Can Simple Rules Control Development of a Pioneer Vertebrate Neuronal Network Generating Behavior?

Abstract

How do the pioneer networks in the axial core of the vertebrate nervous system first develop? Fundamental to understanding any full-scale neuronal network is knowledge of the constituent neurons, their properties, synaptic interconnections, and normal activity. Our novel strategy uses basic developmental rules to generate model networks that retain individual neuron and synapse resolution and are capable of reproducing correct, whole animal responses. We apply our developmental strategy to young Xenopus tadpoles, whose brainstem and spinal cord share a core vertebrate plan, but at a tractable complexity. Following detailed anatomical and physiological measurements to complete a descriptive library of each type of spinal neuron, we build models of their axon growth controlled by simple chemical gradients and physical barriers. By adding dendrites and allowing probabilistic formation of synaptic connections, we reconstruct network connectivity among up to 2000 neurons. When the resulting "network" is populated by model neurons and synapses, with properties based on physiology, it can respond to sensory stimulation by mimicking tadpole swimming behavior. This functioning model represents the most complete reconstruction of a vertebrate neuronal network that can reproduce the complex, rhythmic behavior of a whole animal. The findings validate our novel developmental strategy for generating realistic networks with individual neuron-and synapse-level resolution. We use it to demonstrate how early functional neuronal connectivity and behavior may in life result from simple developmental "rules," which lay out a scaffold for the vertebrate CNS without specific neuron-to-neuron recognition.

A simple decision to move in response to touch reveals basic sensory memory and mechanisms for variable response times

“…The model used for these hdINs was described previously (Roberts et al . ). The hexN spikes activated AMPA and NMDA receptor channels with maximum conductances of 0.25 and 0.1 nS, respectively.…”

“…Synapses were implemented using the same equations and parameters as previously (Roberts et al 2014). Specifically, when the membrane potential of the presynaptic neuron's axonal compartment crossed 0 mV, AMPA and NMDA receptors in the postsynaptic neuron's dendrite/soma compartment were activated.…”

“…Initially, we connected a random subset of hexNs (with a connection probability of 0.2) to five model hdINs (with no connections between them). The model used for these hdINs was described previously (Roberts et al 2014). The hexN spikes activated AMPA and NMDA receptor channels with maximum conductances of 0.25 and 0.1 nS, respectively.…”

“…During synchrony, each side escapes inhibition by firing quickly before inhibition arrives from the other side. Synchronous firing of the two sides can occur in the tadpole (Li et al 2014) and model tadpole networks show that it is more common when both sides receive similar, fast-rising excitation (Wang & Rinzel, 1992;Li et al 2014;Roberts et al 2014). It is hard to see how this type of motor output serves a useful function.…”

Synaptic specificity is collectively determined by partner identity, location and activity

“…During development, neurons follow global molecular guidance cues that instruct them to terminate in a specific 3D location of the nervous system (Couton et al, 2015;; Fukuhara et al, 2013;; Mauss et al, 2009;; Sürmeli et al, 2011;; Zlatic et al, 2003; Zlatic et al, , 2009). It has been proposed that precise positioning of pre--and postsynaptic partners in the same location could reduce neuronal availability enough to generate specific connections (Balaskas et al, 2019;Li et al, 2007;Peters and Feldman, 1976;Rees et al, 2017;Roberts et al, 2014). Within this framework connectivity could result simply from promiscuous interactions in a delimited location where partner neurons independently converge, with no need for specific partner--recognition molecules.…”