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1. Multiple memories can be simultaneously reactivated during sleep as effectively as a single memory

   https://doi.org/10.1038/s42003-020-01512-0  

   Schechtman, Eitan; Antony, James W.; Lampe, Anna; Wilson, Brianna J.; Norman, Kenneth A.; Paller, Ken A. (December 2021, Communications Biology)

   null (Ed.)

   Abstract Memory consolidation involves the reactivation of memory traces during sleep. If different memories are reactivated each night, how much do they interfere with one another? We examined whether reactivating multiple memories incurs a cost to sleep-related benefits by contrasting reactivation of multiple memories versus single memories during sleep. First, participants learned the on-screen location of different objects. Each object was part of a semantically coherent group comprised of either one, two, or six items (e.g., six different cats). During sleep, sounds were unobtrusively presented to reactivate memories for half of the groups (e.g., “meow”). Memory benefits for cued versus non-cued items were independent of the number of items in the group, suggesting that reactivation occurs in a simultaneous and promiscuous manner. Intriguingly, sleep spindles and delta-theta power modulations were sensitive to group size, reflecting the extent of previous learning. Our results demonstrate that multiple memories may be consolidated in parallel without compromising each memory’s sleep-related benefit. These findings highlight alternative models for parallel consolidation that should be considered in future studies. 

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2. Roles of feedback and feed-forward networks of dopamine subsystems: insights from Drosophila studies

   https://doi.org/10.1101/lm.053807.123  

   Davidson, Andrew M; Hige, Toshihide (May 2024, Learning & Memory)

   Across animal species, dopamine-operated memory systems comprise anatomically segregated, functionally diverse subsystems. Although individual subsystems could operate independently to support distinct types of memory, the logical interplay between subsystems is expected to enable more complex memory processing by allowing existing memory to influence future learning. Recent comprehensive ultrastructural analysis of theDrosophilamushroom body revealed intricate networks interconnecting the dopamine subsystems—the mushroom body compartments. Here, we review the functions of some of these connections that are beginning to be understood. Memory consolidation is mediated by two different forms of network: A recurrent feedback loop within a compartment maintains sustained dopamine activity required for consolidation, whereas feed-forward connections across compartments allow short-term memory formation in one compartment to open the gate for long-term memory formation in another compartment. Extinction and reversal of aversive memory rely on a similar feed-forward circuit motif that signals omission of punishment as a reward, which triggers plasticity that counteracts the original aversive memory trace. Finally, indirect feed-forward connections from a long-term memory compartment to short-term memory compartments mediate higher-order conditioning. Collectively, these emerging studies indicate that feedback control and hierarchical connectivity allow the dopamine subsystems to work cooperatively to support diverse and complex forms of learning. 

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3. Models of heterogeneous dopamine signaling in an insect learning and memory center

   https://doi.org/10.1371/journal.pcbi.1009205  

   Jiang, Linnie; Litwin-Kumar, Ashok (August 2021, PLOS Computational Biology)

   Morrison, Abigail (Ed.)

   The Drosophila mushroom body exhibits dopamine dependent synaptic plasticity that underlies the acquisition of associative memories. Recordings of dopamine neurons in this system have identified signals related to external reinforcement such as reward and punishment. However, other factors including locomotion, novelty, reward expectation, and internal state have also recently been shown to modulate dopamine neurons. This heterogeneity is at odds with typical modeling approaches in which these neurons are assumed to encode a global, scalar error signal. How is dopamine dependent plasticity coordinated in the presence of such heterogeneity? We develop a modeling approach that infers a pattern of dopamine activity sufficient to solve defined behavioral tasks, given architectural constraints informed by knowledge of mushroom body circuitry. Model dopamine neurons exhibit diverse tuning to task parameters while nonetheless producing coherent learned behaviors. Notably, reward prediction error emerges as a mode of population activity distributed across these neurons. Our results provide a mechanistic framework that accounts for the heterogeneity of dopamine activity during learning and behavior. 

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4. Hierarchical architecture of dopaminergic circuits enables second-order conditioning in Drosophila

   https://doi.org/10.7554/eLife.79042  

   Yamada, Daichi; Bushey, Daniel; Li, Feng; Hibbard, Karen L; Sammons, Megan; Funke, Jan; Litwin-Kumar, Ashok; Hige, Toshihide; Aso, Yoshinori (January 2023, eLife)

   Dopaminergic neurons with distinct projection patterns and physiological properties compose memory subsystems in a brain. However, it is poorly understood whether or how they interact during complex learning. Here, we identify a feedforward circuit formed between dopamine subsystems and show that it is essential for second-order conditioning, an ethologically important form of higher-order associative learning. The Drosophila mushroom body comprises a series of dopaminergic compartments, each of which exhibits distinct memory dynamics. We find that a slow and stable memory compartment can serve as an effective ‘teacher’ by instructing other faster and transient memory compartments via a single key interneuron, which we identify by connectome analysis and neurotransmitter prediction. This excitatory interneuron acquires enhanced response to reward-predicting odor after first-order conditioning and, upon activation, evokes dopamine release in the ‘student’ compartments. These hierarchical connections between dopamine subsystems explain distinct properties of first- and second-order memory long known by behavioral psychologists. 

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5. The dopamine membrane transporter plays an active modulatory role in synaptic dopamine homeostasis

   https://doi.org/10.1002/jnr.24965  

   Formisano, Rosaria; Rosikon, Katarzyna D.; Singh, Abhyudai; Dhillon, Harbinder S. (November 2021, Journal of Neuroscience Research)

   Abstract Modulatory mechanisms of neurotransmitter release and clearance are highly controlled processes whose finely tuned regulation is critical for functioning of the nervous system. Dysregulation of the monoamine neurotransmitter dopamine can lead to several neuropathies. Synaptic modulation of dopamine is known to involve pre‐synaptic D2 auto‐receptors and acid sensing ion channels. In addition, the dopamine membrane transporter (DAT), which is responsible for clearance of dopamine from the synaptic cleft, is suspected to play an active role in modulating release of dopamine. Using functional imaging on theCaenorhabditis elegansmodel system, we show that DAT‐1 acts as a negative feedback modulator to neurotransmitter vesicle fusion. Results from our fluorescence recovery after photo‐bleaching (FRAP) based experiments were followed up with and reaffirmed using swimming‐induced paralysis behavioral assays. Utilizing our numerical FRAP data we have developed a mechanistic model to dissect the dynamics of synaptic vesicle fusion, and compare the feedback effects of DAT‐1 with the dopamine auto‐receptor. Our experimental results and the mechanistic model are of potential broader significance, as similar dynamics are likely to be used by other synaptic modulators including membrane transporters for other neurotransmitters across species. 

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