Kevin Daly, Ph.D.
Currently accepting new graduate students!
Adaptive behavioral choices require accurate information about environmental conditions.
As behaviors unfold, sensory systems continuously provide updated information about
the ongoing changes in the environment (what is referred to as exafferent sensory
activation) but must do so within the context of reafference, self-
(or behaviorally-) induced sensory activation.
My laboratory focuses our research efforts on understanding the mechanisms underlying motor neural networks communication, in the form of corollary discharges or predictive motor signals, to sensory networks and how those downstream sensory networks use this information to disambiguate environmentally generated stimuli from motor-driven reafference. Finally, we use behavioral analyses to understand the role of these circuits in affect sensory motor performance. Examples of predictive motor circuits are numerous and diverse across the animal kingdom, yet they remain among the least studied and understood circuits in the brain. Predictive motor circuits have been identified or inferred across all sensory modalities, and there are likely many such circuits that project any given sensory pathway. Importantly, failure of predictive motor circuits underlies sensory-based hallucinations in human brain diseases such as schizophrenia and Parkinsons disease. Because patients cannot accurately disambiguate reafference from exafference, this often leads to maladaptive behaviors. Therefore, understanding predictive motor circuits is foundational to understanding and ultimately curing these profound diseases of the brain.
We use the model organism Drosophila melanogaster to study predictive motor circuits that ascend from motor centers in the ventral nerve cord (VNC) to multiple sensory networks in the brain. Our research is guided in large part by newly generated electron microscopy (EM) -based, brain and VNC volume reconstructions that allow us to generate reasonably comprehensive “connectomes” of the nervous system (Fig. 1A). The term connectome refers to the comprehensive mapping of all synapses in the nervous system. Within these two volumes are two pairs of ascending histamine immunoreactive neurons (AHNs) that we have characterized in detail (Fig.1B). Once identified in the volume, neurons can be completely reconstructed including identification of nearly all synapses, both from and onto the AHNs. As shown in Figure 2 once all synapses are mapped, we reconstructed all upstream partners (downstream partners not shown) to a point that they can be classified. This provides a clear understanding of the demographics of the AHNs connectivity. These EM volume reconstructions also allow us to identify circuits motifs that we can then interrogate at the circuit level using transgenic approaches available in no other model organism. For example, my laboratory has developed several “split” Gal4 and “LexA” lines that allow us to express transgenic
tools specifically in the AHNs as well as their up and downstream targets. Figure 2C-E highlight the connectivity (2C) and morphology (2D) of all upstream descending command neurons (DNs). Among these DNs are a cluster of 15 pairs of DNs called DNg02 which provide the greatest overall input onto the AHNs. Using Neuronbridge, the morphologies of the DNg02 from the EM volumes, were compared against a databases of Gal4 and other driver lines for genetic lines of flies with Gal 4 expression neurons of similar morphology to the DNg02. Once good driver lines are in hand, it allowed to create a split Gal4 (Fig. 2E), which then was used to determine the neurotransmitter DNg02 releases, determine receptors expressed, monitor physiological function and behavior while we manipulate neuron function to determine their role in network function. For example, we can express the optogenetic tool CsChrimson to drive DNg02, and GCaMP to monitor the AHNs (Fig 3A). Here we show light activation of DNg02 results in increased fluorescence in the AHNs indicating that as predicted, DNg02 excite AHNs.
New students joining the Daly Laboratory will have access to state of the art approaches including:
- GCaMPs and GEVIs for functional imaging neurons of interest
- 2-photon and wide field epifluorescence microscopy
- Confocal and super resolution fluorescence imaging.
- Optogenetic, thermogenetic, and chemogenetic tools for targeted manipulation of neurons of interest
- Other genetic reagents such as reaper and botox to ablate/disable neurons of interest
- Immuno- and HCR-based techniques to image the expression of neurotransmitters and receptors
- Extensive behavioral assays of courtship, grooming, and locomotion (walking and flight) using high speed video imaging with AI-based kinematic tracking/analysis.
Mentorship and lab culture: The Daly laboratory personnel work as a team even though each graduate student has their own projects. Graduate students are expected to onboard, train, and mentor at least one undergraduate researcher at a time under my guidance. Undergraduate and graduate students joining my lab should expect to conduct novel basic anatomical, physiological, and behavioral research on predictive motor circuit structure and function using techniques such as those described above. Analysis of EM volumes reveals that the AHNs are 2 pairs among some 1860 ascending neurons, the vast majority of which have never studied and most of which are situated to provide motor information from the VNC to the brain. Although, there is an expected timeline to complete major milestones, each student will create an individual development plan with my consultation to set goals and review progress/problems. Students report progress weekly in lab and/or individual meetings and feedback on progress quality and quantity is given regularly. It is also expected that the students arrange and hold at least one degree committee meeting annually. The laboratory has a handbook which describes each students’ roles and responsibilities, as well as expectations for authorship/coauthorship. Our goal is to have students collaborating with each other within and between laboratories.
If you are a prospective student interested in conducting research in this field of study please contact me.
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