MTL neurons phase-lock to human hippocampal theta

Abstract

Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1,854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2-4Hz) or fast (6-10Hz) theta bands, with a significant subset exhibiting nested slow theta x beta frequency (13-20Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.

Theta-phase locking of single neurons during human spatial memory

“…2C ). This finding replicates previous observations of strong theta-phase locking in the human medial temporal lobe ( 34 , 36 ) and indicates that there is a tight temporal relationship between single-neuron activity and local low-frequency activity in the human medial temporal lobe.…”

“…These studies showed that, during a virtual spatial navigation task, neurons in widespread brain regions including hippocampus, amygdala, and parahippocampal regions were phase locked to oscillations in the theta-frequency range ( 34 ). Similar to observations in rodents ( 32 , 33 ), theta-phase locking also occurred between neurons in extrahippocampal regions and the hippocampal theta rhythm in patients performing another set of virtual spatial navigation tasks ( 36 ). In a recognition memory task with static images, stronger theta-phase locking was associated with successful memory formation as assessed with spike-field coherence ( 35 ).…”

“…A prominent observation on the relationship between single neurons and theta-frequency local field potentials is theta-phase locking ( 31 – 36 ). This phenomenon describes that a neuron activates at similar theta phases over time, for example at theta peaks or troughs.…”

“…In rodents, theta-phase locking has been described in a variety of neurons including spatially-modulated neurons representing locations and directions ( 31 , 37 , 42 – 45 ). Due to its high prevalence both within and across brain regions, theta-phase locking has been suggested to organize the activity of single neurons into neuronal assemblies ( 22 , 30 , 36 ), to enable interregional communication between neurons ( 32 , 33 , 36 , 46 ), and to trigger which neurons become linked during encoding to participate in the same replay events during consolidation ( 42 ). Phase locking of neuronal assemblies at distinct theta phases may furthermore help separate different mnemonic processes such as encoding and retrieval ( 45 , 47 , 48 ).…”

Morpho-electric diversity of human hippocampal CA1 pyramidal neurons

“… 2 , 20 A slower theta rhythm directly impacts theories on human brain function, since the slower cycle could allow an increased number of neuronal assemblies to interact and lock to the same cycle. 16 , 21 This could translate to the association of an increased number of items in working memory compared to rodents and thus increased human cognitive flexibility. 22 , 23 …”