Exploratory and locomotor activity, learning and memory functions in somatostatin receptor subtype 4 gene-deficient mice in relation to aging and sex

Nikolett Szentes,Éva Borbély,Valéria Tékus,Violetta Mohos,Zsuzsanna Helyes

doi:10.1007/s11357-019-00059-1

Abstract

The inhibitory neuropeptide somatostatin regulates several functions in the nervous system including memory. Its concentrations decrease by age leading to functional alterations, but there are little known about the receptorial mechanism. We discovered that somatostatin receptor 4 (sst4) mediates analgesic, anti-depressant, and anti-inflammatory effects without endocrine actions, and it is a unique target for drug development. We investigated the exploratory and locomotor activities and learning and memory functions of male and female sst4gene-deficient mice compared with their wild-types (WT) at ages of 3, 12, 17 months in the Y-maze test, open field test (OFT), radial-arm maze (RAM) test and novel object recognition (NOR) test. Young sst4 gene-deficient females visited, repeated, and missed significantly less arms than the WTs in the RAM; males showed decreased exploration in the NOR. Young mice moved significantly more, spend longer time in OFT center, and visited more arms in the Y-maze than older ones. Young WT females spend significantly longer time in the OFT center, visited, missed and repeated more arms of the RAM than males. Old males found more rewards than females. Young males explored longer the novel object than young females and older males in the NOR; the recognition index was smaller in females. We conclude that aging and sex are important factors of behavioral parameters that should be focused on in such studies. Sst4 is likely to influence locomotion and exploratory behavior only in young mice, but not during normal aging, which is a beneficial feature of a good drug target focusing on the elderly.

Highlights

Aging strongly influences cognitive functions, memory, and learning
It is well established in a variety of species including humans (Vedovelli et al 2017), rats (Casad 1990; Tenk et al 2017), and mice (Ashpole et al 2017; Fang et al 2017; Reglodi et al 2018; Spik and Sonntag 1989; Ungvari et al 2017a) that peptide neurotransmitters, such as somatostatin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, insulin-like growth factor 1, growth hormone (GH), neurotrophic factor, connective tissue growth factor, play important regulatory roles in age-related diseases, and both their brain and peripheral concentrations change throughout aging
This test is suitable for rodent memory and route-learning capabilities, where we investigated the exploratory behavior of the mice for new ways (Holcomb et al 1999; Hullmann et al 2017)

Summary

Introduction

Aging strongly influences cognitive functions, memory, and learning. Learning slows down, but memory does not necessarily worsen in the aging population that is continuously increasing in the twenty-first century. Somatostatin inhibits the release of several excitatory and inhibitory neurotransmitters, such as serotonin, acetylcholine, glutamate, and GABA (Baraban and Tallent 2004) It plays a role in sensory perception and pain, motor functions, sleep, cognitive performance (Helyes et al 2009; Matsuoka et al 1994), and neurodegenerative disorders (Martel et al 2012; Tuboly and Vecsei 2013), neuroendocrine and emotional regulation, anxiety and depression (Engin et al 2008; Lin and Sibille 2015). Our team has provided strong proof-of-concept evidence for systemic anti-inflammatory and analgesic effects of somatostatin released from the activated capsaicin-sensitive peptidergic sensory nerves at the periphery called “sensocrine” function (Szolcsányi et al 2004; Thán et al 2000)

Methods

Results

Conclusion