Immune-mediated mechanisms are increasingly recognised as a cause of epilepsy even in the absence of an immune response against a specifical neuronal antigen. In some cases, these autoimmune processes are clearly pathogenic, for example acute seizures in autoimmune encephalitis, whereas in others this is less clear, for example autoimmune-associated epilepsy. Recent research has provided novel insights into the clinical, paraclinical and immunopathogenetic mechanisms in these conditions. I will provide an overview of clinical and paraclinical features of immune-associated seizures. Furthermore, I will describe specific immunopathogenic examples implicating lymphoid follicular autoimmunisation and intrathecal B cells in these conditions. These insights into immunopathogenesis may help to explain the role of current and immunotherapies in these conditions.

Epileptogenesis is a gradual and dynamic process leading to difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including the activation of inflammatory processes.  The use of human brain tissue represents a crucial strategy to advance our understanding of the underlying neuropathology and the molecular and cellular basis of epilepsy and related cognitive and behavioral comorbidities,  The mounting evidence obtained during the past decade has emphasized the critical role of inflammation  in the pathophysiological processes implicated in a large spectrum of genetic and acquired forms of  focal epilepsies. Dissecting the cellular and molecular mediators of  the pathological immune responses and their convergent and divergent mechanisms, is a major requisite for delineating their role in the establishment of epileptogenic networks. The role of small regulatory molecules involved in the regulation of  specific pro- and anti-inflammatory pathways  and the crosstalk between neuroinflammation and oxidative stress will be addressed.    The observations supporting the activation of both innate and adaptive immune responses in human focal epilepsy will be discussed and elaborated, highlighting specific inflammatory pathways as potential targets for antiepileptic, disease-modifying therapeutic strategies.

Caroline Williams-Gray is a Principal Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and an honorary consultant neurologist specializing in Parkinson’s disease and movement disorders. She leads a translational research group investigating the clinical and biological heterogeneity of PD, with the ultimate goal of developing more targeted therapies for different Parkinson’s subtypes. Her recent work has focused on the theory that the immune system plays a significant role in mediating the heterogeneity of PD and its progression. Her lab is investigating this using blood and CSF -based immune markers, PET neuroimaging and neuropathology in stratified PD cohorts; and she is leading the first randomized controlled trial repurposing a peripheral immunosuppressive drug (azathioprine) to slow the progression of PD.

Observational data have become a popular source of evidence for causal effects when no randomized controlled trial exists, or to supplement information provided by those. In practice, a wide range of designs and analytical choices exist, and one recent approach relies on the target trial emulation framework. This framework is particularly well suited to mimic what could be obtained in a specific randomized controlled trial, while avoiding time-related selection biases. In this abstract, we present how this framework could be useful to emulate trials in malignant melanoma, and the challenges faced when planning such a study using longitudinal observational data from a cohort study. More specifically, two questions are envisaged: duration of immune checkpoint inhibitors, and trials comparing treatment strategies for BRAF V600-mutant patients (targeted therapy as 1st line, followed by immunotherapy as 2nd line, vs. immunotherapy as 2nd line followed by targeted therapy as 1st line). Using data from 1027 participants to the MELBASE cohort, we detail the results for the emulation of a trial where immune checkpoint inhibitor would be stopped at 6 months vs. continued, in patients in response or with stable disease.

Life Perceives is a symposium bringing together scientists and artists for an open exploration of how “perception” can be understood as a phenomenon that does not only belong to humans, or even the so-called “higher organisms”, but exists across the entire spectrum of life in a myriad of forms. The symposium invites leading practitioners from the arts and sciences to present unique insights through short talks, open discussions, and artistic interventions that bring us slightly closer to the life worlds of plants and fungi, microbial communities and immune systems, cuttlefish and crows. What do we mean when we talk about perception in other species? Do other organisms have an experience of the world? Or does our human-centred perspective make understanding other forms of life on their own terms an impossible dream? Whatever your answers to these questions may be, we hope to unsettle them, and leave you more curious than when you arrived.

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer’s disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches." https://doi.org/10.1016/j.neuron.2022.10.015

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030

Talk(1): Fetal and maternal NLRP3 signaling is required for preterm labor and birth. (DOI: 10.1172/jci.insight.158238) Talk(2): Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice (DOI: 10.1073/pnas.2123267119)

Social insects fight disease as a collective. Their colonies are protected against disease by the combination of the individual immune defenses of all colony members and their jointly performed nest- and colony-hygiene. This social immunity is achieved by cooperative behaviors to reduce pathogen load of the colony and to prevent transmission along the social interaction networks of colony members. Individual and social immunity interact: performance of sanitary care can affect future disease susceptibility, yet also vice versa, individuals differing in susceptibility adjust their sanitary care performance to their individual risk of infection. I present the integrated approach we use to understand how colony protection arises from the individual and collective actions of colony members and how it affects pathogen communities and hence disease ecology.

Microglia, traditionally classified as immune-responsive, adjust synaptic connections during development and disease. However, their role in the adult nervous system has been mostly diminished to an observer. In my research group, we are interested in how microglia are involved in establishing and maintaining accurate neuronal circuit function in the retina and in the visual cortex. In my talk, I will introduce our strategies how to decipher the microglia’s functional identity and how this information guided us to microglia enabled extracellular matrix remodeling and reinstatment of juvenile-like plasticity in the adult brain.

Thoughts and emotions can impact physiology. This connection is evident by the emergence of disease following stress, psychosomatic disorders, or recovery in response to placebo treatment. Nevertheless, this fundamental aspect of physiology remains largely unexplored. In this talk, I will focus on the brain’s involvement in regulating the peripheral immune response and explore the question of how the brain evaluates and represents the state of the immune system it regulates.

Accumulating data indicate that the brain can affect immunity, as evidenced, for example, by the effects of stress, stroke, and reward system activity on the peripheral immune system. However, our understanding of this neuroimmune interaction is still limited. Importantly, we do not know how the brain evaluates and represents the state of the immune system. In this talk, I will present our latest study from our lab, designed to test the existence of immune-related information in the brain and determine its relevance to immune regulation. We hypothesized that the InsCtx, specifically the posterior InsCtx (as a primary cortical site of interoception in the brain), is especially suited to contain such a representation of the immune system. Using activity-dependent cell labeling in mice (FosTRAP), we captured neuronal ensembles in the InsCtx that were active under two different inflammatory conditions (dextran sulfate sodium [DSS]-induced colitis and zymosan-induced peritonitis). Chemogenetic reactivation of these neuronal ensembles was sufficient to broadly retrieve the inflammatory state under which these neurons were captured. Moreover, using retrograde neuronal tracing, we found an anatomical efferent pathway linking these InsCtx neurons to the inflamed peripheral sites. Taken together, we show that the brain can store and retrieve specific immune responses, extending the classical concept of immunological memory to neuronal representations of inflammatory information.

Menstruation is a normal physiological process in women occurring as a result of changes in two ovarian produced hormones – estrogen and progesterone. As a result of these fluctuations, women experience different symptoms in their bodies – their immune system changes (Sekigawa et al, 2004), there are changes in their cardiovascular and digestive system (Millikan, 2006), as well as skin (Hall and Phillips, 2005). But these hormone fluctuations produce major changes in their behavioral pattern as well causing: anxiety, sadness, heightened irritability and anger (Severino and Moline, 1995) which is usually classified as premenstrual syndrome (PMS). In some cases these symptoms severely impair women’s lives and professional help is required. The official diagnosis according to DSM-5 (2013) is premenstrual dysphoric disorder (PMDD). Despite its ubiquitous presence the origins of PMS and PMDD are poorly understood. Some efforts to understand the underlying brain state during the menstruation cycle were performed by using TMS (Smith et al, 1999; 2002; 2003; Inghilleri et al, 2004; Hausmann et al, 2006). But all of these experiments suffer from major shortcomings - no control groups and small number of subjects. Our plan is to address all of these shortcomings and make this the biggest (to our knowledge) experiment of its kind which will, hopefully, provide us with some much needed answers.

Reflex circuits in the nervous system integrate changes in the environment with physiology. Compact clusters of brain neuron cell bodies, termed nuclei, are essential for receiving sensory input and for transmitting motor outputs to the body. These nucelii are critical relay stations which process incoming information and convert these signals to outgoing action potentials which regulate immune system functions. Thus, reflex neural circuits maintain parameters of immunological physiology within a narrow range optimal for health. Advances in neuroscience and immunology using optogenetics, pharmacogenetics, and functional mapping offer a new understanding of the importance of neural circuitry underlying immunity, and offer direct paths to new therapies.

Traumatic brain injury (TBI), a leading cause of acquired epilepsy, results in primary cellular injury as well as secondary neurophysiological and inflammatory responses which contribute to epileptogenesis. I will present our recent studies identifying a role for neuro-immune interactions, specifically, the innate immune receptor Toll-like receptor 4 (TLR4), in enhancing network excitability and cell loss in hippocampal dentate gyrus early after concussive brain injury. I will describe results indicating that the transient post-traumatic increases in dentate neurogenesis which occurs during the same early post-injury period augments dentate network excitability and epileptogenesis. I will provide evidence for the beneficial effects of targeting TLR4 and neurogenesis early after brain injury in limiting epileptogenesis. We will discuss potential mechanisms for convergence of the post-traumatic neuro-immune and neurogenic changes and the implications for therapies to reduce neurological deficits and epilepsy after brain injury.

Gestational exposure to environmental toxins, infections, and stressors are epidemiologically linked to neurodevelopmental disorders with strong male-bias, such as autism spectrum disorder. We modeled some of these prenatal risk factors in mice, by co-exposing pregnant dams to an environmental pollutant and limited-resource stress, which robustly dysregulated the maternal immune system. Male but not female offspring displayed long-lasting behavioral abnormalities and alterations in the activity of brain networks encoding social interactions, along with disruptions of gut structure and microbiome composition. Cellularly, prenatal stressors impaired microglial synaptic pruning in males during early postnatal development. Precise inhibition of microglial phagocytosis during the same critical period mimicked the impact of prenatal stressors on the male-specific social deficits. Conversely, modifying the gut microbiome rescued the social and cellular deficits, indicating that environmental stressors alter neural circuit formation in males via impairing microglia function during development, perhaps via a gut-brain disruption.

In this lecture, Dr Stevens will discuss recent work that implicates brain immune cells, called microglia, in sculpting of synaptic connections during development and their relevance to autism, schizophrenia and other brain disorders. Her recent work revealed a key role for microglia and a group of immune related molecules called complement in normal developmental synaptic pruning, a normal process required to establish precise brain wiring. Emerging evidence suggests aberrant regulation of this pruning pathway may contribute to synaptic and cognitive dysfunction in a host of brain disorders, including schizophrenia. Recent research has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in complement C4, gene plays a well-known role in the immune system but also helps sculpt developing synapses in the mouse visual system (Sekar et al., 2016). Together these findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. Stevens will discuss this and ongoing work to understand the mechanisms by which complement and microglia prune specific synapses in the brain. A deeper understanding of how these immune mechanisms mediate synaptic pruning may provide novel insight into how to protect synapses in autism and other brain disorders, including Alzheimer’s and Huntington’s Disease.

There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis (MS). International agencies are engaging to expedite the development of novel strategies capable of modifying disease progression, abrogating persistent CNS inflammation, and support degenerating axons in people with progressive MS. Understanding why regeneration fails in the progressive MS brain and developing new regenerative approaches is a key priority for the Pluchino Lab. In particular, we aim to elucidate how the immune system, in particular its cells called myeloid cells, affects brain structure and function under normal healthy conditions and in disease. Our objective is to find how myeloid cells communicate with the central nervous system and affect tissue healing and functional recovery by stimulating mechanisms of brain plasticity mechanisms such as the generation of new nerve cells and the reduction of scar formation. Applying combination of state-of-the-art omic technologies, and molecular approaches to study murine and human disease models of inflammation and neurodegeneration, we aim to develop experimental molecular medicines, including those with stem cells and gene therapy vectors, which slow down the accumulation of irreversible disabilities and improve functional recovery after progressive multiple sclerosis, stroke and traumatic injuries. By understanding the mechanisms of intercellular (neuro-immune) signalling, diseases of the brain and spinal cord may be treated more effectively, and significant neuroprotection may be achieved with new tailored molecular therapeutics.

Inflammation is a key component of the innate immune response. Primarily designed to remove noxious agents and limit their detrimental effects, the prolonged and/or inappropriately scaled innate immune response may be detrimental to the host and lead to a chronic disease. Indeed, there is increasing evidence suggesting that a chronic deregulation of immunity may represent one of the key elements in the pathobiology of many brain disorders. Microglia are the principal immune cells of the brain. The consensus today is that once activated microglia/macrophages can acquire a wide repertoire of profiles ranging from the classical pro-inflammatory to alternative and protective phenotypes. Recently, we described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation involving RNA binding protein SRSF3. Here we will discuss the implications of SRSF3 and other endogenous immune regulators in deregulation of immunity observed in different models of brain pathologies. Furthermore, we will discuss whether targeting SRSF3 and mRNA translation may open novel avenues for therapeutic modulation of immune response in the brain.

Peripheral nerve injury can cause debilitating disease and immune-cell mediated destruction of the affected nerve. While the focus of most studies has been on the nerve-degenerative response, the effect of loss of innervation on lymph node function is largely unclear. Here, I will discuss the cellular and molecular events caused by local denervation and loss of direct neural input to the popliteal lymph node that induce an inflammatory response and lymph node expansion.

On April 22, 2021, Dr. Alan J Thompson of the University College London and the UCL Institute of Neurology, London, UK will deliver the Hughlings Jackson Lecture entitled, “Making Progress in Progressive MS – the Ultimate Challenge!” Established in 1935, the Hughlings Jackson Lecture is The Neuro’s premier scientific lecture. It honors the legacy of British neurologist John Hughlings Jackson (1835-1911) who pioneered the development of neurology as a medical specialty. Talk Abstract : The international focus on progressive MS, driven by the Progressive MS Alliance amongst others, together with recent encouraging results from clinical trials have raised the profile and emphasised the importance of understanding, treating and ultimately preventing progression in MS. Effective treatment for Progressive MS is now regarded as the single most important issue facing the MS community. There are several important challenges to developing new treatments for progressive MS. Fundamental to any development in treatment is a better understanding of the mechanisms of tissue injury underpinning progression which will in turn allow the identification of new targets against which treatments can be directed. There are additional complications in determining when progression actually starts, determining the impact of aging and defining the progressive clinical phenotypes – an area which has become increasingly complex in recent months. Evaluating potential new treatments in progressive MS also poses particular challenges including trial design and the selection of appropriate clinical and imaging outcomes - in particular, identifying an imaging biomarker for phase II trials of progressive MS. Despite these challenges, considerable progress is being made in developing new treatments targeting the innate immune system and exploring neuroprotective strategies. Further advances are being driven by a number of international networks, funded by the Progressive MS Alliance. Overall we are seeing encouraging progress as a result of co-ordinated global collaboration which offers real possibilities for truly effective treatment of progression.

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these two evolutionarily highly conserved systems is long recognized, the pathophysiological mechanisms regulating their reciprocal crosstalk in cardiovascular diseases became object of investigation only more recently. In the last years, our group elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. In my talk, I will focus on the molecular mechanisms that regulate the neuro-immune crosstalk in hypertension. I will elaborate on the mechanistic insights into this brain-spleen axis led us uncover a new molecular pathway mediating the neuroimmune interaction established by noradrenergic-mediated release in the spleen of placental growth factor (PlGF), an angiogenic growth factor potentially targetable with pharmacological approaches.

The microbiota-gut-brain axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of brain development and behaviour during early life, adolescence & ageing. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or by way of microbial metabolites such as short chain fatty acids. Studies in animal models have shown that the development of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics. Recently, the gut microbiota has been implicated in regulating the stress response, and social behaviour. Moreover, fundamental brain processes from adult hippocampal neurogenesis to myelination to microglia activation have been shown to be regulated by the microbiome. Further studies will focus on understanding the mechanisms underlying such brain effects and how they can be exploited by microbiota-targeted interventions including ‘psychobiotics’ and diet

The synapse is the core component of the nervous system and synapse formation is the critical step in the assembly of neuronal circuits. The assembly and maturation of synapses requires the contribution of secreted and membrane-associated proteins, with neuronal activity playing crucial roles in regulating synaptic strength, neuronal membrane properties, and neural circuit refinement. The molecular mechanisms of synapse assembly and refinement have been so far largely examined on a gene-by-gene basis and with a perspective fully centered on neuronal cells. However, in the last years, the involvement of non-neuronal cells has emerged. Among these, microglia, the resident immune cells of the central nervous system, have been shown to play a key role in synapse formation and elimination. Contacts of microglia with dendrites in the somatosensory cortex were found to induce filopodia and dendritic spines via Ca2+ and actin-dependent processes, while microglia-derived BDNF was shown to promote learning-dependent synapse formation. Microglia is also recognized to have a central role in the widespread elimination (or pruning) of exuberant synaptic connections during development. Clarifying the processes by which microglia control synapse homeostasis is essential to advance our current understanding of brain functions. Clear answers to these questions will have important implications for our understanding of brain diseases, as the fact that many psychiatric and neurological disorders are synaptopathies (i.e. diseases of the synapse) is now widely recognized. In the last years, my group has identified TREM2, an innate immune receptor with phagocytic and antiinflammatory properties expressed in brain exclusively by microglia, as essential for microglia-mediated synaptic refinement during the early stages of brain development. The talk will describe the role of TREM2 in synapse elimination and introduce the molecular actors involved. I will also describe additional pathways by which the immune system may affect the formation and homeostasis of synaptic contacts.

Microglia are the immune cells of the brain, and play increasingly appreciated roles in synapse formation, brain plasticity, and cognition. A growing appreciation that the immune system involved in diseases like schizophrenia, epilepsy, and neurodegenerative diseases has led to renewed interest in how microglia regulate synaptic connectivity. Our group previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel regulator of microglial activation and function. I will discuss a mechanism by which microglia regulate synaptic plasticity and long-term memories by engulfing brain extracellular matrix (ECM) proteins. These studies raise the question of how these pathways may be altered or could be modified in the context of disease.

Are the immune system, brain, mind and mood related? Could this explain why chronic low-grade peripheral inflammation is also noted in approximately 1/3 of those with major depressive disorder (MDD)? The field recognized today as immunopsychiatry was founded on scientific evidence that germinated over 30 years ago. Since, it has been understood that (i) there could be a causal link between inflammation and depression, (ii) select blood immune markers show robust potential as biomarkers for inflammation-linked depression, and more generally, (iii) Descartes' theories on mind-body dualism were biologically erroneous. Nonetheless, the mechanistic brain-immune axis in the trinity formulating inflammation-linked depression i.e. psycho-neuro-immunology, still remains unclear. This talk will discuss findings from our recent investigation endeavored to unpack this by linking functional connectivity abnormalities with peripheral immune markers.

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Both prematurity and IUGR are associated with perinatal systemic inflammation, a key factor associated with neuroinflammation and identified to be the best predictor of subsequent neurological impairments. Most of pharmacological candidates have failed to demonstrate any beneficial effect to prevent perinatal brain damage. In contrast, environmental enrichment based on developmental care, skin-to-skin contact and vocal/music intervention appears to confer positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the perinatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. Excessive cortisol release in response to perinatal stress induces pro-inflammatory and brain-programming effects. These deleterious effects are known to be balanced by Oxytocin (OT), a neuropeptide playing a key role during the perinatal period and parturition, in social behavior and regulating the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with perinatal brain damage, we recently reported that Carbetocin, a brain permeable long-lasting OT receptor (OTR) agonist, was associated with a significant reduction of activated microglia, the primary immune cells of the brain. Moreover this reduced microglia reactivity was associated to a long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the causality between the endogenous OT and central inflammation response to injury has not been established and will be further studied by the lab.

One of the major challenges in developing therapeutics for the neurodegenerative disorders is the blood-brain barrier, limiting the availability of systemically administered therapies such as recombinant proteins or monoclonal antibodies from reaching the brain. Direct central nervous system (CNS) gene therapy using adeno-associated virus vectors expressing a therapeutic protein, monoclonal antibody or inhibiting RNA-coding sequences has two characteristics ideal for therapy of neurodegenerative disorders: circumventing the blood-brain barrier by directly expressing the therapy in the brain and the ability to provide persistent therapy with only a single administration. There are several critical parameters relevant to successful CNS gene therapy, including choice of vector, design of the gene to be expressed, delivery/route of administration, dose and anti-vector immune responses. The presentation will focus on these issues, the current status of clinical trials of gene therapy for neurodegeneration and specific challenges that will need to be overcome to ensure the success of these therapies.

The gut microbiota is emerging as an important modulator of brain function and behavior, as several recent discoveries reveal substantial effects of the microbiome on neurophysiology, neuroimmunity and animal behavior. Despite these findings supporting a “microbiome-gut-brain axis”, the molecular and cellular mechanisms that underlie interactions between the gut microbiota and brain remain poorly understood. To uncover these, the Hsiao laboratory is mining the human microbiota for microbial modulators of host neuroactive molecules, investigating the impact of microbiota-immune system interactions on neurodevelopment and examining the microbiome as an interface between gene-environment interactions in neurological diseases. In particular, our research on effects of the maternal microbiome on offspring development in utero are revealing novel interactions between microbiome-dependent metabolites and fetal thalamocortical axonogenesis. Overall, we aim to dissect biological pathways for communication between the gut microbiota and nervous system, toward understanding fundamental interactions between physiological systems that impact brain and behavior.

After an injury in the adult mammalian central nervous system, lesioned axons fail to regenerate. This failure to regenerate contrasts with the remarkable potential of axons to grow during embryonic development and after an injury in the peripheral nervous system. Peripheral sensory neurons with cell soma in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Decades of research have focused on the signaling pathways elicited by injury in sensory neurons and in Schwann cells that insulate axons as central mechanisms regulating nerve repair. However, neuronal microenvironment is far more complex and is composed of multiple cell types including endothelial, immune and glial cells. Whether the microenvironment surrounding neuronal soma contribute to the poor regenerative outcomes following central injuries remains largely unexplored. To answer this question, we performed a single cell transcriptional profiling of the DRG neuronal microenvironment response to peripheral and central injuries. In dissecting the roles of the microenvironment contribution, we have focused on a poorly studied population of Satellite Glial Cells (SGC) surrounding the neuronal cell soma. This study has uncovered a previously unknown role for SGC in nerve regeneration and defined SGC as transcriptionally distinct from Schwann cells while sharing similarities with astrocytes. Upon a peripheral injury, SGC contribute to axon regeneration via Fatty acid synthase (Fasn)-PPARα signaling pathway. Through repurposing fenofibrate, an FDA- approved PPARα agonist used for dyslipidemia treatment, we were able to rescue the impaired regeneration in mice lacking Fasn in SGC. Our analysis reveals that in response to central injuries, SGC do not activate the PPAR signaling pathway. However, induction of this pathway with fenofibrate treatment, rescued axon regeneration following an injury to the central nerves. Collectively, our results uncovered a previously unappreciated role of the neuronal microenvironment differential response in central and peripheral injuries.

We recently analyzed a large cohort of multiple sclerosis (MS) autopsy cases of the Netherlands Brain Bank (NBB) and showed that 57% of the lesion in advanced MS is active (containing activated microglia/macrophages). These active lesions correlated with disease severity and differed between males and female MS patients.1 Already in normal appearing white matter microglia show early signs of demyelination.5 T cells are also frequently present in advanced stages of MS and have a tissue resident memory (Trm) phenotype, are more frequently CD8+ then CD4+, are located perivascular, enriched in active and mixed active/inactive MS lesions and correlated with lesion activity, lesion load and disease severity.2-4 Like Trm cells, B cells are located perivascular and were also enriched in active MS lesions but in lower numbers and a proportion of the MS patients had almost no detectable B cells in the regions analyzed. MS patients with limited presence of B cells had less severe MS, and less active and mixed active /inactive lesions. We conclude that advanced MS is characterize by a high innate and adaptive immune activity which is heterogeneous and relates to the clinical disease course.

Emerging genetic studies of late-onset Alzheimer’s Disease implicate the brain’s resident macrophages in the pathogenesis of AD. More than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells; yet we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis. Using single-cell RNA sequencing and spatial transcriptomics we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in the human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. We identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of Alzheimer’s disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.

Immune cells and their derived molecules have major impact on brain function. Mice deficient in adaptive immunity have impaired cognitive and social function compared to that of wild-type mice. Importantly, replenishment of the T cell compartment in immune deficient mice restored proper brain function. Despite the robust influence on brain function, T cells are not found within the brain parenchyma, a fact that only adds more mystery into these enigmatic interactions between T cells and the brain. Our results suggest that meningeal space, surrounding the brain, is the site where CNS-associated immune activity takes place. We have recently discovered a presence of meningeal lymphatic vessels that drain CNS molecules and immune cells to the deep cervical lymph nodes. This communication between the CNS and the peripheral immunity is playing a key role in neurophysiology and in several CNS disorders. Interestingly, meningeal lymphatics are impaired in aging and their dysfunction may be related to age-related cognitive decline as well as to Alzheimer’s pathology. In addition to providing new insights into age-related disorders, meningeal lymphatics may also serve as a novel therapeutic target for these diseases and are worth of in-depth mechanistic exploration.

Carnosine is a natural dipeptide widely distributed in mammalian tissues and exists at particularly high concentrations in skeletal and cardiac muscles and brain. A growing body of evidence shows that carnosine is involved in many cellular defense mechanisms against oxidative stress, including inhibition of amyloid-β (Aβ) aggregation, modulation of nitric oxide (NO) metabolism, and scavenging both reactive nitrogen and oxygen species. Different types of cells are involved in the innate immune response, with macrophage cells representing those primarily activated, especially under different diseases characterized by oxidative stress and systemic inflammation such as depression and cardiovascular disorders. Microglia, the tissue-resident macrophages of the brain, are emerging as a central player in regulating key pathways in central nervous system inflammation; with specific regard to Alzheimer’s disease (AD) these cells exert a dual role: on one hand promoting the clearance of Aβ via phagocytosis, on the other hand increasing neuroinflammation through the secretion of inflammatory mediators and free radicals. The activity of carnosine was tested in an in vitro model of macrophage activation (M1) (RAW 264.7 cells stimulated with LPS + IFN-γ) and in a well-validated model of Aβ-induced neuroinflammation (BV-2 microglia treated with Aβ oligomers). An ample set of techniques/assays including MTT assay, trypan blue exclusion test, high performance liquid chromatography, high-throughput real-time PCR, western blot, atomic force microscopy, microchip electrophoresis coupled to laser-induced fluorescence, and ELISA aimed to evaluate the antioxidant and anti-inflammatory activities of carnosine was employed. In our experimental model of macrophage activation (M1), therapeutic concentrations of carnosine exerted the following effects: 1) an increased degradation rate of NO into its non-toxic end-products nitrite and nitrate; 2) the amelioration of the macrophage energy state, by restoring nucleoside triphosphates and counterbalancing the changes in ATP/ADP, NAD+/NADH and NADP+/NADPH ratio obtained by LPS + IFN-γ induction; 3) a reduced expression of pro-oxidant enzymes (NADPH oxidase, Cyclooxygenase-2) and of the lipid peroxidation product malondialdehyde; 4) the rescue of antioxidant enzymes expression (Glutathione peroxidase 1, Superoxide dismutase 2, Catalase); 5) an increased synthesis of transforming growth factor-β1 (TGF-β1) combined with the negative modulation of interleukines 1β and 6 (IL-1β and IL-6), and 6) the induction of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1). In our experimental model of Aβ-induced neuroinflammation, carnosine: 1) prevented cell death in BV-2 cells challenged with Aβ oligomers; 2) lowered oxidative stress by decreasing the expression of inducible nitric oxide synthase and NADPH oxidase, and the concentrations of nitric oxide and superoxide anion; 3) decreased the secretion of pro-inflammatory cytokines such as IL-1β simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1; 4) prevented Aβ-induced neurodegeneration in primary mixed neuronal cultures challenged with Aβ oligomers and these neuroprotective effects was completely abolished by SB431542, a selective inhibitor of type-1 TGF-β receptor. Overall, our data suggest a novel multimodal mechanism of action of carnosine underlying its protective effects in macrophages and microglia and the therapeutic potential of this dipeptide in counteracting pro-oxidant and pro-inflammatory phenomena observed in different disorders characterized by elevated levels of oxidative stress and inflammation such as depression, cardiovascular disorders, and Alzheimer’s disease.

Membrane interfaces formed at junctions between cells are often associated with characteristic patterns of membrane protein organization, such as in epithelial tissues and between cells of the immune system. While this organization can be influenced by receptor clustering, lipid domain formation, and cytoskeletal dynamics, this talk will describe how cell surface molecular height can directly contribute to the spatial arrangement of membrane proteins and downstream signaling. Using a new optical method for characterizing molecular height, together with experiments using giant vesicles in vitro systems and live immune cells, we are investigating how cell surface molecular heights can be key contributors to cell-cell communication.

The Chiu laboratory focuses on neuro-immune interactions in pain, itch, and tissue inflammation. Dr. Chiu’s research has uncovered molecular interactions between the nervous system, the immune system and microbes that modulates host defense. He has found that sensory neurons can directly detect bacterial pathogens and their toxins to produce pain. Neurons in turn release neuropeptides that modulate immune cells in host defense. These interactions occur at major tissue barriers in the body including the gut, skin and lungs. In this talk, he will discuss these major neuro-immune interactions and how understanding them could lead to novel approaches to treat pain or inflammation.

Genome-wide association studies implicate microglia in Alzheimer’s disease (AD) pathogenesis, but how microglia contribute to cognitive decline in AD is unclear. Emerging research suggests microglia, the resident macrophages of the central nervous system, to be active participants in brain wiring. One mechanism by which microglia help eliminate synapses is through the classical complement pathway (C1q, CR3/C3). Data from multiple laboratories collectively suggest that there may be an aberrant reactivation of the complement-dependent pruning pathway in multiple models of neurologic diseases including AD. These data altogether suggest that microglia participate in synaptic pathology. However, how and which synapses are targeted are unknown. Furthermore, whether microglia directly impair synaptic function is unknown. Primary goals of my laboratory are to understand how higher cognitive functions such as learning and memory involve microglial biology in the healthy adult brain and dissect immune mechanisms behind the region-specific vulnerability of synapse loss and neuronal dysfunction during disease. Mechanistic insight into local signals that regulate neuroglia interactions will be key to developing potential therapeutic avenues to target in disease.

We have developed a robotic platform allowing us to monitor cytokines dynamics (including IL-2, IFN-g, TNF, IL-6) of immune cells in vitro, with unprecedented resolution. To understand the complex emerging dynamics, we use interpretable machine learning techniques to build a generative model of cytokine response. We discover that, surprisingly, immune activity is encoded into one global parameter, encoding ligand antigenic properties and to a less extent ligand quantity. Based on this we build a simple interpretable model which can fully explain the broad variability of cytokines dynamics. We validate our approach using different lines of cells and different ligands. Two processes are identified, connected to timing and intensity of cytokine response, which we successfully modulate using drugs or by changing conditions such as initial T cell numbers. Our work reveals a simple "cytokine code", which can be used to better understand immune response in different contexts including immunotherapy. More generally, it reveals how robotic platforms and machine learning can be leveraged to build and validate systems biology models.

In this talk, Dr. Eyo will his present research on microglia, the brain’s resident immune cell. After providing some background to these cells, Dr. Eyo will highlight two aspects of his research. First, some of his previous work elucidating microglial dynamic activity during development as well as mechanisms regulating their demise during simulated developmental ischemia will be discussed. Second, research will be presented clarifying mechanisms underlying the interactions between microglia and neurons with a special focus on seizure disorders. Together, these findings highlight microglia as a critical cell type in brain function in development and brain pathology