficits in BMEC-like cells in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as promising targets for ameliorating BBB deficits.

This drug review provides a comprehensive analysis of a novel antipsychotic called lumateperone, marketed as Caplyta. Lumateperone gained FDA approval in 2019 for treating schizophrenia and later, in 2021, for treating bipolar depression. The review begins by delving into lumateperone's mechanism of action, which involves the partial agonism of the dopamine D2 receptor as well as its unique effects on the dopamine transporter, N-methyl-D-aspartate (NMDA) receptor, and serotonin transporter. Additionally, the study examines lumateperone's distinctive pharmacokinetics. Moreover, this review assesses lumateperone's metabolic profile and highlights its favorable outcomes regarding mean body weight, BMI, and waist circumference, surpassing those of other second-generation antipsychotic medications. The study explicitly emphasizes the efficacy and safety of lumateperone in treating schizophrenia and bipolar depression associated with bipolar I and II disorders. An extensive investigation of multiple clinical trials provides compelling evidence of lumateperone's advantages over existing antipsychotic medications. The review also acknowledges the limitations of lumateperone compared to other antipsychotics. In conclusion, this drug review underscores the importance of further research to uncover the additional limitations of lumateperone while acknowledging its promising benefits and potential for advancing treatment options.

The word mad has historically been associated with the psyche, emotions, and abnormal behavior. Dementia is a common symptom among psychiatric disorders or mad (schizophrenia, depression, bipolar disorder) patients. Autophagy/mitophagy is a protective mechanism used by cells to get rid of dysfunctional cellular organelles or mitochondria. Autophagosome/mitophagosome abundance in autophagy depends on microtubule-associated protein light chain 3B (LC3B-II) and autophagy-triggering gene (ATG) which functions as an autophagic biomarker for phagophore production and quick mRNA disintegration. Defects in either LC3B-II or the ATG lead to dysregulated mitophagy-and-autophagy-linked dementia (MAD). The impaired MAD is closely associated with schizophrenia, depression, and bipolar disorder. The pathomechanism of psychosis is not entirely known, which is the severe limitation of today's antipsychotic drugs. However, the reviewed circuit identifies new insights that may be especially helpful in targeting biomarkers of dementia. Neuro-theranostics can also be achieved by manufacturing either bioengineered bacterial and mammalian cells or nanocarriers (liposomes, polymers, and nanogels) loaded with both imaging and therapeutic materials. The nanocarriers must cross the BBB and should release both diagnostic agents and therapeutic agents in a controlled manner to prove their effectiveness against psychiatric disorders. In this review, we highlighted the potential of microRNAs (miRs) as neuro-theranostics in the treatment of dementia by targeting autophagic biomarkers LC3B-II and ATG. Focus was also placed on the potential for neuro-theranostic nanocells/nanocarriers to traverse the BBB and induce action against psychiatric disorders. The neuro-theranostic approach can provide targeted treatment for mental disorders by creating theranostic nanocarriers.

Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility.

We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology.

FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05).

Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1β, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood-brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.

The neurovascular unit (NVU) is a dynamic center for substance exchange between the blood and the brain, making it an essential gatekeeper for central nervous system (CNS) homeostasis. Recent evidence supports a role for the NVU in modulating brain function and cognition. In addition, alterations in NVU processes are observed in response to stress, although the mechanisms via which they can affect mood and cognitive functions remain elusive. Here, we summarize recent studies of neurovascular regulation of emotional processes and cognitive function, including under stressful conditions. We also highlight relevant RNA-sequencing (RNA-seq) databases aiming to profile the NVU along with innovative tools to study and manipulate NVU function that can be exploited in the context of cognition and stress research throughout development, aging, or brain disorders.