Reduced exploratory behavior in neuronal nucleoredoxin knockout mice

Abstract

Nucleoredoxin is a thioredoxin-like redoxin that has been recognized as redox modulator of WNT signaling. Using a Yeast-2-Hybrid screen, we identified calcium calmodulin kinase 2a, Camk2a, as a prominent prey in a brain library. Camk2a is crucial for nitric oxide dependent processes of neuronal plasticity of learning and memory. Therefore, the present study assessed functions of NXN in neuronal Nestin-NXN -/- deficient mice. The NXN-Camk2a interaction was confirmed by coimmunoprecipitation, and by colocalization in neuropil and dendritic spines. Functionally, Camk2a activity was reduced in NXN deficient neurons and restored with recombinant NXN. Proteomics revealed reduced oxidation in the hippocampus of Nestin-NXN -/- deficient mice, including Camk2a, further synaptic and mitochondrial proteins, and was associated with a reduction of mitochondrial respiration. Nestin-NXN -/- mice were healthy and behaved normally in behavioral tests of anxiety, activity and sociability. They had no cognitive deficits in touchscreen based learning & memory tasks, but omitted more trials showing a lower interest in the reward. They also engaged less in rewarding voluntary wheel running, and in exploratory behavior in IntelliCages. Accuracy was enhanced owing to the loss of exploration. The data suggested that NXN maintained the oxidative state of Camk2a and thereby its activity. In addition, it supported oxidation of other synaptic and mitochondrial proteins, and mitochondrial respiration. The loss of NXN-dependent pro-oxidative functions manifested in a loss of exploratory drive and reduced interest in reward in behaving mice.

Trehalose Reduces Nerve Injury Induced Nociception in Mice but Negatively Affects Alertness

“…It is of note that SNI, per se, does not affect behavior in IntelliCages in place preference learning and reversal learning tasks [ 47 ], and the placebo-treated mice behaved normally for their age in comparison with previous studies [ 47 , 48 ]. Hence, although the drinking volume was increased for both groups in Phenomaster cages owing to the mildly sweet taste of the placebo and trehalose water, 24 h lickings in IntelliCages were within the normal range for the mice age [ 47 , 48 ]. There was no evidence that the rewarding appeal of trehalose water was lower than that of placebo water.…”

Nucleoredoxin – a redox modulator of calcium calmodulin kinase 2a promoting the exploratory behavior in mice

“…Only limited data are available so far giving information about the role of NXN in functional mechanisms in neurons (Urbainsky et al, 2018). Interestingly, our previous experiments revealed Camk2a as a prey in a Yeast-2-Hybrid-screening with NXN as a bait using a total brain library (Tran et al, 2021). This has prompted us to investigate the impact of NXN on neuronal plasticity, because Camk2a is the key protein for neuronal plasticity through regulating LTP and LTD during neuronal activity Lamsa, Irvine, Giese, & Kullmann, 2007).…”

“…LacZ histochemistry, RNA and protein analysis of NXN expression were conducted by Lucie Valek and IntelliCage parameters were analyzed as described in (Tran et al, 2021) by Irmgard Tegeder.…”

“…The tasks are described in Tab. 4.17 and abbreviations of behavioral parameters are summarized in our previous publication (Tran et al, 2021). The tasks followed established protocols (Albuquerque et al, 2013;Hardt et al, 2017).…”

“…Behavioral parameters were introduced as independent variables, and then stepwise removed to find the strongest discriminant candidates. IntelliCage data were analyzed with IntelliCage Plus® software (TSE) and with FlowR (NewBehavior) (Krackow et al, 2010;Voikar et al, 2018) for analyses of time courses and circadian parameters by Irmgard Tegeder (Tran et al, 2021). Data were exported to tab separated txt files for further analyses in Excel, Prism, SPSS and OriginPro.…”