Dopamine Neurons Mediate Learning and Forgetting through Bidirectional Modulation of a Memory Trace

Abstract

SUMMARY It remains unclear how memory engrams are altered by experience, such as new learning, to cause forgetting. Here, we report that short-term aversive memory in Drosophila is encoded by and retrieved from the mushroom body output neuron MBOn-γ2αʹ1. Pairing an odor with aversive electric shock creates a robust depression in the calcium response of MBOn-γ2αʹ1 and increases avoidance to the paired odor. Electric shock after learning, which activates the cognate dopamine neuron DAn-γ2αʹ1, restores the response properties of MBOn-γ2αʹ1 and causes behavioral forgetting. Conditioning with a second odor restores the responses of MBOn-γ2αʹ1 to a previously learned odor while depressing responses to the newly learned odor, showing that learning and forgetting can occur simultaneously. Moreover, optogenetic activation of DAn-γ2αʹ1 is sufficient for the bidirectional modulation of MBOn-γ2αʹ1 response properties. Thus, a single DAn can drive both learning and forgetting by bidirectionally modulating a cellular memory trace.

Cholinergic relay from punishment- to reward-encoding dopamine neurons signals punishment withdrawal as reward inDrosophila

“…MBON-γ1ped decreases CS-odor response during reversal, while its CS+ odor response is unchanged ( Figure 3E), also consistent with prior observations . In contrast to MBON-α'2 and MBON-β'2mp, MBON-γ2α'1 decreases CS+ odor response during acquisition and increases during reversal (Figure 3F), consistent with prior observations (Berry et al, 2018). MBON-α'2 does not appear to encode intrinsic valence (Aso et al, 2014b), nor is there any obvious anatomical substrate for connectivity with PAM-β'2a (Aso et al, 2014a).…”

“…Shock-responsive PPL1-γ2α'1 is the only DAN that projects its dopaminergic terminals to the same MB compartment innervated by the dendrites of MBON-γ2α'1 (Berry et al, 2018).…”

“…DANs are anatomically classified as PPL1 or PAM DANs, which are viewed generally as encoding negative and positive reinforcement signals respectively (Schwaerzel et al, 2003;Riemensperger et al, 2005;Claridge-Chang et al, 2009;Mao and Davis, 2009;Liu et al, 2012;Das et al, 2014;Lin et al, 2014;Kirkhart and Scott, 2015). DANs secrete dopamine into the specific compartments they innervate, where they induce plasticity of KC-MBON synapses, thus modulating MBON odor responses and odor-evoked behavior (Sejourne et al, 2011;Pai et al, 2013;Placais et al, 2013;Aso et al, 2014b;Bouzaiane et al, 2015;Cohn et al, 2015;Hige et al, 2015;Owald et al, 2015;Perisse et al, 2016;Hattori et al, 2017;Berry et al, 2018;Handler et al, 2019;Zhang et al, 2019).…”

“…In Drosophila, as in mammals, reward-encoding DANs are thought to underlie the extinction of aversive memories, as silencing reward-encoding DANs using a broadly-expressed PAM genetic driver impairs extinction . While much is known about learning-induced changes in odor-evoked neural activity in MBONs (Sejourne et al, 2011;Pai et al, 2013;Placais et al, 2013;Bouzaiane et al, 2015;Cohn et al, 2015;Hige et al, 2015;Owald et al, 2015;Perisse et al, 2016;Hattori et al, 2017;Berry et al, 2018;Handler et al, 2019;Zhang et al, 2019), few studies have assessed changes in DAN odor responses during acquisition (Riemensperger et al, 2005;Mao and Davis, 2009;Dylla et al, 2017), and none during reversal. DANs respond to various positive and negative reinforcers such as sugar, electric shock, and noxious heat, but it remains unknown in any model organism or learning paradigm how DAN signals are generated in response to withdrawal of negative reinforcement, nor how the absence of negative reinforcement is encoded as positive reinforcement.…”

Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics

“…These observations could be 489 interpreted as indicating that NO regulates forgetting. However, it is an open question 490 whether the signaling pathways for forgetting, which presumably induce recovery from 491 synaptic depression (Berry et al, 2018;Cohn et al, 2015), are related to signaling 492 cascades downstream of NO and guanylate cyclase, which appear to be able to induce 493 memory without prior induction of synaptic depression by dopamine. Lack of detectable 494 1-day memory formation after spaced training with PPL1-γ1pedc can be viewed as a 495 balance between two distinct, parallel biochemical signals, one induced by dopamine and 496 the other by NO, rather than the loss of information (that is, forgetting).…”