Tognolina, M. | Search bioRxiv

bioRxiv2025

From injury to recovery: Functional neuronal regeneration after traumatic brain injury in the telencephalon of the young adult African turquoise killifish

Neuronal loss caused by neurodegenerative diseases and traumatic brain injuries (TBI) often results in long-term disabilities, highlighting the urgent need for further research and effective regenerative strategies. In mammals, neurogenic capacity is inherently limited and declines further with age. In contrast, the young adult killifish demonstrates a remarkable ability to regenerate neurons in the telencephalon following TBI. However, it remains unknown whether and when these newly generated neurons functionally integrate into existing circuits, as traditional histological analysis of fixed tissue offers only static insights into this dynamic process. To this end, we optimized a retroviral vector strategy to label dividing stem cells and their progeny, including newborn neurons. By introducing a combination of novel approaches i.e., retroviral vector labeling, electrophysiology and a conditioned place avoidance test, we investigated the generation, morphology, and synaptic integration of newborn neurons following TBI in the dorsomedial (Dm) zone of the telencephalon, a region homologous to the mammalian amygdala in other teleost fish. Our results show that injury-induced adult-born neurons functionally integrate into existing circuits, and that killifish can achieve functional behavioral recovery after TBI. While previous histological assessments using a stab-wound injury suggested a 30-day recovery period, our functional data reveal that full behavioral recovery requires approximately 50 days. At this point, fish successfully relearn to avoid a conditioned place, and the new neurons exhibit mature morpho-electric characteristics, including abundant dendritic spines. Electrophysiological analysis revealed that newborn neurons in an injured environment take longer to mature when compared to neurons in naive killifish. Together, our findings demonstrate that structural regeneration aligns with functional recovery, and establish retroviral vectors as a powerful tool for birth dating injury-induced neurogenesis in teleosts. Killifish thus represent a promising model for studying interventions aimed at enhancing neuronal maturation and integration after brain injury. Key pointsO_LIA retroviral vector strategy allows specific and sparse labeling of adult-born neurons in the killifish brain. C_LIO_LIThe Dm zone in the telencephalon of the killifish is responsible for avoidance learning and memory and thus homologous to the mammalian amygdala. C_LIO_LIIn young adult killifish, upon Dm injury, adult-born neurons mature morphologically and functionally in 50 days, which is slower than in constitutive neurogenesis. C_LIO_LIThe timing and extent of behavioral recovery from such injury aligns with morpho-electric observations. C_LI

neuroscience↗

bioRxiv2020

Cellular-resolution mapping uncovers spatial adaptive filtering at the cerebellum input stage

Long-term synaptic plasticity, in the form of either potentiation or depression (LTP or LTD), is thought to provide the substrate for adaptive computations in brain circuits. Although molecular and cellular processes of plasticity have been clarified to a considerable extent at individual synapses, very little is known about the spatiotemporal organization of LTP and LTD in local microcircuits. Here, we have combined multi-spot two-photon laser microscopy and realistic modeling to map the distribution of plasticity in multi-neuronal units of the cerebellar granular layer activated by stimulating an afferent mossy fiber bundle. The units, composed by ~300 active neurons connected to ~50 glomeruli, showed potentiation concentrated in the core and depression in the periphery. This plasticity was effectively accounted for by an NMDA receptor and calcium-dependent induction rule and was regulated by local microcircuit mechanisms in the inhibitory Golgi cell loops. The organization of LTP and LTD created effective spatial filters tuning the time-delay and gain of spike retransmission at the cerebellum input stage and provided a plausible basis for the spatiotemporal recoding of input spike patterns anticipated by the motor learning theory.

neuroscience↗

bioRxiv2019

Parameter tuning differentiates granule cell subtypes enriching the repertoire of retransmission properties at the cerebellum input stage

The cerebellar granule cells (GrCs) form an anatomically homogeneous neuronal population which, in its canonical description, discharges regularly without adaptation. We show here that GrCs in fact generate diverse response patterns to current injection and synaptic activation, ranging from adaptation to acceleration of firing. Adaptation was predicted by parameter optimization in detailed GrC computational models based on the available knowledge on GrC ionic channels. The models also predicted that acceleration required the involvement of additional mechanisms. We found that yet unrecognized TRPM4 currents in accelerating GrCs could specifically account for firing acceleration. Moreover, adapting GrCs were better in transmitting high-frequency mossy fiber (MF) bursts over a background discharge than accelerating GrCs. This implied that different electroresponsive patterns corresponded to specific synaptic properties reflecting different neurotransmitter release probability. The correspondence of pre- and post-synaptic properties generated effective MF-GrC transmission channels, which could enrich the processing of input spike patterns and enhance spatio-temporal recoding at the cerebellar input stage.

neuroscience↗