Brain-state dependent activity and selective cortical innervation of identified GABAergic medial septal neurons

Rhythmicity facilitates the coordination of neuronal activity, and these rhythms are detected as oscillations of different frequencies, such as 5-12 Hz theta oscillations. Degradation of these rhythms, e.g. through neurodegeneration, causes cognitive deficits including memory impairment. Temporally ordered firing sequences of cortical principal cells such as ‘place cells’ support spatial navigation. These temporal sequences are distributed across different regions of the temporal cortex and are coordinated by rhythmic inhibition from presynaptic cortical GABAergic interneurons. However, it is not clear how the diverse temporal specificity of interneurons is coordinated to govern the excitability of these pyramidal cell assemblies. Subcortical GABAergic neurons of the medial septum innervate cortical interneurons, but the rules of innervation of identified types of cortical cells in different cortical regions are largely unknown. For my DPhil, I have hypothesized that specialized, distinct types of medial septal GABAergic neurons contribute to brain-state dependent network activity through selective cortical connectivity in targeted areas. To address my hypothesis, I have used in vivo extracellular recordings of single medial septal cells in head-restrained awake drug-free mice followed by juxtacellular labelling of recorded cells. I have found the following: (1) In Chapter 3, I demonstrate the diversity of the medial septal neuronal population. I combined electrophysiological, anatomical and immunohistochemical methods to identify and define single medial septal neurons; (2) Based on these initial characterisations, in Chapter 4, I have established that two identified subpopulations of GABAergic high-rhythmic firing neurons (HRNs), Teevra and Orchid cells, selectively target interneurons in restricted regions of the cortex. Teevra cells are short burst firing GABAergic medial septal neurons that selectively innervate axo-axonic cells in hippocampal area CA3, bypassing CA1, CA2, and the dentate gyrus (Joshi, Salib et al., 2017). Orchid cells, however, are long burst firing GABAergic medial septal neurons primarily innervating the entorhinal cortex and the presubiculum and target distinct subpopulations of GABAergic interneurons (Viney, Salib et al., 2018). (3) After identifying HRNs, in Chapter 5 I present my novel observations and definitions of GABAergic low-rhythmic firing neurons (LRNs) of the medial septum that preferentially target interneurons in the dentate gyrus and CA3. As a population, LRNs strongly reduce their firing during sleep-related hippocampal sharp-wave ripple oscillations and have a low burst incidence in contrast to HRNs (Salib et al, 2019). (4) In addition, I have documented several individual HRNs with novel firing patterns and cortical projections including neurons innervating the entorhinal cortex, parasubiculum and ventral subiculum. (5) I have also recorded multi-unit activity with chronically implanted electrodes in the medial septum of freely moving mice with the aim to investigate previously defined HRNs across the sleep-wake cycle. Overall, my results demonstrate the existence of a diverse and dynamic medial septal neuronal population that includes three distinct subgroups of identified GABAergic cortically-projecting neurons. My findings suggest specialised functional roles of these projections in the coordination of cortico-cortical circuits. While the two defined subgroups of HRNs are likely to coordinate the temporal dynamics of glutamatergic inputs to CA1 via CA3 and the entorhinal cortex, LRNs likely contribute to the modulation of neural circuits during mnemonic processes such as dentate gyrus-dependent memory discrimination.