Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function

Abstract

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) has been shown to activate the eIF2α kinase PERK to directly regulate translation initiation. Tight control of PERK-eIF2α signaling has been shown to be necessary for normal long-lasting synaptic plasticity and cognitive function, including memory. In contrast, chronic activation of PERK-eIF2α signaling has been shown to contribute to pathophysiology, including memory impairments, associated with multiple neurological diseases, making this pathway an attractive therapeutic target. Herein, using multiple genetic approaches we show that selective deletion of the PERK in mouse midbrain dopaminergic (DA) neurons results in multiple cognitive and motor phenotypes. Conditional expression of phospho-mutant eIF2α in DA neurons recapitulated the phenotypes caused by deletion of PERK, consistent with a causal role of decreased eIF2α phosphorylation for these phenotypes. In addition, deletion of PERK in DA neurons resulted in altered de novo translation, as well as changes in axonal DA release and uptake in the striatum that mirror the pattern of motor changes observed. Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non-pathological state, and also provide new insight concerning the onset of neuropsychiatric disorders that accompany UPR failure.

Aerobic Exercise Alleviates the Impairment of Cognitive Control Ability Induced by Sleep Deprivation in College Students: Research Based on Go/NoGo Task

“…By comparing the comprehensive performance of the subjects in the Go-Nogo task at two time points: 30 min and 1 h after exercise, it was found that exercise had a significant time-course benefit in promoting cognitive control function after sleep deprivation, including cognitive control advantages in both response execution and response inhibition that could be maintained until 1 h after the end of exercise. The reason for this time-course benefit may be that neurotransmitters such as dopamine (Longo et al, 2021 ) and 5-ht secreted during exercise still play a role in neuromodulation after cessation of exercise, which is speculated to be partially confirmed in the detection of blood 5-ht after exercise. The results of correlation analysis also showed that there was a highly significant positive correlation between hit rate and 5-ht content changes, and a highly significant negative correlation between commission errors and ICV and 5-ht content changes in college students after exercise intervention.…”

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

“…In mice, reducing PERK activity can also prove beneficial; knockdown of Perk in the CA1 hippocampus region in aging mice reverses agerelated declines in memory and neuronal excitability (Sharma et al, 2018). However, the outcome of neuronal PERK inhibition in mammals appears cell-specific; deletion of Perk specifically in mouse dopaminergic neurons leads to a range of both cognitive and motor phenotypes via the dysregulation of de novo translation and dopamine release (Longo et al, 2021). Taken together, these murine studies demonstrate the complexity involved in inhibiting PERK activity; reducing PERK function has the potential to affect both the beneficial acute and deleterious chronic modes of signaling.…”

Cell type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behaviour in fragile X syndrome model mice

“…Novel home cage test. The novel home cage (NHC) test was used to assess the spontaneous horizontal motor activity as novelty-induced exploratory response 90,91 .…”

“…Drag test. The drag test was performed as previously described 90,93 and gives information regarding the time to initiate (akinesia) and execute (bradykinesia) a movement. Briefly, mice were lifted from the tail (allowing the forepaws to rest on the table) and dragged backwards at a constant speed (∼20 cm/s) for a fixed distance (100 cm).…”

“…Fluorescence was quantified using ImageJ software (NIH, USA) as previously described 90,97 . Dendritic spine density.…”