A developmental framework linking neurogenesis and circuit formation in the Drosophila CNS

Abstract

The mechanisms specifying neuronal diversity are well-characterized, yet it remains unclear how or if these mechanisms regulate neural circuit assembly. To address this, we mapped the developmental origin of 160 interneurons from seven bilateral neural progenitors (neuroblasts), and identify them in a synapse-scale TEM reconstruction of the Drosophila larval CNS. We find that lineages concurrently build the sensory and motor neuropils by generating sensory and motor hemilineages in a Notch-dependent manner. Neurons in a hemilineage share common synaptic targeting within the neuropil, which is further refined based on neuronal temporal identity. Connectome analysis shows that hemilineage-temporal cohorts share common connectivity. Finally, we show that proximity alone cannot explain the observed connectivity structure, suggesting hemilineage/temporal identity confers an added layer of specificity. Thus, we demonstrate that the mechanisms specifying neuronal diversity also govern circuit formation and function, and that these principles are broadly applicable throughout the nervous system.

Models of heterogeneous dopamine signaling in an insect learning and memory center

“…The diversity of dopamine neuron activity challenges models of mushroom body learning that assume these neurons convey global reward or punishment signals. Part of this discrepancy is likely due to the intricate connectivity among output neurons, dopamine neurons, and other neurons that form synapses with them [ 48 , 52 , 53 ]. We therefore modeled these neurons and their connections, which we refer to collectively as the mushroom body “output circuitry,” as a recurrent neural network ( Fig 1A ).…”

“…In the absence of an explicit correspondence between neurons in our model and their biological counterparts, direct analysis of the connectivity in our optimized networks is unlikely to be sufficient to do so. Future studies should build models that incorporate recently available mushroom body wiring diagrams to further constrain models [ 49 , 50 , 52 , 53 ].…”

“…Due to the well-characterized anatomy of the mushroom body and knowledge of this plasticity rule, our approach allows us to generate predictions about the activity of multiple neuron types [ 28 , 48 ]. Comprehensive synapse-level wiring diagrams for the output circuitry of the mushroom body have recently become available, which will allow the connectivity of models constructed with our approach to be further constrained by data [ 49 – 53 ]. As the dynamics of our models, including the dopamine-gated plasticity, are optimized end-to-end only for overall task performance, our model predictions do not require a priori assumptions on what signals the dopamine neurons encode.…”

Sequential addition of neuronal stem cell temporal cohorts generates a feed-forward circuit in the Drosophila larval nerve cord

“…), which is specified by temporal transcription factor expression in neuroblasts (Isshiki et al, 2001). It has been suggested that these genetic mechanisms specifying neuronal diversity are also likely to govern circuit formation and function (Mark et al, 2021) (Sagner & Briscoe, 2019).…”

“…These data linked temporal cohorts to differential circuit function. More recently, in other lineages (i.e., NB1-2, NB2-1, NB3-1, NB4-1, NB5-2, NB7-1, NB 7-4), neurons within temporal cohorts were shown to share similarities in their synaptic partnerships (Meng et al, 2019) (Meng et al, 2020) (Mark et al, 2021). Furthermore, the number of neurons in lineage that are segregated into a given temporal cohorts can be altered by manipulating temporal factor expression in neuronal stem cells (Meng et al, 2019) (Meng et al, 2020).…”