Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms

Abstract

The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus.

Functional Connectivity Pattern of the Internal Hippocampal Network in Awake Pigeons: A Resting-State fMRI Study

“…This finding is of high relevance since a recent study by Atoji et al [2016] found that glutamatergic neurons of DM project to SL, a characteristic which is shared by glutamatergic neurons in the mammalian Ammon's horn. In mammals, the septum projects back to the hippocampus and drives hippocampal theta rhythms, which are essential for learning and memory functions [Winson, 1978;Leutgeb and Mizumori, 1999;Vandecasteele et al, 2014;Robinson et al, 2016]. The lack of functional connectivity between SL and the analyzed hippocampal regions could indicate an important functional difference of SL in the avian hippocampal network.…”

“…Interestingly, the lateral septum (SL) receives input from DM but neither SL nor medial septum have strong back projections [Atoji and Wild, 2004;Atoji et al, 2016]. The lack of strong reciprocal connectivity is an important difference to the mammalian hippocampus where the medial septum has a strong cholinergic and glutamatergic back projections to the hippocampus that drive hippocampal theta rhythms, thereby facilitating learning and memory [Winson, 1978;Leutgeb and Mizumori, 1999;Strange et al, 2014;Vandecasteele et al, 2014;Herold et al, 2015;Robinson et al, 2016]. A further critical area is the TPO (area temporo-parietooccipitalis) that has reciprocal connections with the CDL and is also connected to CDL via the dorsal thalamus [Atoji and Wild, 2005].…”

Models of spatial and temporal dimensions of memory

“…The effects of medial septum inactivation could be due to loss of GABAergic input that can drive network theta rhythm activity [38], or to loss of the cellular effects of cholinergic modulation that normally shift network dynamics from sharp-wave spiking to theta rhythm dynamics [38,39] and normally enhance the influence of external sensory input [40]. The loss of spatial coding could also be due to the loss of glutamatergic input from the medial septum that contributes to coding of running speed in the hippocampus [41,42]. …”

Potential roles of cholinergic modulation in the neural coding of location and movement speed

“…Thereby activation of cholinergic MSDB neurons supports the temporal organization of neuronal spiking and synaptic inputs. Recently, (Robinson et al, 2016) showed that the optogenetic activation of glutamatergic MSDB neurons increases the rhythmicity of spontaneously generated hippocampal theta oscillations through a mechanism dependent on local septal connections. Since glutamatergic neurons can excite both cholinergic and GABAergic MSDB neurons (Xu et al, 2015), these data corroborate the hypothesis of a medial septal relay with a central role for GABAergic MSDB neurons for rhythmic control over cortex and hippocampus.…”