Tibor Harkany

FWF funds Cluster of Excellence Neuronal Circuits in Health and Disease with 21 million euros: MedUni Vienna-led consortium investigates the role of inhibitory neurons in the development of diseases Scientists from MedUni Vienna together with other research institutions from Austria will carry out a large-scale project in the field of brain research as part of the Cluster of Excellence Neuronal Circuits in Health and Disease funded by the Austrian Science Fund FWF and the Federal Ministry of Education, Science and Research. The funding volume of the FWF amounts to 21 million euros. Biomedical research and technological advances in the 21st century are accelerating at unmatched speed in almost any field. From the design of artificial intelligence systems outperforming human operators, to vaccine development in record times, humanitys greatest aspirations for the first time seem within reach. Yet, the last decades have seen only moderate progress in our understanding of the pathologies that afflict the very organ that is the fundamental basis for all these accomplishments the brain. It is the complexity of the human brain that accounts for the most formidable achievements of the mind while at the same time determines the intricacy of its diseases. At present, the evolution of neuroscience allows for deconstructing the brain into functional units, which are interconnected nerve cells that produce specific behaviors. Understanding the organization and function of neuronal circuits is the challenge that this Cluster of Excellence will take on. A team of frontrunners of neuroscience research in Austria will benefit from cutting-edge innovation to address how the brains functional modules, develop, process, and store information to control behaviors. A specific focus will be on a cell type that is indispensable from any neuronal circuit: inhibitory neurons. This is because the ubiquitous existence of their many subtypes in all neuronal circuits drives the inherent flexibility of the human brain to perceive and filter environmental stimuli and execute proportionate responses. Genetic deficits in these inhibitory GABA cells are linked to neuropsychiatric disorders. Thus, by fostering our many experimental strategies, patient cohorts, and computational models, we will not only advance our knowledge of the brain, the core driver of human development, but also set the path to meet the needs of its medical management. It is a once-in-a-generation opportunity to unite leaders of the Austrian Neuroscience community, including both discovery research and clinical experts, to join a large-scale effort for tangible advances in understanding brain function and develop treatments for brain diseases. explains Tibor Harkany, Director of Research, about the objectives of the Cluster of Excellence. Understanding when, how and why a particular subtype of GABA neurons is assigned to a specific task in a given neuronal circuit will deliver causality to both behaviors and diseases, and produce the first and most critical steps towards the personalized therapy of neuropsychiatric diseases.

The brain is the most sophisticated biological system, with its functions safeguarded by the seamless interaction of its many cell types. Single-cell biology approached brain complexity by the charting of neurons because of their stable molecular signatures. However, only half of the brain is made up by neurons, with mainly astrocytes making up the remaining part. Astrocytes have been viewed as support cells for neurons. With a focus on the hypothalamus, we will challenge this ‘neuron-centric’ view. We hypothesize that the many receptors, transporters, and signal transduction mechanisms in hypothalamic astroglia make them equivalent or even superior to neurons in defining endocrine output by dynamically sensing environmental signals at high temporal resolution. Here, innovative molecular and cellular manipulations guided by single-cell profiling will be used to interrogate i) astroglial diversity and ii) functional plasticity, iii) if switching astroglial features in neurocircuits could reprogram endocrine output, and iv) if illicit drugs drive endocrine impairment by exploiting astroglia as entry points to the brain. We will focus on and compare the astroglial control of the circuit designs of two dopamine neuron subtypes, which we have identified as sensitive to either amphetamine or cannabinoids. Thus, outcomes will produce new understanding on hypothalamic organization and non-neuronal substrates of drug susceptibility. Consequently, a therapeutic perspective will emerge.

The extraordinary number, unique features, and coordinated interplay of nerve cells underpin the computational capacity and adaptive potential of the brain. Astrocytes also reside in the brain, with their numbers equivalent to or even exceeding those of neurons. Yet, the level of molecular diversity, functional competence and spatial segregation amongst astrocytes to prime, support, monitor or even command particular neuronal operations are incompletely understood. This gap of knowledge is particularly unexpected for the hypothalamus, where astrocytes are poised to sense circulating hormones and nutrients to modulate neuroendocrine output. Our insights in how obesity impacts the identity, functional competence, and neuronal interplay of astrocytes is also fragmented. Here, single-cell biology, experimental models, and hypothesis-driven candidate testing are combined for a new classification of hypothalamic astrocytes, and their interplay with neurons in health and metabolic disease.

Evolutionary success drives continuous human adaptation. A pervasive challenge is the substantial change in the composition and nutritional value of diets available. This is particularly relevant for child-bearing women because metabolic bias through diet composition can adversely affects pregnancy outcomes. Even though clinical and experimental studies correlate maternal obesity during pregnancy (affecting ~30% world-wide) with congenital metabolic illnesses, a causal relationship between maternal obesity, impairment in neuroendocrine development and ensuing deficits in metabolic control of affected offspring is as yet missing. The hypothalamus is the neuroendocrine interface linking the brain and periphery. Thus, we hypothesize that maternal obesity could evoke permanent molecular changes in hypothalamic neurons of the offspring to compromise their plasticity and adaptive repertoire. This notion is on the backdrop of our recent success in defining, by singe-cell RNA-seq and brain-wide imaging, the developmental trajectory of neurons that build the mammalian hypothalamus, and in discovering the function of novel neuronal subtypes. Here, we will determine molecular, cellular and network-level changes in the hypothalamus of offspring born to obese mothers. We will combine single-cell RNA-seq and ATAC-seq in the same neurons to precisely catalogue permanent modifications to gene expression at successive developmental stages in mice. We will particularly interrogate molecular determinants that can impair the neuronal circuitry controlling food intake, including leptin and endocannabinoid interplay as a candidate. We will complement these data by identifying novel cellular sites of hormone secretion that shape brain and bodily architecture and are sensitive to maternal obesity. Overall, our work will produce new understanding of the life-long consequences of metabolic programming of the developing brain.