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.

Microglia are the brain macrophages, eliciting multifaceted functions to maintain brain homeostasis across lifetime. To achieve this, microglia are able to sense a plethora of signals in their close environment. In the lab, we investigate the effect of nutrients on microglia function for several reasons: 1) Microglia express all the cellular machinery required to sense nutrients; 2) Eating habits have changed considerably over the last century, towards diets rich in fats and sugars; 3) This so-called "Western diet" is accompanied by an increase in the occurrence of neuropathologies, in which microglia are known to play a role. In my talk, I will present data showing how variations in nutrient intake alter microglia function, including exacerbation of synaptic pruning, with profound consequences for neuronal activity and behavior. I will also show unpublished data on the mechanisms underlying the effects of nutrients on microglia, notably through the regulation of their metabolic activity.

Despite the profound effects of nutrition and physical activity on human health, our understanding of the molecules mediating the salutary effects of specific foods or activities remains remarkably limited. Here, we share our ongoing studies that use unbiased and high-resolution metabolomics technologies to uncover the molecules and molecular effectors of diet and exercise. We describe how exercise stimulates the production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Ablation of Lac-Phe biosynthesis in mice increases food intake and obesity after exercise. We also describe the discovery of an orphan metabolite, BHB-Phe. Ketosis-inducible BHB-Phe is a congener of exercise-inducible Lac-Phe, produced in CNDP2+ cells when levels of BHB are high, and functions to lower body weight and adiposity in ketosis. Our data uncover an unexpected and underappreciated signaling role for metabolic fuel derivatives in mediating the cardiometabolic benefits of diet and exercise. These data also suggest that diet and exercise may mediate their physiologic effects on energy balance via a common family of molecules and overlapping signaling pathways.

Parkinson’s Disease (PD), the most common neurodegenerative movement disorder, is based on a complex interplay between genetic predispositions, aging processes, and environmental influences. In order to better understand the gene-environment axis in PD, we pursue a multi-omics approach to comprehensively interrogate genome-wide changes in histone modifications, DNA methylation, and hydroxymethylation, accompanied by transcriptomic profiling in cell and animal models of PD as well as large patient cohorts. Furthermore, we assess the plasticity of epigenomic modifications under influence of environmental factors using longitudinal cohorts of sporadic PD cases as well as mouse models exposed to specific environmental factors. Here, we present gene expression changes in PD mouse models in context of aging as well as environmental enrichment and high-fat diet.

Habitual consumption of a “Western diet”, containing higher than recommended levels of simple sugars and saturated fatty acids, is associated with cognitive impairments in humans and in various experimental animal models. Emerging findings reveal that the specific mnemonic processes that are disrupted by Western diet consumption are those that rely on the hippocampus, a brain region classically linked with memory control and more recently with the higher-order control of food intake. Our laboratory has established rat models in which excessive consumption of different components of a Western diet during the juvenile and adolescent periods of development yields long-term impairments in hippocampal-dependent memory function without concomitant increases in total caloric intake, body weight, or adiposity. Our ongoing work is investigating alterations in the gut microbiome as a potential underlying neurobiological mechanism linking early life unhealthy dietary factors to adverse neurocognitive outcomes.

Lifestyle factors such as sleep, diet, stress, and exercise, profoundly influence cardiovascular health. Seeking to understand how lifestyle affects our biology is important for at least two reasons. First, it can expose a particular lifestyle’s biological impact, which can be leveraged for adopting specific public health policies. Second, such work may identify crucial molecular mechanisms central to how the body adapts to our environments. These insights can then be used to improve our lives. In this talk, I will focus on recent work in the lab exploring how lifestyle factors influence cardiovascular health. I will show how combining tools of neuroscience, hematology, immunology, and vascular biology helps us better understand how the brain shapes leukocytes in response to environmental perturbations. By “connecting the dots” from the brain to the vessel wall, we can begin to elucidate how lifestyle can both maintain and perturb salutogenesis.

Our everyday behaviours, such as physical activity, sleep, diet, meditation, and social connections, have a potent impact on our mental health and the health of our brain. BrainPark is working to harness this power by developing lifestyle-based interventions for mental health and investigating how they do and don’t change the brain, and for whom they are most effective. In this webinar, Dr Rebecca Segrave and Dr Chao Suo will discuss BrainPark’s approach to developing lifestyle-based interventions to help people get better control of compulsive behaviours, and the multi-modality neuroimaging approaches they take to investigating outcomes. The webinar will explore two current BrainPark trials: 1. Conquering Compulsions - investigating the capacity of physical exercise and meditation to alter reward processing and help people get better control of a wide range of unhelpful habits, from drinking to eating to cleaning. 2. The Brain Exercise Addiction Trial (BEAT) - an NHMRC funded investigation into the capacity of physical exercise to reverse the brain harms caused by long-term heavy cannabis use. Dr Rebecca Segrave is Deputy Director and Head of Interventions Research at BrainPark, the David Winston Turner Senior Research Fellow within the Turner Institute for Brain and Mental Health, and an AHRPA registered Clinical Neuropsychologist. Dr Chao Suo is Head of Technology and Neuroimaging at BrainPark and a Research Fellow within the Turner Institute for Brain and Mental Health.

Modeling neural responses to naturalistic stimuli has been instrumental in advancing our understanding of the visual system. Dominant computational modeling efforts in this direction have been deeply rooted in preconceived hypotheses. In contrast, hypothesis-neutral computational methodologies with minimal apriorism which bring neuroscience data directly to bear on the model development process are likely to be much more flexible and effective in modeling and understanding tuning properties throughout the visual system. In this study, we develop a hypothesis-neutral approach and characterize response selectivity in the human visual cortex exhaustively and systematically via response-optimized deep neural network models. First, we leverage the unprecedented scale and quality of the recently released Natural Scenes Dataset to constrain parametrized neural models of higher-order visual systems and achieve novel predictive precision, in some cases, significantly outperforming the predictive success of state-of-the-art task-optimized models. Next, we ask what kinds of functional properties emerge spontaneously in these response-optimized models? We examine trained networks through structural ( feature visualizations) as well as functional analysis (feature verbalizations) by running `virtual' fMRI experiments on large-scale probe datasets. Strikingly, despite no category-level supervision, since the models are solely optimized for brain response prediction from scratch, the units in the networks after optimization act as detectors for semantic concepts like `faces' or `words', thereby providing one of the strongest evidences for categorical selectivity in these visual areas. The observed selectivity in model neurons raises another question: are the category-selective units simply functioning as detectors for their preferred category or are they a by-product of a non-category-specific visual processing mechanism? To investigate this, we create selective deprivations in the visual diet of these response-optimized networks and study semantic selectivity in the resulting `deprived' networks, thereby also shedding light on the role of specific visual experiences in shaping neuronal tuning. Together with this new class of data-driven models and novel model interpretability techniques, our study illustrates that DNN models of visual cortex need not be conceived as obscure models with limited explanatory power, rather as powerful, unifying tools for probing the nature of representations and computations in the brain.

The human gut microbiome has emerged as a key player in the bidirectional communication of the gut-brain axis, affecting various aspects of homeostasis and pathophysiology. Until recently, the majority of studies that seek to explore the mechanisms underlying the microbiome-gut-brain axis cross-talk relied almost exclusively on animal models, and particularly gnotobiotic mice. Despite the great progress made with these models, various limitations, including ethical considerations and interspecies differences that limit the translatability of data to human systems, pushed researchers to seek for alternatives. Over the past decades, the field of in vitro modelling of tissues has experienced tremendous growth, thanks to advances in 3D cell biology, materials, science and bioengineering, pushing further the borders of our ability to more faithfully emulate the in vivo situation. Organ-on-chip technology and bioengineered tissues have emerged as highly promising alternatives to animal models for a wide range of applications. In this talk I’ll discuss our progress towards generating a complete platform of the human microbiota-gut-brain axis with integrated monitoring and sensing capabilities. Bringing together principles of materials science, tissue engineering, 3D cell biology and bioelectronics, we are building advanced models of the GI and the BBB /NVU, with real-time and label-free monitoring units adapted in the model architecture, towards a robust and more physiologically relevant human in vitro model, aiming to i) elucidate the role of microbiota in the gut-brain axis communication, ii) to study how diet and impaired microbiota profiles affect various (patho-)physiologies, and iii) to test personalised medicine approaches for disease modelling and drug testing.

Environmental insults alter brain function and behaviour inboth rodents and people. One putative underlying mechanism that has receivedsubstantial attention recently is the gut microbiota, the ecosystem ofsymbiotic microorganisms that populate the intestinal tract, which is known toplay a role in brain health and function via the gut-brain axis. Two keyenvironmental insults known to affect both brain function and behaviour, andthe gut microbiome, are poor diet and psychological stress. While there isstrong evidence for interactions between the microbiome and host physiology inthe context of chronic stress, little is known about the role of the microbiomein the host response to acute stress. Determining the underlying mechanisms bywhich stress may provoke functional changes in the gut and brain is criticalfor developing therapeutics to alleviate adverse consequences of traumaticstress.

Large scale genetic studies and associated functional investigations have tremendously augmented our knowledge about the mechanisms underlying epileptic seizures, and sometimes also accompanying developmental problems. Pharmacotherapy of the epilepsies is routinely guided by trial and error, since predictors for a response to specific antiepileptic drugs are largely missing. The recent advances in the field of genetic epilepsies now offer an increasing amount of either well fitting established or new re-purposing therapies for genetic epilepsy syndromes based on understanding of the pathophysiological principles. Examples are provided by variants in ion channel or transporter encoding genes which cause a broad spectrum of epilepsy syndromes of variable severity and onset, (1) the ketogenic diet for glucose transporter defects of the blood-brain barrier, (2) Na+ channel blockers (e.g. carbamazepine) for gain-of-function Na+ channel mutations and avoidance of those drugs for loss-of-function mutations, and (3) specific K+ channel blockers for mutations with a gain-of-function defect in respective K+ channels. I will focus in my talk on the latter two including the underlying mechanisms, their relation to clinical phenotypes and possible therapeutic implications. In conclusion, genetic and mechanistic studies offer promising tools to predict therapeutic effects in rare epilepsies.

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

Rapid communication between the gut and the brain about recently consumed nutrients is critical for regulating food intake and maintaining energy homeostasis. We have shown that the infusion of nutrients directly into the gastrointestinal tract rapidly inhibits hunger-promoting AgRP neurons in the arcuate nucleus of the hypothalamus and suppresses subsequent feeding. The mechanism of this inhibition appears to be dependent upon macronutrient content, and can be recapitulated by a several hormones secreted in the gut in response to nutrient ingestion. In high-fat diet-induced obese mice, the response of AgRP neurons to nutrient-related stimuli are broadly attenuated. This attenuation is largely irreversible following weight loss and may represent a mechanism underlying difficulty with weight loss and propensity for weight regain in obesity.

Reducing protein intake (and that of key amino acids) extends lifespan, especially during mid-life and early late-life. Yet, due to a powerful protein appetite, reducing protein in the diet leads to increased food intake, promoting obesity – which shortens lifespan. That is the protein paradox. In the talk I will bring together pieces of the jigsaw, including: specific nutrient appetites, protein leverage, macronutrient interactions on appetite and ageing, the role of branched-chain amino acids and FGF-21, and then I will conclude by showing how these pieces fit together and play out in the modern industrialised food environment to result in the global pandemic of obesity and metabolic disease.

Diets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.