Kosse, CL; (2018) Functional properties of GAD65 neurons in the lateral hypothalamus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The brain’s ability to sense energy levels and adjust behaviour accordingly is vital for survival in mammals. The lateral hypothalamus (LH), which contains energy-spending (orexin) and energy-conserving melanin-concentrating hormone (MCH) neurons, is thought to be the brain’s master energy sensor and generator of motivated behaviour. Recently, other classes of non-MCH, non-orexin neurons, such as vesicular GABA transporter (VGAT) and glutamic acid decarboxylase 65 (GAD65) expressing neurons, have been discovered in the LH. VGATLH neurons have been shown to be essential for appetitive and consummatory behaviour. However, the properties and behavioural roles of GAD65LH neurons remain unclear, and are the focus of this thesis. The thesis’ three parts examine cellular, circuit, and behavioural roles of GAD65LH neurons. Firstly, whole cell patch clamping was used to determine firing responses of GAD65LH neurons to injections of oscillatory input currents. GAD65LH neurons were found to have similar frequency-preferences of firing resonance to those of VGAT and MCH neurons, whilst orexin neurons showed a different, “high frequency inhibited” frequency-preference profile. Moreover, histochemistry was employed to characterise GAD65LH neurons further by quantifying their overlap with other GABAergic LH cell types. It was found that GAD65LH neurons overlapped only partially with VGATLH neurons, and that neuropeptide Y (NPY) and leptin receptor (LepRb) expressing neurons were largely distinct from GAD65LH cells. Secondly, cell-type specific channelrhodopsin-assisted circuit mapping was used to probe up- and downstream functional targets of GAD65LH neurons. It was found that GAD65LH neurons were excited by orexin neurons and inhibited by VGATLH neurons, and that they preferentially inhibited MCHLH and NPYLH neurons. Finally, chemogenetic excitation or inhibition of GAD65LH cell activity was used to investigate the role of these cells in behaviour. It was found that GAD65LH neurons were weight-loss-promoting, and essential and sufficient for normal locomotor activity. Overall, these results define and characterise a new cellular network component in LH function.

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