Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila

Abstract

When animals learn, plasticity in brain networks that respond to specific cues results in a change in the behavior that these cues elicit. Individual network components in the mushroom bodies of the fruit fly Drosophila melanogaster represent cues, learning signals and behavioral outcomes of learned experience. Recent findings have highlighted the importance of dopamine-driven plasticity and activity in feedback and feedforward connections, between various elements of the mushroom body neural network. These computational motifs have been shown to be crucial for long term olfactory memory consolidation, integration of internal states, re-evaluation and updating of learned information. The often recurrent circuit anatomy and a prolonged requirement for activity in parts of these underlying networks, suggest that self-sustained and precisely timed activity is a fundamental feature of network computations in the insect brain. Together these processes allow flies to continuously adjust the content of their learned knowledge and direct their behavior in a way that best represents learned expectations and serves their most pressing current needs.

Figure 1

The mushroom body is the center for associative learning. (a) Sensory cues are represented as activity in sparse populations of cholinergic Kenyon cells (KCs, grey). KCs send their neurites into the lobes of the mushroom body (light grey background), where they make en passant synapses with the output neurons (MBONs). Mushroom body-innervating dopaminergic neurons (DANs) provide the reinforcement signal during aversive and appetitive associative learning. (b) KCs are organized into three subtypes which make up the lobes of the mushroom body neuropil (individual representative KCs shown in dark grey). (c) The presynaptic fields of the different DAN classes tile the mushroom body into non-overlapping compartments. (d) The dendritic tufts of distinct MBONs match the compartmentalization of the DAN teminals. Aversively reinforcing DANs in the paired posterior lateral 1 (PPL1) cluster (red) overlap with approach-promoting MBONs (blue), while DANs of the protocerebral anterior medial (PAM) cluster, which are largely appetitively reinforcing (green), overlap with avoidance-promoting MBONs (orange). The transmitters used by each class of neuron is noted: ACh, acetylcholine; DA, dopamine; GABA, γ-aminobutiryc acid; Glu, glutamate.

Figure 2

Dopamine drives plasticity at KC output synapses to alter behavior upon learning. During training (top), cue-driven KC activation (dark grey) coincides with the activity of either aversive (red, left) or appetitive (green, right) DANs and induces specific synaptic plasticity at the KC to MBON synapse (shaded green/red semicircle). Upon memory retrieval (bottom), the cue-driven response of the MBON network is skewed because of the synaptic modification imposed by learning (smaller semicircle): to avoidance behavior by the reduced drive of approach-promoting MBONs in the case of aversive learning (left), and towards approach behavior as a consequence of the reduced drive of avoidance-promoting MBONs in appetitive learning (right).

Figure 3

Feed-forward, feed-back and feed-across networks in the mushroom body. (a) Feed forward inhibition regulates state dependent expression of food memory retrieval. Hunger state controls odor-driven behavior by relaying hunger-dependent dNPF signaling (purple) through the PPL1-MP1 DANs (red) and the GABAergic MVP2 neuron (blue). The MVP2 neuron feeds forward inhibition to the M4/M6 group of glutamatergic MBONs (orange). In a satiated fly, approach behavior is counterbalanced by the avoidance-promoting M4/M6 MBONs, which are not inhibited by MVP2. In a hungry fly, the MVP2 neuron is active and inhibits the M4/M6 MBONs, reducing avoidance and facilitating approach behavior. (b) A closed feedback loop involving the MBON from the α1 compartment, the αβ Kenyon cells and the DANs innervating the α1 compartment has been proposed to stabilize memory after learning. Blocking any of these neurons immediately after sugar reward learning cripples behavioral approach measured 24 h later [50^•], although a functional connection between the glutamatergic α1 MBON and α1 DANs has not been demonstrated. (c) A feedback and feed-across recurrency is crucial for memory reconsolidation. Experiencing training-related cues can switch stable memories back into a labile state and reconsolidation is then required for the memory to return to a persistent condition [9^••]. The reconsolidation process requires the activity of the cholinergic MBON-γ2α′1 which in turn recruits two different sets of dopaminergic neurons: the PPL1-γ2α′1 DANs, which are required during memory retrieval, and a group of PAM-DANs which innervate different compartments and are required in the period following retrieval. These cholinergic MBON-DAN connections are excitatory [9^••].

Figure 4

KCs, MBONs and DANs form microcircuits within a compartment [5••, 7••]. KCs (black) form cholinergic excitatory connections with MBONs (orange) and also synapse onto DANs (green). KC to DAN connections appear to be excitatory and may modulate the dopaminergic reinforcement signal within a compartment to influence learning [60]. DANs synapse onto KCs and MBONs. Activation of DANs seems to lead to a slow but direct activation of MBONs which potentially allows a local excitatory feedback loop between KCs, DANs and MBONs [5^••].