By K Meechan
This is the final part of a 2-part post: part 1 gave a brief introduction to the first two layers of the fly olfactory system (ORNs and PNs). Part 2 moves on to look at higher order processing.
While we know a lot about the first layers of the olfactory system, the processing in the Lateral Horn (LH), Mushroom Body (MB) and beyond is less well understood. Many open questions remain as to exactly how odour information is processed by these centres, and how this results in appropriate behavioural responses.
The Lateral Horn
The LH is thought to be involved in mediating innate responses to odours. This is suggested by various experiments that lesion or inactivate the MB – when the MB is not functional, associative learning is impaired, but innate responses to odours are preserved. This suggests that transfer of olfactory information through the LH alone is sufficient for innate responses.
Consistent with its role in innate behaviour, the areas of the LH that olfactory PNs target are consistent and stereotyped. Different classes of PN target different zones of the LH, allowing different regions to respond to different sets of odours. For example, the posterior-dorsal LH is mainly targeted by PNs that respond to fruit odours, whereas the anterior-ventral LH is mostly targeted by pheromone responsive PNs. Each PN class has a stereotyped axonic branching pattern, allowing it to target the same regions from animal to animal.
Various Lateral Horn Neurons (LHNs) receive input from PNs in the LH. Some of these have broad odour tuning, receiving input from a variety of PN classes, while others are more selective, receiving input from fewer PN types. The number of classes of LHNs, what they respond to, and their role in processing odours is not fully understood.
The Mushroom Body
The MB is a massively parallel processing structure important for associative learning and memory. Its major component are Kenyon Cells (KCs), whose axons form the different ‘lobes’ of the MB. These approximately 2000 KCs are split into three different classes which form the γ, α′/β′, and α/β lobes.
PNs connect to KCs in a globular structure known as the Mushroom Body Calyx, made up of the dendrites of these ~2000 KCs. Connectivity between PNs and KCs does not appear to be stereotyped, with seemingly random connectivity between specific types of PNs and individual KCs (at least within each class). This is consistent with the MB’s role in learning and memory; these circuits must change their response with experience and therefore cannot be expected to be entirely consistent between different individuals.
Each KC receives on average ~6 inputs from a random selection of PNs. This allows different odours to activate sparse subpopulations of the KCs in the MB – only around 5-20% of all KCs will respond to a given odour.
The major outputs of the MB are the Mushroom Body Output Neurons (MBONs) – a group of only 34 neurons per hemisphere, representing 21 cell types. MBONs receive KC input in specific, segregated domains of the lobes referred to as ‘compartments’. Different MBON types localise their dendrites to different compartments, collectively tiling the MB lobes with little overlap. Different MBON types then project to different regions of the fly brain to eventually mediate a behavioural response (e.g. approach or avoidance of an odour).
The final major contributors to the MB are the dopaminergic neurons (DANs) – over 100 DANs (of 20 types) target their axons to the MB. Like the MBONs, DANs innervate specific compartments of the MB, collectively tiling the MB but overlapping minimally. Therefore, different types of MBON (with dendrites occupying specific compartments) are modulated by the action of different DANs.
DANs are thought to be key to plasticity in the MB – they release dopamine to signal behavioural significance (e.g. a positive (appetitive) response like from a sugar reward, or a negative (aversive) response like from an electric shock). For example, a number of experiments have shown that direct activation of DANs can substitute for the presence of stimuli like sugar reward / electric shock to induce approach or avoidance in response to an associated odour. The nature of the memory formed (aversive or appetitive) depends on the type of DAN activated.
Dopamine acts by modifying the properties of synapses between KCs and MBONs. This therefore allows the response of the MB to change with experience – i.e. learning! While it was generally assumed that associative learning would strengthen KC-MBON connections, it has surprisingly been found to weaken them. Dopamine release in a particular compartment generally results in long-term depression of the KC-MBON synapses there, and therefore an attenuation of the response of the MBON in that compartment. Attenuation of an MBON that mediates attractive responses will bias towards aversion; while attenuation of an MBON that mediates aversive responses will bias towards attraction.
The details of how the MB mediates learning are complex, and much work still remains to be done – the roles of the different compartments and the various MBONs & DANs that target them are not yet fully understood.
Using a connectomic approach, our lab aims to reconstruct olfactory circuits at synaptic resolution (i.e. down to individual neuron morphologies and synaptic connections).
These detailed reconstructions will allow us to address a wide range of open questions:
- How do neurons in the LH interpret odour information and inform appropriate behavioural responses?
- How do the MB and LH interact to allow experience to change the fly’s response to innately attractive or aversive odours?
- What are the targets of MBONs and how do these ultimately govern motor behaviour?
And many more!
Ultimately, we want to gain a full understanding of how olfactory information is processed in the fly brain. As the vertebrate olfactory system (including that of humans) has a very similar structure, this should give valuable insights relevant to a range of organisms. More broadly, it offers a great opportunity to dig into the details of exactly how a sensory system is wired – at the scale of individual connections – and how this interacts with other systems in the brain.
Hige T. What can tiny mushrooms in fruit flies tell us about learning and memory? Neurosci Res. 2017. doi:10.1016/j.neures.2017.05.002.
Grabe V, Sachse S. Fundamental principles of the olfactory code. Biosystems. 2017. doi:10.1016/j.biosystems.2017.10.010.
de Belle JS, Heisenberg M. Associative odor learning in Drosophila abolished by chemical ablation of mushroom bodies. Science. 1994. doi:10.1126/science.8303280
Heimbeck G, Bugnon V, Gendre N, Keller A, Stocker RF. A central neural circuit for experience-independent olfactory and courtship behavior in Drosophila melanogaster. Proc Natl Acad Sci U S A. 2001;98(26):15336-15341. doi:10.1073/pnas.011314898.
Marin EC, Jefferis GSXE, Komiyama T, et al. Representation of the glomerular olfactory map in the Drosophila brain. Cell. 2002;109(2):243-255. doi:10.1016/S0092-8674(02)00700-6.
Jefferis GSXE, Potter CJ, Chan AM, et al. Comprehensive maps of Drosophila higher olfactory centers: spatially segregated fruit and pheromone representation. Cell. 2007;128(6):1187-1203. doi:10.1016/j.cell.2007.01.040.
Chiang A-S, Lin C-Y, Chuang C-C, et al. Three-Dimensional Reconstruction of Brain-wide Wiring Networks in Drosophila at Single-Cell Resolution. Curr Biol. 2011;21(1):1-11. doi:10.1016/j.cub.2010.11.056.
Costa M, Manton JD, Ostrovsky AD, Prohaska S, Jefferis GSXE. NBLAST: Rapid, Sensitive Comparison of Neuronal Structure and Construction of Neuron Family Databases. Neuron. 2016;91(2):293-311. doi:10.1016/j.neuron.2016.06.012.
Fişek M, Wilson RI. Stereotyped connectivity and computations in higher-order olfactory neurons. Nat Neurosci. 2014;17(2):280-288. doi:10.1038/nn.3613.
Aso Y, Hattori D, Yu Y, et al. The neuronal architecture of the mushroom body provides a logic for associative learning. Elife. 2014;3:e04577. doi:10.7554/eLife.04577.
Caron SJC, Ruta V, Abbott LF, Axel R. Random convergence of olfactory inputs in the Drosophila mushroom body. Nature. 2013;497(7447):113-117. doi:10.1038/nature12063.
Murthy M, Fiete I, Laurent G. Testing Odor Response Stereotypy in the Drosophila Mushroom Body. Neuron. 2008;59(6):1009-1023. doi:10.1016/j.neuron.2008.07.040.
Owald D, Waddell S. Olfactory learning skews mushroom body output pathways to steer behavioral choice in Drosophila. Curr Opin Neurobiol. 2015;35:178-184. doi:10.1016/j.conb.2015.10.002.
Honegger KS, Campbell RAA, Turner GC. Cellular-Resolution Population Imaging Reveals Robust Sparse Coding in the Drosophila Mushroom Body. J Neurosci. 2011;31(33):11772-11785. doi:10.1523/JNEUROSCI.1099-11.2011.
Liu C, Plaa̧ais PY, Yamagata N, et al. A subset of dopamine neurons signals reward for odour memory in Drosophila. Nature. 2012;488(7412):512-516. doi:10.1038/nature11304.
Owald D, Felsenberg J, Talbot CB, et al. Activity of defined mushroom body output neurons underlies learned olfactory behavior in Drosophila. Neuron. 2015;86(2):417-427. doi:10.1016/j.neuron.2015.03.025.
Zheng Z, Scott Lauritzen J, Perlman E, et al. A complete electron microscopy volume of the brain of adult Drosophila. 2017. doi:10.1101/140905.
Image Credit: Adult brain and segmented neuropils – Template brain created by Arnim Jenett (Janelia Research Campus), Kazunori Shinomiya and Kei Ito (Tokyo University) [Ito et al., 2014] Then transformed to the EM template FAFB [Zheng et al., 2017]