Biology subjects

Franklin, J. P.

Publications and source records attributed to Franklin, J. P..

5 recordsLinked to original sources

bioRxiv2025

Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates

The endoplasmic reticulum (ER)s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimers disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in hiPSC-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ERs capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalising ER dysfunction in neurodegeneration. This mechanism could apply universally to Ca2+-firing cells.

cell biology↗

bioRxiv2024

Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior

Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brains reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving.

neuroscience↗

bioRxiv2024

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs of abuse; specifically, astrocytes within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration of cocaine and extinction or protracted abstinence (45 days). However, the mechanisms that elicit these morphological modifications are unknown. The current study aims to elucidate the molecular modifications that lead to observed astrocyte structural changes in rats across cocaine abstinence using astrocyte-specific RiboTag and RNA-seq, as an unbiased, comprehensive approach to identify genes whose transcription or translation change within NAc astrocytes following cocaine self-administration and extended abstinence. Using this method, our data reveal cellular processes including cholesterol biosynthesis that are altered specifically by cocaine self-administration and abstinence, suggesting that astrocyte involvement in these processes is changed in cocaine-abstinent rats. Overall, the results of this study provide insight into astrocyte functional adaptations that occur due to cocaine exposure or during cocaine withdrawal, which may pinpoint further mechanisms that contribute to cocaine-seeking behavior.

neuroscience↗

bioRxiv2022

Abstinence-dependent effects of long-access cocaine self-administration on nucleus accumbens astrocytes are observed in male, but not female rats

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA, 2 hours/day) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here we assess the effects of long-access (LgA, 6 hours/day) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive ([~]40%) reductions in surface area, volume, and postsynaptic colocalization 45 days, but not 24 hours after the last self-administration session. In contrast, no effect of self-administration was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. The results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.

neuroscience↗

bioRxiv2020

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats.

Post-traumatic stress disorder (PTSD) is a psychiatric illness that can increase the risk for developing an alcohol use disorder (AUD). While clinical data has been useful in identifying similarities in the neurobiological bases of these disorders, preclinical models are essential for understanding the mechanism(s) by which PTSD increases the risk of developing AUD. The purpose of these studies was to examine if exposure of male Long-Evans rats to the synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) would increase alcohol self-administration, potentially by facilitating transfer of salience towards cues, and alter neuronal response to alcohol as measured by the immediate early gene c-Fos. In Experiment 1 rats exposed to repeated (4x) TMT showed reductions in goal-tracking behavior in Pavlovian conditioned approach, and increases in alcohol self-administration. In Experiment 2 rats exposed to repeated TMT showed blunted basolateral amygdala c-Fos response to alcohol, and increased correlation between medial prefrontal cortex and amygdala subregions. In Experiment 3 rats exposed to single, but not repeated TMT showed increases in alcohol self-administration, and no change in anxiety-like behavior or hyperarousal. In Experiment 4, rats showed no habituation of corticosterone response after 4 TMT exposures. In summary, exposure of male rats to TMT can cause escalations in alcohol self-administration, reductions in goal-tracking behavior, and reduction in BLA response to alcohol. These studies outline and utilize a novel preclinical model that can be used to further neurobiological understanding of the relationship between PTSD and AUD.

neuroscience↗