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Disentangling amygdala contributions to replay-mediated, hippocampal-dependent memory consolidation

Periodic Reporting for period 1 - VALENCE-REPLAY (Disentangling amygdala contributions to replay-mediated, hippocampal-dependent memory consolidation)

Reporting period: 2017-10-15 to 2019-10-14

Information based economies rely on a highly skilled workforce, where individuals work increasingly with their minds rather than their hands. A mentally healthy workforce is central if Europe is to achieve its economic and development goals. One ingredient of good mental health is adequate sleep, which increasingly takes second place to busy, demanding lifestyles. Sleep can affect mental function in two interrelated ways: through regulation of emotional reactivity and through its role in offline memory consolidation. While these two factors have been studied mostly in isolation the underlying brain dynamics and interactions between relevant brain areas remain poorly studied.
This project investigated how the emotional content of wake experience influences memory processing in periods of sleep. Two brain structures, the hippocampus and amygdala, are indispensable brain areas for memory formation and emotional processing, respectively. Their interaction during sleep remains is under-studied. Studies that begin to examine this issue have focused on rodent behavioral tasks with negative valence such as fear conditioning while much less has been done in the context of positive valence.
Here the electrophysiological underpinnings of interaction between the ventral hippocampus and the basolateral amygdala were investigated using a novel behavioral paradigm, that allows to study offline periods after animals are exposed to a positive valence stimulus.
Results suggest that the two brain structures extend their interactions into periods of rest supporting a mechanistic role for ventral hippocampus and amygdala in memory consolidation processes. While results are of basic nature, they highlight the significance of sleep in emotional memory processing. Further investigations will be needed to examine how these results might relate to sleep and mental well-being in humans.
To study the interaction of these brain areas, a novel paradigm was developed to be compatible with multiple acute electrophysiological recordings from the same animal with high counts of behavioral trials and isolated single neurons. To this end, the paradigm was developed in head-fixed rodents allowing well controlled exposures to stimuli that carry varying valence. The paradigm includes a treadmill on which the animal can run. The speed of running, in turn, controls a circular rotating platform (the carousel) that is placed in front of the animal. With each full rotation, the animal experiences different stimuli at particular locations of this platform. This experimental setup allows for up to 100 trials in one recording session thus providing sufficient statistical power for analysis of cell sequences and reactivations thereof, while at the same time allowing for exposures of physical stimuli such as conspecifics. Detail behavioral quantification is also incorporated in this setup through the monitoring of the carousel position in front of the animal together with the speed of running, video of the face that covers whisker, nose, eye, licking movements, as well as pupil size. Armed with these behavioral measures the degree of influence that the different stimuli have on the recorded animal could be explored. Accordingly, behavioral responses were observed to inanimate objects situated at various places on the carousel as well as strong responses to the presence of a conspecific (including strong pupil dilation, frequent stopping in the vicinity of the conspecific as well as increasing sniffing and changes to the ear position). Subsequently, the electrophysiological technique was implemented, first starting with recordings from a single brain structure, the dorsal hippocampus, during the behavioral task. These recordings confirmed the presence of electrophysiological signatures that are ubiquitous in naturally behaving mice such as single neurons whose activity is tuned to specific locations of the environment as well as sharp wave ripple oscillations which are highly synchronous events that excite large portions of the hippocampal network and are important for memory consolidation processes during sleep. Next, the necessary technical upgrades were performed allowing for simultaneous dual site recordings of single neuron resolution activity in the ventral hippocampus and basolateral amygdala. Importantly, the technique allows for simultaneous recordings from the same brain hemisphere. The recordings revealed novel findings showing that some cells in the basolateral amygdala are preferentially recruited during the hippocampal sharp wave ripple events. These observations confirmed the the interaction between the two brain structures during periods of rest and quiescence thus providing a basis for further investigations. Finally, the dual site recordings were combined with the previously behavioral task in a cohort of animals. Data has been collected and the analysis is ongoing. Preliminary results suggest that the coupling between these two structures goes beyond simple brain state dynamics with cells specifically recruited in the behavior experiencing a greater level of reactivation during subsequent rest. Analysis of cell sequences and their reactivation is currently ongoing and when finished will be disseminated through a scientific journal publication.
The developed behavioral paradigm has also been successfully put to use in testing novel technologies for recording from hundreds of cells at the same time from 1024 channels. The results were communicated in scientific meetings and a manuscript has been published in the biorxiv preprint server.
This action has enabled a contribution to the European society by studying a timely subject that relates to well being of the EU population. It enabled first steps into the investigation of how amygdala and hippocampus interact during periods of rest. This research line is of importance when tying to understand how memory and emotional regulation processes interact during sleep and what impact they might have in supporting normal wake behavior. Therefore, this study adds to the already many reasons why sleep is such an indispensable biological process. With additional studies especially in humans, the results could influence health programs across Europe by highlighting the importance of sleep in emotional regulation.
This action has successfully supported high-quality training of the recipient in state-of-the-art neuroscience techniques. The training has paved the way for the transfer of acquired knowledge to less conventional animal models. The action has formed the basis for further work and grant writing using the acquired techniques to study closely related research questions in memory and learning. The fellow was able to further develop his student supervision skills by supervising undergraduate and postgraduate level students. The grantee received training and experience in project and budget management but also provided the valuable opportunity to attend advanced competitive courses and conferences in the field of memory and learning. The fellow extended his scientific network through collaborations within the EU one of which leading to successfully testing of novel brain electrode interfaces with high channel count (1024 simultaneously channels) while other collaborations are already in place focused on knowledge sharing on advanced electrophysiological analysis techniques.
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