A Critical Period That Shapes Motor Circuits

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News & views mode to transverse vibrations. This previously e-mails: [email protected]; Phys. Rev. Lett. 119, 057604 (2017). unseen vortex motion indicates that an [email protected] 5. Luk’yanchuk, I., Sené, A. & Vinokur, V. M. Phys. Rev. B 98, 024107 (2018). instability accompanies a structural transi- 1. Li, Q. et al. Nature 592, 376–380 (2021). 6. Landau, L. D. & Lifshitz, E. M. Phys. Z. Sowjet. 8, 153–169 tion to a state in which the vortex centres form 2. Zhang, Q., Herchig, R. & Ponomareva, I. Phys. Rev. Lett. (1935). a zigzag chain. Compared with the 0.08-THz 107, 177601 (2011). 7. Kittel, C. Phys. Rev. 70, 965–971 (1946). 3. Gui, Z. & Bellaiche, L. Phys. Rev. B 89, 064303 8. De Guerville, F., Luk’yanchuk, I., Lahoche, L. & mode, those at 0.3–0.4 THz are associated (2014). El Marssi, M. Mater. Sci. Eng. B 120, 16–20 (2005). with more-intricate vortex dynamics and can 4. Hlinka, J., Paściak, M., Körbel, S. & Marton, P. 9. Yadav, A. K. et al. Nature 530, 198–201 (2016). be less easily attributed to a particular type of vibration. Neuroscience To unravel the full picture of vortex dynamics, future work needs to distinguish between inter-vortex motion, intra-vortex motion and vortex bending. Moreover, the A critical period that longitudinal mode of vibration must be identified. This mode is associated with a sequence shapes motor circuits of alternating displacements of domain walls (the boundaries between domains) and has Laura Sancho & Nicola J. Allen remarkable properties that arise from the associated dynamics of surface charges. A mechanism has been found in fruit flies that enables In metals, surface charges oscillate at fre- cells called astrocytes to signal to neurons, closing quencies corresponding to ultraviolet light 15 a developmental window during which locomotor (about 10 Hz), and the collective oscillations are known as plasmons. Similarly, in a ferro- behaviour is shaped. See p.414 electric film, the longitudinal mode causes surface charges to oscillate at terahertz frequencies, and the collective oscillations can be There are times in an organism’s development Next, Ackerman and colleagues asked if thought of as polarization plasmons. In such a when parts of the forming nervous system the changes in dendrite shape translated film, as in metals, a quantity called the dielec- are particularly sensitive to changing inputs. into changes in the numbers of excitatory tric constant is negative when the frequency Disrupting these critical periods can have and inhibitory synaptic connections on the of an applied electric field is lower than the lifelong effects on neuronal connectivity aCC and RP2 motor neurons (these synapses plasmon oscillation frequency. Surprisingly, and brain function1. For example, there is a activate and inhibit neuronal activity, respec- the dielectric constant in the ferroelectric critical period during childhood for language tively). Optogenetic silencing of the neurons film remains negative as the frequency of the acquisition2. And altered critical periods have resulted in a reduction in inhibitory-synapse applied field tends to zero, resulting in a nega- been suggested to play a part in neurodevel- numbers and an increase in excitatory syn- tive-capacitance effect5 — a phenomenon that opmental disorders, including autism spec- apses. Together, the expansion of dendrites promises to reduce the power consumption of trum disorder3 and schizophrenia4. Critical and the shift in synapse composition allowed next-generation nanoscale electronic devices. periods have been extensively described in the the neurons to rebalance neuronal activity, The past decade has seen remarkable pro- visual system1, but, until now, there has been counteracting the effect of optogenetic silenc- gress in developing terahertz semiconduc- less focus on non-sensory systems. Ackerman ing. Optogenetic activation of aCC and RP2 tor devices, working in the frequency range et al.5 close this gap on page 414. The authors neurons led to a decrease in the number of between radio waves and infrared light. The identify a critical period for motor-circuit excitatory synapses, but not to an increase potential applications of these devices span development in the fruit fly Drosophila in inhibitory synapses, perhaps owing to the wireless transmission of vast amounts of melanogaster, and establish the cellular and limited amount of cell membrane available for data, detection of distant security threats, molecular underpinnings of critical-period the formation of connections after dendrite 6G wireless technology and opportunities closure in this system. retraction. Together, this first batch of find- for non-invasive medical imaging. Li and During a critical period, neuronal con- ings indicates that there is a critical period for colleagues’ discovery that polarization vorti- nections can be reshaped in several ways. homeostatic changes to dendritic structure ces in nanoscale ferroelectric films can vibrate Ackerman et al. mainly address homeostatic and synapse number in the developing motor at terahertz-level frequencies could help to plasticity, in which changes occur across an system of D. melanogaster (Fig. 1a, b). scale down terahertz devices to the nano- entire neuron — including in the size of struc- What induces these changes? Neurons scale and achieve high-speed, high-density tures called dendrites, which receive synaptic are often in close contact with cells called data processing driven by electric fields. Such connections from other neurons, in synapse astrocytes, which help to regulate synaptic advances might enable the development of numbers and in the strength of electrical development and maintain brain function7. terahertz optoelectronics and plasmonics impulses transmitted by synapses6. Ackerman et al. therefore used genetic engi- (plasmon-based photonics), ultrafast data First, the authors used a technique called neering to eliminate all astrocytes in their exchange and intra-chip communications in optogenetics to activate or inhibit neuronal fruit flies. Dendritic remodelling continued emerging computer circuits. activity in two classes of neuron called aCC beyond eight hours after larval hatching in and RP2 motor neurons. When they silenced the mutant flies, but there was no increase Igor Luk’yanchuk is at the Laboratory of the neurons, both the length and volume of the in the amount of remodelling that occurred Condensed Matter Physics, University cells’ dendrites increased. By contrast, opto- before the eight-hour period had elapsed. of Picardie, Amiens 80039, France, genetic activation led to dendritic retraction. These findings indicate that astrocytes reg- and in the Faculty of Physics, Southern These changes occurred only when neuronal ulate the timing of critical-period closure for Federal University, Rostov-on-Don, Russia. activity was manipulated in the 8 hours after the aCC/RP2 system, but not the potential Valerii M. Vinokur is at Terra Quantum AG, larval hatching, and just 15 minutes of manip- for plasticity during this time. This is a key Rorschach 9400, Switzerland. ulation was necessary to see effects. distinction, because it suggests that different

of Nlg2 and Nrx-1 production are still to be a Critical period determined. Can these proteins be regulated by dendritic retraction or expansion? Would 0 h after hatching 8 h dendritic retraction result from a decrease in nlg2 expression in astrocytes? The authors provide compelling evidence for the prominent role of astrocytes in regulating closure of a critical period. Astrocytes b Dendrites modified c Dendrites stabilized regulate aspects of critical-period plasticity 9 Neuron in the mammalian visual system , including Dendrite silencing through the actions of the secreted proteins Neuron chordin-like 1 (ref. 10) and hevin11. The pres- Dendrite Astrocyte dendrite expansion ent work demonstrates that astrocytes can regulate critical periods not just in sensory Nrx-1 systems, but also in motor systems. Identifying Microtubules Motor neuron Neuron the mechanisms that govern critical-period Nlg2 stabilized activation closure is of particular interest because alter- Dendrite retraction ations in closure can disrupt proper neuro development — the findings could therefore Figure 1 | Shaping a motor circuit. a, Ackerman et al.5 have identified a critical period during which motor lead to insight into mechanisms involved circuits involving motor neurons called aCC and RP2 are shaped in the fruit fly Drosophila melanogaster. In in neurodevelopmental disorders such as the eight hours after larval hatching, structures called dendrites, which receive synaptic inputs from other schizophrenia3. Furthermore, identifying neurons, can be modified, but these dendrites stabilize after the critical period has closed. b, Silencing the mechanisms of critical-period closure can activity of the neurons during the critical period leads to the expansion of dendrites. By contrast, neuronal enable researchers to understand how the activation leads to dendrite retraction. c, The critical period closes as neighbouring cells called astrocytes brain becomes less plastic in adulthood, pro- mature. The maturing cells produce the protein Nlg2, which interacts with Nrx-1 protein on the neuronal viding new avenues for therapeutics aimed at dendrite. This interaction leads to the stabilization of structures called microtubules, which, in turn, increasing neural plasticity after brain injury prevents further dendritic remodelling. or disease. The work also shows that the role of astro- mechanisms underlie the two phenomena. in astrocytes or nrx-1 in aCC/RP2 dendrites cytes in regulating critical periods extends to Consequently, Ackerman and colleagues closed the critical period prematurely, short- invertebrates, thus highlighting the centrality sought to identify the mechanisms involved ening it to four hours after larval hatching. of these cells to nervous system development in the closure of the critical period. They used Disrupting critical periods can have lasting and maturation. It is becoming apparent that a technique called an RNA interference screen consequences for neural-circuit function and astrocytes and related cell types (collectively to inhibit the translation of different messen- behaviour. Indeed, Ackerman and co-workers called glia) are master regulators of neuronal ger RNA molecules into protein in the astro- found that extending the critical period plasticity, particularly in the context of homeo cytes of larvae, and then analysed the time at (through manipulation of either nrx-1 or nlg2) static and circuit changes. Moving forwards, which the critical period closed in each of the resulted in abnormal locomotor behaviour, research into critical periods must take into resulting flies. This allowed them to identify with the larvae moving in abnormal spiralling account the contribution of glia. genes that might regulate closure of the critical period. There were several genes for which “The work demonstrates Laura Sancho and Nicola J. Allen are in the RNA interference led to an extension of the Molecular Neurobiology Laboratory, critical period, but in many cases their inhibi- that astrocytes can regulate Salk Institute for Biological Studies, La Jolla, tion also had a profound impact on astrocyte developmental windows California 92037, USA. shape, making it hard to dissociate a role in known as critical periods in e-mails: [email protected]; astrocyte development from a specific role motor systems.” [email protected] in regulating the critical period. The authors chose to focus on the gene nlg2, inhibition of which extended the critical period without altering astrocyte shape. patterns 1.5 days after the manipulation — a The equivalent gene family in mice, neuro good time period to analyse because, at this 1. Espinosa, J. S. & Stryker, M. P. Neuron 75, 230–249 (2012). ligins, has been linked to astrocyte maturation stage, the larvae are actively feeding and mov- 2. Friedmann, N. & Rusou, D. Curr. Opin. Neurobiol. 35, during the critical period in the visual cortex of ing through the culture medium. These alter- 27–34 (2015). the brain, and astrocyte maturation coincides ations in behaviour highlight the importance 3. LeBlanc, J. J. & Fagiolini, M. Neural Plastic. 2011, 921680 8 (2011). closely with the closure of this critical period . of proper timing for critical periods. 4. Insel, T. R. Nature 478, 187–193 (2010). In D. melanogaster, Nlg2 protein interacts Ackerman and colleagues’ work raises ques- 5. Ackerman, S. D., Perez-Catalan, N. A., Freeman, M. R. & with the protein neurexin-1 (Nrx-1), which tions for future experiments. For example, Doe, C. Q. Nature 592, 414–420 (2021). 6. Turrigiano, G. G. & Nelson, S. B. Nature Rev. Neurosci. 5, Ackerman and colleagues found to be located how does the interaction between Nlg2 and 97–107 (2004). in motor neuron dendrites. The authors Nrx-1 regulate the critical period? The current 7. Allen, N. J. Annu. Rev. Cell Dev. Biol. 30, 439–463 (2014). showed that inhibition of nrx-1 in aCC and RP2 work identified a role for the interaction in 8. Stogsdill, J. A. et al. Nature 551, 192–197 (2017). 9. Sancho, L., Contreras, M. & Allen, N. J. Neurosci. Res. neurons using RNA interference extended the stabilizing structural polymers called micro- https://doi.org/10.1016/j.neures.2020.11.005 (2021). critical period — thus, Nrx-1 is probably the tubules, and so in stabilizing the structure of 10. Blanco-Suarez, E., Liu, T.-F., Kopelevich, A. & Allen, N. J. neuronal receptor for astrocytic Nlg2 in reg- dendrites themselves. However, the mecha- Neuron 100, 1116–1132 (2018). 11. Singh, S. K. et al. Cell 164, 183–196 (2016). ulation of critical-period closure (Fig. 1c). In nism leading to microtubule stability remains line with this idea, overexpressing either nlg2 to be explored. Furthermore, the dynamics This article was published online on 7 April 2021.