A Hypothesis for Theta Rhythm Frequency Control in CA1 Microcircuits.

Computational models of neural circuits with varying levels of biophysical detail have been generated in pursuit of an underlying mechanism explaining the ubiquitous hippocampal theta rhythm. However, within the theta rhythm are at least two types with distinct frequencies associated with different behavioral states, an aspect that must be considered in pursuit of these mechanistic explanations. Here, using our previously developed excitatory-inhibitory network models that generate theta rhythms, we investigate the robustness of theta generation to intrinsic neuronal variability by building a database of heterogeneous excitatory cells and implementing them in our microcircuit model. We specifically investigate the impact of three key "building block" features of the excitatory cell model that underlie our model design: these cells' rheobase, their capacity for post-inhibitory rebound, and their spike-frequency adaptation. We show that theta rhythms at various frequencies can arise dependent upon the combination of these building block features, and we find that the speed of these oscillations are dependent upon the excitatory cells' response to inhibitory drive, as encapsulated by their phase response curves. Taken together, these findings support a hypothesis for theta frequency control that includes two aspects: (i) an internal mechanism that stems from the building block features of excitatory cell dynamics; (ii) an external mechanism that we describe as "inhibition-based tuning" of excitatory cell firing. We propose that these mechanisms control theta rhythm frequencies and underlie their robustness.

Deciphering the Contribution of Oriens-Lacunosum/Moleculare (OLM) Cells to Intrinsic θ Rhythms Using Biophysical Local Field Potential (LFP) Models.

Oscillations in local field potentials (LFPs) are prevalent and contribute to brain function. An understanding of the cellular correlates and pathways affecting LFPs is needed, but many overlapping pathways in vivo make this difficult to achieve. A prevalent LFP rhythm in the hippocampus associated with memory processing and spatial navigation is the θ (3-12 Hz) oscillation. θ rhythms emerge intrinsically in an in vitro whole hippocampus preparation and this reduced preparation makes it possible to assess the contribution of different cell types to LFP generation. We focus on oriens-lacunosum/moleculare (OLM) cells as a major class of interneurons in the hippocampus. OLM cells can influence pyramidal (PYR) cells through two distinct pathways: by direct inhibition of PYR cell distal dendrites, and by indirect disinhibition of PYR cell proximal dendrites. We use previous inhibitory network models and build biophysical LFP models using volume conductor theory. We examine the effect of OLM cells to ongoing intrinsic LFP θ rhythms by directly comparing our model LFP features with experiment. We find that OLM cell inputs regulate the robustness of LFP responses without affecting their average power and that this robust response depends on coactivation of distal inhibition and basal excitation. We use our models to estimate the spatial extent of the region generating LFP θ rhythms, leading us to predict that about 22,000 PYR cells participate in intrinsic θ generation. Besides obtaining an understanding of OLM cell contributions to intrinsic LFP θ rhythms, our work can help decipher cellular correlates of in vivo LFPs.

Combining Theory, Model, and Experiment to Explain How Intrinsic Theta Rhythms Are Generated in an In Vitro Whole Hippocampus Preparation without Oscillatory Inputs.

Scientists have observed local field potential theta rhythms (3-12 Hz) in the hippocampus for decades, but understanding the mechanisms underlying their generation is complicated by their diversity in pharmacological and frequency profiles. In addition, interactions with other brain structures and oscillatory drives to the hippocampus during distinct brain states has made it difficult to identify hippocampus-specific properties directly involved in theta generation. To overcome this, we develop cellular-based network models using a whole hippocampus in vitro preparation that spontaneously generates theta rhythms. Building on theoretical and computational analyses, we find that spike frequency adaptation and postinhibitory rebound constitute a basis for theta generation in large, minimally connected CA1 pyramidal (PYR) cell network models with fast-firing parvalbumin-positive (PV+) inhibitory cells. Sparse firing of PYR cells and large excitatory currents onto PV+ cells are present as in experiments. The particular theta frequency is more controlled by PYR-to-PV+ cell interactions rather than PV+-to-PYR cell interactions. We identify two scenarios by which theta rhythms can emerge, and they can be differentiated by the ratio of excitatory to inhibitory currents to PV+ cells, but not to PYR cells. Only one of the scenarios is consistent with data from the whole hippocampus preparation, which leads to the prediction that the connection probability from PV+ to PYR cells needs to be larger than from PYR to PV+ cells. Our models can serve as a platform on which to build and develop an understanding of in vivo theta generation.