An integrative sensor of body states: how the mushroom body modulates behavior depending on physiological context

Abstract

The brain constantly compares past and present experiences to predict the future, thereby enabling instantaneous and future behavioral adjustments. Integration of external information with the animal's current internal needs and behavioral state represents a key challenge of the nervous system. Recent advancements in dissecting the function of the Drosophila mushroom body (MB) at the single-cell level have uncovered its three-layered logic and parallel systems conveying positive and negative values during associative learning. This review explores a lesser-known role of the MB in detecting and integrating body states such as hunger, thirst, and sleep, ultimately modulating motivation and sensory-driven decisions based on the physiological state of the fly. State-dependent signals predominantly affect the activity of modulatory MB input neurons (dopaminergic, serotoninergic, and octopaminergic), but also induce plastic changes directly at the level of the MB intrinsic and output neurons. Thus, the MB emerges as a tightly regulated relay station in the insect brain, orchestrating neuroadaptations due to current internal and behavioral states leading to short- but also long-lasting changes in behavior. While these adaptations are crucial to ensure fitness and survival, recent findings also underscore how circuit motifs in the MB may reflect fundamental design principles that contribute to maladaptive behaviors such as addiction or depression-like symptoms.

Figure 1.

The MB as a panel control of body states. (Left) The MB integrates sensory information about the environment and the current context and behavioral state to regulate sensory valence according to the physiological needs of the fly in a moment-to-moment basis. As different internal states are being signaled in common or interconnected circuitries, this supports a tight regulation by body needs of the expression of the behavior that is most adaptive at each moment (e.g., eat and remember associated cues when starving). (Right, top and bottom) Information about the environment and behavioral state is sensed and signaled to the intrinsic and output layers of the MB (comprised of KCs and MB MBONs, respectively) through the input layer. The input layer contains a broad array of circuitries distributed all over the brain, including dopaminergic (DANs; green), serotonergic (5-HT; purple), and peptidergic (such as allatostatin A [AstA] and neuropeptide-F [NPF]; yellow) populations. The full name of these neural populations can be found in the text. (Bottom right) Short-lived and long-lasting plastic changes at the level of the three MB layers allow the fly to adapt its behavior instantaneously and in the future based on previous experience. Recurrent connectivity between the input, intrinsic, and output circuitries further potentiates plasticity across MB layers.

Figure 2.

Complex integration of neuromodulatory signals by the MB mediates labile and enduring behavioral changes. Neuromodulators such as dopamine (DA), serotonin (5HT), and octopamine (OA) are signaled to specific MB lobes, allowing for representations of the behavioral state and behavioral adaptations. DAN and MBON innervations divide the MB lobes into 15 compartments and each type of DAN and MBON projecting to a specific compartment is named accordingly. The same compartment and circuits can integrate different signals to regulate distinct responses (e.g., γ5 mediating changes in climbing behavior and motivation to court in response to dopamine and serotonin, respectively). The modulation of different needs and behaviors by interconnected or common circuits might facilitate complex regulatory interactions (e.g., changes in activity in β′2 regulating arousal might affect the consolidation of ethanol memories). Arrows not linked to any compartment in the γ lobe denote not known compartment assignment. For simplicity, some KC subtypes are not shown. Based on data from Krashes et al. (2009), Keleman et al. (2012), Bräcker et al. (2013), Cohn et al. (2015), Musso et al. (2015), Sitaraman et al. (2015a,b), Perisse et al. (2016), Ries et al. (2017), Sayin et al. (2019), Senapati et al. (2019), Kobler et al. (2020), Scaplen et al. (2020), Sun et al. (2020), and Zolin et al. (2021). Please note that representative examples are shown due to space constraints. For a more detailed overview of behaviors, states, and circuits involved in different behavioral adaptations, see Supplemental Table S1.

Figure 3.

Selected publications for state-dependent modulations in the MB. Each physiological or behavioral state reviewed in this article for its role in modulating plasticity in the MB and changing behavioral output is represented by four to nine publications. Please note that these publications are selected to give a broad overview covering most of the diverse lines of research. The studies marked with an asterisk indicate that the involvement of the MB was not tested and remains to assessed. For a brief summary of the key findings of these studies, see Supplemental Table S1. (MB) Mushroom body, (KCs) Kenyon cells, (MBONs) mushroom body output neurons, (DANs) dopaminergic neurons, (PAM DANs) protocerebral anterior medial dopaminergic neurons, (PPL1 DANs) protocerebral posterior lateral dopaminergic neurons, (OANs) octopaminergic neurons, (APL) anterior paired lateral neurons (GABAergic), (DPM) dorsal paired medial neurons (GABAergic and serotonergic), (NPF) neuropeptide-F neurons, (AL) antennal lobe, (LH) lateral horn.