Environmental enrichment induces behavioural disturbances in neuropeptide Y knockout mice

Reichmann, Florian; Wegerer, Vanessa; Jain, Piyush; Mayerhofer, Raphaela; Hassan, Ahmed M.; Fröhlich, Esther E.; Bock, Elisabeth; Pritz, Elisabeth; Herzog, Herbert; Holzer, Peter; Leitinger, Gerd

doi:10.1038/srep28182

Cited by 23 publications

(19 citation statements)

References 64 publications

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“…Studies have proposed that hippocampal neurogenesis 54 , synaptogenesis enhancement 55 , neuropeptideY 56 and serotonin levels in frontal cortex 57 may underlie EE induced decrease in anxiety. Thus, it is plausible that EE causes decrease in anxiety independent of Tmem132d in HAB mice.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex

et al. 2018

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TMEM132D is a candidate gene, where risk genotypes have been associated with anxiety severity along with higher mRNA expression in the frontal cortex of panic disorder patients. Concurrently, in a high (HAB) and low (LAB) trait anxiety mouse model, Tmem132d was found to show increased expression in the anterior cingulate cortex (aCC) of HAB as compared to LAB mice. To understand the molecular underpinnings underlying the differential expression, we sequenced the gene and found two single-nucleotide polymorphisms (SNPs) in the promoter differing between both lines which could explain the observed mRNA expression profiles using gene reporter assays. In addition, there was no difference in basal DNA methylation in the CpG Island that encompasses the HAB vs. LAB Tmem132d promoter region. Furthermore, we found significantly higher binding of RNA polymerase II (POLR2A) to the proximal HAB-specific SNP (rs233264624) than the corresponding LAB locus in an oligonucleotide pull-down assay, suggesting increased transcription. Virus mediated overexpression of Tmem132d in the aCC of C57BL/6 J mice could confirm its role in mediating an anxiogenic phenotype. To model gene–environmental interactions, HAB mice exposed to enriched environment (HAB-EE) responded with decreased anxiety levels but, had enhanced Tmem132d mRNA expression as compared to standard-housed HAB (HAB-SH) mice. While LAB mice subjected to unpredictable chronic mild stress (LAB-UCMS) exhibited higher anxiety levels and had lower mRNA expression compared to standard-housed LAB (LAB-SH) mice. Chromatin immunoprecipitation revealed significantly higher binding of POLR2A to rs233264624 in HAB-EE, while LAB-UCMS had lower POLR2A binding at this locus, thus explaining the enhanced or attenuated expression of Tmem132d compared to their respective SH controls. To further investigate gene–environment interactions, DNA methylation was assessed using Illumina 450 K BeadChip in 74 panic disorder patients. Significant methylation differences were observed in two CpGs (cg26322591 and cg03283235) located in TMEM132D depending on the number of positive life events supporting the results of an influence of positive environmental cues on regulation of Tmem132d expression in mice.

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Section: Discussionmentioning

confidence: 99%

Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex

et al. 2018

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“…Studies have confirmed that NPY neurons are involved in the regulation of anxiety in mice ( 128 ). Moreover, direct injection or overexpression of NPY in the brain exerts anti-anxiety effects in rodents ( 129 ), and knockout of NPY exacerbates the anxiety phenotype in mice ( 130 ). In rodents, the alleviation of anxiety caused by overexpression of Y1R also corroborates the above findings ( 131 ).…”

Section: Npy Indirectly Regulates the Immune Responsementioning

confidence: 99%

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

Chen

Liu

et al. 2020

Front. Immunol.

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Neuropeptide Y (NPY), which is widely distributed in the nervous system, is involved in regulating a variety of biological processes, including food intake, energy metabolism, and emotional expression. However, emerging evidence points to NPY also as a critical transmitter between the nervous system and immune system, as well as a mediator produced and released by immune cells. In vivo and in vitro studies based on gene-editing techniques and specific NPY receptor agonists and antagonists have demonstrated that NPY is responsible for multifarious direct modulations on immune cells by acting on NPY receptors. Moreover, via the central or peripheral nervous system, NPY is closely connected to body temperature regulation, obesity development, glucose metabolism, and emotional expression, which are all immunomodulatory factors for the immune system. In this review, we focus on the direct role of NPY in immune cells and particularly discuss its indirect impact on the immune response.

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“…Enriched environments (EE) in laboratory rodents comprise housing in large cages equipped with toys and exercise items that stimulate playful behavior and physical activity. This manipulation may enhance cognitive abilities (He et al, 2017 ; Zeleznikow-Johnston et al, 2017 ) and diminish anxiety- and depressive-like behaviors (Galani et al, 2007 ; Nicolas et al, 2015 ; Reichmann et al, 2016 ; Aujnarain et al, 2018 ). Behavioral and cognitive effects of EE have been linked to increased neurogenesis and elevated expression of hippocampal brain-derived neutrophic factor (BDNF; Schloesser et al, 2010 ; Novkovic et al, 2015 ), and improved synaptic and transcriptomic capacity (Hüttenrauch et al, 2016 ; Zhang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Post-weaning Environmental Enrichment in Male CD-1 Mice: Impact on Social Behaviors, Corticosterone Levels and Prefrontal Cytokine Expression in Adulthood

McQuaid

Dunn

Jacobson‐Pick

et al. 2018

Front. Behav. Neurosci.

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Environmental enrichment is typically associated with enhanced well-being, improved cognitive function and stress resilience. However, in some instances grouping adult male mice in enriched conditions promoted a stressful environment, which resulted in elevated endocrine, monoamine and inflammatory outcomes in response to subsequent stressor exposure. The current investigation examined whether raising male mice in an enriched environment (EE) would modulate social and anxiety-like behaviors in early adulthood and influence brain expression of pro-inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Immediately after weaning (postnatal day [PD] 21), CD-1 male mice were housed with their siblings (3/cage) for 6 weeks in an EE or a standard (SE) environment. Body weights and aggressive interactions were monitored weekly. Social avoidance behaviors in the social interaction test and anxiety-like behaviors in the elevated-plus maze were examined in early adulthood. Ninety minutes following the behavioral tests, mice were sacrificed and a blood sample and the prefrontal cortex (PFC) were collected for the determination of plasma corticosterone levels as well as cytokine and BDNF mRNA expression. Mice raised in an EE exhibited more wounds and gained less weight than mice housed in a SE. Enriched mice also spent a greater amount of time in proximity of a social target in the social interaction test and made fewer transitions into the closed arms of the elevated-plus maze. Interestingly, the elevated plasma corticosterone and upregulated prefrontal interleukin (IL)-1β expression observed after the social interaction test among the SE mice were not apparent among those housed in an EE. Enrichment also increased prefrontal BDNF expression, especially among mice that experienced the social interaction test. These results suggest that although raising male mice in an EE may elicit aggressive interactions between sibling cage-mates (as indicated by a high number of wounds), this environment also enhances social behaviors and limits the corticosterone and cytokine impacts of mild social stressors encountered in early adulthood.

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Environmental enrichment induces behavioural disturbances in neuropeptide Y knockout mice

Cited by 23 publications

References 64 publications

Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex

Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

Post-weaning Environmental Enrichment in Male CD-1 Mice: Impact on Social Behaviors, Corticosterone Levels and Prefrontal Cytokine Expression in Adulthood

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