Impact of High Fat Diet on Central Cardiac Circuits: When The Wanderer is Lost

Cardiac vagal motor drive originates in the brainstem's cardiac vagal motor neurons (CVNs). Despite well-established cardioinhibitory functions in health, our understanding of CVNs in disease is limited. There is a clear connection of cardiovascular regulation with metabolic and energy expenditure systems. Using high fat diet as a model, this talk will explore how metabolic dysfunction impacts the regulation of cardiac tissue through robust inhibition of CVNs. Specifically, it will present an often overlooked modality of inhibition, tonic gamma-aminobuytric acid (GABA) A-type neurotransmission using an array of techniques from single cell patch clamp electrophysiology to transgenic in vivo whole animal physiology. It also will highlight a unique interaction with the delta isoform of protein kinase C to facilitate GABA A-type receptor expression.

How the brain barriers ensure CNSimmune privilege”

Britta Engelhard’s research is devoted to understanding thefunction of the different brain barriers in regulating CNS immunesurveillance and how their impaired function contributes toneuroinflammatory diseases such as Multiple Sclerosis (MS) orAlzheimer’s disease (AD). Her laboratory combines expertise invascular biology, neuroimmunology and live cell imaging and hasdeveloped sophisticated in vitro and in vivo approaches to studyimmune cell interactions with the brain barriers in health andneuroinflammation.

Why age-related macular degeneration is a mathematically tractable disease

Among all prevalent diseases with a central neurodegeneration, AMD can be considered the most promising in terms of prevention and early intervention, due to several factors surrounding the neural geometry of the foveal singularity. • Steep gradients of cell density, deployed in a radially symmetric fashion, can be modeled with a difference of Gaussian curves. • These steep gradients give rise to huge, spatially aligned biologic effects, summarized as the Center of Cone Resilience, Surround of Rod Vulnerability. • Widely used clinical imaging technology provides cellular and subcellular level information. • Data are now available at all timelines: clinical, lifespan, evolutionary • Snapshots are available from tissues (histology, analytic chemistry, gene expression) • A viable biogenesis model exists for drusen, the largest population-level intraocular risk factor for progression. • The biogenesis model shares molecular commonality with atherosclerotic cardiovascular disease, for which there has been decades of public health success. • Animal and cell model systems are emerging to test these ideas.

Brain-heart interactions at the edges of consciousness

Various clinical cases have provided evidence linking cardiovascular, neurological, and psychiatric disorders to changes in the brain-heart interaction. Our recent experimental evidence on patients with disorders of consciousness revealed that observing brain-heart interactions helps to detect residual consciousness, even in patients with absence of behavioral signs of consciousness. Those findings support hypotheses suggesting that visceral activity is involved in the neurobiology of consciousness and sum to the existing evidence in healthy participants in which the neural responses to heartbeats reveal perceptual and self-consciousness. Furthermore, the presence of non-linear, complex, and bidirectional communication between brain and heartbeat dynamics can provide further insights into the physiological state of the patient following severe brain injury. These developments on methodologies to analyze brain-heart interactions open new avenues for understanding neural functioning at a large-scale level, uncovering that peripheral bodily activity can influence brain homeostatic processes, cognition, and behavior.

Blood-brain barrier dysfunction in epilepsy: Time for translation

The neurovascular unit (NVU) consists of cerebral blood vessels, neurons, astrocytes, microglia, and pericytes. It plays a vital role in regulating blood flow and ensuring the proper functioning of neural circuits. Among other, this is made possible by the blood-brain barrier (BBB), which acts as both a physical and functional barrier. Previous studies have shown that dysfunction of the BBB is common in most neurological disorders and is associated with neural dysfunction. Our studies have demonstrated that BBB dysfunction results in the transformation of astrocytes through transforming growth factor beta (TGFβ) signaling. This leads to activation of the innate neuroinflammatory system, changes in the extracellular matrix, and pathological plasticity. These changes ultimately result in dysfunction of the cortical circuit, lower seizure threshold, and spontaneous seizures. Blocking TGFβ signaling and its associated pro-inflammatory pathway can prevent this cascade of events, reduces neuroinflammation, repairs BBB dysfunction, and prevents post-injury epilepsy, as shown in experimental rodents. To further understand and assess BBB integrity in human epilepsy, we developed a novel imaging technique that quantitatively measures BBB permeability. Our findings have confirmed that BBB dysfunction is common in patients with drug-resistant epilepsy and can assist in identifying the ictal-onset zone prior to surgery. Current clinical studies are ongoing to explore the potential of targeting BBB dysfunction as a novel treatment approach and investigate its role in drug resistance, the spread of seizures, and comorbidities associated with epilepsy.

Neurovascular Interactions: Mechanisms, Imaging, Therapeutics

Astrocyte reprogramming / activation and brain homeostasis

Astrocytes are multifunctional glial cells, implicated in neurogenesis and synaptogenesis, supporting and fine-tuning neuronal activity and maintaining brain homeostasis by controlling blood-brain barrier permeability. During the last years a number of studies have shown that astrocytes can also be converted into neurons if they force-express neurogenic transcription factors or miRNAs. Direct astrocytic reprogramming to induced-neurons (iNs) is a powerful approach for manipulating cell fate, as it takes advantage of the intrinsic neural stem cell (NSC) potential of brain resident reactive astrocytes. To this end, astrocytic cell fate conversion to iNs has been well-established in vitro and in vivo using combinations of transcription factors (TFs) or chemical cocktails. Challenging the expression of lineage-specific TFs is accompanied by changes in the expression of miRNAs, that post-transcriptionally modulate high numbers of neurogenesis-promoting factors and have therefore been introduced, supplementary or alternatively to TFs, to instruct direct neuronal reprogramming. The neurogenic miRNA miR-124 has been employed in direct reprogramming protocols supplementary to neurogenic TFs and other miRNAs to enhance direct neurogenic conversion by suppressing multiple non-neuronal targets. In our group we aimed to investigate whether miR-124 is sufficient to drive direct reprogramming of astrocytes to induced-neurons (iNs) on its own both in vitro and in vivo and elucidate its independent mechanism of reprogramming action. Our in vitro data indicate that miR-124 is a potent driver of the reprogramming switch of astrocytes towards an immature neuronal fate. Elucidation of the molecular pathways being triggered by miR-124 by RNA-seq analysis revealed that miR-124 is sufficient to instruct reprogramming of cortical astrocytes to immature induced-neurons (iNs) in vitro by down-regulating genes with important regulatory roles in astrocytic function. Among these, the RNA binding protein Zfp36l1, implicated in ARE-mediated mRNA decay, was found to be a direct target of miR-124, that be its turn targets neuronal-specific proteins participating in cortical development, which get de-repressed in miR-124-iNs. Furthermore, miR-124 is potent to guide direct neuronal reprogramming of reactive astrocytes to iNs of cortical identity following cortical trauma, a novel finding confirming its robust reprogramming action within the cortical microenvironment under neuroinflammatory conditions. In parallel to their reprogramming properties, astrocytes also participate in the maintenance of blood-brain barrier integrity, which ensures the physiological functioning of the central nervous system and gets affected contributing to the pathology of several neurodegenerative diseases. To study in real time the dynamic physical interactions of astrocytes with brain vasculature under homeostatic and pathological conditions, we performed 2-photon brain intravital imaging in a mouse model of systemic neuroinflammation, known to trigger astrogliosis and microgliosis and to evoke changes in astrocytic contact with brain vasculature. Our in vivo findings indicate that following neuroinflammation the endfeet of activated perivascular astrocytes lose their close proximity and physiological cross-talk with vasculature, however this event is at compensated by the cross-talk of astrocytes with activated microglia, safeguarding blood vessel coverage and maintenance of blood-brain integrity.

OpenSFDI: an open hardware project for label-free measurements of tissue optical properties with spatial frequency domain imaging

Spatial frequency domain imaging (SFDI) is a diffuse optical measurement technique that can quantify tissue optical absorption and reduced scattering on a pixel by-pixel basis. Measurements of absorption at different wavelengths enable the extraction of molar concentrations of tissue chromophores over a wide field, providing a noncontact and label-free means to assess tissue viability, oxygenation, microarchitecture, and molecular content. In this talk, I will describe openSFDI, an open-source guide for building a low-cost, small-footprint, multi-wavelength SFDI system capable of quantifying absorption and reduced scattering as well as oxyhemoglobin and deoxyhemoglobin concentrations in biological tissue. The openSFDI project has a companion website which provides a complete parts list along with detailed instructions for assembling the openSFDI system. I will also review several technological advances our lab has recently made, including the extension of SFDI to the shortwave infrared wavelength band (900-1300 nm), where water and lipids provide strong contrast. Finally, I will discuss several preclinical and clinical applications for SFDI, including applications related to cancer, dermatology, rheumatology, cardiovascular disease, and others.

Diverse applications of artificial intelligence and mathematical approaches in ophthalmology

Ophthalmology is ideally placed to benefit from recent advances in artificial intelligence. It is a highly image-based specialty and provides unique access to the microvascular circulation and the central nervous system. This talk will demonstrate diverse applications of machine learning and deep learning techniques in ophthalmology, including in age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries, and cataract, the leading cause of blindness worldwide. This will include deep learning approaches to automated diagnosis, quantitative severity classification, and prognostic prediction of disease progression, both from images alone and accompanied by demographic and genetic information. The approaches discussed will include deep feature extraction, label transfer, and multi-modal, multi-task training. Cluster analysis, an unsupervised machine learning approach to data classification, will be demonstrated by its application to geographic atrophy in AMD, including exploration of genotype-phenotype relationships. Finally, mediation analysis will be discussed, with the aim of dissecting complex relationships between AMD disease features, genotype, and progression.

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease

Obesity and Brain – Bidirectional Influences

The regulation of body weight relies on homeostatic mechanisms that use a combination of internal signals and external cues to initiate and terminate food intake. Homeostasis depends on intricate communication between the body and the hypothalamus involving numerous neural and hormonal signals. However, there is growing evidence that higher-level cognitive function may also influence energy balance. For instance, research has shown that BMI is consistently linked to various brain, cognitive, and personality measures, implicating executive, reward, and attentional systems. Moreover, the rise in obesity rates over the past half-century is attributed to the affordability and widespread availability of highly processed foods, a phenomenon that contradicts the idea that food intake is solely regulated by homeostasis. I will suggest that prefrontal systems involved in value computation and motivation act to limit food overconsumption when food is scarce or expensive, but promote over-eating when food is abundant, an optimum strategy from an economic standpoint. I will review the genetic and neuroscience literature on the CNS control of body weight. I will present recent studies supporting a role of prefrontal systems in weight control. I will also present contradictory evidence showing that frontal executive and cognitive findings in obesity may be a consequence not a cause of increased hunger. Finally I will review the effects of obesity on brain anatomy and function. Chronic adiposity leads to cerebrovascular dysfunction, cortical thinning, and cognitive impairment. As the most common preventable risk factor for dementia, obesity poses a significant threat to brain health. I will conclude by reviewing evidence for treatment of obesity in adults to prevent brain disease.

Unique features of oxygen delivery to the mammalian retina

Like all neural tissue, the retina has a high metabolic demand, and requires a constant supply of oxygen. Second and third order neurons are supplied by the retinal circulation, whose characteristics are similar to brain circulation. However, the photoreceptor region, which occupies half of the retinal thickness, is avascular, and relies on diffusion of oxygen from the choroidal circulation, whose properties are very different, as well as the retinal circulation. By fitting diffusion models to oxygen measurements made with oxygen microelectrodes, it is possible to understand the relative roles of the two circulations under normal conditions of light and darkness, and what happens if the retina is detached or the retinal circulation is occluded. Most of this work has been done in vivo in rat, cat, and monkey, but recent work in the isolated mouse retina will also be discussed.

Taking the pulse of ageing: the role of cerebrovascular risk factors in ageing and dementia

Cerebrovascular support is critical for healthy cognitive ageing. Reduced cerebral blood flow in ageing is caused, among other things, by hypertension, arteriosclerosis (i.e. stiffening of the arteries) and plaque formation. Arterial stiffness is predictive of cognitive decline, is a critical risk factor for cerebrovascular accidents, and has been linked to heightened risks for Alzheimer’s Disease and other forms of dementia. The elasticity of cerebral arteries is influenced by lifestyle factors, including cardiorespiratory fitness. Monica will discuss data obtained in their laboratory with new noninvasive measures of cerebrovascular health (pulse-DOT, a diffuse optical tomographic method for studying cerebral arteriosclerosis), in conjunction with structural and functional brain measures and cognitive assessments. These findings support a model in which localised changes in arteriosclerosis lead to specific profiles of structural, functional, and cognitive declines, paving a way to individualised interventions.

MBI Webinar on preclinical research into brain tumours and neurodegenerative disorders

WEBINAR 1 Breaking the barrier: Using focused ultrasound for the development of targeted therapies for brain tumours presented by Dr Ekaterina (Caty) Salimova, Monash Biomedical Imaging Glioblastoma multiforme (GBM) - brain cancer - is aggressive and difficult to treat as systemic therapies are hindered by the blood-brain barrier (BBB). Focused ultrasound (FUS) - a non-invasive technique that can induce targeted temporary disruption of the BBB – is a promising tool to improve GBM treatments. In this webinar, Dr Ekaterina Salimova will discuss the MRI-guided FUS modality at MBI and her research to develop novel targeted therapies for brain tumours. Dr Ekaterina (Caty) Salimova is a Research Fellow in the Preclinical Team at Monash Biomedical Imaging. Her research interests include imaging cardiovascular disease and MRI-guided focused ultrasound for investigating new therapeutic targets in neuro-oncology. - WEBINAR 2 Disposition of the Kv1.3 inhibitory peptide HsTX1[R14A], a novel attenuator of neuroinflammation presented by Sanjeevini Babu Reddiar, Monash Institute of Pharmaceutical Sciences The voltage-gated potassium channel (Kv1.3) in microglia regulates membrane potential and pro-inflammatory functions, and non-selective blockade of Kv1.3 has shown anti-inflammatory and disease improvement in animal models of Alzheimer’s and Parkinson’s diseases. Therefore, specific inhibitors of pro-inflammatory microglial processes with CNS bioavailability are urgently needed, as disease-modifying treatments for neurodegenerative disorders are lacking. In this webinar, PhD candidate Ms Sanju Reddiar will discuss the synthesis and biodistribution of a Kv1.3-inhibitory peptide using a [64Cu]Cu-DOTA labelled conjugate. Sanjeevini Babu Reddiar is a PhD student at the Monash Institute of Pharmaceutical Sciences. She is working on a project identifying the factors governing the brain disposition and blood-brain barrier permeability of a Kv1.3-blocking peptide.

Dissecting the neural circuits underlying prefrontal regulation of reward and threat responsivity in a primate

Gaining insight into the overlapping neural circuits that regulate positive and negative emotion is an important step towards understanding the heterogeneity in the aetiology of anxiety and depression and developing new treatment targets. Determining the core contributions of the functionally heterogenous prefrontal cortex to these circuits is especially illuminating given its marked dysregulation in affective disorders. This presentation will review a series of studies in a new world monkey, the common marmoset, employing pathway-specific chemogenetics, neuroimaging, neuropharmacology and behavioural and cardiovascular analysis to dissect out prefrontal involvement in the regulation of both positive and negative emotion. Highlights will include the profound shift of sensitivity away from reward and towards threat induced by localised activations within distinct regions of vmPFC, namely areas 25 and 14 as well as the opposing contributions of this region, compared to orbitofrontal and dorsolateral prefrontal cortex, in the overall responsivity to threat. Ongoing follow-up studies are identifying the distinct downstream pathways that mediate some of these effects as well as their differential sensitivity to rapidly acting anti-depressants.

Why is the suprachiasmatic nucleus such a brilliant circadian time-keeper?

Circadian clocks dominate our lives. By creating and distributing an internal representation of 24-hour solar time, they prepare us, and thereby adapt us, to the daily and seasonal world. Jet-lag is an obvious indicator of what can go wrong when such adaptation is disrupted acutely. More seriously, the growing prevalence of rotational shift-work which runs counter to our circadian life, is a significant chronic challenge to health, presenting as increased incidence of systemic conditions such as metabolic and cardiovascular disease. Added to this, circadian and sleep disturbances are a recognised feature of various neurological and psychiatric conditions, and in some cases may contribute to disease progression. The “head ganglion” of the circadian system is the suprachiasmatic nucleus (SCN) of the hypothalamus. It synchronises the, literally, innumerable cellular clocks across the body, to each other and to solar time. Isolated in organotypic slice culture, it can maintain precise, high-amplitude circadian cycles of neural activity, effectively, indefinitely, just as it does in vivo. How is this achieved: how does this clock in a dish work? This presentation will consider SCN time-keeping at the level of molecular feedback loops, neuropeptidergic networks and neuron-astrocyte interactions.

Monash Biomedical Imaging highlights from 2021 and looking ahead to 2022

Despite the challenges COVID-19 has continued to present, Monash Biomedical Imaging (MBI) has had another outstanding year in terms of publications and scientific output. In this webinar, Professor Gary Egan, Director of MBI, will present an overview of MBI’s achievements during 2021 and outline the biomedical imaging research programs and partnerships in 2022. His presentation will cover: • MBI operational and research achievements during 2021 • Biomedical imaging technology developments and research outcomes during 2021 • Linked laboratories and research teams at MBI • Progress on the development of a cyclotron and precision radiopharmaceutical facility at Clayton • Emerging research opportunities at the Monash Heart Hospital in cardiology and cardiovascular disease. Professor Gary Egan is Director of Monash Biomedical Imaging, Director of the ARC Centre of Excellence for Integrative Brain Function and a Distinguished Professor at the Turner Institute for Brain and Mental Health, Monash University. He is also lead investigator of the Victorian Biomedical Imaging Capability, and Deputy Director of the Australian National Imaging Facility. His substantive body of published work has made a significant impact on the neuroimaging and neuroscience fields. He has sustained success in obtaining significant grants to support his own research and the development of facilities to advance biomedical imaging.

​Improving the identification of cardiometabolic risk in early psychosis

People with chronic schizophrenia die on average 10-15 years sooner than the general population, mostly due to physical comorbidity. While sociodemographic, chronic lifestyle and iatrogenic factors are important contributors to this comorbidity, a growing body of research is beginning to suggest that early signs of cardiometabolic dysfunction may be present from the onset of psychosis in some young adults, and may even be detectable before the onset of psychosis. Given that primary prevention is the best means to prevent the onset of more chronic and severe cardiometabolic phenotypes such as CVD, there is clear need to be able to identify young adults with psychosis who are most at risk of future adverse cardiometabolic outcomes, such that the most intensive interventions can be directed in an informed way to attenuate the risk or even prevent those adverse outcomes from occurring.In this talk, Ben will first outline some recent advances in our understanding of the association between cardiometabolic and schizophrenia spectrum disorders. He will then introduce the field of cardiometabolic risk prediction, and highlight how existing tools developed for older general population adults are unlikely to be suitable for young people with psychosis. Finally, he will discuss the current state of play and the future of the Psychosis Metabolic Risk Calculator (PsyMetRiC), a novel clinically useful cardiometabolic risk prediction algorithm tailored for young people with psychosis, which has been developed and externally validated using data from three psychosis early intervention services in the UK.

Neurovascular signaling pathways in the mammalian retina

As a developmental outpocket of the brain, the retina exhibits features commonly found in most brain areas, including neurovascular interactions. In this presentation I will discuss various pathways that contribute to neurovascular interactions in the mammalian retina and present newly uncovered elements that likely participate in these pathways. Information obtained from retina could improve our understanding of neurovascular coupling pathways throughout the brain.

The influence of menstrual cycle on the indices of cortical excitability

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.

Evidence for the role of glymphatic dysfunction in the development of Alzheimer’s disease

Glymphatic perivascular exchange is supported by the astroglial water channel aquaporin-4 (AQP4), which localizes to perivascular astrocytic endfeet surrounding the cerebral vasculature. In aging mice, impairment of glymphatic function is associated with reduced perivascular AQP4 localization, yet whether these changes contribute to the development of neurodegenerative disease, such as Alzheimer’s disease (AD), remains unknown. Using post mortem human tissue, we evaluated perivascular AQP4 localization in the frontal cortical gray matter, white matter, and hippocampus of cognitively normal subjects and those with AD. Loss of perivascular and increasing cellular localization of AQP4 in the frontal gray matter was specifically associated with AD status, amyloid β (Aβ) and tau pathology, and cognitive decline in the early stages of disease. Using AAV-PHP.B to drive expression on non-perivascular AQP4 in wild type and Tg2576 (APPSwe, mouse model of Aβ deposition) mice, increased cellular AQP4 localization did not slow glymphatic function or change Aβ deposition. Using the Snta1 knockout line (which lacks perivascular AQP4 localization), we observed that loss AQP4 from perivascular endfeet slowed glymphatic function in wild type mice and accelerated Aβ plaque deposition in Tg2576 mice. These findings demonstrate that loss of perivascular AQP4 localization, and not increased cellular AQP4 localization, slows glymphatic function and promotes the development of AD pathology. To evaluate whether naturally occurring variation in the human AQP4 gene, or the alpha syntrophin (SNTA1), dystrobrevin (DTNA) or dystroglycan (DAG1) genes (whose products maintain perivascular AQP4 localization) confer risk for or protection from AD pathology or clinical progression, we evaluated 56 tag single nucleotide polymorphisms (SNPs) across these genes for association with CSF AD biomarkers, MRI measures of cortical and hippocampal atrophy, and longitudinal cognitive decline in the Alzheimer’s Disease Neuroimaging Initiative I (ADNI I) cohort. We identify 25 different significant associations between AQP4, SNTA1, DTNA, and DAG1 tag SNPs and phenotypic measures of AD pathology and progression. These findings provide complimentary human genetic evidence for the contribution of perivascular glymphatic dysfunction to the development of AD in human populations.

Metabolic and functional connectivity relate to distinct aspects of cognition

A major challenge of cognitive neuroscience is to understand how the brain as a network gives rise to our cognition. Simultaneous [18F]-fluorodeoxyglucose positron emission tomography functional magnetic resonance imaging (FDG-PET/fMRI) provides the opportunity to investigate brain connectivity not only via spatially distant, synchronous cerebrovascular hemodynamic responses (functional connectivity), but also glucose metabolism (metabolic connectivity). However, how these two modalities of brain connectivity differ in their relation to cognition is unknown. In this webinar, Dr Katharina Voigt will discuss recent findings demonstrating the advantage of simultaneous FDG-PET/fMRI in providing a more complete picture of the neural mechanisms underlying cognition, that calls for a combination of both modalities in future cognitive neuroscience. Dr Katharina Voigt is a Research Fellow within the Turner Institute for Brain and Mental Health, Monash University. Her research interests include systems neuroscience, simultaneous PET-MRI, and decision-making.

From Vulnerable Plaque to Vulnerable Brain: Understanding the Role of Inflammation in Vascular Health, Stroke, and Cerebrovascular Disease

Every year around 100,000 people in the UK will have a stroke. Stroke is a leading cause of adult disability, and cerebrovascular disease more broadly is a major cause of dementia. Understanding these diseases – both acute and chronic manifestations of cerebrovascular disease – requires consideration not only of the brain itself, but also the blood vessels supplying it. Atherosclerosis – the hardening of arteries as we age – may predispose to stroke by triggering the formation of blood clots that block the blood supply to the brain, but also involves inflammation that may cause chronic damage to the brain and prime both the brain and body for injury. Understanding this interaction between systemic disease and brain health may have important implications for our understanding of healthy ageing and provide novel therapeutic approaches for reducing the burden of cerebrovascular disease. This talk will consider how advances in imaging may facilitate our understanding of the processes underlying atherosclerosis and how it affects the brain in stroke, as well as work currently underway to translate this understanding into improving treatments for stroke.

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Isabelle Brunet (France) – Neurovascular development Debby Silver (USA) - Dynamic post-transcriptional control of cortical development Robin Vigouroux (France) – Evolution of binocular vision Patricia Garcez (Brazil) – Beyond microcephaly: how Zika virus impacts brain development

Migraine Headache: the revolution and its evolution

This seminar will focus on the extraordinary shift in migraine research during the last 4 decades with the discovery of the trigeminovascular system (TVS) and it’s major impact on pathophysiology and treatment.  Compelling evidence supporting the importance of TVS, cortical spreading depression and parameningeal inflammation will be explored as will the implications of newly discovered microvascular channels within the meninges on an attack.

Developing metal-based radiopharmaceuticals for imaging and therapy

Personalised medicine will be greatly enhanced with the introduction of new radiopharmaceuticals for the diagnosis and treatment of various cancers, as well as cardiovascular disease and brain disorders. The unprecedented interest in developing theranostic radiopharmaceuticals is mainly due to the recent clinical successes of radiometal-based products including: • 177LuDOTA-TATE (trade name Lutathera, FDA approved in 2018), a peptide-based tracer that is used for treating metastatic neuroendocrine tumours • Ga 68 PSMA-11 (FDA approved in 2020), a positron emission tomography agent for imaging prostate-specific membrane antigen positive lesions in men with prostate cancer. In this webinar, Dr Brett Paterson and PhD candidate Mr Cormac Kelderman will present their research on developing the chemistry and radiochemistry to produce new radiometal-based imaging and therapy agents. They will discuss the synthesis of new molecules, the optimisation of the radiochemistry, and results from preclinical evaluations. Dr Brett Paterson is a National Imaging Facility Fellow at Monash Biomedical Imaging and academic group leader in the School of Chemistry, Monash University. His research focuses on the development of radiochemistry and new radiopharmaceuticals. Cormac Kelderman is a PhD candidate under the supervision of Dr Brett Paterson in the School of Chemistry, Monash University. His research focuses on developing new bis(thiosemicarbazone) chelators for technetium-99m SPECT imaging.

Neuronal and Vascular Dysfunction in Optic Neuropathies: New Insights from Live Imaging Studies

Magnetic Resonance Measures of Brain Blood Vessels, Metabolic Activity, and Pathology in Multiple Sclerosis

The normally functioning blood-brain barrier (BBB) regulates the transfer of material between blood and brain. BBB dysfunction has long been recognized in multiple sclerosis (MS), and there is considerable interest in quantifying functional aspects of brain blood vessels and their role in disease progression. Parenchymal water content and its association with volume regulation is important for proper brain function, and is one of the key roles of the BBB. There is convincing evidence that the astrocyte is critical in establishing and maintaining a functional BBB and providing metabolic support to neurons. Increasing evidence suggests that functional interactions between endothelia, pericytes, astrocytes, and neurons, collectively known as the neurovascular unit, contribute to brain water regulation, capillary blood volume and flow, BBB permeability, and are responsive to metabolic demands. Increasing evidence suggests altered metabolism in MS brain which may contribute to reduced neuro-repair and increased neurodegeneration. Metabolically relevant biomarkers may provide sensitive readouts of brain tissue at risk of degeneration, and magnetic resonance offers substantial promise in this regard. Dynamic contrast enhanced MRI combined with appropriate pharmacokinetic modeling allows quantification of distinct features of BBB including permeabilities to contrast agent and water, with rate constants that differ by six orders of magnitude. Mapping of these rate constants provides unique biological aspects of brain vasculature relevant to MS.

Neuroimmune interactions in Cardiovascular Diseases

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.

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Mapping early brain network changes in neurodegenerative and cerebrovascular disorders: a longitudinal perspective

The spatial patterning of each neurodegenerative disease relates closely to a distinct structural and functional network in the human brain. This talk will mainly describe how brain network-sensitive neuroimaging methods such as resting-state fMRI and diffusion MRI can shed light on brain network dysfunctions associated with pathology and cognitive decline from preclinical to clinical dementia. I will first present our findings from two independent datasets on how amyloid and cerebrovascular pathology influence brain functional networks cross-sectionally and longitudinally in individuals with mild cognitive impairment and dementia. Evidence on longitudinal functional network organizational changes in healthy older adults and the influence of APOE genotype will be presented. In the second part, I will describe our work on how different pathology influences brain structural network and white matter microstructure. I will also touch on some new data on how brain network integrity contributes to behavior and disease progression using multivariate or machine learning approaches. These findings underscore the importance of studying selective brain network vulnerability instead of individual region and longitudinal design. Further developed with machine learning approaches, multimodal network-specific imaging signatures will help reveal disease mechanisms and facilitate early detection, prognosis and treatment search of neuropsychiatric disorders.

The immunopathology of advanced multiple sclerosis

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.

When spontaneous waves meet angiogenesis: a case study from the neonatal retina

By continuously producing electrical signals, neurones are amongst the most energy-demanding cells in the organism. Resting ionic levels are restored via metabolic pumps that receive the necessary energy from oxygen supplied by blood vessels. Intense spontaneous neural activity is omnipresent in the developing CNS. It occurs during short, well-defined periods that coincide precisely with the timing of angiogenesis. Such coincidence cannot be random; there must be a universal mechanism triggering spontaneous activity concurrently with blood vessels invading neural territories for the first time. However, surprisingly little is known about the role of neural activity per se in guiding angiogenesis. Part of the reason is that it is challenging to study developing neurovascular networks in tri-dimensional space in the brain. We investigate these questions in the neonatal mouse retina, where blood vessels are much easier to visualise because they initially grow in a plane, while waves of spontaneous neural activity (spreading via cholinergic starburst amacrine cells) sweep across the retinal ganglion cell layer, in close juxtaposition with the growing vasculature. Blood vessels reach the periphery by postnatal day (P) 7-8, shortly before the cholinergic waves disappear (at P10). We discovered transient clusters of auto-fluorescent cells that form an annulus around the optic disc, gradually expanding to the periphery, which they reach at the same time as the growing blood vessels. Remarkably, these cells appear locked to the frontline of the growing vasculature. Moreover, by recording waves with a large-scale multielectrode array that enables us to visualise them at pan-retinal level, we found that their initiation points are not random; they follow a developmental centre-to-periphery pattern similar to the clusters and blood vessels. The density of growing blood vessels is higher in cluster areas than in-between clusters at matching eccentricity. The cluster cells appear to be phagocytosed by microglia. Blocking Pannexin1 (PANX1) hemichannels activity with probenecid completely blocks the spontaneous waves and results in the disappearance of the fluorescent cell clusters. We suggest that these transient cells are specialised, hyperactive neurones that form spontaneous activity hotspots, thereby triggering retinal waves through the release of ATP via PANX1 hemichannels. These activity hotspots attract new blood vessels to enhance local oxygen supply. Signalling through PANX1 attracts microglia that establish contact with these cells, eventually eliminating them once blood vessels have reached their vicinity. The auto-fluorescence that characterises the cell clusters may develop only once the process of microglial phagocytosis is initiated.

Carnosine negatively modulates pro-oxidant activities of M1 peripheral macrophages and prevents neuroinflammation induced by amyloid-β in microglial cells

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.

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