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

Abstract

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 the Drosophila mushroom 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.

Figure 1.

Basic anatomy and function of the Drosophila MB. (A) Arrangement of the MB lobes and 15 MB compartments. (Red) α/β Lobes, (blue) α′/β′ lobes, (yellow) γ lobe. (B) Schematic illustrating the anatomy underlying the valence balance model, which proposes that odor-directed behavior is executed based on the balance of valence-related output from the MBON population. In general, punishment-encoding PPL1-DANs (orange) innervate compartments that activate approach-promoting MBONs, and reward-encoding PAM-DANs (teal) innervate compartments that activate avoidance-promoting MBONs. The depression of KC–MBON synapses by dopamine therefore promotes the appropriate behavior by biasing behavior toward avoidance (in the case of modulation by DANs activated by punishment) or approach (in the case of modulation by DANs activated by reward).

Figure 2.

The interconnected nature of feedback and feed-forward networks underlying memory consolidation, memory update, and higher-order conditioning. Each square with thick blue borders represents a compartment of the MB. Connecting lines emerging from the top half of a square (white) represent output from KC axons, and connecting lines ending in the bottom half of a square (orange) represent input to the DANs innervating this compartment. Connecting lines ending in a point denote excitatory connections, while those ending in a perpendicular bar denote inhibitory connections. Each circle represents an MBON. For simplicity, only connections that are directly mentioned in this review are drawn, although some of the connections are not physiologically confirmed. Note that this integrated illustration highlights the role of MBON-γ1pedc and MBON-γ2α′1 as hub neurons interconnecting different compartments and involvement of the circuits around the γ5 compartment in multitudes of functions. (A) Feedback loop from α/β KCs to MBON-α1 to PAM-α1; involved in the consolidation of appetitive memory (Ichinose et al. 2015). (B) Excitatory feedback loop from γ KCs to MBON-γ5β′2a to PAM-γ5; involved in the consolidation of courtship memory (Krüttner et al. 2015; Zhao et al. 2018). Together with the connection illustrated in E, this circuit is also implicated in the extinction of aversive memory (Felsenberg et al. 2018). (C) Inhibitory feedback loop from MBON-γ1pedc to PPL1-γ1pedc; involved in the consolidation of appetitive memory (Pavlowsky et al. 2018). (D) Depression of MBON-γ1pedc olfactory activity is considered to disinhibit PPL1-α′2α2 and PPL1-α3; involved in the consolidation of aversive memory (Awata et al. 2019; Schnitzer et al. 2022). (E) Depression of MBON-γ1pedc olfactory activity is also considered to disinhibit MBON-γ5β′2a, leading to excitatory feedback from MBON-γ5β′2a to PAM-γ5 via the circuit illustrated in B; involved in the extinction of aversive memory (Felsenberg et al. 2018). (F) Feed-forward excitation from MBON-γ2α′1 to PAM-β′2a and PAM-γ5; involved in the reversal of aversive memory (McCurdy et al. 2021) and in learning relative aversive value (Villar et al. 2022). (G) Excitatory feedback loop from MBON-γ2α′1 to PPL1-γ2α′1; involved in the reconsolidation of appetitive memory (Felsenberg et al. 2017). (H) Depression of MBON-α1 disinhibits SMP353/354, activating SMP108, which excites PAM-β′2a and PAM-γ5 among other PAM-DANs; involved in second-order conditioning (Aso et al. 2023; Yamada et al. 2023).