Conservation of Phenotypes in the Roman High- and Low-Avoidance Rat Strains After Embryo Transfer

Abstract

The Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains are bi-directionally bred for their good versus non-acquisition of two-way active avoidance, respectively. They have recently been re-derived through embryo transfer (ET) to Sprague-Dawley females to generate specific pathogen free (SPF) RHA-I/RLA-I rats. Offspring were phenotyped at generations 1 (G1, born from Sprague-Dawley females), 3 and 5 (G3 and G5, born from RHA-I and RLA-I from G2-G4, respectively), and compared with generation 60 from our non-SPF colony. Phenotyping included two-way avoidance acquisition, context-conditioned fear, open-field behaviour, novelty-seeking, baseline startle, pre-pulse inhibition (PPI) and stress-induced increase in plasma corticosterone concentration. Post-ET between-strain differences in avoidance acquisition, context-conditioned freezing and novelty-induced self-grooming are conserved. Other behavioural traits (i.e. hole-board head-dipping, novel object exploration, open-field activity, startle, PPI) differentiate the strains at G3-G5 but not at G1, suggesting that the pre-/post-natal environment may have influenced these co-segregated traits at G1, though further selection pressure along the subsequent generations (G1-G5) rescues the typical strain-related differences.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

“…Moreover, relative to RLAs, RHA rats display several impairments in schizophrenia-relevant phenotypes, such as prepulse inhibition (PPI; Oliveras et al, 2015; Río-Álamos et al, 2019), latent inhibition (LI; Fernández-Teruel et al, 2006), spatial working memory (Oliveras et al, 2015) and reversal learning (Río-Álamos et al, 2019) as well as a trend towards a reduction of some types of social behavior (Coppens et al, 2012; Del Rio et al, 2014; see “RHA Rats as a Model of Deficits in Attentional Processes, Cognitive Impairments and Other Features Relevant for Schizophrenia Research” section). These behavioral profiles are consistent with findings of a reduced volume and function of the medial prefrontal cortex (mPFCx), hippocampus (HC) and amygdala (AMY) of RHA vs. RLA rats (Río-Álamos et al, 2017a, 2019). Finally, as it would be expected from a model with translational value, compared with RLAs, RHA rats also show more intense behavioral sensitization following the repeated administration of psychostimulants (Corda et al, 2005; Giorgi et al, 2005a, 2007) and enhanced vulnerability to drug abuse/addiction (Fattore et al, 2009), which are associated with a more robust mesolimbic dopaminergic tone (Giorgi et al, 1997, 2003, 2005b; Piras et al, 2003; Lecca et al, 2004; see “The Roman Rats as a Genetic Model of Vulnerability to Drug Addiction” section).…”

“…In parallel, early studies on emotional aspects showed that RLA rats were more sensitive to classical Pavlovian aversive conditioning than their RHA counterparts (Imada, 1972) and displayed more robust hormonal responses (i.e., increments in the plasma concentrations of corticosterone, prolactin, and ACTH) to several types of acute psychological and physical stressors (Gentsch et al, 1981, 1982). These neuroendocrine findings have been replicated in many subsequent studies (Castanon et al, 1992; Castanon and Mormède, 1994; Steimer et al, 1998; Steimer and Driscoll, 2003; Carrasco et al, 2008; Díaz-Morán et al, 2012; Río-Álamos et al, 2017a,b).…”

“…Among the former, some of the earliest demonstrations suggesting between-line differences in anxiety were the increased defecation and reduced exploratory activity observed in RLA rats in the open field test (Gentsch et al, 1981, 1982) and their avoidance of the illuminated center of the hexagonal tunnel maze (Driscoll and Bättig, 1982; Martin et al, 1982). These results have been corroborated in numerous studies (Fernández-Teruel et al, 1991a, 1992a,b, 1994, 1997, 2002b; Escorihuela et al, 1997, 1999; Steimer and Driscoll, 2003; Estanislau et al, 2013; Tapias-Espinosa et al, 2018) and extended to other novelty-based, unconditioned conflict conditions, such as the hyponeophagia test, the light/dark box, the elevated plus-maze and the elevated zero-maze, in which RLA rats consistently display higher levels of behavioral inhibition and anxiety responses, which include avoidance of open/illuminated spaces, freezing, reduced exploratory activity and increased self-grooming (Ferré et al, 1995; Steimer et al, 1998; Escorihuela et al, 1999; Fernández-Teruel et al, 2002b; Steimer and Driscoll, 2003; Estanislau et al, 2013; Río-Alamos et al, 2015; Río-Álamos et al, 2017a,b).…”

“…It is noteworthy that, compared with their RHA counterparts, RLA rats display a more pronounced neural activation of the HC and AMY, as reflected by increased c-fos expression, when exposed to different novelty-based conflict situations (Meyza et al, 2009). Accordingly, the volume of the HC and AMY is larger (Río-Álamos et al, 2017a), and the neuronal density is higher in both brain areas of RLA vs. RHA rats (Garcia-Falgueras et al, 2012; Gómez et al, 2009c). In addition, the activity of the phospholipase C signaling cascade is higher in the HC of RLA vs. RHA rats (Sallés et al, 2001).…”

“…These rats are bidirectionally selected and bred for their rapid (RHA) vs. extremely poor (RLA) ability to acquire the two-way active avoidance response in a shuttle box. More than four decades of research have characterized RHA rats as less fearful, anxious and stress-sensitive than their RLA counterparts (Steimer and Driscoll, 2003; Driscoll et al, 2009; Río-Álamos et al, 2017a,b). Remarkably, compared with RLAs, RHA rats display an impulsive phenotype, as shown by their response profiles in the delayed response latency 20 (DRL-20), schedule-induced polydipsia, and 5-choice serial reaction time (5CSRT) tasks (Zeier et al, 1978; Moreno et al, 2010; Merchán et al, 2019; see “The Roman Rats: A Genetic Model of Differential Anxiety, Novelty Seeking, Impulsivity, Attention Deficits and Associated Traits” section).…”