Explore the vast range of titles available.

Hippocampal theta oscillations orchestrate faster beta-to-gamma oscillations facilitating the segmentation of neural representations during navigation and episodic memory. Supra-theta rhythms of hippocampal CA1 are coordinated by local interactions as well as inputs from the entorhinal cortex (EC) and CA3 inputs. However, theta-nested gamma-band activity in the medial septum (MS) suggests that the MS may control supra-theta CA1 oscillations. To address this, we performed multi-electrode recordings of MS and CA1 activity in rodents and found that MS neuron firing showed strong phase-coupling to theta-nested supra-theta episodes and predicted changes in CA1 beta-to-gamma oscillations on a cycle-by-cycle basis. Unique coupling patterns of anatomically defined MS cell types suggested that indirect MS-to-CA1 pathways via the EC and CA3 mediate distinct CA1 gamma-band oscillations. Optogenetic activation of MS parvalbumin-expressing neurons elicited theta-nested beta-to-gamma oscillations in CA1. Thus, the MS orchestrates hippocampal network activity at multiple temporal scales to mediate memory encoding and retrieval. Timing is key for efficient coding and communication across brain areas. Here, the authors found that the medial septum orchestrates hippocampal network activity at multiple temporal scales likely mediating memory encoding and retrieval.

Rhythmic theta frequency (~5–12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of ‘upstream’ and ‘downstream’ cortico-cortical circuits involved in mnemonic functions.

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.