Activity of the brain's noradrenergic (NA) neurons plays a major role in cognitive processes, including the ability to adapt behavior to changing environmental circumstances. Here, we used the ...NR1DbhCre transgenic mouse strain to test how NMDA receptor‐dependent activity of NA neurons influenced performance in tasks requiring sustained attention, attentional shifting and a trade‐off between exploration and exploitation. We found that the loss of NMDA receptors caused irregularity in activity of NA cells in the locus coeruleus and increased the number of neurons with spontaneous burst firing. On a behavioral level, this was associated with increased impulsivity in the go/no‐go task and facilitated attention shifts in the attentional set‐shifting task. Mutation effects were also observed in the two‐armed bandit task, in which mutant mice were generally more likely to employ an exploitative rather than exploratory decision‐making strategy. At the same time, the mutation had no appreciable effects on locomotor activity or anxiety‐like behavior in the open field. Taken together, these data show that NMDA receptor‐dependent activity of brain's NA neurons influences behavioral flexibility.
Loss of NMDA receptors on noradrenergic neurons enhances performance in the attentional set‐shifting task.
The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including ...Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.
Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in ...dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.
Midbrain dopamine (DA) neurons play a crucial role in the formation of conditioned associations between environmental cues and appetitive events. Activation of N-methyl-d-aspartate (NMDA) receptors ...is a key mechanism responsible for the generation of conditioned responses of DA neurons to reward cues. Here, we tested the effects of the cell type-specific inactivation of NMDA receptors in DA neurons in adult mice on stimulus-reward learning. Animals were trained in a Pavlovian learning paradigm in which they had to learn the predictive value of two conditioned stimuli, one of which (CS+) was paired with the delivery of a water reward. Over the course of conditioning, mutant mice learned that the CS+ predicted reward availability, and they approached the reward receptacle more frequently during CS+ trials than CS- trials. However, conditioned responses to the CS+ were weaker in the mutant mice, possibly indicating that they did not attribute incentive salience to the CS+. To further assess whether the attribution of incentive salience was impaired by the mutation, animals were tested in a conditioned reinforcement test. The test revealed that mutant mice made fewer instrumental responses paired with CS+ presentation, confirming that the CS+ had a weaker incentive value. Taken together, these results indicate that reward prediction learning does occur in the absence of NMDA receptors in DA neurons, but the ability of reward-paired cues to invigorate and reinforce behavior is attenuated.
Molecular mechanisms underlying the differences between chronic neuropathic and inflammatory pain are still poorly understood. Identifying those differences should provide insight into the molecular ...mechanism underlying features unique for neuropathic pain, such as allodynia. We have performed screening for differentially expressed genes in the spinal cord in the rat models of neuropathic and inflammatory pain. Using BD Atlas Rat 4K arrays we found several differences in expression of secretion-related genes between inflammatory and neuropathic pain. Development of the latter was characterized by up-regulated expression of genes associated with immune response and microglia activation and also, to a lesser extent, with cytoskeleton rearrangement. The relative increase in abundance of four genes, intercellular adhesion molecule 1 (ICAM-1), calcitonin gene related peptide (CGRP), tissue inhibitor of metalloproteinase 1 (TIMP-1), chemokine-like receptor 1 was confirmed by reverse transcription Real-Time PCR (qPCR) validation in the spinal cord in neuropathic pain. Levels of transcripts corresponding to ICAM-1 and TIMP-1 were also increased in the dorsal root ganglia (DRG) of neuropathic rats. Our data point at the importance of immune response- and microglia activation-related genes in the development of chronic neuropathic pain, and suggest that expression of CGRP gene in the dorsal horn of the spinal cord could be involved in persistence of its symptoms.
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