Defining how GABAergic inhibition coordinates the firing and tuning of head direction cell types across the anterodorsal nucleus of the thalamus

Head direction (HD) cells are a core component of our spatial navigation system, establishing our inner compass. The anterodorsal nucleus (AD) is a distinct nucleus within the thalamus that contains one the highest densities of HD cells in the brain. To this date, the diversity of HD cells remains poorly understood.

My preliminary data suggests there are subtypes of AD HD cells that have different firing and bursting patterns in vivo. Yet, unlike other areas, the AD lacks local GABAergic interneurons. Studies have demonstrated direct GABAergic projections from the thalamic reticular nucleus (TRN) to AD specifically, however, whether there is a direct contribution from TRN cells to AD HD cells firing

properties and whether other, unexplored extrathalamic, inhibitory projections to AD contribute to HD cells' burst firing or HD tuning remain unclear.

The overarching goal of this proposal is to define the role of GABAergic inhibition in shaping AD HD cell firing and HD tuning. To reach this goal, I propose the following aims:

1) To define new subtypes of AD HD cells in an innovative way by clustering in vivo firing patterns, HD properties, morphology and location of single labelled AD HD cells. 2) To define the inhibitory inputs onto AD HD cells. 3) To establish the contribution of inhibitory inputs to the bursting mode and HD tuning of AD HD cells.

To that end, I will use a customized recording setup that allows 1) for juxtacellular recording and labelling of single HD cells in AD in head-restrained awake mice and 2) for optogenetic manipulations of GABAergic inputs within and outside the receptive field. I will also apply cutting-edge tracing techniques to obtain a brain-wide mapping of all GABAergic input onto AD.

Finally, I will perform functional validation of major inputs using patch-clamp recording from AD cells ex vivo. Understanding the intricate mechanisms underlying HD tuning will promote significant advancements in our knowledge of spatial navigation.