Professor Herbert Herzog

Current available projects:

Project 1: Anorexia: The Starving Brain

Eating disorders affect approximately 5% of the Australian population overall, and 10% of women. Without treatment, up to 25% of people with anorexia nervosa die and even the 20% of people recovering from anorexia have lifelong consequences from the disease including increased risk of osteoporosis, hearth failure, infertility, etc.

The precise causes of anorexia nervosa are unknown, but environmental and psychological factors often cited as playing a role. However, in addition of being a mental disorder, anorexia nervosa is associated with profound underlying metabolic defects such that the brain does not recognize the under fed state of the body. Under normal conditions, weight loss activates strong physiological mechanisms that protect against further weight loss. This ‘famine reaction’ is triggered by natural brain chemicals in a part of the brain called the hypothalamus, with effects include irrepressible hunger, lethargy and sharp reductions in metabolic rate. Paradoxically, people with anorexia nervosa do not demonstrate these expected responses to weight loss and in fact show increased activity that worsens the condition, suggesting perturbations in the natural brain chemicals responsible for the famine reaction. If we understood exactly which chemicals in the brain were responsible for mediating the famine reaction, how they worked, as well as how these molecules are perturbed in anorexia nervosa, then we could develop novel treatment strategies to target the physical causes of this debilitating disorder. To achieve these goals, we have established the Activity-based anorexia (ABA) mouse model in our laboratory and will use this model to test various transgenic mouse lines to identify the critical neuronal component that are associated with anorexia associated hyperactivity and feeding reduction.

Project 2: Brainstem feeding circuitries as intervention points for obesity treatment

Obesity is a global epidemic and a key contributor to the burden of chronic disease and disability Obesity results from the sustained imbalance between food intake and energy expenditure, both of which had long been considered under the primary control of neuronal networks originating from the hypothalamus and the brainstem. Importantly, almost all receptors that recognise gut peptides known to regulate both satiety and feeding are expressed on brainstem neurons, thus as a relay centre for critical information on energy status from the periphery, the brainstem is an ideal target for obesity intervention.

We will employ an innovative approach that will comprehensively capture all neuronal contributions in the brainstem that influence feeding behaviour under fasting and/or refeeding conditions. To achieve this, we have established (published recently in the journal Neuron) powerful Fos-promoter dependent TetTag system, which exploits the early gene activation marker Fos as a tool to identify as well as label all active neurons. This approach contrasts with the single gene candidate approach which only provides information on one pathway. We will use the TetTag system to 1) drive chemogenetic ‘designer receptor exclusively activated by designer drugs’ DREADD’s specifically from these Fos responsive neurons to define their specific functions in fasting and re-feeding; 2) determine the transcriptomic profile as well as the dynamic changes that occur upon changes in energy intake via translational ribosomal affinity purification (TRAP) technology, and 3) map the critical downstream projection sites of the fasting-refeeding controlling brainstem neuronal network via neuronal tracing.

Project 3: Critical neuronal circuits controlling hibernation and torpor-like states

Energy conserving strategies such as torpor and hibernation are important survival mechanisms that endothermic organism utilise to deal with environmental challenges like starvation and cold exposure to conserve energy, reduce core body temperature, lower metabolic rate and decrease locomotor activity. While neuronal circuits in the brain have been implicated in this process the exact underlying mechanism of initiating and controlling torpor-like states is still unknown.

Brain stem nuclei such as the NTS, which is generally known as the primary integrative centre for cardiovascular-respiratory control in the central nervous system, has now also been demonstrated to be involved in thermoregulation and metabolic control. Therefore, we hypothesised that brainstem circuities may also be involved in initiating and maintaining torpor like effects, and we employed a systematic, unbiased approach utilising the well-established early gene marker Fos as an indicator of neuronal activation in response to fasting induced torpor and identified novel targets within this area, specifically the NPFF neuronal network. We now aim to determine the underlying mechanism that initiates and controls torpor by utilising a set of different NPFF and NPFF receptor transgenic mouse models in combination with sophisticated chemo- and optogenetic technologies.