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A centre for neural control The axon initial segment (AIS) at the base of each nerve fibre, where clusters of sodium channels generate the action potential that then propagates along the axon, is a focus of much attention from neuroscientists working on the nature of neuronal excitability. As the source of a nerve impulse, it seems a logical point at which to regulate neural activity. Two papers in this issue confirm that the AIS is a source of intrinsic neuronal plasticity. Matthew Grubb and Juan Burrone show that electrical activity reversibly alters the position of the AIS in cultured hippocampal neurons. They suggest that the resulting increase in intrinsic excitability may fine-tune neuronal excitability during development, and point to potential targets for the control of epilepsy. Hiroshi Kuba, Yuki Oichi and Harunori Ohmori show that the size of the AIS increases in bird auditory neurons deprived of sound stimulation. Again intrinsic excitability increases, possibly contributing to the maintenance of the auditory pathway. Such neuronal plasticity may compensate some forms of hearing loss. A nerve cell sends signals to others through action potentials, which begin at the 'initial segment' of the neuron's axon. It is now shown that changes in electrical activity can alter the position of this initial segment in cultured rat hippocampal neurons. The resulting increase in intrinsic excitability — the tendency to fire action potentials — represents a new form of neuronal plasticity and could provide a new target in the control of epilepsy. In neurons, the axon initial segment (AIS) is a specialized region near the start of the axon that is the site of action potential initiation 1 , 2 , 3 , 4 , 5 , 6 . The precise location of the AIS varies across and within different neuronal types 7 , 8 , and has been linked to cells’ information-processing capabilities 8 ; however, the factors determining AIS position in individual neurons remain unknown. Here we show that changes in electrical activity can alter the location of the AIS. In dissociated hippocampal cultures, chronic depolarization with high extracellular potassium moves multiple components of the AIS, including voltage-gated sodium channels, up to 17 μm away from the soma of excitatory neurons. This movement reverses when neurons are returned to non-depolarized conditions, and depends on the activation of T- and/or L-type voltage-gated calcium channels. The AIS also moved distally when we combined long-term LED (light-emitting diode) photostimulation with sparse neuronal expression of the light-activated cation channel channelrhodopsin-2; here, burst patterning of activity was successful where regular stimulation at the same frequency failed. Furthermore, changes in AIS position correlate with alterations in current thresholds for action potential spiking. Our results show that neurons can regulate the position of an entire subcellular structure according to their ongoing levels and patterns of electrical activity. This novel form of activity-dependent plasticity may fine-tune neuronal excitability during development.

Neuronal function is intimately tied to axodendritic polarity. Neurotransmitter release, for example, is usually the role of the axon. There are widespread exceptions to this rule, however, including many mammalian neuronal types that can release neurotransmitter from their dendrites. In the mouse olfactory bulb, closely related subclasses of dopaminergic interneuron differ markedly in their polarity, with one subtype lacking an axon entirely. These axon-bearing and anaxonic dopaminergic subclasses have distinct developmental profiles and sensory responses, but how their fundamental polarity differences translate to functional outputs remains entirely unknown. Here, we provide anatomical evidence for distinct neurotransmitter release strategies among these closely related dopaminergic subtypes: anaxonic cells release from their dendrites, while axon-bearing neurons release exclusively from their intermittently myelinated axon. These structural differences are linked to a clear functional distinction: anaxonic, but not axon-bearing, dopaminergic neurons are capable of self-inhibition. Our findings suggest that variations in polarity can produce striking distinctions in neuronal outputs, and that even closely related neuronal subclasses may play entirely separate roles in sensory information processing.

Recent developments have used light‐activated channels or transporters to modulate neuronal activity. One such genetically‐encoded modulator of activity, channelrhodopsin‐2 (ChR2), depolarizes neurons in response to blue light. In this work, we first conducted electrophysiological studies of the photokinetics of hippocampal cells expressing ChR2, for various light stimulations. These and other experimental results were then used for systematic investigation of the previously proposed three‐state and four‐state models of the ChR2 photocycle. We show the limitations of the previously suggested three‐state models and identify a four‐state model that accurately follows the ChR2 photocurrents. We find that ChR2 currents decay biexponentially, a fact that can be explained by the four‐state model. The model is composed of two closed (C1 and C2) and two open (O1 and O2) states, and our simulation results suggest that they might represent the dark‐adapted (C1‐O1) and light‐adapted (C2‐O2) branches. The crucial insight provided by the analysis of the new model is that it reveals an adaptation mechanism of the ChR2 molecule. Hence very simple organisms expressing ChR2 can use this form of light adaptation.

The light-gated cation channel Channelrhodopsin-2 (ChR2) is a powerful and versatile tool for controlling neuronal activity. Currently available versions of ChR2 either distribute uniformly throughout the plasma membrane or are localised specifically to somatodendritic or synaptic domains. Localising ChR2 instead to the axon initial segment (AIS) could prove an extremely useful addition to the optogenetic repertoire, targeting the channel directly to the site of action potential initiation, and limiting depolarisation and associated calcium entry elsewhere in the neuron. Here, we describe a ChR2 construct that we localised specifically to the AIS by adding the ankyrinG-binding loop of voltage-gated sodium channels (Na(v)II-III) to its intracellular terminus. Expression of ChR2-YFP-Na(v)II-III did not significantly affect the passive or active electrical properties of cultured rat hippocampal neurons. However, the tiny ChR2 currents and small membrane depolarisations resulting from AIS targeting meant that optogenetic control of action potential firing with ChR2-YFP-Na(v)II-III was unsuccessful in baseline conditions. We did succeed in stimulating action potentials with light in some ChR2-YFP-Na(v)II-III-expressing neurons, but only when blocking KCNQ voltage-gated potassium channels. We discuss possible alternative approaches to obtaining precise control of neuronal spiking with AIS-targeted optogenetic constructs and propose potential uses for our ChR2-YFP-Na(v)II-III probe where subthreshold modulation of action potential initiation is desirable.

Most neurogenesis in the mammalian brain is completed embryonically, but in certain areas the production of neurons continues throughout postnatal life. The functional properties of mature postnatally generated neurons often match those of their embryonically produced counterparts. However, we show here that in the olfactory bulb (OB), embryonic and postnatal neurogenesis produce functionally distinct subpopulations of dopaminergic (DA) neurons. We define two subclasses of OB DA neuron by the presence or absence of a key subcellular specialisation: the axon initial segment (AIS). Large AIS-positive axon-bearing DA neurons are exclusively produced during early embryonic stages, leaving small anaxonic AIS-negative cells as the only DA subtype generated via adult neurogenesis. These populations are functionally distinct: large DA cells are more excitable, yet display weaker and – for certain long-latency or inhibitory events – more broadly tuned responses to odorant stimuli. Embryonic and postnatal neurogenesis can therefore generate distinct neuronal subclasses, placing important constraints on the functional roles of adult-born neurons in sensory processing. Most of your brain cells were born before you were. But in mammals, including humans, some of these brain cells, also known as nerve cells or neurons, are created after birth. These later-generated neurons are often extremely similar to their counterparts produced in the womb, and also seem to perform a similar role once they are fully mature. However, it has not been entirely clear if the later-produced neurons may also have a specific purpose. Neurons are made of a cell body with a cable-like structure called axon that transmits information to more distant neurons, and dendrites, which are branches that receive information from other neurons. Neurons use different signalling molecules to communicate, one of which is called dopamine, and the neurons that use this specific signal are called dopaminergic neurons. Now, Galliano et al. wanted to test if neurons created in the womb, and neurons created after birth, are really so similar. To investigate this, they compared the dopaminergic neurons from mice found in the first part of the brain to process information about smell – the olfactory bulb. These specific neurons are known to have diverse properties and can also be produced after birth. Galliano et al. studied their development, form and purpose, and discovered that only neurons produced in the womb can possess an axon. Moreover, the axon-bearing cells had a different form and functional properties to their axon-less cousins, and also showed some subtle differences in their ability to respond to smell. This demonstrates that two very different types of dopaminergic neurons in the olfactory bulb are produced at different stages during the development. A better knowledge of such basic brain-developmental features is essential for the wider goal of understanding how the brain operates, and to discover ways to repair it when it is not working properly. Neurons created after birth in particular, might enable us to develop new treatment strategies; for example, adding new dopaminergic neurons to replace those lost in degenerative disorders such as Parkinson’s Disease. When developing such regenerative therapies, why not learn lessons from how the brain can achieve this naturally?

The axon initial segment (AIS) is a specialized neuronal compartment involved in the maintenance of axo-dendritic polarity and in the generation of action potentials. It is also a site of significant structural plasticity-manipulations of neuronal activity and can produce changes in AIS position and/or size that are associated with alterations in intrinsic excitability. However, to date all activity-dependent AIS changes have been observed in experiments carried out on fixed samples, offering only a snapshot, population-wide view of this form of plasticity. To extend these findings by following morphological changes at the AIS of individual neurons requires reliable means of labeling the structure in live preparations. Here, we assessed five different immunofluorescence-based and genetically-encoded tools for live-labeling the AIS of dentate granule cells (DGCs) in dissociated hippocampal cultures. We found that an antibody targeting the extracellular domain of neurofascin provided accurate live label of AIS structure at baseline, but could not follow rapid activity-dependent changes in AIS length. Three different fusion constructs of GFP with full-length AIS proteins also proved unsuitable: while neurofascin-186-GFP and Na β4-GFP did not localize to the AIS in our experimental conditions, overexpressing 270kDa-AnkyrinG-GFP produced abnormally elongated AISs in mature neurons. In contrast, a genetically-encoded construct consisting of a voltage-gated sodium channel intracellular domain fused to yellow fluorescent protein (YFP-Na II-III) fulfilled all of our criteria for successful live AIS label: this construct specifically localized to the AIS, accurately revealed plastic changes at the structure within hours, and, crucially, did not alter normal cell firing properties. We therefore recommend this probe for future studies of live AIS plasticity and .

Key Points The adult brain is a plastic place. Neuronal responses to a changing environment can occur at the level of molecules, spines, dendrites, axons and, with processes of adult neurogenesis, at the level of entire cells. Neurogenesis definitely occurs in two regions of the adult brain: the subventricular zone (SVZ) lining the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. Neuroblasts from the SVZ migrate along the rostral migratory stream (RMS) to provide new inhibitory granule cells and glomerular cells in the olfactory bulb. Newborn cells from the SGZ migrate to the granular layer of the dentate gyrus, where most of them become excitatory granule cells. The functional maturation of adult-born cells always involves the expression of neurotransmitter receptors before synaptic activity, and the presence of (excitatory) GABA (γ-aminobutyric acid)-mediated influences prior to glutamatergic input. But other maturational features depend on specific cell types, with, for example, olfactory bulb granule cells being late to develop sodium-based action potentials. Factors intrinsic to adult-born cells influence many facets of their maturation. Proliferation and cell fate decisions are particularly strongly controlled by the proteins expressed by neuroblasts. Factors extrinsic to adult-born cells also have a huge influence on all processes of neurogenesis. In this way, adult neurogenesis represents another weapon in the brain's plasticity armoury for dealing with a constantly changing world. With respect to its possible functions, adult neurogenesis might alter the olfactory bulb and hippocampus at the cellular, network and system levels. Computational models suggest that cell turnover might be especially beneficial for the learning of new information. Definitive experiments to demonstrate the function(s) of adult neurogenesis await manipulations that can specifically and completely eliminate it. However, numerous lines of correlative and intervention evidence suggest that hippocampal neurogenesis might be crucial for spatial learning, and that olfactory bulb neurogenesis could be important for sensory discrimination. Lledo and colleagues provide an up-to-date review of recent developments in our understanding of neurogenesis in the adult brain, with a comparative view of the generation of new neurons in the olfactory bulb and the dentate gyrus. The adult brain is a plastic place. To ensure that the mature nervous system's control of behaviour is flexible in the face of a varying environment, morphological and physiological changes are possible at many levels, including that of the entire cell. In two areas of the adult brain — the olfactory bulb and the dentate gyrus — new neurons are generated throughout life and form an integral part of the normal functional circuitry. This process is not fixed, but highly modulated, revealing a plastic mechanism by which the brain's performance can be optimized for a given environment. The functional benefits of this whole-cell plasticity, however, remain a matter for debate.

Neuronal function is intimately tied to axodendritic polarity. Neurotransmitter release, for example, is usually the role of the axon. There are widespread exceptions to this rule, however, including many mammalian neuronal types that can release neurotransmitter from their dendrites. In the mouse olfactory bulb, closely related subclasses of dopaminergic interneuron differ markedly in their polarity, with one subtype lacking an axon entirely. These axon-bearing and anaxonic dopaminergic subclasses have distinct developmental profiles and sensory responses, but how their fundamental polarity differences translate to functional outputs remains entirely unknown. Here, we provide anatomical evidence for distinct neurotransmitter release strategies among these closely related dopaminergic subtypes: anaxonic cells release from their dendrites, while axon-bearing neurons release exclusively from their intermittently myelinated axon. These structural differences are linked to a clear functional distinction: anaxonic, but not axon-bearing, dopaminergic neurons are capable of self-inhibition. Our findings suggest that variations in polarity can produce striking distinctions in neuronal outputs, and that even closely related neuronal subclasses may play entirely separate roles in sensory information processing.

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing revealed that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing and immunostaining demonstrated ACE2 expression in support cells, stem cells, and perivascular cells; in contrast, neurons in both the olfactory epithelium and bulb did not express ACE2 message or protein. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients. Competing Interest Statement DL is an employee of Mars, Inc. None of the other authors have competing interests to declare. Footnotes * now includes new DropSeq dataset, new human olfactory epithelium staining, new mouse olfactory epithelium and bulb staining * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680959/bin/srep18178-s2.xls * https://doi.org/10.1371/journal.pone.0113170.s014 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52464 * https://advances.sciencemag.org/highwire/filestream/217162/field_highwire_adjunct_files/0/aax0396_Data_file_S1.xlsx * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139522 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99251 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120199 * https://www.genomique.eu/cellbrowser/HCA/