Hippocampal UCP2 is essential for cognition and resistance to anxiety but not required for the benefits of exercise

Wang, D.; Zhai, Xiaofeng; Chen, P.; Yang, Mingliang; Zhao, Junqing; Dong, Jing; Liu, H.

doi:10.1016/j.neuroscience.2014.06.060

Cited by 17 publications

(18 citation statements)

References 34 publications

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“…D) A forest plot showing that Ucp2 had higher expression in bHRs in four out of the five adult datasets included in the adult meta-analysis (effect of phenotype: β=1.29, p=1.27E-04, FDR=3.83E-02). This direction of effect mirrors findings in the literature showing that Ucp2 knockout mice have higher anxiety-like behavior and lower locomotor activity, as well as greater sensitivity to stress (63, 64, 66, 67), much like our bLR rats. E) In the behavioral data accompanying the MBNI_RNASeq_F37 dataset, Ucp2 showed a trend towards a positive relationship with percent of time spent in the anxiogenic open arms of the EPM (β=0.03, R 2 =0.22, p=5.16E-02).…”

Section: Resultssupporting

confidence: 88%

“…Within our transcriptomic meta-analysis, we found that a narrow part (1.4 MB) of this region was enriched for bHR/bLR differentially-expressed genes, including Ucp2. In the literature, similar to our bLR rats, Ucp2-KO mice showed higher anxiety-like behavior and lower locomotor activity at baseline, and lowered resilience to stress (63, 64, 66, 67). Therefore, it seems likely that genetic variation on chromosome 1 is driving differential expression in Ucp2 in a manner that may directly contribute to bHR/bLR differences in exploratory locomotion and the propensity for internalizing behaviors.…”

Section: Discussionsupporting

confidence: 87%

See 1 more Smart Citation

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

Birt

Hagenauer

Clinton

et al. 2019

Preprint

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2For over 16 years, we have selectively-bred rats to react differently to a novel, anxiety-3 inducing environment, exhibiting either high or low exploratory activity. These "bred High 4 Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a general model for extreme 5 manifestations of behavioral inhibition and temperament, showing large differences in a variety 6 of internalizing and externalizing behaviors relevant to both mood and substance abuse 7 disorders. The current study elucidated persistent differences in gene expression related to 8 bHR/bLR phenotype across development (P7, P14, P21) and adulthood within the 9 hippocampus, a brain structure critical for emotional regulation. To do this, we meta-analyzed 10 eight transcriptional profiling datasets (microarray and RNA-Seq) spanning 43 generations of 11 selective breeding (n=2-6 rats per group per dataset; total n per meta-analysis: adult: n=46, P7: 12 n=22, P14: n=49, P21: n=21). By cross-referencing these results with a concurrent exome 13 sequencing study performed on our colony, we pinpointed several genes that are strongly 14 implicated in bHR/bLR behavioral phenotype, including two genes previously associated with 15 energy metabolism and mood: Thyrotropin releasing hormone receptor (Trhr) and the 16 mitochondrial protein Uncoupling protein 2 (Ucp2). Our meta-analysis also highlighted robust 17 bHR/bLR functional differences in the hippocampus, including a network essential for 18 neurodevelopmental programming, cell proliferation, and differentiation, which centered on the 19 hub genes Bone morphogenetic protein 4 (Bmp4) and the canonical Marker of proliferation 20 (Mki67). Another functional theme was microglial activation and phagocytosis, including 21 differential expression of pro-inflammatory Complement C1q A chain (C1qa) and the anti- 22inflammatory Milk fat globule-EGF factor 8 (Mfge8), situated within a chromosomal loci 23 implicated by our concurrent genetic study. Given the newly-discovered role of microglia in 24 synaptic pruning in relationship to neuronal activity during both development and adulthood, we 25 propose that these functional pathways have the capability to not only direct bHR and bLR rats 26 along a different developmental trajectory, but to set the stage for a widely-different reactivity to 27 the environment. 28 29 30 35 36 Both mood disorders and substance abuse disorders affect approximately 8-10% of 37 adults in the United States each year (1, 2). Due to high comorbidity, these disorders are often 38 classified as either internalizing and externalizing. Internalizing disorders are associated with 39 neuroticism, anxiety, and depression, whereas externalizing disorders are associated with 40 greater risk-taking and novelty-seeking, as seen in mania, substance abuse, and impulse-41 control disorders (3). This pattern of comorbidity is thought to represent a spectrum of latent 42 liability, which arises from a complex interplay of genetic risk and environmental factors, such as 43 stress and childhood adversity...

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

Birt

Hagenauer

Clinton

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Another example involves the uncoupling protein 2 (UCP2), a member of the mitochondrial transporter superfamily that uncouples oxidative phosphorylation to ATP synthesis. Its deficiency, either ubiquitously [80] or specifically in the hippocampus [81] leads, as well, to anxiety-like behaviors.…”

Section: Studies Targeting Genes That Regulate Other Mitochondrial Prmentioning

confidence: 99%

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Filiou

Sandi

2019

Trends in Neurosciences

116

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Accumulating data highlight the contribution of brain mitochondria and bioenergetics to psychiatric disorders and stress-related pathologies. Although anxiety has not received much attention in this booming literature, a bidirectional interplay between anxiety and brain mitochondria and metabolism has recently started to emerge. Substantial observations indicate alterations in mitochondria and metabolism in highly anxious individuals and, conversely, anxiety symptoms in humans suffering from mitochondrial disorders. Genetic and pharmacological efforts have made substantial progress at advancing the causal involvement of specific mitochondrial and metabolic factors in anxiety. In this review, we discuss this converging evidence and highlight the relevance to develop a research focus on targeting mitochondria as a promising approach to alleviate anxiety.

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“…Requirement of neuroprotecting role of UCP2 has already been documented as a prevention of neuronal death and brain dysfunction after stroke and brain trauma ( 275 ) and upon UCP2 downregulation by antisense oligonucleotides, which resulted in impaired learning and memory of the mice ( 421 ). UCP2 expression in astrocytes was linked to the increased survival of dopaminergic neurons upon Parkinson disease ( 258 ).…”

Section: Involvement Of Ucps In Redox Homeostasis and Redox Regmentioning

confidence: 99%

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox SignalingReviewing Editors:Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

Ježek

Holendová

Garlid

et al. 2018

Antioxidants & Redox Signaling

109

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Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling.Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells.Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling.Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714.

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Hippocampal UCP2 is essential for cognition and resistance to anxiety but not required for the benefits of exercise

Cited by 17 publications

References 34 publications

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox SignalingReviewing Editors:Jerzy Beltowski, Joseph Burgoyne, Gabor Csanyi, Sergey Dikalov, Frank Krause, Anibal Vercesi, and Jeremy Ward

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