Nature over Nurture: Functional neuronal circuits emerge in the absence of developmental activity

Abstract

During development, the complex neuronal circuitry of the brain arises from limited information contained in the genome. After the genetic code instructs the birth of neurons, the emergence of brain regions, and the formation of axon tracts, it is believed that neuronal activity plays a critical role in shaping circuits for behavior. Current AI technologies are modeled after the same principle: connections in an initial weight matrix are pruned and strengthened by activity-dependent signals until the network can sufficiently generalize a set of inputs into outputs. Here, we challenge these learning-dominated assumptions by quantifying the contribution of neuronal activity to the development of visually guided swimming behavior in larval zebrafish. Intriguingly, dark-rearing zebrafish revealed that visual experience has no effect on the emergence of the optomotor response (OMR). We then raised animals under conditions where neuronal activity was pharmacologically silenced from organogenesis onward using the sodium-channel blocker tricaine. Strikingly, after washout of the anesthetic, animals performed swim bouts and responded to visual stimuli with 75% accuracy in the OMR paradigm. After shorter periods of silenced activity OMR performance stayed above 90% accuracy, calling into question the importance and impact of classical critical periods for visual development. Detailed quantification of the emergence of functional circuit properties by brain-wide imaging experiments confirmed that neuronal circuits came 'online' fully tuned and without the requirement for activity-dependent plasticity. Thus, we find that complex sensory guided behaviors can be wired up by activity-independent developmental mechanisms.

Extreme distributions in the preconfigured developing brain

“…These results are difficult to reconcile with the hypothesis that brain structure is initially “diffuse” and only later acquires the structural organization that is typical of the adult brain 29,30,71 . Rather, they support several recent studies that have highlighted the importance of “nature over nurture” 72,73 in establishing neural circuits and the distributions of their parameters. For instance, in neuronal cultures, the variance of glutamatergic synaptic sizes does not differ between networks that are silenced from plating onwards, and networks that are spontaneously active 7 .…”

“…Along the same lines, in vivo blocking of synaptic transmission in the hippocampus of anesthetized rats does not alter the distribution of spine sizes 76 . Even more surprisingly, completely abolishing all central nervous system activity for the first four days of life of the larval zebrafish only minimally impacts the tuning and functionality of neurons, and the ability of the fish to learn a complex visuomotor task 72 . Intriguingly, similar concepts are beginning to percolate also in the field of artificial intelligence 77 , which has been traditionally dominated by a bottom-up and learning-based approach.…”

NMDA receptor activation drives early synapse formationin vivo

“…1E). These findings align with previous work indicating that action potential firing is not involved in synapse formation ( 12 ) but suggest that NMDARs play a role in the formation of SC synapses during an early, prenatal developmental time window in vitro .…”

“…However, the discovery that the postnatal abolition of all excitatory transmission by genetic deletion of ionotropic glutamate receptors, including NMDARs, in hippocampal CA1 pyramidal neurons (PNs) was not associated with any changes to synapse densities or dendritic arbor structure cast doubt on this role ( 11 ). Indeed, recent evidence in zebrafish demonstrates that action potential firing is not required for the formation of circuits underlying visual behaviors ( 12 ). Hence, the current prevailing view is that synaptogenesis is driven by genetically encoded molecular cues, with activity playing a role only in subsequent refinement ( 13 ).…”

Protosequences in human cortical organoids model intrinsic states in the developing cortex

“…In summary, our analysis of spontaneous activity generated by stem cell derived human brain organoids, demonstrates that structured spiking sequences can emerge when completely devoid of sensory experience and motor output, supporting the pre-configured brain hypothesis. Recent work pharmacologically blocking neuronal activity during development of the central nervous system in larval zebrafish did not significantly alter neuronal responses relative to unperturbed animals 83 , suggesting that complex sensory systems are hard-wired by activity-independent mechanisms. Brain organoids offer a heuristic opportunity to understand how exogenous inputs can be used to refine neuronal circuits and enable new studies into the genetic mechanisms that govern assembly of functional circuitry during early human brain development.…”