tus

Urothelial Resurfacing with Irreversible Electroporation for Adjuvant Therapy of Bladder Cancer

PROJECT SUMMARY Over 70% of bladder cancer (BCa) patients are diagnosed with early-stage and localized non-muscle invasive disease (NMIBC), yet achieving durable cancer-free survival remains a significant challenge. Most of these patients will experience local tumor recurrence within five years following standard of care (SoC) transurethral resection of bladder tumor (TURBT) and intravesical adjuvant chemo- or immunotherapy. Recurrence is driven by microscopic tumors and premalignant lesions dispersed within the urothelial layer that survive and escape these treatments. As TURBT effectively treats tumors visible on imaging, current research has predominantly focused on drugs and biologics for improving intravesical adjuvant therapy. In this proposal we pose the provocative question whether a TURBT-like ablative technique can be extended to debulk malignancy in the entire bladder and investigate the synergy with intravesical adjuvant therapy in improving outcomes. Our objective is to address this technology and knowledge gap by developing and validating whole bladder urothelial resurfacing (WBUR) using irreversible electroporation (IRE). During IRE, microsecond-long pulsed electric fields (PEF) are used to induce rapid cell death by catastrophic permeabilization of the cell membrane, without affecting the extracellular matrix (ECM) within the treated tissue. In prior work, we designed devices that utilized this unique mechanism of IRE for performing penetrative ablation in the ureter, bile duct and bronchus of swine while preserving lumen function. Our findings provided strong rationale for IRE being an ideal candidate for WBUR as alternate techniques such as thermal ablation or ionizing radiation must be performed with extreme care in the bladder to avoid perforation or fistula formation. In subsequent preliminary work we developed technology to demonstrate the feasibility and safety of WBUR with IRE in a rat model of BCa and scalability in human-sized swine bladder. In Aim 1, we will investigate the cancer treatment efficacy of combination WBUR and intravesical adjuvant therapy. In Aim 2, validate WBUR derived liquid biopsy for monitoring cancer status. In Aim 3, engineer PEF delivery strategy to enhance the safety and specificity of WBUR. The innovation of our proposed work is defined by developing whole bladder ablation as a debulking strategy and examining its synergy with SOC adjuvant therapy (Aim 1), enabled by new electrode paradigm and PEF delivery strategy (Aim 3), monitoring by an unconventional liquid biopsy approach (Aim 2). Our work can immediately aid the management of NMIBC patients who cannot undergo radical cystectomy, with future application as a cancer prevention strategy in high-risk patients. Success of individual aims will result in major contributions to the topics of IRE, BCa treatment and diagnosis.

Biostatistics, Ethics, Data Management, Research Design and Community Engagement(BEDRoC) Core

Biostatistics, Ethics, Data Management, Research Design and Community Engagement (BEDRoC) Core Abstract The Biostatistics, Ethics, Data Management, Research Design and Community Engagement (BEDRoC) Core will promote and support aging with serious illness science for the Center for Aging with Serious Illness (CASI). BEDRoC will provide expertise in statistical design and analysis, research ethics, and community engagement for all components of CASI. The Core's services will support the Research Project Leaders (RPLs) and Pilot Project Leaders (PPLs) and build capacity for the broader Dartmouth Health aging research community to conduct rigorous, impactful research to inform and improve care delivery for older adults with serious illness. BEDRoC includes expertise in mixed methods approaches that feature both quantitative and qualitative research methods to provide a comprehensive understanding of the complex issues related to aging with serious illness, ethical approaches to consent in research trials, multidimensional quality of life measurement, and innovative modeling approaches to studying clinical decision making. BEDRoC faculty have actively collaborated in study planning with each RPL, serving as both mentors and experienced collaborators on the three different projects involving decision aids for patients considering carotid revascularization, a patient-reported outcome-directed referral intervention to improve referral rates to palliative care services, and a pilot trial for a virtual/home-based exercise and a weight management osteoarthritis treatment program in older patients with osteoarthritis and multimorbidity. The BEDRoC Core will further support CASI by establishing an innovative training curriculum with workshops, tutorials, resources, and services, offered locally to RPLs and PPLs and extended to regional and national investigators in the IDeA network. In addition to their primary individual project mentors, each RPL will receive training and guidance from BEDRoC leaders through co-mentoring and RPL-focused works-in-progress sessions. BEDRoC will also provide access to a comprehensive inventory of patient-reported outcomes instruments, which are crucial in geriatric research to provide validated measures of health status, quality of life and functional ability outcomes. BEDRoC will coordinate with the Administrative and Mentoring Core to integrate community advisors in guiding their activities in support of the RPLs. BEDRoC will also enable research collaboration with and within the larger Dartmouth and IDeA investigator communities. The BEDRoC Core will build capacity for aging research and disseminate new resources to RPLs and PPLs, including innovative solutions created through robust community engagement. These services, resources, and solutions will ensure all projects operate in a cohesive, complementary, and collaborative manner to study approaches to improving the health of older patients with serious illness.

Maternal Depression and Antidepressant Effects on Fetal Brain Structure and Function (FABMOMS)

PROJECT ABSTRACT Major depressive disorder (MDD) is one of the most common diseases in childbearing women, with a prevalence of 12.7% in pregnancy and 21.9% the year after birth. Exposure to maternal stress and depressive symptoms alters fetal/infant neurodevelopment, functional brain connectivity, and networks implicated in stress processing. About 5% of pregnant women are prescribed a serotonin selective or serotonin norepinephrine reuptake inhibitor (collectively, SRI). Remission of maternal MDD is crucial to the health and functioning of the mother and family. In observational studies typical of this field, differentiating the effects of drug exposure on offspring from the sequelae of the underlying psychiatric disease, both physiological and psychosocial, is challenging. Substantial progress has been made using sophisticated study designs and analytic approaches with large pregnancy cohorts that reduce the risk of spurious associations. Increased rates of overall and cardiac defects, stillbirth, preterm birth, and fetal growth have been largely explained by confounding by factors associated with both MDD and these outcomes rather than SRI exposure. Assessing the neurobehavioral development of children exposed in utero to SRI is the current research priority in this field. Our team pioneered the development of novel and safe fetal and neonatal quantitative magnetic resonance imaging (qMRI) tools, which will be combined with an evaluation of maternal heart rate variability to explore associations between exposures to stress, psychiatric symptoms and SRI on fetal and neonatal brain structure and function. The overarching goal of this project is to evaluate the separate and interactive effects of exposure to antidepressants in utero and maternal MDD on fetal and infant brain structure and function, with a specific focus on the hippocampus. We will accomplish this by evaluating four groups of pregnant women who have: 1) MDD treated with SRI to remission), 2) MDD treated with SRI (non-remitted, with both depressive symptom and SRI exposure), 3) MDD untreated with antidepressants, and 4) no current MDD or SRI treatment. Maternal assessments will occur at intake and in the early third trimesters and in then newborn period (at the time of fetal/newborn MRI) after birth. Maternal and infant evaluations will continue at 6 and 12 months postpartum. Maternal psychosocial and psychiatric status will provide extensive data on the context in which mothers experience pregnancy and infant care and allow adjustment for factors that will inevitably differ across groups. Lastly, we will explore the effects of maternal choline on MDD and offspring brain development. As these exposures and neurodevelopmental studies are conducted, exploring primary preventive strategies is a public health imperative. We will explore a potential mediator, poor maternal choline intake, a modifiable risk factor for both maternal MDD and altered fetal hippocampal growth and infant neurobehavior.

Improving Disease-Modifying Therapy Uptake among Patients with Multiple Sclerosis

Project Summary/Abstract Recent advances in the epidemiology of multiple sclerosis (MS) indicate that its prevalence is similar among White (238 per 100,000) and Black (226 per 100,000) populations. These data challenge historic assumptions about individuals with northern European heritage having higher risk and prevalence of MS. Evidence also suggests that MS incidence may be higher than previously recognized in the United States and increasing over time with more individuals identified and diagnosed year over year. MS continues to impose significant and growing burden on patients, healthcare systems and society. These health differences in the diagnosis, treatment and symptom management of MS in light of the increasing prevalence of MS in the US are an important public health issue that requires broader urgent research and policy attention to reduce the overall disease burden. In this study, we will use real-world data derived from the electronic health records (EHR) from four large academic medical centers (University of Kentucky, University of Virginia, Virginia Commonwealth University, and University of Southern California). Extracted EHR data from these four medical centers will be deidentified, combined, and harmonized. We will use this combined data set to examine (1) whether there are any differences in the timely treatment of disease modifying therapy (DMT) among different MS populations, (2) any disparities in the management of symptoms and comorbidities, (3) how non-medical factors of health such as income, education, and health insurance status (patientlevel), linguistically appropriate care provision (provider-level), and neighborhood factors (system-level) affect these outcomes and influence disparities across populations, and (4) assess whether disparities exist in the risks of cardiovascular disease CVD and mortality in MS subgroups and examine if these disparities can be reduced with improved treatment of MS and vascular comorbidities. In pursuing these objectives, we will identify clinical solutions (e.g., optimal DMT sequences) and non-medical factors such as neighborhood factors such as poverty, educational achievement, crime rates, civic participation, and housing quality, access to care factors, and cultural and linguistic match between providers and patients that substantially contribute to health disparities. For actionable solutions, we will rank-order these factors by their relative importance in addressing disparities, which will guide decision-making at the policy, system, and provider level. Our long-term objective is to develop public health strategies and scalable solutions to reduce overall burden in the management of MS. This project is expected to help policy makers and health system administrators in prioritizing interventions and to have implications for clinical practice in improving care of all patients with MS in neurology clinics, at the healthcare system level, and for national health policy.

Effects of Apolipoprotein A4 on Lipid Metabolism via Sympathetic Regulation

Obesity increases the risks and progression of hypertriglyceridemia, metabolic dysfunction- associated steatotic liver disease (MASLD), and cardiovascular diseases. Previous studies demonstrate that a single injection of apolipoprotein A4 (APOA4) elevates sympathetic neural activity and fatty acid β-oxidation in adipose tissues; and consistent infusion of APOA4 in obese mice fed a high-fat diet lowers fat mass, reduces hypertriglyceridemia, elevates brown adipose tissue thermogenesis, and attenuates steatosis and enhances sympathetic neural activity in the liver. This project hypothesizes that APOA4 reduces hypertriglyceridemia by regulating lipid metabolism through sympathetic stimulation in adipose tissues (Specific Aim 1) and sympathetic action in the liver (Specific Aim 2). The role of sympathetic action via the neurotransmitter norepinephrine and adrenergic receptor-mediated pathways will be investigated, and their necessity in APOA4-mediated lipid metabolism will be tested. A strength of this project is the interdisciplinary collaboration between investigators with established successful collaboration and publications. The project will provide physiological, molecular, and neurochemical mechanisms underlying how APOA4 differentially regulates metabolism through sympathetic activation in various types of adipose tissues and the liver in male and female obese mice. Findings would provide impetus to develop unique, novel, targeted therapeutic applications against hypertriglyceridemia and MASLD. Importantly, this project will expose undergraduates and graduate students to meritorious research, provide students with hands-on biomedical research experience, and strengthen research environment at R15 eligible institutions.

Post-diagnosis changes in body composition and renal cell cancer survival

ABSTRACT Significance. Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and most lethal subtype, and there is great interest in the identification of potentially modifiable prognostic factors. Although weight status seems to be relevant, the relationship between body mass index (BMI) at diagnosis and survival among ccRCC patients indicates that mortality is lowest among those classified as overweight or obese at the time of diagnosis by BMI. This has resulted in confusion in clinical guidance for weight management among ccRCC patients. Recent work involving body composition features (adipose and muscle tissue) has provided some insight, but we do not understand how weight or body composition changes after diagnosis relate to survival, nor how these changes relate to pathological and molecular tumor features— information which is needed to resolve this controversy. Rigorous analytical approaches are further required to accurately address these questions. Innovation. Our study is highly innovative in that 1) we will be the first to leverage a large-scale cohort of ccRCC patients with multiple assessments of weight and body composition from diagnosis onward; 2) we will examine tumor characteristics, including molecular features, as potential drivers of these changes; and 3) we will use a rigorous joint modeling approach to simultaneously model the post-diagnosis trajectories of weight and body composition and their relationships with cancer outcomes in the most statistically sound manner. Our findings will inform clinical management of, and identify modifiable body composition features to improve survival for the growing number of ccRCC patients. Approach. We will use available data from the RESOLVE cohort, an NCI-funded retrospective cohort of 1,239 Stage I-III clear-cell renal cell carcinoma (ccRCC) patients diagnosed between 2000-2020 at Memorial Sloan Kettering Cancer Center. These data include clinical and patient-level factors collected from the medical record, including repeated height and weight assessments, body composition measures from existing computed tomography scans, pathological and molecular tumor characteristics, and overall survival (OS) and disease-free survival (DFS). We will use a joint modeling approach to simultaneously model changes in post-diagnosis body weight (Aim 1) and OS and DFS, as well as post-diagnosis changes in muscle and adipose tissue features (Aim 2) and OS and DFS. Models will include molecular tumor characteristics as predictors of these longitudinal trajectories. Impact. These results will provide crucial insight into the relationship between body composition changes and outcomes among ccRCC patients, and potentially identify tumor-related characteristics driving these associations. These results will resolve apparent paradoxes around the relationship between obesity and ccRCC mortality and identify potential targets for nutrition and physical activity interventions on body composition.

A novel MRI method for noninvasive imaging of bone quality in type 2 diabetes

ABSTRACT: Type 2 diabetes mellitus (T2DM) affects 500 million of the global population, which is expected to increase to 800 million in 20 years. One of the multiple complications involved with T2DM is the significantly increased bone fracture risk and post-fracture mortality. Dual-energy X-ray absorptiometry (DXA) scans are routinely performed to measure bone mineral density (BMD) and associated fracture risk. However, T2DM patients often show preserved or even elevated BMD despite the significantly increased fracture risk. This mismatch between the BMD measurement and actual fracture risk hampers the accurate assessment of fracture risk and the appropriate treatment of T2DM that considers patient bone health. The lack of an accurate fracture risk assessment tool also confounds the evaluation of the bone health effect of antidiabetic drugs, including recently highlighted glucagon-like peptide-1 receptor agonists (e.g., semaglutide) and sodium-glucose cotransporter-2 inhibitors. Previous studies have suggested that bone quality, rather than bone quantity, as represented by BMD, is a crucial factor contributing to fracture risk in T2DM settings. Collagen crosslinking via advanced glycation end-products (AGEs) in cortical bone has been identified as a distinctive bone quality characteristic of T2DM patients, which explains the increased bone fragility. Although this finding is highly promising for improving the bone health management of T2DM patients, currently, no non-invasive method can monitor collagen crosslinking in the bones. This proposal aims to develop an ultrashort echo time (UTE) MRI-based method for measuring the degree of bone collagen crosslinking by quantifying magnetization transfer between water and collagen in the bone. This method, termed UTE-quantitative magnetization transfer (UTE-qMT) MRI, measures not only the quantity of macromolecules (e.g., collagen) in the bone but also the rates of exchange between water and macromolecular protons, which are related to the degree of collagen crosslinking. The proposal will develop and optimize the accelerated UTE-qMT method for reliably measuring the exchange rate in Aim 1. The optimized technique will be validated by correlating exchange rates with AGE-driven collagen crosslinking and subsequent compromise of bone mechanical properties in Aim 2. Finally, the optimized UTE-qMT MRI method will be translated to animal and human studies to demonstrate its clinical feasibility for investigating the effect of antidiabetic drugs on bone health in patients with T2DM in Aim 3. The successful completion of these aims will enable rapid and accurate assessment of bone fracture risk in patients with T2DM. Furthermore, noninvasively probing bone quality can also accurately assess the effect of antidiabetic drugs on bone health and aid in screening novel T2DM therapeutics for their impact on bone health.

Targeting subtype specification as a driver of PDAC health disparities

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks (people with African genetic ancestry) have significantly higher incidence rates of PDAC and decreased survival times compared to Caucasians (White genetic ancestry) even after socioeconomic status and tumor stages are controlled. Therefore, it is possible different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The unique molecular characteristics that distinguish PDAC tumors between racial groups exhibiting disparities have the potential to identify new therapeutic targets. In a previous study, we identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative proteomic data. While these PDAC subtypes are predictive of therapeutic response, this has not yet been analyzed in disparity factor balanced studies. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks and Whites. PDAC tumors from Black patients display features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflamed microenvironment expressing complement proteins that can promote resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. Strategies are needed to modulate subtype to improve response to chemotherapy. Toward this goal, our proteomic analysis identified polycomb repressor complex 1 (PRC1) protein RNF2 as being upregulated in PDACs from Blacks compared to Whites. We have also discovered that RNF2 regulates mRNA expression of the PDAC subtype specification factor GATA6 and inhibiting RNF2 promotes a molecular shift toward the more chemosensitive Classical subtype of PDAC. Therapeutic targeting can be achieved with Tazemetostat that inhibits the upstream PRC2 to prevent RNF2 binding the GATA6 promoter leading to its increased expression. Additionally, the Inflammatory subtype characterized by innate immune complement protein activation could be targeted with another FDA approved drug, Avacopan, which has not previously been studied in PDAC. Therefore, the Specific Aims of this proposal are designed to: 1) Evaluate the extent to which Tazemetostat treatment impacts chemotherapy-induced subtype plasticity in patient derived organoids; and 2) To determine the extent to which strategies targeting pathways associated with PDAC disparities affect progression and subtype characteristics in vivo. The successful completion of these aims has the potential to be moved quickly into phase I clinical trials since both Tazemetostat and Avacopan are FDA approved drugs. Furthermore, if successful, this project has the potential to mitigate health disparities in PDAC and broadly improve patient outcomes by implementing new precision interventions. The mouse models we propose faithfully recapitulate pancreatic cancer's clinical syndrome, histopathology and molecular properties, including the often-unique features of the stromal and immune responses that constitute the complex desmoplasia of this disease, which cannot be addressed using in vitro model systems

Stability in disrupted maternal representations over the perinatal period: Contributors and consequences

Abstract High-quality mother-infant relationships promote social, emotional, and cognitive development while protecting against poor child behavioral, health, and psychological adaptation that create risk for long- term negative outcomes. As mothers transition to parenthood, their own experiences of being cared for influence their emerging views of parenting and representations of their developing child. Evidence suggests that ‘disrupted’ maternal representations of the child, i.e., representations characterized by mixed communication, role merging, extreme withdrawal, and other unusual psychological processes, are tied to both poor child socioemotional adjustment and both insecure and disorganized attachment. However, it is unclear whether disrupted representations that emerge during pregnancy remain stable across the first several years of the child’s life. In addition, to date, research has not examined how change/stability in these representations may affect maternal caregiving and subsequent child adaptation. Using data from a longitudinal, multi-method study, this proposed project will examine the stability of maternal representations of the child for 99 women living in high risk contexts using the Working Model of the Child Interview during the third trimester and again when the child is two years of age. Mothers’ demographic characteristics (i.e. SES and relationship status), interpersonal violence experiences (i.e. child maltreatment or intimate violence exposure), psychological health (i.e. depressive, anxious, and PTSD symptoms), and parenting stress (i.e. perceptions of the child as difficult and parent-child interactions as dysfunctional) are measured as well to examine influences on representation stability. Finally, the observed quality of maternal caregiving and child adaptation are measured and examined in relation to stability in maternal representations of the child. Findings from this study have the potential to identify which mother-child dyads are at greatest risk for poor adaptation across the perinatal period and to delineate the contributors and consequences of maternal representational stability. These findings will serve as an important step towards informing the development or modification of existing prevention/intervention approaches that are targeted specifically towards mother-child dyads who are most at need.

2026 Thiol-Based Redox Regulation and Signaling Gordon Research Conference and Gordon Research Seminar

PROJECT SUMMARY This proposal requests support for the 10th meeting of the biennial Gordon Research Conference (GRC) and associated Gordon Research Seminar (GRS) on Thiol-Based Redox Regulation and Signaling to be held at the Rey Don Jaime Grand Hotel, Castelldefels, Spain on July 11-12 (GRS) and July 12-17 (GRC), 2026. Regulation of protein function through the post-translational modification of specific cysteine residues (thiol oxidation) plays an important role in cellular adaptation to local and global changes to endogenous and environmental oxidants. A key challenge for the redox-signaling field is to understand how thiol-based signaling mechanisms are integrated into cellular redox homeostasis and how these events facilitate communication between molecules, organelles, cells, and tissues to initiate and coordinate a specialized biological outcome. Significant emphasis for the 2026 meeting will be placed on an exploration of a wider range of cysteine thiol chemistry placed within a cellular context of other, often competing, oxidative or acyl modifications, some of which derive from environmental exposures, and contribute to cancer, aging and the progression of disease. In addition, we will discuss new insights into how cellular redox status impacts metabolic disease and new mathematical and analytical approaches to understand how redox gradients or “waves” impact the spatial and temporal aspects of signaling. A long-term objective is to use this new information to develop diagnostics and therapeutics for a wide range of redox-associated diseases that impact public health. This meeting provides a unique forum for extensive and immersive interaction among chemists, biologists, structural biologists and redox tool-builders, interested in a range of animal and cellular model systems, with clinical researchers and physicians focused on disease processes. While the thematic area of the conference is intentionally broad, its relevance to specialized NIH institutes is highly significant. Not only is redox toxicity proposed as a primary driver of chemically-induced pathology in humans, notably in aging and age-associated diseases, protection from these pathologies by “supersulfides” holds considerable promise. In keeping with the GRC tradition, the 2026 meeting will highlight presentations that emphasize unpublished work, creating a distinctive intellectual experience that enhances the excitement of the meeting. Investigators new to the meeting, junior investigators and graduate and post-graduate trainees will be welcomed. The associated GRS will provide a more intimate forum where graduate and postdoctoral trainees present their research to their peers, while receiving constructive comments from a few senior investigators who serve as mentors. We intend that the GRS/GRC meetings will attract and increase retention of junior scientists in the field of redox biology. We anticipate that the GRC will enhance the education of researchers at all career levels, generate new ideas and collaborations aimed at understanding thiol-based redox regulation and dysfunction, and enable future progress in the prevention, detection, and treatment of a wide-range of human diseases associated with perturbations in redox homeostasis.

Personalized medicine and predictive health and wellness: Adding the chemical component

Wearable sensors that detect and quantify biomarkers in retrievable biofluids (e.g., interstitial fluid, sweat, tears) provide information on human dynamic physiological and psychological states. This information can transform health and wellness by providing actionable feedback. Due to outdated and insufficiently sensitive technologies, current on-body sensing systems have capabilities limited to pH, and a few high-concentration electrolytes, metabolites, and nutrients. As such, wearable sensing systems cannot detect key low-concentration biomarkers indicative of stress, inflammation, metabolic, and reproductive status.  We are revolutionizing sensing. Our electronic biosensors detect virtually any signaling molecule or metabolite at ultra-low levels. We have monitored serotonin, dopamine, cortisol, phenylalanine, estradiol, progesterone, and glucose in blood, sweat, interstitial fluid, and tears. The sensors are based on modern nanoscale semiconductor transistors that are straightforwardly scalable for manufacturing. We are developing sensors for >40 biomarkers for personalized continuous monitoring (e.g., smartwatch, wearable patch) that will provide feedback for treating chronic health conditions (e.g., perimenopause, stress disorders, phenylketonuria). Moreover, our sensors will enable female fertility monitoring and the adoption of more healthy lifestyles to prevent disease and improve physical and cognitive performance.

Inducing short to medium neuroplastic effects with Transcranial Ultrasound Stimulation

Sound waves can be used to modify brain activity safely and transiently with unprecedented precision even deep in the brain - unlike traditional brain stimulation methods. In a series of studies in humans and non-human primates, I will show that Transcranial Ultrasound Stimulation (TUS) can have medium- to long-lasting effects. Multiple read-outs allow us to conclude that TUS can perturb neuronal tissues up to 2h after intervention, including changes in local and distributed brain network configurations, behavioural changes, task-related neuronal changes and chemical changes in the sonicated focal volume. Combined with multiple neuroimaging techniques (resting state functional Magnetic Resonance Imaging [rsfMRI], Spectroscopy [MRS] and task-related fMRI changes), this talk will focus on recent human TUS studies.

BrainLM Journal Club

Connor Lane will lead a journal club on the recent BrainLM preprint, a foundation model for fMRI trained using self-supervised masked autoencoder training. Preprint: https://www.biorxiv.org/content/10.1101/2023.09.12.557460v1 Tweeprint: https://twitter.com/david_van_dijk/status/1702336882301112631?t=Q2-U92-BpJUBh9C35iUbUA&s=19

Social and non-social learning: Common, or specialised, mechanisms? (BACN Early Career Prize Lecture 2022)

The last decade has seen a burgeoning interest in studying the neural and computational mechanisms that underpin social learning (learning from others). Many findings support the view that learning from other people is underpinned by the same, ‘domain-general’, mechanisms underpinning learning from non-social stimuli. Despite this, the idea that humans possess social-specific learning mechanisms - adaptive specializations moulded by natural selection to cope with the pressures of group living - persists. In this talk I explore the persistence of this idea. First, I present dissociations between social and non-social learning - patterns of data which are difficult to explain under the domain-general thesis and which therefore support the idea that we have evolved special mechanisms for social learning. Subsequently, I argue that most studies that have dissociated social and non-social learning have employed paradigms in which social information comprises a secondary, additional, source of information that can be used to supplement learning from non-social stimuli. Thus, in most extant paradigms, social and non-social learning differ both in terms of social nature (social or non-social) and status (primary or secondary). I conclude that status is an important driver of apparent differences between social and non-social learning. When we account for differences in status, we see that social and non-social learning share common (dopamine-mediated) mechanisms.

What shapes the transcriptional identity of a neuron?

Within the vertebrate neocortex and other telencephalic structures, molecularly-defined neurons tend to segregate at first order into GABAergic types and glutamatergic types. Two fundamental questions arise: (1) do non-telencephalic neurons similarly segregate by neurotransmitter status, and (2) do GABAergic (or glutamatergic) types sampled in different structures share many molecular features in common, beyond the few genes directly responsible for neurotransmitter synthesis and release? To address these questions, we used single-nucleus RNA sequencing, analyzing over 2.4 million brain cells sampled from 16 locations in a primate (the common marmoset). Unexpectedly, we find the answer to both is “no”. I will discuss implications for generalizing associations between neurotransmitter utilization and other phenotypes, and share ongoing efforts to map the biodistributions of cell types in the primate brain.

Redox and mitochondrial dysregulation in epilepsy

Epileptic seizures render the brain uniquely dependent on energy producing pathways. Studies in our laboratory have been focused on the role of redox processes and mitochondria in the context of abnormal neuronal excitability associated with epilepsy. We have shown that that status epilepticus (SE) alters mitochondrial and cellular redox status, energetics and function and conversely, that reactive oxygen species and resultant dysfunction can lead to chronic epilepsy. Oxidative stress and neuroinflammatory pathways have considerable crosstalk and targeting redox processes has recently been shown to control neuroinflammation and excitability. Understanding the role of metabolic and redox processes can enable the development of novel therapeutics to control epilepsy and/or its comorbidities.

Neuroscience of socioeconomic status and poverty: Is it actionable?

SES neuroscience, using imaging and other methods, has revealed generalizations of interest for population neuroscience and the study of individual differences. But beyond its scientific interest, SES is a topic of societal importance. Does neuroscience offer any useful insights for promoting socioeconomic justice and reducing the harms of poverty? In this talk I will use research from my own lab and others’ to argue that SES neuroscience has the potential to contribute to policy in this area, although its application is premature at present. I will also attempt to forecast the ways in which practical solutions to the problems of poverty may emerge from SES neuroscience. Bio: Martha Farah has conducted groundbreaking research on face and object recognition, visual attention, mental imagery, and semantic memory and - in more recent times - has been at the forefront of interdisciplinary research into neuroscience and society. This deals with topics such as using fMRI for lie detection, ethics of cognitive enhancement, and effects of social deprivation on brain development.

What is Cognitive Neuropsychology Good For? An Unauthorized Biography

Abstract: There is no doubt that the study of brain damaged individuals has contributed greatly to our understanding of the mind/brain. Within this broad approach, cognitive neuropsychology accentuates the cognitive dimension: it investigates the structure and organization of perceptual, motor, cognitive, and language systems – prerequisites for understanding the functional organization of the brain – through the analysis of their dysfunction following brain damage. Significant insights have come specifically from this paradigm. But progress has been slow and enthusiasm for this approach has waned somewhat in recent years, and the use of existing findings to constrain new theories has also waned. What explains the current diminished status of cognitive neuropsychology? One reason may be failure to calibrate expectations about the effective contribution of different subfields of the study of the mind/brain as these are determined by their natural peculiarities – such factors as the types of available observations and their complexity, opportunity of access to such observations, the possibility of controlled experimentation, and the like. Here, I also explore the merits and limitations of cognitive neuropsychology, with particular focus on the role of intellectual, pragmatic, and societal factors that determine scientific practice within the broader domains of cognitive science/neuroscience. I conclude on an optimistic note about the continuing unique importance of cognitive neuropsychology: although limited to the study of experiments of nature, it offers a privileged window into significant aspects of the mind/brain that are not easily accessible through other approaches. Biography: Alfonso Caramazza's research has focussed extensively on how words and their meanings are represented in the brain. His early pioneering studies helped to reformulate our thinking about Broca's aphasia (not limited to production) and formalised the logic of patient-based neuropsychology. More recently he has been instrumental in reconsidering popular claims about embodied cognition.

Interpersonal synchrony of body/brain, Solo & Team Flow

Flow is defined as an altered state of consciousness with excessive attention and enormous sense of pleasure, when engaged in a challenging task, first postulated by a psychologist, the late M. Csikszentmihayli. The main focus of this talk will be “Team Flow,” but there were two lines of previous studies in our laboratory as its background. First is inter-body and inter-brain coordination/synchrony between individuals. Considering various rhythmic echoing/synchronization phenomena in animal behavior, it could be regarded as the biological, sub-symbolic and implicit origin of social interactions. The second line of precursor research is on the state of Solo Flow in game playing. We employed attenuation of AEP (Auditory Evoked Potential) to task-irrelevant sound probes as an objective-neural indicator of such a Flow status, and found that; 1) Mutual link between the ACC & the TP is critical, and 2) overall, top-down influence is enhanced while bottom-up causality is attenuated. Having these as the background, I will present our latest study of Team Flow in game playing. We found that; 3) the neural correlates of Team Flow is distinctively different from those of Solo Flow nor of non-flow social, 4) the left medial temporal cortex seems to form an integrative node for Team Flow, receiving input related to Solo Flow state from the right PFC and input related to social state from the right IFC, and 5) Intra-brain (dis)similarity of brain activity well predicts (dis)similarity of skills/cognition as well as affinity for inter-brain coherence.

Mechanisms of sleep-seizure interactions in tuberous sclerosis and other mTORpathies

An intriguing, relatively unexplored therapeutic avenue to investigate epilepsy is the interaction of sleep mechanisms and seizures. Multiple lines of clinical observations suggest a strong, bi-directional relationship between epilepsy and sleep. Epilepsy and sleep disorders are common comorbidities. Seizures occur more commonly in sleep in many types of epilepsy, and in turn, seizures can cause disrupted sleep. Sudden unexplained death in epilepsy (SUDEP) is strongly associated with sleep. The biological mechanisms underlying this relationship between seizures and sleep are poorly understood, but if better delineated, could offer novel therapeutic approaches to treating both epilepsy and sleep disorders. In this presentation, I will explore this sleep-seizure relationship in mouse models of epilepsy. First, I will present general approaches for performing detailed longitudinal sleep and vigilance state analysis in mice, including pre-weanling neonatal mice. I will then discuss recent data from my laboratory demonstrating an abnormal sleep phenotype in a mouse model of the genetic epilepsy, tuberous sclerosis complex (TSC), and its relationship to seizures. The potential mechanistic basis of sleep abnormalities and sleep-seizure interactions in this TSC model will be investigated, focusing on the role of the mechanistic target of rapamycin (mTOR) pathway and hypothalamic orexin, with potential therapeutic applications of mTOR inhibitors and orexin antagonists. Finally, similar sleep-seizure interactions and mechanisms will be extended to models of acquired epilepsy due to status epilepticus-related brain injury.

JAK/STAT regulation of the transcriptomic response during epileptogenesis

Temporal lobe epilepsy (TLE) is a progressive disorder mediated by pathological changes in molecular cascades and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures and cognitive dysfunction. Targeting these cascades could prevent or reverse symptom progression and has the potential to provide viable disease-modifying treatments that could reduce the portion of TLE patients (>30%) not responsive to current medical therapies. Changes in GABA(A) receptor subunit expression have been implicated in the pathogenesis of TLE, and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been shown to be a key regulator of these changes. The JAK/STAT pathway is known to be involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and synaptogenesis. Our laboratories have shown that a STAT3 inhibitor, WP1066, could greatly reduce the number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced status epilepticus (SE). This suggests promise for JAK/STAT inhibitors as disease-modifying therapies, however, the potential adverse effects of systemic or global CNS pathway inhibition limits their use. Development of more targeted therapeutics will require a detailed understanding of JAK/STAT-induced epileptogenic responses in different cell types. To this end, we have developed a new transgenic line where dimer-dependent STAT3 signaling is functionally knocked out (fKO) by tamoxifen-induced Cre expression specifically in forebrain excitatory neurons (eNs) via the Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. Most recently, we have demonstrated that STAT3 KO in excitatory neurons (eNSTAT3fKO) markedly reduces the progression of epilepsy (SRS frequency) in the intrahippocampal kainate (IHKA) TLE model and protects mice from kainic acid (KA)-induced memory deficits as assessed by Contextual Fear Conditioning. Using data from bulk hippocampal tissue RNA-sequencing, we further discovered a transcriptomic signature for the IHKA model that contains a substantial number of genes, particularly in synaptic plasticity and inflammatory gene networks, that are down-regulated after KA-induced SE in wild-type but not eNSTAT3fKO mice. Finally, we will review data from other models of brain injury that lead to epilepsy, such as TBI, that implicate activation of the JAK/STAT pathway that may contribute to epilepsy development.

Why Some Intelligent Agents are Conscious

In this talk I will present an account of how an agent designed or evolved to be intelligent may come to enjoy subjective experiences. First, the agent is stipulated to be capable of (meta)representing subjective ‘qualitative’ sensory information, in the sense that it can easily assess how exactly similar a sensory signal is to all other possible sensory signals. This information is subjective in the sense that it concerns how the different stimuli can be distinguished by the agent itself, rather than how physically similar they are. For this to happen, sensory coding needs to satisfy sparsity and smoothness constraints, which are known to facilitate metacognition and generalization. Second, this qualitative information can under some specific circumstances acquire an ‘assertoric force’. This happens when a certain self-monitoring mechanism decides that the qualitative information reliably tracks the current state of the world, and informs a general symbolic reasoning system of this fact. I will argue that the having of subjective conscious experiences amounts to nothing more than having qualitative sensory information acquiring an assertoric status within one’s belief system. When this happens, the perceptual content presents itself as reflecting the state of the world right now, in ways that seem undeniably rational to the agent. At the same time, without effort, the agent also knows what the perceptual content is like, in terms of how subjectively similar it is to all other possible precepts. I will discuss the computational benefits of this architecture, for which consciousness might have arisen as a byproduct.

Neural mechanisms of altered states of consciousness under psychedelics

Interest in psychedelic compounds is growing due to their remarkable potential for understanding altered neural states and their breakthrough status to treat various psychiatric disorders. However, there are major knowledge gaps regarding how psychedelics affect the brain. The Computational Neuroscience Laboratory at the Turner Institute for Brain and Mental Health, Monash University, uses multimodal neuroimaging to test hypotheses of the brain’s functional reorganisation under psychedelics, informed by the accounts of hierarchical predictive processing, using dynamic causal modelling (DCM). DCM is a generative modelling technique which allows to infer the directed connectivity among brain regions using functional brain imaging measurements. In this webinar, Associate Professor Adeel Razi and PhD candidate Devon Stoliker will showcase a series of previous and new findings of how changes to synaptic mechanisms, under the control of serotonin receptors, across the brain hierarchy influence sensory and associative brain connectivity. Understanding these neural mechanisms of subjective and therapeutic effects of psychedelics is critical for rational development of novel treatments and for the design and success of future clinical trials. Associate Professor Adeel Razi is a NHMRC Investigator Fellow and CIFAR Azrieli Global Scholar at the Turner Institute of Brain and Mental Health, Monash University. He performs cross-disciplinary research combining engineering, physics, and machine-learning. Devon Stoliker is a PhD candidate at the Turner Institute for Brain and Mental Health, Monash University. His interest in consciousness and psychiatry has led him to investigate the neural mechanisms of classic psychedelic effects in the brain.

Learning to see Stuff

Materials with complex appearances, like textiles and foodstuffs, pose challenges for conventional theories of vision. How does the brain learn to see properties of the world—like the glossiness of a surface—that cannot be measured by any other senses? Recent advances in unsupervised deep learning may help shed light on material perception. I will show how an unsupervised deep neural network trained on an artificial environment of surfaces that have different shapes, materials and lighting, spontaneously comes to encode those factors in its internal representations. Most strikingly, the model makes patterns of errors in its perception of material that follow, on an image-by-image basis, the patterns of errors made by human observers. Unsupervised deep learning may provide a coherent framework for how many perceptual dimensions form, in material perception and beyond.

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.

Dancing to a Different Tune: TANGO Gives Hope for Dravet Syndrome

The long-term goal of our research is to understand the mechanisms of SUDEP, defined as Sudden, Unexpected, witnessed or unwitnessed, nontraumatic and non-drowning Death in patients with EPilepsy, excluding cases of documented status epilepticus. The majority of SUDEP patients die during sleep. SUDEP is the most devastating consequence of epilepsy, yet little is understood about its causes and no biomarkers exist to identify at risk patients. While SUDEP accounts for 7.5-20% of all epilepsy deaths, SUDEP risk in the genetic epilepsies varies with affected genes. Patients with ion channel gene variants have the highest SUDEP risk. Indirect evidence variably links SUDEP to seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, autonomic dysfunction, and cardiac arrhythmias. Arrhythmias may be primary or secondary to hormonal or metabolic changes, or autonomic discharges. When SUDEP is compared to Sudden Cardiac Death secondary to Long QT Syndrome, especially to LQT3 linked to variants in the voltage-gated sodium channel (VGSC) gene SCN5A, there are parallels in the circumstances of death. To gain insight into SUDEP mechanisms, our approach has focused on channelopathies with high SUDEP incidence. One such disorder is Dravet syndrome (DS), a devastating form of developmental and epileptic encephalopathy (DEE) characterized by multiple pharmacoresistant seizure types, intellectual disability, ataxia, and increased mortality. While all patients with epilepsy are at risk for SUDEP, DS patients may have the highest risk, up to 20%, with a mean age at SUDEP of 4.6 years. Over 80% of DS is caused by de novo heterozygous loss-of-function (LOF) variants in SCN1A, encoding the VGSC Nav1.1  subunit, resulting in haploinsufficiency. A smaller cohort of patients with DS or a more severe DEE have inherited, homozygous LOF variants in SCN1B, encoding the VGSC 1/1B non-pore-forming subunits. A related DEE, Early Infantile EE (EIEE) type 13, is linked to de novo heterozygous gain-of-function variants in SCN8A, encoding the VGSC Nav1.6. VGSCs underlie the rising phase and propagation of action potentials in neurons and cardiac myocytes. SCN1A, SCN8A, and SCN1B are expressed in both the heart and brain of humans and mice. Because of this, we proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in DEE. We have taken a novel approach to the development of therapeutics for DS in collaboration with Stoke Therapeutics. We employed Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, non-productive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human and mouse cell lines, as well as in mouse brain. We showed that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and SUDEP in the F1:129S-Scn1a+/- x C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein were confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Multisensory encoding of self-motion in the retrosplenial cortex and beyond

In order to successfully navigate through the environment, animals must accurately estimate the status of their motion with respect to the surrounding scene and objects. In this talk, I will present our recent work on how retrosplenial cortical (RSC) neurons combine vestibular and visual signals to reliably encode the direction and speed of head turns during passive motion and active navigation. I will discuss these data in the context of RSC long-range connectivity and further show our ongoing work on building population-level models of motion representation across cortical and subcortical networks.

Molecular, receptor, and neural bases for chemosensory-mediated sexual and social behavior in mice

For many animals, the sense of olfaction plays a major role in controlling sexual behaviors. Olfaction helps animals to detect mates, discriminate their status, and ultimately, decide on their behavioral output such as courtship behavior or aggression. Specific pheromone cues and receptors have provided a useful model to study how sensory inputs are converted into certain behavioral outputs. With the aid of recent advances in tools to record and manipulate genetically defined neurons, our understanding of the neural basis of sexual and social behavior has expanded substantially. I will discuss the current understanding of the neural processing of sex pheromones and the neural circuitry which controls sexual and social behaviors and ultimately reproduction, by focusing on rodent studies, mainly in mice, and the vomeronasal sensory system.

Contrasting neuronal circuits driving reactive and cognitive fear

The last decade in the field of neuroscience has been marked by intense debate on the meaning of the term fear. Whereas some have argued that fear (as well as other emotions) relies on cognitive capacities that are unique to humans, others view it as a negative state constructed from essential building blocks. This latter definition posits that fear states are associated with varying readouts that one could consider to be parallel processes or serial events tied to a specific hierarchy. Within this framework, innate defensive behaviors are considered to be common displays of fear states that lie under the control of hard-wired brain circuits. As a general rule, these defensive behaviors can be classified as either reactive or cognitive based on a thread imminence continuum. However, while evidence of the neuronal circuits that lead to these divergent behavioral strategies has accrued over the last decades, most literature has considered these responses in isolation. As a result, important misconceptions have arisen regarding how fear circuits are distributed in the brain and the contribution of specific nodes within these circuits to defensive behaviors. To mitigate the status quo, I will conduct a systematic comparison of brain circuits driving the expression of freezing and active avoidance behavior, which I will use as well-studied proxies of reactive and cognitive fear, respectively. In addition, I propose that by integrating associative information with interoceptive and exteroceptive signals the central nucleus of the amygdala plays a crucial role in biasing the selection of defensive behaviors.

Inclusive Basic Research

Methodology for understanding the basic phenomena of life can be done in vitro or in vivo, under tightly-controlled experimental conditions designed to limit variability. However stringent the protocol, these experiments do not occur in a cultural vacuum and they are often subject to the same societal biases as other research disciplines. Many researchers uphold the status quo of biased basic research by not questioning the characteristics of their experimental animals, or the people from whom their tissue samples were collected. This means that our fundamental understanding of life has been built on biased models. This session will explore the ways in which basic life sciences research can be biased and the implications of this. We will discuss practical ways to assess your research design and how to make sure it is representative.

The Evolution of Looking and Seeing: New Insights from Colorful Jumping Spiders

During communication, alignment between signals and sensors can be critical. Signals are often best perceived from specific angles, and sensory systems can also exhibit strong directional biases. However, we know little about how animals establish and maintain such signaling alignment during communication. To investigate this, we characterized the spatial dynamics of visual courtship signal- ing in the jumping spider Habronattus pyrrithrix. The male performs forward-facing displays involving complex color and movement patterns, with distinct long- and short-range phases. The female views displays with 2 distinct eye types and can only perceive colors and fine patterns of male displays when they are presented in her frontal field of view. Whether and how courtship interactions pro- duce such alignment between male display and female field of view is unknown. We recorded relative positions and orientations of both actors throughout courtship and established the role of each sex in maintaining signaling alignment. Males always oriented their displays toward the female. However, when females were free to move, male displays were consistently aligned with female princi- pal eyes only during short-range courtship. When female position was fixed, signaling alignment consistently occurred during both phases, suggesting that female movement reduces communication efficacy. When female models were experimentally rotated to face away during courtship, males rarely repositioned themselves to re-align their display. However, males were more likely to present cer- tain display elements after females turned to face them. Thus, although signaling alignment is a function of both sexes, males appear to rely on female behavior for effective communication

Sparse expansion in cerebellum favours learning speed and performance in the context of motor control

The cerebellum contains more than half of the brain’s neurons and it is essential for motor control. Its neural circuits have a distinctive architecture comprised of a large, sparse expansion from the input mossy fibres to the granule cell layer. For years, theories of how cerebellar architectural features relate to cerebellar function have been formulated. It has been shown that some of these features can facilitate pattern separation. However, these theories don’t consider the need for it to learn fast in order to control smooth and accurate movements. Here, we confront this gap. This talk will show that the expansion to the granule cell layer in the cerebellar cortex improves learning speed and performance in the context of motor control by considering a cerebellar-like network learning an internal model of a motor apparatus online. By expressing the general form of the learning rate for such a system, this talk will provide a calculation of how increasing the number of granule cells diminishes the effect of noise and increases the learning speed. The researchers propose that the particular architecture of cerebellar circuits modifies the geometry of the error function in a favourable way for learning faster. Their results illuminate a new link between cerebellar structure and function.

The evolutionary and psychological origins of reciprocal cooperation

If only those behaviours evolve that increase the actor’s own survival and reproductive success, then it might come as a surprise that cooperative behaviours, i.e. providing benefits to others, are a widespread phenomenon. Many animals cooperate even with unrelated individuals in various contexts, like providing care or food. One possibility to explain these behaviours is reciprocity. Reciprocal cooperation, i.e. helping those that were helpful before, is a ubiquitous and important trait of human sociality. Still, the evolutionary origin of it is largely unclear, mainly because it is believed that other animals do not exchange help reciprocally. Consequently, reciprocity is suggested to have evolved in the human lineage only. In contrast to this, I propose that reciprocity is not necessarily cognitively demanding and likely to be widespread. In my talk, I will first shed light on the mechanisms of reciprocal cooperation in Norway rats (Rattus norvegicus). In a series of studies, my colleagues and I have demonstrated that Norway rats reciprocally exchange goods and services between and within different commodities and independent of kinship. Furthermore, to understand the evolutionary origins of human reciprocity, and whether it is shared with other animals, I will then discuss evidence for reciprocity in non-human primates, which are our closest living relatives. A thorough analysis of the findings showed that reciprocity is present and, for example, not confined to unrelated individuals, but that the choice of commodities can impact the likelihood of reciprocation. Based on my findings, I conclude that reciprocal cooperation in non-human animals is present but largely neglected and not restricted to humans. In order to deepen our understanding of the evolutionary origins of reciprocity in more general, future studies should investigate when and how reciprocity in non-human animals emerged and how it is maintained.

HCN2: a key ion channel driving pain, migraine and tinnitus

Gene Therapy for Neurodegeneration

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.

Neuroendocrine control of female germline stem cell increase in the fruit fly Drosophila melanogaster

The development and maintenance of many tissues are fueled by stem cells. Many studies have addressed how intrinsic factors and local signals from neighboring niche cells maintain stem cell identity and proliferative potential. In contrast, it is poorly understood how stem cell activity is controlled by systemic, tissue-extrinsic signals in response to environmental cues and changes in physiological status. Our laboratory has been focusing on female germline stem cells (fGSCs) in the fruit fly Drosophila melanogaster as a model system and studying neuroendocrine control of fGSC increase. The increase of fGSCs is induced by mating stimuli. We have previously reported that mating-induced fGSC increase is regulated by the ovarian steroid hormone and the enteroendocrine peptide hormone [Ameku & Niwa, PLOS Genetics 2016; Ameku et al. PLOS Biology 2018]. In this presentation, we report our recent finding showing a neuronal mechanism of mating-induced fGSC increase. We first found that the ovarian somatic cell-specific RNAi for Oamb, a G protein-coupled receptor for the neurotransmitter octopamine, failed to induce fGSC proliferation after mating. Both ex vivo and in vivo experiments revealed that octopamine and Oamb positively regulated mating-induced fGSC increase via intracellular Ca 2+ signaling. We also found that a small subset of octopaminergic neurons directly projected to the ovary, and neuronal activity of these neurons was required for mating-induced fGSC increase. This study provides a mechanism describing how the neuronal system controls stem cell behavior through stem cell niche signaling [Yoshinari et al. eLife 2020]. Here I will also present our recent data showing how the neuroendocrine system couples fGSC behavior to multiple environmental cues, such as mating and nutrition.

Generation Covid-19: Should the fetus be worried?

Historically pregnant women and their unborn baby have been amongst those with the poorest outcomes in previous epidemics, most notably the Zika virus. For much of 2020, with the emergence of the novel coronavirus, the effect on the fetus remains unclear. While initial reports suggest that vertical transmission with SARS-CoV2 is reassuringly rare, the complex socioeconomic, domestic and broader maternal lifestyle factors which can influence a child’s lifelong well-being have been modulated during the experience of this pandemic. The developing brain is particularly susceptible to maternal stress, resulting in permanent structural changes and increased incidence of behavioural and mental health illness later in childhood. A large international longitudinal survey is being undertaken by the Department of Psychology to better understand the impact of the pandemic on those yet to be born.

Blood is thicker than water

According to Hamilton’s inclusive fitness hypothesis, kinship is an organizing principle of social behavior. Behavioral evidence supporting this hypothesis includes the ability to recognize kin and the adjustment of behavior based on kin preference with respect to altruism, attachment and care for offspring in insect societies. Despite the fundamental importance of kinship behavior, the underlying neural mechanisms are poorly understood. We repeated behavioral experiments by Hepper on behavioral preference of rats for their kin. Consistent with Hepper’s work, we find a developmental time course for kinship behavior, where rats prefer sibling interactions at young ages and express non-sibling preferences at older ages. In probing the brain areas responsible for this behavior, we find that aspiration lesions of the lateral septum but not control lesions of cingulate cortices eliminate the behavioral preference in young animals for their siblings and in older rats for non-siblings. We then presented awake and anaesthetized rats with odors and calls of age- and status-matched kin (siblings and mothers) and non-kin (non-siblings and non-mothers) conspecifics, while performing in vivo juxta-cellular and whole-cell patch-clamp recordings in the lateral septum. We find multisensory (olfactory and auditory) neuronal responses, whereby neurons typically responded preferentially but not exclusively to individual social stimuli. Non-kin-odor responsive neurons were found dorsally, while kin-odor responsive neurons were located in ventrally in the lateral septum. To our knowledge such an ordered representation of response preferences according to kinship has not been previously observed and we refer this organization as nepotopy. Nepotopy could be instrumental in reading out kinship from preferential but not exclusive responses and in the generation of differential behavior according to kinship. Thus, our results are consistent with a role of the lateral septum in organizing mammalian kinship behavior.

Evaluating different facets of category status for promoting spontaneous transfer

Existing accounts of analogical transfer highlight the importance of comparison-based schema abstraction in aiding retrieval of relevant prior knowledge from memory. In this talk, we discuss an alternative view, the category status hypothesis—which states that if knowledge of a target principle is represented as a relational category, it is easier to activate as a result of categorizing (as opposed to cue-based reminding)—and briefly review supporting evidence. We then further investigate this hypothesis by designing study tasks that promote different facets of category-level representations and assess their impact on spontaneous analogical transfer. A Baseline group compared two analogous cases; the remaining groups experienced comparison plus another task intended to impact the category status of the knowledge representation. The Intension group read an abstract statement of the principle with a supporting task of generating a new case. The Extension group read two more positive cases with the task of judging whether each exemplified the target principle. The Mapping group read a contrast case with the task of revising it into a positive example of the target principle (thereby providing practice moving in both directions between type and token, i.e., evaluating a given case relative to knowledge and using knowledge to generate a revised case). The results demonstrated that both Intension and Extension groups led to transfer improvements over Baseline (with the former demonstrating both improved accessibility of prior knowledge and ability to apply relational concepts). Implications for theories of analogical transfer are discussed.

Neurobiology of Social Behavior

Social interactions are central to the human experience, yet it is also one of the faculty of the brain that is the most impaired by mental illness. Similarly, social interactions are essential for animals to survive, reproduce, and raise their young. Over the years, my lab has attempted to decipher the unique characteristics of social recognition: what are the unique cues that trigger distinct social behaviors, what is the nature and identity of social behavior circuits, how is the function of these circuits different in males and females and how are they modulated by the animal physiological status? In this lecture, I will describe our recent progress in using genetic, imaging, molecular and behavioral approaches to understand how the brain controls specific social behaviors in both males and females, and how areas throughout the brain participate in the positive and negative controls of specific social interactions. I will also describe how new approaches of single cell transcriptomics have enabled us to uncover specific cell populations involved in distinct social behaviors and the basis of their activity modulation according to the animal state.

African Neuroscience: Current Status and Prospects

Understanding the function and dysfunction of the brain remains one of the key challenges of our time. However, an overwhelming majority of brain research is carried out in the Global North, by a minority of well-funded and intimately interconnected labs. In contrast, with an estimated one neuroscientist per million people in Africa, news about neuroscience research from the Global South remains sparse. Clearly, devising new policies to boost Africa’s neuroscience landscape is imperative. However, the policy must be based on accurate data, which is largely lacking. Such data must reflect the extreme heterogeneity of research outputs across the continent’s 54 countries. We have analysed all of Africa’s Neuroscience output over the past 21 years and uniquely verified the work performed in African laboratories. Our unique dataset allows us to gain accurate and in-depth information on the current state of African Neuroscience research, and to put it into a global context. The key findings from this work and recommendations on how African research might best be supported in the future will be discussed.

Neuroscience Investigations in the Virgin Lands of African Biodiversity

Africa is blessed with a rich diversity and abundance in rodent and avian populations. This natural endowment on the continent portends research opportunities to study unique anatomical profiles and investigate animal models that may confer better neural architecture to study neurodegenerative diseases, adult neurogenesis, stroke and stem cell therapies. To this end, African researchers are beginning to pay closer attention to some of her indigenous rodents and birds in an attempt to develop spontaneous laboratory models for homegrown neuroscience-based research. For this presentation, I will be showing studies in our lab, involving cellular neuroanatomy of two rodents, the African giant rat (AGR) and Greater cane rat (GCR), Eidolon Bats (EB) and also the Striped Owl (SO). Using histological stains (Cresyl violet and Rapid Golgi) and immunohistochemical biomarkers (GFAP, NeuN, CNPase, Iba-1, Collagen 2, Doublecortin, Ki67, Calbindin, etc), and Electron Microscopy, morphology and functional organizations of neuronal and glial populations of the AGR , GCR, EB and SO brains have been described, with our work ongoing. In addition, the developmental profiles of the prenatal GCR brains have been chronicled across its entire gestational period. Brains of embryos/foetuses were harvested for gross morphological descriptions and then processed using immunofluorescence biomarkers to determine the pattern, onset, duration and peak of neurogenesis (Pax6, Tbr1, Tbr2, NF, HuCD, MAP2) and the onset and peak of glial cell expressions and myelination in the prenatal GCR. The outcome of these research efforts has shown unique neuroanatomical expressions and networks amongst Africa’s rich biodiversity. It is hopeful that continuous effort in this regard will provide sufficient basic research data on neural developments and cellular neuroanatomy with subsequent translational consequences.

The kainic acid induced status epilepticus: Comparative study of the hippocampus ultrastructure in Wistar rats

FENS Forum 2024

The modulation of social decision-making function by dominance status in male mice

COSYNE 2023

Altered sensory gating in persons with tinnitus in response to regular and irregular auditory oddball sequences

Changes of Golgi apparatus morphology in epilepsy

Characterization of the antiapoptotic and neuroprotective effect of dapsone in a model of status epilepticus induced with kainic acid in rats

Cognitive status of individuals with aphasia- electrophysiological markers

Communication between the nucleus incertus and the medial septum and the entorhinal cortex

A comparative approach in vertebrate neuroscience: the Zebrafish (Danio rerio) and Giant Danio (Devario aequipinnatus)

Control of the activity of midbrain dopaminergic neurons by the nucleus incertus of the brain stem – electrophysiological, anatomical and behavioural studies in rats

Dentate gyrus of the ventral hippocampus under control of brainstem nucleus incertus - electrophysiological, anatomical and neurochemical studies in rat

Does the stress of threatening social evaluation increase the preference for status signals?

Dopaminergic modulation of nucleus incertus to interpeduncular nucleus input – a possible neuronal mechanism for stress-induced novelty preference deficiencies

Dynamic integration of space and social status in the mammalian hypothalamus

An early life maternal neglect paradigm induces alterations on anticipatory behaviour, prefrontal signalling and social status stability in adult rats

Effects of reproductive status on cognitive function and behavioral flexibility of female mice in the Intellicage home cage environment

Excitatory oxytocin receptor signalling in the rat brainstem nucleus incertus – impact on arousal and related behaviours

A fully automated maze apparatus to characterize spatial strategies in cluttered environments

Household Tobacco Smoking Status and the Temperament Dimension of Effortful Control among U.S. Young Children

Inflammation pattern after rat spinal cord injury with a comparative analysis of contusion vs transection experimental models

Low-dose 7,8-Dihydroxyflavone Administration after Status Epilepticus Prevents Epilepsy Development

Metabolic syndrome status and fitness determine the association of insulin resistance with abnormal brain functional dynamics and cognition in pre-diabetes

Neurochemical profiles of nucleus incertus neurons and their connections with the medial septum in the rat brain

Neuroectodermal stem cells improve the functional and morphological outcome after chronic spinal cord contusion injury

Neuropathological alterations in individuals with tinnitus: a post-mortem study

Noise-induced alterations in the behavior of the Caribbean hermit crab (Coenobita clypeatus) during the shell selection test

Patterns of collateralization of midline brainstem raphe and incertus nuclei to the septohippocampal system

Preclinical study of the therapeutic efficacy on functional recovery of the adipose stromal vascular fraction after spinal contusion in the rat

CB2, a receptor to target during epileptogenesis: evidence from studies in rat pups subjected to status epilepticus

Regulation of the apoptosis/autophagy switch by propionic acid in ventromedial hypothalamus of rats with type 2 diabetes mellitus

Reorganization of forebrain populations in a model of chronic epilepsy induced by status epilepticus

Study of bottlenose dolphin (Tursiops truncatus) acoustic communication during human-dolphin interaction using AI methods

In vivo administration of metabolic precursors ameliorates metabolic impairment following severe contusive spinal cord injury in a mouse model

Antioxidant effect of combined administration of metformin and propionate in a rat model of type 2 diabetes mellitus

FENS Forum 2024

Comparative study of temporal inflammation pattern of two models of spinal cord injury: Contusion versus transection

FENS Forum 2024

Dynamic integration of space and social status in the mammalian hypothalamus

FENS Forum 2024

Effects of social status on prefrontal and hippocampal structure and function in adult female rhesus macaques

FENS Forum 2024

Epigenetic mechanism affects microglia status and synaptic pruning mechanism

FENS Forum 2024

An ergonomic rodent head fixation apparatus for closed-loop cursor control

FENS Forum 2024

Exacerbation of tauopathy following mild and repeated spinal contusions in the hTauP301S mouse model

FENS Forum 2024

Experience and reactivation status determine engram synapse structural connectivity

FENS Forum 2024