Biology subjects

Clemens, K.

Publications and source records attributed to Clemens, K..

3 recordsLinked to original sources

bioRxiv2025

Sodium Butyrate Rescues Neurodevelopmental Deficits Following Perinatal Methadone Exposure

Prenatal opioid exposure (POE) induces long-term neurodevelopmental, behavioral and cognitive deficits for which no targeted treatments are available. The mechanisms underlying POE deficits are poorly understood, but have been linked to a range of central, peripheral, and enteric nervous system changes. Emerging evidence indicates that maternal microbiota changes may also contribute to these long-term deficits in offspring. Here we test the efficacy of the short-chain fatty acid sodium butyrate (NaB) to mitigate POE-induced deficits in a rat model. Both methadone and sodium butyrate treatments altered dam microbiota composition and function: notably methadone disrupted dam gene expression of microbial enzymes critical for butyric acid production and reduced faecal butyric acid levels. In postnatal day 9 pups, methadone increased gut barrier permeability that was reversed with NaB, and enzymatic disruptions were observed in pups at postnatal day 21 that resolved in adulthood. POE induced anxiety-like behavior in adolescence, and adult deficits in working spatial memory and attentional processing that were partially rescued in rats that had received prenatal NaB. POE was associated with decreased myelination in the hippocampus, and this was partially reversed by NaB. Together these results highlight for the first time the link between the gut-brain axis in animal models of POE. Furthermore, they provide the first indication in a rat model of NaB as a simple yet effective treatment to significantly improve the outcomes of children born with POE.

animal behavior and cognition↗

bioRxiv2024

Dorsomedial striatal neuroinflammation causes excessive goal-directed action control by disrupting homeostatic astrocyte function

Compulsive actions are typically thought to reflect the dominance of habits over goal-directed action. To address this, we mimicked the striatal neuroinflammation that is frequently exhibited in individuals with compulsive disorders in rats, by injecting the endotoxin lipopolysaccharide into the posterior dorsomedial striatum, and assessed the consequences for behavioural control. Surprisingly, this manipulation caused rats to acquire and maintain goal-directed actions under conditions that would otherwise produce habits. Immunohistochemical analyses indicated that these behaviours were a result of astrocytic proliferation. To probe this further, we chemogenetically activated the Gi-pathway in striatal astrocytes, which altered the firing properties of nearby medium spiny neurons and modulated goal-directed action control. Together, results show that striatal neuroinflammation is sufficient to bias action selection toward excessive goal-directed control via dysregulated astrocyte function. If translatable, our findings suggest that, contrary to conventional views, individuals with striatal neuroinflammation might be more prone to maladaptive goal-directed actions than habits, and future interventions should aim to restore appropriate action control.

animal behavior and cognition↗

bioRxiv2022

Neuronal growth regulator 1 (NEGR1) promotes synaptic targeting of glutamic acid decarboxylase 65 (GAD65)

Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored cell adhesion molecule encoded by an obesity susceptibility gene. We demonstrate that NEGR1 accumulates in GABAergic inhibitory synapses in hypothalamic neurons, a GABA-synthesizing enzyme GAD65 attaches to the plasma membrane, and NEGR1 promotes clustering of GAD65 at the synaptic plasma membrane. GAD65 is removed from the plasma membrane with newly formed vesicles. The association of GAD65 with vesicles results in increased GABA synthesis. In NEGR1 deficient mice, the synaptic targeting of GAD65 is decreased, the GABAergic synapse densities are reduced, and the reinforcing effects of food rewards are blunted. In mice fed a high fat diet, levels of NEGR1 are increased and GAD65 abnormally accumulates at the synaptic plasma membrane. Our results indicate that NEGR1 regulates a previously unknown step required for synaptic targeting and functioning of GAD65, which can be affected by bidirectional changes in NEGR1 levels causing disruptions in the GABAergic signaling controlling feeding behavior.

neuroscience↗