Neural development, injury and pain
Our research seeks to understand how neurons and organs communicate. This is bi-directional – nerves control many organ functions and the organs can, in turn, release substances that can have a major impact on the function of their nerve supply. Many aspects of this communication are disrupted by injury or disease. We are especially intrigued by the organ-neuron patterns of communication that are established during development because these mechanisms may be re-created or adapted during adulthood to restore normal function.
Our research is especially relevant to an exciting new area of research, bioelectronic medicine. This means using implanted devices (instead of drugs) to control clinical conditions. To develop function-specific miniaturised implants that control organ dysfunction, it is essential to first generate a precise map of neural pathways, their connections with the organs and the spinal cord. Construction of these maps is a high priority of our research and fundamental to translation of our research to the clinical context.
We are exploring these issues in the neural circuits that are required for voiding/continence and reproduction – important human functions that require complex reflexes to occur at behaviourally appropriate times. This requires precise regulation of the pelvic nervous system by the brain and spinal cord. These components of the nervous system are also interesting because of their sexual dimorphism, which impacts on how nerve-organ communication is established and how it is influenced by clinical problems. By understanding fundamental neurobiological mechanisms, we aim to address issues such: as the factors that initiate pelvic pain conditions, how neural activity may influence the growth and repair of epithelia, and how sex differences in this part of the nervous system are established. Together, these will guide us towards development of novel approaches to treat clinical conditions in the urogenital system.
Our multidisciplinary approach uses rodent models and human specimens to study the development, anatomy, and function of the pelvic nervous system, spinal cord and connectivity with high order brain centres. We use advanced microscopic imaging and neuroanatomical techniques extensively in our work, but are also expert in other approaches such as primary cell culture (including co-cultures of adult neurons and urothelial cells), cellular neurophysiology and neuropharmacology and, through collaboration, bioinformatics analysis of specific neural populations.
Our research related to development of new medical devices is conducted in collaboration with colleagues at the Bionics Institute.
Our research is supported by the National Institutes of Health SPARC common fund program and the NIH-funded GenitoUrinary Development Molecular Anatomy Project database (GUDMAP), which aims to provide high resolution molecular and anatomical maps of the developing kidney and genitourinary tract.
Professor Janet Keastjkeast@unimelb.edu.au
Theme 1: Building components of the connectome for the urogenital nervous system
Projects in this area are especially suited to students with a strong background in neuroanatomy or neurophysiology. Development of devices to control urogenital function first needs a high-resolution map of neuronal connections with each tissue and region of the urogenital system, its relevant sensory and motor ganglia, the lumbosacral spinal cord and brainstem. Some elements of this map are known but there are many gaps. We are combining dye and viral tracing approaches with combinatorial expression mapping and advanced microscopy (including light sheet microscopy) to precisely map connections of distinct nerve types at the macroscopic, mesoscopic and microscopic levels. We are also mapping activity of circuit components using immediate early gene expression patterns after conscious bladder activity, evoked by natural stimulation or activation of a miniaturised device built by our collaborators at the Bionics Institute.
Projects in this area are especially suited to students with a strong background in developmental biology or neural structures. Urogenital function is regulated by autonomic neurons in the pelvic ganglia (known as the inferior hypogastric plexus in people) and sensory neurons in lumbosacral dorsal root ganglia. In comparison to other parts of the autonomic nervous system, the pelvic ganglia are very unusual. For example, they are very different in males and females, and they continue to be very sensitive to actions of steroids, even in adults. Most unusually, they are mixed sympathetic-parasympathetic ganglia, leading to questions of how these ganglia develop, and how their connections with two different regions of the spinal cord (lumbar and sacral) are determined correctly when they first form. Very little is known about how this part of the autonomic nervous system develops and what initiates its sexual dimorphism. These are critical to understanding developmental abnormalities and may also point to mechanisms that can be activated in adults to repair axons after injury. Other projects are available to investigate the unique features of developing sacral nociceptive neurons that are later involved in sexually dimorphic pelvic pain conditions.
Projects in this area are especially suited to students with a strong background in cell biology or neural structures. The urothelium lining the bladder has two major functions: (i) a barrier, to protect the bladder tissues and their nerve supply from substances within urine, and (ii) as sensory transducer that responds to chemical and mechanical stimulation by releasing substances to activate sensory axons in the bladder wall. Whereas the barrier function is well accepted, the transducer properties have been inferred by strong but indirect evidence. This is relevant to understanding how the urothelium signals to nearby sensory nerve terminals and, conversely, how nerves may regulate epithelial growth and repair. This is relevant to conditions such as cystitis when the urothelium is damaged or conditions when growth is dysregulated. We have developed a neuro-urothelial co-culture system so can now directly study intercellular communication between urothelial cells and sensory or autonomic neurons. One project will focus on the signalling from the urothelium to the sensory nerves, using compartmentalised cultures in microfluidic chambers, immunofluorescence and live-cell imaging. Another project will examine growth-promoting signals from the neurons that can impact on urothelial cell proliferation in vitro and their ability to drive repair in vivo.