Highlights d Glutamylated tubulin is enriched in cilia of foxj1-expressing cells in the zebrafish d Motile ciliated ependymal cells in the zebrafish forebrain are highly diverse d Gmnc drives the transition from mono-to multiciliated cells at juvenile stage d Lack of multiciliation does not impact brain and spine morphogenesis

The developing brain undergoes drastic alterations. Here, we investigated developmental changes in the habenula, a brain region that mediates behavioral flexibility during learning, social interactions, and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations that lead to an increase in the structural and functional diversity of cell types, inputs, and functional modules. As the habenula develops, it sequentially transforms into a multisensory brain region that can process visual, olfactory, mechanosensory, and aversive stimuli. Moreover, we observed that the habenular neurons display spatiotemporally structured spontaneous activity that shows prominent alterations and refinement with age. These alterations in habenular activity are accompanied by sequential neurogenesis and the integration of distinct neural clusters across development. Last, we revealed that habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the functional properties of habenular neurons and their precise birthdate.

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus able to reach the central nervous system (CNS) after primary infection in oronasal mucosa. HSV-1 establishes latency inside neurons due the repression of its gene expression process, which is related to periodic reactivations in response to cellular stress conditions, constituting a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). The immediate-early gene Arc plays an essential role in neuronal morphology, synaptic plasticity and memory formation. Arc acts as a hub protein, interacting with components of the endocytic machinery required for AMPA receptor (AMPAR) recycling as well as with proteins of the post-synaptic density and actin cytoskeleton. However, to date, no studies have evaluated whether persistent neurotropic HSV-1 infection modulates the expression or function of Arc protein in brain tissue. Here, we report that neuronal in vivo and in vitro infection of HSV-1 significantly increases Arc protein levels, showing a robust perinuclear distribution in neuronal cell lines, a process that is dependent on an active HSV-1 replication cycle. Finally, we found that silencing Arc protein caused a decrease in HSV-1 proteins and viral progeny, suggesting that Arc is involved in the lifecycle of HSV-1. Our studies strongly suggest that pathogenicity of HSV-1 neuronal reactivations in humans could be mediated in part by Arc neuronal upregulation and its potential role in endocytic trafficking and AMPA-neuronal function impairment. Further studies are necessary to define whether this phenomenon could have repercussions in cognition and learning processes in infected individuals.

Herpes simplex virus type HSV-is a ubiquitous and neurotropic pathogen and is the most common cause of acute sporadic encephalitis in humans. This virus is characterized by establishing a persistent latent infection in neurons of its hosts for life. The pathogenic mechanisms of HSV-at the central nervous system CNS are not completely elucidated. Besides, evidences suggest that HSV-establish latency in the CNS in humans and that this condition would not be harmless, especially in people whose immune system is declined. This trait has been strongly suggested as a risk factor for the development of neurodegenerative pathologies such as Alzheimer's disease. Currently, it is unclear whether a neuron, which undergoes viral reactivation and produces infectious particles, survives and resumes latency, loses functionality, or is killed. These data highlight the need for more studies at cellular and molecular levels to understand the strategies used by the virus and the host cells during both productive and latent infection. The present chapter discusses the current investigations about HSV-infection at the CNS and the potential risk of neuronal dysfunction and chronic neurological diseases.

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. The primary infection in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny is transported anterogradely to the primary site of infection. In late stages of neuronal infection, axonal damage is known to occur. However, the impact of HSV-1 infection on morphology and functional integrity at earlier stages of infection in neuronal dendrites is unknown. Previously, we demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances the expression of Arc protein -a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc may alter the functionality of the infected neurons having an impact on dendritic spine dynamics. In this study we demonstrated that HSV-1 infection causes structural disassembly and functional deregulation in cultured cortical neurons, through protein homeostasis alteration with intracellular accumulation of Arc, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. Our findings reveal progressive deleterious effects of HSV-1 infection on excitatory neuronal synapse function and dendritic morphology, supporting the thesis of the infectious origin of neurodegenerative processes.

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