Biology subjects

Erickson, T.

Publications and source records attributed to Erickson, T..

6 recordsLinked to original sources

bioRxiv2025

Convergent and divergent neural and behavioral responses to chronic cocaine use in macaques

Chronic cocaine use leads to physical dependence, psychological addiction, and various health problems such as cardiovascular issues and cognitive impairments. This condition continues to be extremely difficult to treat, as we grapple with its neural and behavioral complexities. What we are missing is a comprehensive account on how naive brains react to occasional and chronic cocaine use, abstinence and re-exposure within subject. We tracked naive macaques using precision functional mapping before, during and after chronic cocaine self-administration over a period of nine months. We analyzed the entire brain to illustrate the pervasive impact of chronic cocaine use on overall function. Although we set out to map the "addiction" connectome, we found that the neural correlates of chronic drug use and recovery are more complex that can be captured by a singular, canonical connectome. We provide a preclinical model that maps the progression of the macaque functional connectome from a naive state through chronic cocaine use, recovery and re-exposure. We demonstrate that the "addiction" connectome is dynamic and is characterized by the interaction of subject by drug by time. Occasional cocaine use, whether initial or re-exposure, overrides individual differences, leading to a strong homogenous effect across subjects, or convergence. However, the brains response to prolonged cocaine use becomes more individualized, resulting in the divergence of effects across subjects. This can be explained by heterogeneity in cocaine-induced effects and in their associated timescales. Abstinence-induced neural alterations converged across subjects after 1-month, but by 2 months, individual trajectories revealed heterogeneity, possibly indicating differences in recovery.

neuroscience↗

bioRxiv2024

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafish vps4a mutants

Mutations in human VPS4A are associated with neurodevelopmental defects, including motor delays and defective muscle tone. VPS4A encodes a AAA-ATPase required for membrane scission, but how mutations in VPS4A lead to impaired control of motor function is not known. Here we identified a mutation in zebrafish vps4a, T248I, that affects sensorimotor transformation. In biochemical experiments we show the T248I mutation reduces the ATPase activity of Vps4a and disassembly of its substrate, ESCRT filaments, which mediate membrane scission. Consistent with the established role for Vps4a in the endocytic pathway and exosome biogenesis, vps4aT248I mutants have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes. Resembling the central form of hypotonia in human VPS4A patients, motor neurons and muscle cells are unaffected in mutant zebrafish as touch sensitivity is intact. Unlike somatosensory function, optomotor responses, vestibulospinal (VS), and acoustic startle reflexes are severely impaired in vps4aT248I mutants, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings indicate that visual ability is largely reduced in the mutants, however, in vivo imaging of tone-evoked responses in the inner ear and ascending auditory pathway show comparable activity. Further investigation of central pathways in vps4aT248I mutants revealed that sensory cues failed to fully activate neurons in the VS and medial longitudinal fasciculus (MLF) nuclei that directly innervate motor neurons. Our results suggest that a defect in sensorimotor transformation underlies the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a. Significance StatementHere we present a T248I mutation in vps4a, which causes sensorimotor defects in zebrafish larvae. Spanning biochemical to systems level analyses, our study indicates that a reduction in Vps4a enzymatic activity leads to endosomal defects and reduced exosome biogenesis, resulting in pronounced deficits in vision and sensorimotor transformation of auditory and vestibular cues. We suggest that the mechanisms underlying this type of dysfunction in zebrafish may also contribute to the condition seen in human patients with de novo mutations in the human VPS4A orthologue.

neuroscience↗

bioRxiv2023

A sensation for inflation: initial swim bladder inflation in larval zebrafish is mediated by the mechanosensory lateral line.

Larval zebrafish achieve neutral buoyancy by swimming up to the surface and taking in air through their mouths to inflate their swim bladders. We define this behavior as surfacing. Little is known about the sensory basis for this underappreciated behavior of larval fish. A strong candidate is the mechanosensory lateral line, a hair cell-based sensory system that detects hydrodynamic information from sources like water currents, predators, prey, and surface waves. However, a role for the lateral line in mediating initial inflation of the swim bladder has not been reported. To explore the connection between the lateral line and surfacing, we utilized a genetic mutant (lhfpl5b-/-) that renders the zebrafish lateral line insensitive to mechanical stimuli. We observe that approximately half of these lateral line mutants over-inflate their swim bladders during initial inflation and become positively buoyant. Thus, we hypothesize that larval zebrafish use their lateral line to moderate interactions with the air-water interface during surfacing to regulate swim bladder inflation. To test the hypothesis that lateral line defects are responsible for swim bladder over-inflation, we show exogenous air is required for the hyperinflation phenotype and transgenic rescue of hair cell function restores normal inflation. We also find that chemical ablation of anterior lateral line hair cells in wild type larvae causes hyperinflation. Furthermore, we show that manipulation of lateral line sensory information results in abnormal inflation. Finally, we report spatial and temporal differences in the surfacing behavior between wild type and lateral line mutant larvae. In summary, we propose a novel sensory basis for achieving neutral buoyancy where larval zebrafish use their lateral line to sense the air-water interface and regulate initial swim bladder inflation.

animal behavior and cognition↗

bioRxiv2023

Regionalized protein localization domains in the hair cell kinocilium

Sensory hair cells are the receptors for auditory, vestibular, and lateral line sensory organs in vertebrates. These cells are distinguished by "hair"-like projections from their apical surface collectively known as the hair bundle. Along with the staircase arrangement of actin-filled stereocilia, the hair bundle features a single, non-motile, true cilium called the kinocilium. The kinocilium plays important roles in bundle development and the mechanics of sensory detection. To understand more about kinocilial development and structure, we performed a transcriptomic analysis of zebrafish hair cells looking for cilia-associated genes that have yet to be characterized in hair cells. Here, we focus on three such genes - ankef1a, odf3l2a, and saxo2 - because the human or mouse orthologs are either associated with sensorineural hearing loss or are located near uncharacterized deafness loci. We made transgenic fish that express fluorescently tagged versions of their proteins, demonstrating their localization to the kinocilia of zebrafish hair cells. Furthermore, we find that Ankef1a, Odf3l2a, and Saxo2 exhibit distinct localization patterns along the length of the kinocilium and within the cell body. Lastly, we report a novel overexpression phenotype for Saxo2. Overall, these results suggest that the hair cell kinocilium is regionalized along its proximal-distal axis and set the groundwork to understand more about the roles of these kinocilial proteins in hair cells.

cell biology↗

bioRxiv2022

Alone in a crowd: Effect of a nonfunctional lateral line on expression of the social hormone parathyroid hormone 2.

Parathyroid hormone 2 (Pth2) is a vertebrate-specific neuropeptide whose thalamic expression is upregulated by social contact with conspecifics. However, social interactions fail to stimulate pth2 expression in isolated zebrafish whose lateral line hair cells have been chemically ablated. These results suggest that modulation of pth2 by social context is acutely dependent on mechanosensory information from the lateral line. However, it is unclear how a congenital loss of lateral line function influences the ability of zebrafish to interpret their social environment. In this study, we measure pth2 levels in zebrafish mutants lacking hair cell function in either the lateral line only, or in both the inner ear and lateral line. Socially-raised lateral line mutants express lower levels of pth2 relative to wild type siblings, but there is no further reduction when all sensory hair cells are nonfunctional. However, social isolation of hair cell mutants causes a further reduction in pth2 expression, pointing to additional unidentified sensory cues that influence pth2 production. Lastly, we report that social context modulates fluorescent transgenes driven by the pth2 promoter. Altogether, these data suggest that lateral line mutants experience a form of isolation, even when raised in a social environment. SUMMARY STATEMENTExpression of the pro-social neuropeptide pth2 is downregulated in larval zebrafish with a congenital loss of lateral line function. Thus, even in social environments, fish with compromised lateral lines may experience a form of isolation.

neuroscience↗

bioRxiv2019

The lhfpl5 ohnologs lhfpl5a and lhfpl5b are required for mechanotransduction in distinct populations of sensory hair cells in zebrafish.

1Hair cells sense and transmit auditory, vestibular, and hydrodynamic information by converting mechanical stimuli into electrical signals. This process of mechano-electrical transduction (MET) requires a mechanically-gated channel localized in the apical stereocilia of hair cells. In mice, lipoma HMGIC fusion partner-like 5 (LHFPL5) acts as an auxiliary subunit of the MET channel whose primary role is to correctly localize PCDH15 and TMC1 to the mechanotransduction complex. Zebrafish have two lhfpl5 genes (lhfpl5a and lhfpl5b), but their individual contributions to MET channel assembly and function have not been analyzed. Here we show that the zebrafish lhfpl5 genes are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific to hair cells of the lateral line organ. Consequently, lhfpl5a mutants exhibit defects in auditory and vestibular function, while disruption of lhfpl5b affects hair cells only in the lateral line neuromasts. In contrast to previous reports in mice, localization of Tmc1 does not depend upon Lhfpl5 function in either the inner ear or lateral line organ. In both lhfpl5a and lhfpl5b mutants, GFP-tagged Tmc1 and Tmc2b proteins still localize to the stereocilia of hair cells. Using a stably integrated GFP-Lhfpl5a transgene, we show that the tip link cadherins Pcdh15a and Cdh23, along with the Myo7aa motor protein, are required for correct Lhfpl5a localization at the tips of stereocilia. Our work corroborates the evolutionarily conserved co-dependence between Lhfpl5 and Pcdh15, but also reveals novel requirements for Cdh23 and Myo7aa to correctly localize Lhfpl5a. In addition, our data suggest that targeting of Tmc1 and Tmc2b proteins to stereocilia in zebrafish hair cells occurs independently of Lhfpl5 proteins.

neuroscience↗