Periodic Reporting for period 4 - CholAminCo (Synergy and antagonism of cholinergic and dopaminergic systems in associative learning)
Periodo di rendicontazione: 2021-11-01 al 2023-10-31
Learning, memory and attention are under the control of our ‘inner drug’ systems including acetylcholine and dopamine, also known as neuromodulators. However, how these neuromodulators work together during complex processes such as learning is not known. Because diseases of learning, like dementia, are treated with drugs acting on the acetylcholine and dopamine system, it is important to investigate this problem to later develop more specific and efficient cures. Therefore, we are investigating these two systems in parallel in a set of technically challenging mouse experiments. We revealed how acetylcholine and dopamine acts both synergistically or competitively during learning and memory processes.
We specifically aimed to investigate neurons expressing acetylcholine (cholinergic neurons) or dopamine (dopaminergic neurons) in mice performing different associative learning tasks. We designed a custom-built, open source setup for these studies that we have published (Solari et al., 2018, Open source tools for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations, Frontiers in Systems Neuroscience). We also developed software tools to speed up the experiments, made freely available (Szell et al., 2020, OPETH: Open Source Solution for Real-time Peri-event Time Histogram Based on Open Ephys, Frontiers in Neuroinformatics; software downloadable from github repository). In addition, we introduced a new micro-CT-based method to allow more precise mouse surgeries (Kiraly et al., 2020, In vivo localization of chronically implanted electrodes and optic fibers in mice, Nature Communications) and also achieved fully automated mouse training in reduced-stress environment (Birtalan et al., 2020, Efficient training of mice on the 5-choice serial reaction time task in an automated rodent training system, Scientific Reports).
We first investigated cholinergic neurons separately and found that these cells come in two clearly distinct types. The first type emits tight packages of action potentials, called bursts, which specifically signal reinforcing events (rewards and punishments) and strongly engage the cerebral cortex. The second type is incapable of burst firing; instead, these cells show slow rhythmic activity, often independent of each other, but occasionally synchronizing with cortical activity, thus influencing behavioral performance. We propose that these two types of cholinergic neurons have different roles in associative learning. These results are published (Laszlovszky et al., 2020, Distinct synchronization, cortical coupling and behavioural function of basal forebrain cholinergic neuron types, Nature Neuroscience).
We compared the activity of the cholinergic and dopaminergic neuromodulatory systems as one of the major goals of this research program. We found that these systems convey partially similar information about predicting future outcomes. The two systems acted similarly when future rewards were predicted; however, opposing activity could be found when negative outcomes (i.e. future punishments) could be predicted (see our publication Hegedus et al., 2022, Cholinergic activity reflects reward expectations and predicts behavioral responses, iScience). In addition, the two systems showed different adaptation speed to a changing environment as well as a surprising complex correlation structure (Sutrgill et al., 2020, Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error, bioRxiv; a final publication is in preparation).
We first investigated cholinergic neurons separately and found that these cells come in two clearly distinct types. The first type emits tight packages of action potentials, called bursts, which specifically signal reinforcing events (rewards and punishments) and strongly engage the cerebral cortex. The second type is incapable of burst firing; instead, these cells show slow rhythmic activity, often independent of each other, but occasionally synchronizing with cortical activity, thus influencing behavioral performance. We propose that these two types of cholinergic neurons have different roles in associative learning. These results are published (Laszlovszky et al., 2020, Distinct synchronization, cortical coupling and behavioural function of basal forebrain cholinergic neuron types, Nature Neuroscience).
We compared the activity of the cholinergic and dopaminergic neuromodulatory systems as one of the major goals of this research program. We found that these systems convey partially similar information about predicting future outcomes. The two systems acted similarly when future rewards were predicted; however, opposing activity could be found when negative outcomes (i.e. future punishments) could be predicted (see our publication Hegedus et al., 2022, Cholinergic activity reflects reward expectations and predicts behavioral responses, iScience). In addition, the two systems showed different adaptation speed to a changing environment as well as a surprising complex correlation structure (Sutrgill et al., 2020, Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error, bioRxiv; a final publication is in preparation).
We think we progressed beyond previous state of art both in terms of techniques and in scientific results.
We developed innovations that increase the efficiency of the experiments by allowing better experimental control (Solari et al., 2018, Open source tools for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations, Frontiers in Systems Neuroscience; Szell et al., 2020, OPETH: Open Source Solution for Real-time Peri-event Time Histogram Based on Open Ephys, Frontiers in Neuroinformatics). We achieved behavior automation that could fully automate part of the experiments (Hegedus et al., 2021, Training protocol for probabilistic Pavlovian conditioning in mice using an open-source head-fixed setup, STAR Protocols; Birtalan et al., 2020, Efficient training of mice on the 5-choice serial reaction time task in an automated rodent training system, Scientific Reports) and non-invasive localization of implants (Kiraly et al., 2020, In vivo localization of chronically implanted electrodes and optic fibers in mice, Nature Communications).
Neuromodulators are rarely studied in parallel and there has not been simultaneous recording of cholinergic and dopaminergic neurons. Achieving such recordings revealed the complex correlations of the two systems. This helps us understand how these neurons encode partially overlapping but also partially divergent behavioral variables. Such knowledge leads us closer to understand how these neuromodulatory systems jointly control learning and memory, which is also important with respect to Alzheimer’s and Parkinson’s disease (Sviatko and Hangya, 2017, Monitoring the Right Collection: The Central Cholinergic Neurons as an Instructive Example, Frontiers in Neural Circuits; Slezia et al., 2023, Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease, Scientific Reports).
We developed innovations that increase the efficiency of the experiments by allowing better experimental control (Solari et al., 2018, Open source tools for temporally controlled rodent behavior suitable for electrophysiology and optogenetic manipulations, Frontiers in Systems Neuroscience; Szell et al., 2020, OPETH: Open Source Solution for Real-time Peri-event Time Histogram Based on Open Ephys, Frontiers in Neuroinformatics). We achieved behavior automation that could fully automate part of the experiments (Hegedus et al., 2021, Training protocol for probabilistic Pavlovian conditioning in mice using an open-source head-fixed setup, STAR Protocols; Birtalan et al., 2020, Efficient training of mice on the 5-choice serial reaction time task in an automated rodent training system, Scientific Reports) and non-invasive localization of implants (Kiraly et al., 2020, In vivo localization of chronically implanted electrodes and optic fibers in mice, Nature Communications).
Neuromodulators are rarely studied in parallel and there has not been simultaneous recording of cholinergic and dopaminergic neurons. Achieving such recordings revealed the complex correlations of the two systems. This helps us understand how these neurons encode partially overlapping but also partially divergent behavioral variables. Such knowledge leads us closer to understand how these neuromodulatory systems jointly control learning and memory, which is also important with respect to Alzheimer’s and Parkinson’s disease (Sviatko and Hangya, 2017, Monitoring the Right Collection: The Central Cholinergic Neurons as an Instructive Example, Frontiers in Neural Circuits; Slezia et al., 2023, Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease, Scientific Reports).