Homeostatic synaptic plasticity rescues neural coding reliability.

To survive, animals must recognize reoccurring stimuli. This necessitates a reliable stimulus representation by the neural code. While synaptic transmission underlies the propagation of neural codes, it is unclear how synaptic plasticity can maintain coding reliability. By studying the olfactory system of Drosophila melanogaster, we aimed to obtain a deeper mechanistic understanding of how synaptic function shapes neural coding in the live, behaving animal. We show that the properties of the active zone (AZ), the presynaptic site of neurotransmitter release, are critical for generating a reliable neural code. Reducing neurotransmitter release probability of olfactory sensory neurons disrupts both neural coding and behavioral reliability. Strikingly, a target-specific homeostatic increase of AZ numbers rescues these defects within a day. These findings demonstrate an important role for synaptic plasticity in maintaining neural coding reliability and are of pathophysiological interest by uncovering an elegant mechanism through which the neural circuitry can counterbalance perturbations.

Olfactory stimuli and moonwalker SEZ neurons can drive backward locomotion in Drosophila.

How different sensory stimuli are collected, processed, and further transformed into a coordinated motor response is a fundamental question in neuroscience. In particular, the internal and external conditions that drive animals to switch to backward walking and the mechanisms by which the nervous system supports such behavior are still unknown. In fruit flies, moonwalker descending neurons (MDNs) are considered command-type neurons for backward locomotion as they receive visual and mechanosensory inputs and transmit motor-related signals to downstream neurons to elicit backward locomotion. Whether other modalities converge onto MDNs, which central brain neurons activate MDNs, and whether other retreat-driving pathways exist is currently unknown. Here, we show that olfactory stimulation can elicit MDN-mediated backward locomotion. Moreover, we identify the moonwalker subesophageal zone neurons (MooSEZs), a pair of bilateral neurons, which can trigger straight and rotational backward locomotion. MooSEZs act via postsynaptic MDNs and via other descending neurons. Although they respond to olfactory input, they are not required for odor-induced backward walking. Thus, this work reveals an important modality input to MDNs, a novel set of neurons presynaptic to MDNs driving backward locomotion and an MDN-independent backward locomotion pathway.

GPCR voltage dependence controls neuronal plasticity and behavior.

G-protein coupled receptors (GPCRs) play a paramount role in diverse brain functions. Almost 20 years ago, GPCR activity was shown to be regulated by membrane potential in vitro, but whether the voltage dependence of GPCRs contributes to neuronal coding and behavioral output under physiological conditions in vivo has never been demonstrated. Here we show that muscarinic GPCR mediated neuronal potentiation in vivo is voltage dependent. This voltage dependent potentiation is abolished in mutant animals expressing a voltage independent receptor. Depolarization alone, without a muscarinic agonist, results in a nicotinic ionotropic receptor potentiation that is mediated by muscarinic receptor voltage dependency. Finally, muscarinic receptor voltage independence causes a strong behavioral effect of increased odor habituation. Together, this study identifies a physiological role for the voltage dependency of GPCRs by demonstrating crucial involvement of GPCR voltage dependence in neuronal plasticity and behavior. Thus, this study suggests that GPCR voltage dependency plays a role in many diverse neuronal functions including learning and memory.

Differential Role for a Defined Lateral Horn Neuron Subset in Naïve Odor Valence in Drosophila.

Value coding of external stimuli in general, and odor valence in particular, is crucial for survival. In flies, odor valence is thought to be coded by two types of neurons: mushroom body output neurons (MBONs) and lateral horn (LH) neurons. MBONs are classified as neurons that promote either attraction or aversion, but not both, and they are dynamically activated by upstream neurons. This dynamic activation updates the valence values. In contrast, LH neurons receive scaled, but non-dynamic, input from their upstream neurons. It remains unclear how such a non-dynamic system generates differential valence values. Recently, PD2a1/b1 LH neurons were demonstrated to promote approach behavior at low odor concentration in starved flies. Here, we demonstrate that at high odor concentrations, these same neurons contribute to avoidance in satiated flies. The contribution of PD2a1/b1 LH neurons to aversion is context dependent. It is diminished in starved flies, although PD2a1/b1 neural activity remains unchanged, and at lower odor concentration. In addition, PD2a1/b1 aversive effect develops over time. Thus, our results indicate that, even though PD2a1/b1 LH neurons transmit hard-wired output, their effect on valence can change. Taken together, we suggest that the valence model described for MBONs does not hold for LH neurons.

Muscarinic Modulation of Antennal Lobe GABAergic Local Neurons Shapes Odor Coding and Behavior.

In the antennal lobe (AL), the first olfactory relay of Drosophila, excitatory neurons are predominantly cholinergic. Ionotropic nicotinic receptors play a vital role in the effects of acetylcholine in the AL. However, the AL also has a high expression level of metabotropic muscarinic acetylcholine receptors type A (mAChRs-A). Nevertheless, the neurons expressing them and their role in the AL are unknown. Elucidating their function may reveal principles in olfactory modulation. Here, we show that mAChRs-A shape AL output and affect behavior. We localized mAChRs-A effects to a sub-population of GABAergic local neurons (iLNs), where they play a dual role: direct excitation of iLNs and stabilization of the synapse between receptor neurons and iLNs, which undergoes strong short-term depression. Our results reveal modulatory functions of the AL main excitatory neurotransmitter. Striking similarities to the mammalian olfactory system predict that mammalian glutamatergic metabotropic receptors could be associated with similar modulations.

Inhibitory muscarinic acetylcholine receptors enhance aversive olfactory learning in adult Drosophila.

Olfactory associative learning in Drosophila is mediated by synaptic plasticity between the Kenyon cells of the mushroom body and their output neurons. Both Kenyon cells and their inputs from projection neurons are cholinergic, yet little is known about the physiological function of muscarinic acetylcholine receptors in learning in adult flies. Here, we show that aversive olfactory learning in adult flies requires type A muscarinic acetylcholine receptors (mAChR-A), particularly in the gamma subtype of Kenyon cells. mAChR-A inhibits odor responses and is localized in Kenyon cell dendrites. Moreover, mAChR-A knockdown impairs the learning-associated depression of odor responses in a mushroom body output neuron. Our results suggest that mAChR-A function in Kenyon cell dendrites is required for synaptic plasticity between Kenyon cells and their output neurons.