Mitochondrial dysfunction and exacerbated neuroinflammation are critical factors in the pathogenesis of both familial and non-familial forms of Parkinson’s disease (PD). This study aims to understand the possible ameliorative effects of zonisamide on microglial mitochondrial dysfunction in PD. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and lipopolysaccharide (LPS) co-treated mouse models of PD to investigate the effects of zonisamide on mitochondrial reactive oxygen species generation in microglial cells. Consequently, we utilised a mouse BV2 cell line that is commonly used for microglial studies to determine whether zonisamide could ameliorate LPS-treated mitochondrial dysfunction in microglia. Flow cytometry assay indicated that zonisamide abolished microglial reactive oxygen species (ROS) generation in PD models. Extracellular flux assays showed that LPS exposure to BV2 cells at 1 μg/mL drastically reduced the mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Zonisamide overcame the inhibitory effects of LPS on mitochondrial OCR. Our present data provide novel evidence on the ameliorative effect of zonisamide against microglial mitochondrial dysfunction and support its clinical use as an antiparkinsonian drug.

/pdf/zonisamide-ameliorates-microglial-mitochondriopathy-in-day9dvpk.pdf

Zonisamide Ameliorates Microglial Mitochondriopathy in Parkinson’s Disease Models

Using selective breeding, we have produced two rat lines with highly divergent behaviors: bred Low Responders (bLR) are extremely inhibited and anxious in a novel environment, whereas bred High Responders (bHR) are exploratory and sensation-seeking. These traits map onto temperamental extremes predictive of internalizing vs. externalizing psychiatric disorders in humans and model two divergent paths to drug abuse. To elucidate gene expression underlying these heritable behavioral differences, bHR and bLR rats from the 37th generation of selection were used to produce F0, F1 cross, and F2 intercross generations. We measured exploratory locomotion, anxiety-like behavior, and sensitivity to reward cues (Pavlovian Conditioned Approach) and performed hippocampal RNA sequencing in both F0s (n=24, n=6/phenotype/sex) and F2s (n=250, n=125/sex). Behaviors that diverged during selective breeding remained correlated in F2s, implying a shared genetic basis. F0 bHR/bLR differences in gene expression were robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. Among the bHR/bLR differentially expressed genes (DEGs), 17 were associated with exploratory locomotion in the F2s, seven of which were located within related quantitative trait loci we previously identified in F2s. Convergence between our study and others targeting similar behavioral traits revealed an additional 26 genes related to behavioral temperament. Gene set enrichment analysis pointed to growth and proliferation being upregulated with bHR-like behavior, and mitochondrial function, oxidative stress, and microglial activation being upregulated with bLR-like behavior. Our findings implicate bioenergetic regulation of hippocampal function in shaping temperamental differences, thereby modulating vulnerability to psychiatric and addictive disorders.

https://www.biorxiv.org/content/biorxiv/early/2022/07/15/2022.07.14.500129.full.pdf

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2 Cross of Selectively-Bred Rats

Abstract Genetic factors play a critical role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD), but environmental factors may also be responsible for ADHD symptoms. In this study, Lister hooded rats (LHRs), which are outbred rats that exhibit more hyperactive, inattentive, and impulsive behaviors than Wistar rats, were used as ADHD model animals. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in a large, tall cage with an enriched environment [EE]) until 9 weeks of age. EE rearing decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. LHRs reared in a large flat cage did not exhibit any apparent change in motor activity. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. The rats reared in an EE for 3 weeks from 6 weeks of age also showed an improvement in their ADHD-like behaviors. RNA sequencing revealed that the expression of immediate-early genes in the medial prefrontal cortex (mPFC) of LHRs reared in a standard cage was higher than that in the mPFC of LHRs reared in an EE. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE from childhood or adolescence improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC. 

Rearing in an enriched environment ameliorates the ADHD-like behaviors of Lister hooded rats while suppressing neuronal activities in the medial prefrontal cortex

Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.

/pdf/rearing-in-an-enriched-environment-ameliorates-the-adhd-like-7948phu7.pdf

Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex

S. M. Bak

Papers

Insomnia and depressive behavior of MyD88-deficient mice: Relationships with altered microglial functions