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Oscillatory architecture of memory circuits
Oscillatory architecture of memory circuits
The coordinated activity between remote brain regions underlies cognition and memory function. Although neuronal oscillations have been proposed as a mechanistic substrate for the coordination of information transfer and memory consolidation during sleep, little is known about the mechanisms that support the widespread synchronization of brain regions and the relationship of neuronal dynamics with other bodily rhythms, such as breathing. During exploratory behavior, the hippocampus and the prefrontal cortex are organized by theta oscillations, known to support memory encoding and retrieval, while during sleep the same structures are dominated by slow oscillations that are believed to underlie the consolidation of recent experiences. The expression of conditioned fear and extinction memories relies on the coordinated activity between the mPFC and the basolateral amygdala (BLA), a neuronal structure encoding associative fear memories. However, to date, the mechanisms allowing this long-range network synchronization of neuronal activity between the mPFC and BLA during fear behavior remain virtually unknown. Using a combination of extracellular recordings and open- and closed-loop optogenetic manipulations, we investigated the oscillatory and coding mechanisms mediating the organization and coupling of the limbic circuit in the awake and asleep brain, as well as during memory encoding and retrieval. We found that freezing, a behavioral expression of fear, is tightly associated with an internally generated brain state that manifests in sustained 4Hz oscillatory dynamics in prefrontal-amygdala circuits. 4Hz oscillations accurately predict the onset and termination of the freezing state. These oscillations synchronize prefrontal-amygdala circuits and entrain neuronal activity to dynamically regulate the development of neuronal ensembles. This enables the precise timing of information transfer between the two structures and the expression of fear responses. Optogenetic induction of prefrontal 4Hz oscillations promotes freezing behavior and the formation of long-lasting fear memory, while closed-loop phase specific manipulations bidirectionally modulate fear expression. Our results unravel a physiological signature of fear memory and identify a novel internally generated brain state, characterized by 4Hz oscillations. This oscillation enables the temporal coordination and information transfer in the prefrontal-amygdala circuit via a phase-specific coding mechanism, facilitating the encoding and expression of fear memory. In the search for the origin of this oscillation, we focused our attention on breathing, the most fundamental and ubiquitous rhythmic activity in life. Using large-scale extracellular recordings from a number of structures, including the medial prefrontal cortex, hippocampus, thalamus, amygdala and nucleus accumbens in mice we identified and characterized the entrainment by breathing of a host of network dynamics across the limbic circuit. We established that fear-related 4Hz oscillations are a state-specific manifestation of this cortical entrainment by the respiratory rhythm. We characterized the translaminar and transregional profile of this entrainment and demonstrated a causal role of breathing in synchronizing neuronal activity and network dynamics between these structures in a variety of behavioral scenarios in the awake and sleep state. We further revealed a dual mechanism of respiratory entrainment, in the form of an intracerebral corollary discharge that acts jointly with an olfactory reafference to coordinate limbic network dynamics, such as hippocampal ripples and cortical UP and DOWN states, involved in memory consolidation. Respiration provides a perennial stream of rhythmic input to the brain. In addition to its role as the condicio sine qua non for life, here we provide evidence that breathing rhythm acts as a global pacemaker for the brain, providing a reference signal that enables the integration of exteroceptive and interoceptive inputs with the internally generated dynamics of the hippocampus and the neocortex. Our results highlight breathing, a perennial rhythmic input to the brain, as an oscillatory scaffold for the functional coordination of the limbic circuit, enabling the segregation and integration of information flow across neuronal networks.
in vivo electrophysiology, sleep, memory consolidation, optogenetics, hippocampus, prefrontal cortex, amygdala, slow oscillations, sharp-wave ripples, local field potentials, fear, oscillations, 4Hz, respiration
Karalis, Nikolaos
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Karalis, Nikolaos (2019): Oscillatory architecture of memory circuits. Dissertation, LMU München: Faculty of Medicine
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Abstract

The coordinated activity between remote brain regions underlies cognition and memory function. Although neuronal oscillations have been proposed as a mechanistic substrate for the coordination of information transfer and memory consolidation during sleep, little is known about the mechanisms that support the widespread synchronization of brain regions and the relationship of neuronal dynamics with other bodily rhythms, such as breathing. During exploratory behavior, the hippocampus and the prefrontal cortex are organized by theta oscillations, known to support memory encoding and retrieval, while during sleep the same structures are dominated by slow oscillations that are believed to underlie the consolidation of recent experiences. The expression of conditioned fear and extinction memories relies on the coordinated activity between the mPFC and the basolateral amygdala (BLA), a neuronal structure encoding associative fear memories. However, to date, the mechanisms allowing this long-range network synchronization of neuronal activity between the mPFC and BLA during fear behavior remain virtually unknown. Using a combination of extracellular recordings and open- and closed-loop optogenetic manipulations, we investigated the oscillatory and coding mechanisms mediating the organization and coupling of the limbic circuit in the awake and asleep brain, as well as during memory encoding and retrieval. We found that freezing, a behavioral expression of fear, is tightly associated with an internally generated brain state that manifests in sustained 4Hz oscillatory dynamics in prefrontal-amygdala circuits. 4Hz oscillations accurately predict the onset and termination of the freezing state. These oscillations synchronize prefrontal-amygdala circuits and entrain neuronal activity to dynamically regulate the development of neuronal ensembles. This enables the precise timing of information transfer between the two structures and the expression of fear responses. Optogenetic induction of prefrontal 4Hz oscillations promotes freezing behavior and the formation of long-lasting fear memory, while closed-loop phase specific manipulations bidirectionally modulate fear expression. Our results unravel a physiological signature of fear memory and identify a novel internally generated brain state, characterized by 4Hz oscillations. This oscillation enables the temporal coordination and information transfer in the prefrontal-amygdala circuit via a phase-specific coding mechanism, facilitating the encoding and expression of fear memory. In the search for the origin of this oscillation, we focused our attention on breathing, the most fundamental and ubiquitous rhythmic activity in life. Using large-scale extracellular recordings from a number of structures, including the medial prefrontal cortex, hippocampus, thalamus, amygdala and nucleus accumbens in mice we identified and characterized the entrainment by breathing of a host of network dynamics across the limbic circuit. We established that fear-related 4Hz oscillations are a state-specific manifestation of this cortical entrainment by the respiratory rhythm. We characterized the translaminar and transregional profile of this entrainment and demonstrated a causal role of breathing in synchronizing neuronal activity and network dynamics between these structures in a variety of behavioral scenarios in the awake and sleep state. We further revealed a dual mechanism of respiratory entrainment, in the form of an intracerebral corollary discharge that acts jointly with an olfactory reafference to coordinate limbic network dynamics, such as hippocampal ripples and cortical UP and DOWN states, involved in memory consolidation. Respiration provides a perennial stream of rhythmic input to the brain. In addition to its role as the condicio sine qua non for life, here we provide evidence that breathing rhythm acts as a global pacemaker for the brain, providing a reference signal that enables the integration of exteroceptive and interoceptive inputs with the internally generated dynamics of the hippocampus and the neocortex. Our results highlight breathing, a perennial rhythmic input to the brain, as an oscillatory scaffold for the functional coordination of the limbic circuit, enabling the segregation and integration of information flow across neuronal networks.