Investigation of electrical and behavioral properties of dentate gyrus prodynorphin neurons in Aβ-induced Alzheimer's model transgenic mice

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and the accumulation of abnormal protein aggregates in the brain. The endogenous opioid system is a complex neurochemical system in the body that plays a crucial role in some physiological and psychological processes. Prodynorphin neurons, a part of the endogenous opioid system, are nerve cells that synthesize and release prodynorphin, the precursor polypeptide for various dynorphin opioid peptides. Today, the effect of the opioid system on AD and its role in the mechanism of dementia are not still fully understood. Therefore, this study aimed to investigate a possible relationship between AD and Prodynorphin neurons in the dentate gyrus (DGPdyn), which is a critical region for learning and memory. In this study, ten-weeks-old seventy Pdyn-Cre male mice were used. For electrophysiological studies; Cre-dependent GFP virus, for chemogenetics activation/inhibition studies; hM3D and hM4D viruses, and for optogenetic stimulations; ChR2 virus were injected bilaterally into the dentate gyrus of mice. To create AD-like model, mice were given amyloid beta oligomer (Aβ), while PBS was given intracerebroventricularly to the control groups. Mice were taken into four different behavioral tests. The locomotor levels, the anxiety-like behaviors, the short- and long-term memory states, and the spatial memory/learning levels of the mice were evaluated by performing the open field, the elevated plus maze, the novel object recognition, and Morris water maze (MWM) tests, respectively. In behavioral tests, Chronic inhibition of DGPdyn neurons in the PBS group caused a decrease in locomotor activity, while chronic activation of these neurons in the AB group caused a decrease in velocity (p<0,0001). No effect of these neurons on anxiety-like behavior was observed. In addition, in the AB group, chronic activation of DGPdyn neurons caused a reduction in novel object exploration duration for both short-term memory (p<0,01) and long-term memory (p<0,05), also, the chronic inhibition of these neurons improved spatial memory and learning, which were impaired in the AB-GFP group (p<0,01). Finally, the firing frequency of DGPdyn neurons increased significantly in Aβ -induced mice (p<0.01). These results suggested that Aβ accumulation may disrupt locomotor-related synaptic transmissions of DGPdyn neurons by altering prodynorphin signaling. Furthermore, with an increased DGPdyn electrical activity in AD-like modeling, these neurons may be involved in the progression of AD by inducing cognitive impairment.