Dataset Information

Prepubertal Environmental Enrichment Prevents Dopamine Dysregulation and Hippocampal Hyperactivity in MAM Schizophrenia Model Rats.

ABSTRACT:

Background

Schizophrenia (SCZ) is a neurodevelopmental disorder with a progressive, prolonged course. Early prevention for SCZ is promising but overall lacks support from preclinical evidence. Previous studies have tested environmental enrichment (EE) in certain models of SCZ and discovered a broadly beneficial effect in preventing behavioral abnormalities relevant, yet not specific, to the disorder. Nonetheless, whether EE can prevent dopamine (DA) dysregulation, a hallmark of psychosis and SCZ, had not been tested.

Methods

Using the MAM (methylazoxymethanol acetate) rat model of schizophrenia and saline-treated control animals, we investigated the long-term electrophysiological effects of prepubertal (postnatal day 21-40) EE on DA neurons, pyramidal neurons in the ventral hippocampus, and projection neurons in the basolateral amygdala. Anxiety-related behaviors in the elevated plus maze and locomotor responses to amphetamine were also analyzed.

Results

Prepubertal EE prevented the increased population activity of DA neurons and the associated increase in locomotor response to amphetamine. Prepubertal EE also prevented hyperactivity in the ventral hippocampus but did not prevent hyperactivity in the basolateral amygdala. Anxiety-like behaviors in MAM rats were not ameliorated by prepubertal exposure to EE.

Conclusions

Twenty-day prepubertal EE is sufficient to prevent DA hyperresponsivity in the MAM model, measured by electrophysiological recordings and locomotor response to amphetamine. This effect is potentially mediated by normalizing excessive firing in the ventral hippocampus without affecting anxiety-like behaviors and basolateral amygdala firing. This study identified EE as a useful preventative approach that may protect against the pathophysiological development of SCZ.

SUBMITTER: Zhu X

PROVIDER: S-EPMC7927755 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Onset and progression of neurodegenerative disorders, including synucleinopathies such as Parkinson's disease, have been associated with various environmental factors. A highly compelling association from a therapeutic point of view has been found between a physically active lifestyle and a significantly reduced risk for Parkinson's disease. Mimicking such conditions in animal models by promoting physical activity, social interactions, and novel surroundings yields in a so-called enriched environment known to enhance adult neurogenesis, increase synaptic plasticity, and decelerate neuronal loss. Yet, the genes that connect beneficial environmental cues to the genome and delay disease-related symptoms have remained largely unclear. To identify such mediator genes, we used a 2 × 2 factorial design opposing genotype and environment. Specifically, we compared wildtype to transgenic mice overexpressing human SNCA, a key gene in synucleinopathies encoding alpha-synuclein, and housed them in a standard and enriched environment from weaning to 12 months of age before profiling their hippocampal transcriptome using RNA-sequencing. Under standard environmental conditions, differentially expressed genes were overrepresented for calcium ion binding, membrane, synapse, and other Gene Ontology terms previously linked to alpha-synuclein biology. Upregulated genes were significantly enriched for genes attributed to astrocytes, microglia, and oligodendrocytes. These disturbances in gene activity were accompanied by reduced levels of several presynaptic proteins and the immediate early genes EGR1 and NURR1. Intriguingly, housing transgenic animals in the enriched environment prevented most of these perturbations in gene activity. In addition, a sustained activation specifically in transgenic animals housed in enriched conditions was observed for several immediate early genes including Egr1, Nr4a2/Nurr1, Arc, and Homer1a. These findings suggest a compensatory mechanism through an enriched environment-activated immediate early gene network that prevented most disturbances induced by alpha-synuclein overexpression. This regulatory framework might harbor attractive targets for novel therapeutic approaches that mimic beneficial environmental stimuli.

Project description:Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble A? oligomers (oA?) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oA?-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNF?) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oA? extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oA?, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system.Environmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human A? oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.