Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral tissues of male rats

Pekary, A. Eugene; Sattin, Albert; Lloyd, Robert L.

doi:10.1016/j.peptides.2015.04.003

Cited by 20 publications

(14 citation statements)

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“…In previous studies, Trhr1-KO mice displayed increased anxiety and depressive-like behavior (68) similar to our bLRs. Likewise, the Trh analog, Glu-Trh, decreased anxiety in rats (65). We found that Trhr was the top gene within a bHR-upregulated gene set associated with the ventral dentate gyrus (44), a region of the hippocampus that may be particularly important for emotional regulation and stress (20).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

“…DE genes were also 4.5x more likely to be located within a QTL for exploratory locomotion (LOD>4; Fig 6B). This overlap included two genes previously associated with internalizing and externalizing behaviors (Thyrotropin Releasing Hormone Receptor (Trhr), Uncoupling Protein 2 (Ucp2), Fig 6C, (57)(58)(59)(60)(61)(62)). These results fit our expectation that the influence of bHR/bLR segregating genetic variants on exploratory locomotion is at least partially mediated by effects on gene expression within the hippocampus.…”

Section: Chromosomal Regionsmentioning

confidence: 99%

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. 2021

Biological Psychiatry

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Background: For over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These "bred High Responder" (bHR) and "bred Low Responder" (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders. Methods:Our study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype.Results: Genetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8. Conclusion:These candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment..

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“…TRH and TRH-like peptides have neuroprotective [33], antidepressant [34], anti-epileptic [35], anxiolytic [36], and analeptic properties [37]. These effects may be manifestations of the mod- ulation of glutamatergic toxicity and signaling responsivity by these peptides which are co-released with glutamate into the central and peripheral nervous systems.…”

Section: Introductionmentioning

confidence: 99%

TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms

Pekary

Sattin

2016

Horm Metab Res

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Photoperiod-synchronized rhythms in non-CSN tissues persist in total darkness. Clock genes involved in maintaining regular biorhythms within the suprachiasmatic nucleus (SCN) of the hypothalamus are expressed in extra-CNS tissues and continue periodic expression in vitro. Understanding the details of how the SCN clock is coupled with peripheral clocks is only incompletely understood and may involve a multiplicity of feedback systems. The present study is an extension of our previous work showing that brain levels of TRH (pGlu-His-Pro-NH) and TRH-like peptides (X-TRH: pGlu-X-Pro-NH, where "X" can be any amino acid residue) fluctuate throughout the day-night cycle. Male rats were maintained in a stable environment, lights on 6-18 h. TRH and TRH-like peptides in liver, pancreas, testis, prostate, epididymis, and heart were measured at 3, 10, 16, and 22 h. The greatest change in peptide level was a 12-fold increase for TRH in prostate at 16 h relative to the corresponding value at 3 h. The TRH, Tyr-TRH and Phe-TRH levels in liver declined steadily to about 40% of the 3-h values by 22 h. Changes, in the order of decreasing number of significant increases (↑) and/or decreases (↓), were: testis (5↑, 1↓), liver (3↓), epididymis (2↑), prostate (1↑, 1↓) and heart (1↑). Peptide levels in liver and testis correlated with serum leptin and serum corticosterone, respectively, which are potent releasers of these peptides. Testosterone and glucose were also highly correlated. These tripeptides may participate in the regulation of metabolic and reproductive functions, which change during the day-night cycle.

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Ketamine modulates TRH and TRH-like peptide turnover in brain and peripheral tissues of male rats

Cited by 20 publications

References 65 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

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

TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms

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