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Structural plasticity of modulatory neurons in association to behavioral adaptations

The re-wiring of the modulatory neurons is proposed as a mechanism to adjust feeding-related behaviors that are pronounced after long- term calorie restriction exposure in adult Drosophila brain. I focused on the modulatory DANs innervating the MB. The integration of the hunger signal and the

97 effect of structural decrease on this integration is briefly discussed in section 4.2.4. Here, a detailed discussion is provided in terms of possible signaling integration in association to behavioral adaptation.

It is well known that the DANs innervating proximal lobes of the MB such as γ1 and γ2 is involved in the aversive learning which requires experience-based sensory stimulus integration. Moreover, the optogenetic stimulation of these DANs induce strongly a pronounced memory formation and an underlying corresponding MBON response modulation (Aso et al., 2014a; Claridge-Chang et al., 2009).

Similarly, the DANs that innervate the distal lobes such as γ4 and γ5 is also involved in strong modulation of sugar and thirst memory (Aso et al., 2010; Burke et al., 2012; Claridge-Chang et al., 2009;

Liu et al., 2012; Perisse et al., 2013; Schroll et al., 2006).

However, the role of MB188B DANs, that innervate the γ3, γ4 and β’1 regions of the MB, are not shown to play any role in the context of memory formation. Additionally, the MB188B DANs are known to result in avoidance behavior upon stimulation. However, the valence encoded by these DANs remained unsolved (Aso et al., 2014). Finally, these DANs are not shown to lead a strong postsynaptic modulation in the learning process compared to its more proximal and more distal DAN populations (Louis et al., 2018).

In this study, the role of the MB188B DANs in food uptake was confirmed as a first approach to correlate structural modifications of these DANs with underlying feeding-related behaviors. Since, the inhibition of the MB188B DANs shows a behavioral effect, but not their activation, it is possible that these DANs are constantly active. Thus, the absence of the activity is informative about the hunger state. This phenomenon can be perhaps explained by potential oscillation of the MB188B DANs. The change in the oscillation (or complete suppression) could be an indicator of the internal state. In the literature, there are more examples of oscillatory DANs innervating the MB that are involved in food uptake behaviors. For instance, the frequency of certain oscillatory DANs is translated in terms of the energy level by Drosophila MB (Musso et al., 2015). Additionally, a group of oscillating γ3 innervating DANs is suppressed upon the sugar presentation to the fly.

If the oscillation of the MB188B DANs are responsible for encoding the energy level (or internal state) valence, the long-lasting (or even permanent) changes in the oscillation of these DANs can be achieved by the structural modifications. These changes can then result in the behavioral adaptation according to the food condition.

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Another study showing the MB involvement in the foraging behavior suggests that flies lacking an intact MB shows less centrophobia (fear of freely exploring the center of an arena). The exploration rate of these flies increased when the MB is impaired (Besson and Martin, 2005). A similar study suggests that this enhancement in the exploratory behaviors develops from the downregulation of Drosophila Neuroligin protein Dnlg2 which is found in the synaptic structures of the MB. This protein is responsible for maintaining the structure of the synapses (Corthals et al., 2017). The same study also suggests that Dnlg2 knock-down in the MB results in a decrease in the connectivity between the MB and related neurons. This decrease in connectivity leads to an increase in exploratory behaviors quite similar to the hungry flies that have less centrophobia. As discussed above, here, I suggest that the decrease in the connectivity of these DANs, either on the MB or on the MB-related neurons enhances the foraging-related behaviors and ultimately the food uptake similar to Dnlg2 knock-down flies that has less connectivity to their MB.

Here, it is shown that the connectivity change in MB188B DANs occurs postsynaptically (Figure 3.11).

Similar to this compartmentalized structural refinement, a branch-specific pruning in another DAN group (the DA-WED) and the involvement in the food uptake were also shown by Liu et al., 2017. These DANs are also involved in the motivation for particular nutrition seeking. Interesting enough, the structure of these DANs is compartmentalized in a way that certain branches are responsible for different nutrient types. Additionally, these branches are undergoing pruning when the animal needs to increase the uptake of a specific nutrient(Liu et al., 2017). However, what is remarkable about the structural refinements of the MB188B DANs shown in my study is that it occurs upon long term restriction unlike DA-WED. Additionally, these refinements are rather long-lasting.

All the arguments speculated above are rather an indirect explanation of how structural changes can modulate the feeding behavior. However, a direct evidence showing that the structural changes result in the enhancement of the food uptake was also presented (Figure 3.17). This evidence will be discussed extensively under section 4.7.

All in all, these arguments suggest that the MB188B DANs involve in the state-dependent foraging behavior. Structural modifications in these DANs can help the animal to adjust the corresponding behaviors according to the level of nutrition exposure in a long period.

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