A Hypothesis for Theta Rhythm Frequency Control in CA1 Microcircuits

Abstract

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.

Theta-gamma phase amplitude coupling in a hippocampal CA1 microcircuit

“…However the mechanisms were separate in that the coupling to produce coherent theta did not itself also generate gamma and thus somewhat different to the current model. Of course we do not mean to suggest that slow oscillations themselves cannot be generated by different means (for example [ 14 , 36 , 92 – 94 ]) or that PAC cannot be generated by different means. Indeed a recent model demonstrates PAC emergence in a completely different way using a spatial dimension [ 95 ].…”

“…Hippocampal theta is often found around 8 Hz in-vivo but there are also known to be at least two types of in-vivo hippocampal theta, low (3-7 Hz) and high (7-12 Hz) [ 14 ]. Social stimuli elicit high theta, and fearful stimuli elicit low theta [ 13 ].…”

“…OLMs are often thought to be responsible for CA1 theta [ 20 , 32 , 33 , 53 , 61 , 62 ]. However their precise role has been puzzling [ 14 , 93 , 104 ]. The theta frequency in our model was affected by several factors, including intrinsic properties of the OLM cell, the level of activity of PYR cells presynaptic to the OLMs as well as the strength of OLM-PYR synaptic depression.…”

“…In the hippocampus the phase of a 3 to 10 Hz theta rhythm modulates the amplitude of a faster gamma rhythm above 30 Hz [5][6][7][8][9][10][11]. Different types of theta [12][13][14][15] and gamma [10,[16][17][18][19] can be transmitted from various brain areas but they can also both be generated intrinsically in the hippocampus [14,15,[20][21][22][23][24][25][26][27][28]. Multiple neuronal types are involved in intrinsic hippocampal oscillogenesis and theta-gamma PAC, but the underlying network and cellular mechanisms are debated [29].…”

Cholecystokinin-expressing (CCK+) basket cells are key controllers of theta-gamma coupled rhythms in the hippocampus

“…We built upon earlier modeling studies that brought together minimal ( Ferguson et al, 2017 ) and detailed ( Bezaire et al, 2016b ) CA1 microcircuit models with defined inhibitory cell types that produce theta rhythms and showed that large enough PYR cell networks could initiate theta rhythms with inhibitory cell populations ‘regularizing’ the rhythm. We termed this an ‘inhibition-based tuning’ mechanism ( Chatzikalymniou et al, 2021 ; Skinner et al, 2021 ). The theta rhythm generation is initiated by the PYR cell population which also sets the theta frequency, but the termination of the theta bursts is an inhibition-mediated mechanism which contributes to the robustness and stability of the rhythm.…”