The ventral tegmental area and mesolimbic dopamine system: contribution to thermoregulation assessed through novel neuromodulatory techniques

Author: Anna Antipov

Antipov, Anna, 2021 The ventral tegmental area and mesolimbic dopamine system: contribution to thermoregulation assessed through novel neuromodulatory techniques, Flinders University, College of Medicine and Public Health

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This thesis examined the contribution of dopaminergic neurons of the ventral tegmental area (VTA), a crucial component of the mesolimbic dopamine system, to the process of thermoregulation.

The control of body temperature, as a physiological regulator in response to environmental factors or emotional triggers, is vital to the survival of all animals. However, very little is understood in regard to the neurotransmitters, brain areas and neural pathways that are involved in its regulation. As such, many autonomic conditions, such as Parkinson’s disease and psychogenic fever, which exhibit thermoregulatory symptoms are poorly understood and consequently undertreated.

Dopamine is a neurotransmitter known to be involved in the regulation of central bodily cognitive and motor functions. Recent findings have indicated that it also plays an important role in body temperature. However, its central mechanisms of action are unknown. One of the major nuclei in the brain that contains dopamine-producing neurons is the VTA, which is approximately 30-70% dopaminergic. Thus, the present study aimed to elucidate the specific role of VTA dopamine neurons in the control of thermoregulatory outputs.

Within the past decade new techniques, such as chemogenetics, have emerged which allow for the specific study of neurotransmitter function in defined brain regions. Hence, this study utilized, the designer receptors exclusively activated by designer drugs (DREADDs) system, in conjunction with specifically modified transgenic animals and specially designed ligands to investigate the effect of temporary neuronal population activation on the common thermoregulatory response, known as emotional hyperthermia. Targeted toxins were also applied to determine the effect of dopamine signalling reduction on various thermoregulatory parameters. All biological parameters were assessed in conscious, freely moving animals through the chronic implantation of thermistor probes, locomotor behaviour tracking and food consumption monitoring.

The results presented in this thesis conclusively demonstrate the vital contribution of dopaminergic VTA neurons to the process of thermoregulation; as well as their impact on physiological processes – such as feeding and locomotion. VTA dopaminergic enhancement was found to substantially increase the baseline temperature of animals. This was simultaneously accompanied by changed feeding patterns and locomotor hyperactivity. Specific dopamine receptor influence and feeding behaviour alterations were assessed as a potential contributing factor to the observed temperature elevation. This facilitated the validation of D1 dopamine receptor involvement in the process of body temperature control. Lastly, the influence of the mesolimbic dopamine system, originating in the VTA and projecting to the nucleus accumbens, was assessed. Although this pathway has been implicated in locomotion, feeding and emotional processing behaviours - making it a potential candidate for the control for thermoregulation, it was determined that it is likely not the primary pathway responsible for thermoregulation.

Taken together, the evidence provided in this investigation adds fundamental biological information to the field of integrative neuroscience, which helps the understanding of connections between brain regions and physiological responses. Furthermore, the research conducted validates the use of modern genetic techniques in conscious animal physiological research. Importantly, the identification of a thermoregulatory brain region, as well as the receptor type involved in its function, may assist in the development of new, more effective, and targeted treatments for those suffering with thermoregulatory diseases.

Keywords: dopamine, ventral tegmental area, emotional hyperthermia, chemogenetics, stress, brown adipose tissue, thermoregulation

Subject: Neuroscience thesis

Thesis type: Doctor of Philosophy
Completed: 2021
School: College of Medicine and Public Health
Supervisor: Yoichiro Otsuka