Hippocampal Theta and Ripples with Pontogeniculooccipital Waves

Nature volume 589, pages 96–102 (2021)

Coupling of hippocampal theta and ripples with pontogeniculooccipital waves

Juan F. Ramirez-Villegas, et.al.

Department of Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Tübingen, Germany

International Center for Primate Brain Research, Songjiang, Shanghai, China

Centre for Imaging Sciences, Biomedical Imaging Institute, The University of Manchester, Manchester, UK

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The hippocampus has a major role in encoding and consolidating    long-term memories, and undergoes plastic changes during sleep. These changes require precise homeostatic control by subcortical neuromodulatory structures. The underlying mechanisms of this phenomenon, however, remain unknown. Here, using multi-structure recordings in macaque monkeys, we show that the brainstem transiently modulates hippocampal network events through phasic pontine waves known as pontogeniculooccipital waves (PGO waves). Two physiologically distinct types of PGO wave appear to occur sequentially, selectively influencing high-frequency ripples and low-frequency theta events, respectively. The two types of PGO wave are associated with opposite hippocampal spike-field coupling, prompting periods of high neural synchrony of neural populations during periods of ripple and theta instances. The coupling between PGO waves and ripples, classically associated with distinct sleep stages, supports the notion that a global coordination mechanism of hippocampal sleep dynamics by cholinergic pontine transients may promote systems and synaptic memory consolidation as well as synaptic homeostasis.

Neural activity patterns associated with cognition and behaviour reflect interactions at multiple spatiotemporal scales and hierarchical levels, from molecules,    genes,    neurons    and cellular microcircuits    to large-scale neuronal networks. One such cognitive capacity is the process of learning and formation of various types of memories, which occur during different sleep states. The characteristics of sleep states have been studied with polygraphic recordings, including electromyograms, electrooculograms and electrophysiological recordings. Electrophysiological recordings have revealed the occurrence of intrinsic tonic or phasic neural events in different structures, reflecting short- and long-range interactions between neuronal populations. The hippocampus (HC) is one such structure, exhibiting different activities across sleep states. During non-rapid-eye-movement (NREM) sleep, transient depolarization episodes known as sharp-wave ripples (SWR) are prominently observed in the cornu ammonis subfields and are associated with memory consolidation. By contrast, hippocampal activity during rapid-eye-movement (REM) sleep is characterized by bursts of hippocampal theta (hTheta) oscillations with varying electrical characteristics. Such state-dependent activities are thought to cause enduring embossing of synaptic strength, thereby enabling consolidation of new memories while maintaining existing ones. This process evidently requires precise coordination between these activities, as it emerges in different neurochemical environments prompted by neuromodulation.

To better understand brain-state-dependent activities, we established a methodology for neural-event-triggered functional MRI (NET-fMRI). Our experiments demonstrated that SWR episodes are associated with widespread cortical activations (positive blood oxygen level-dependent (BOLD) responses (PBR)) occurring concurrently with activity suppression (negative BOLD responses (NBR)) in subcortical thalamic,    associational    and midbrain–brainstem neuromodulatory structures. These data revealed a ripple-associated deactivation of the pontine region, including the sites of generation and transfer of PGO waves.

PGO waves are large (>300 μV) biphasic potentials that last approximately 100 ms and propagate from the pons to thalamic nuclei and other brain regions of placental mammals, including human and nonhuman primates. PGO waves have been strongly associated with behavioural performance during semantic memory tasks. The ascending cholinergic activity associated with PGO waves    precedes REM sleep, which is characterized by highly active acetylcholine-releasing neurons linked to strong aminergic demodulation. Conversely, low cholinergic and transient increases in aminergic tone characterize NREM sleep. The predominant NBR in the pontine region, lateral geniculate nucleus (LGN) and the foveal and parafoveal regions of V1 was initially perceived as a marker of this antagonism between neurochemical states enabling the emergence of SWR or PGO waves. Nonetheless, screening of the individual peri-ripple MRI trials revealed that intermixed negative and positive pontine BOLD responses coexist. Notably, the ripple-triggered negative BOLD responses were associated with subsequent rebound-like positive BOLD responses in a manner resembling state transitions.

Given their contrasting polygraphic signatures, it has been commonly assumed that wakefulness, NREM sleep and REM sleep represent mutually exclusive global states. However, a growing body of evidence indicates that many sleep features are local, and that instances of sleep- and wake-like activity may coexist in different brain areas. Concordantly, our data suggest that NREM-related hippocampal SWR complexes—in association with up and down states—occur in alternation with REM-related bouts of hTheta waves, dominated by overall spiking deceleration.

One of the sources of sleep-dependent LTP-inducing stimulation in the brain may be the brainstem. Such activity is often associated with the occurrence of PGO waves.    PGO-wave-associated cells discharge high-frequency spike bursts (>500 Hz) during the states of pre-REM and REM sleep, making them good candidates for generating or modulating plasticity across several brain structures. Indeed, activation of PGO-wave-generating cells by cholinergic agonists prompts changes in the electrical characteristics of PGO waves, accompanied by prominent behavioural effects. In addition, activation of the PGO-wave generator and occurrence of PGO waves themselves are tightly correlated with increases of cAMP response element binding (CREB) proteins, brain-derived nerve growth factor (BDNF), and activity-regulated cytoskeletal protein (ARC) in structures including HC and amygdala.

Our observations of the influence of PGO waves on hippocampal spike–field coupling suggest a putative mechanism that would explain the marked opposite changes in excitability during NREM- and REM-like states. Such complementary mechanisms may be controlled by a common phenomenon spanning sleep states, namely PGO waves. These episodes, representing brainstem cells’ synchronous depolarizations, may correspond to windows for promoting hippocampal plasticity during NREM-like and REM-like states, and might occur through sequences of low-frequency-modulated SWR and hTheta events. This hypothesis is consistent with studies in vitro and in vivo, and highlights the importance of studying brainwide transient mechanisms to understand brain function at a system level.

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