Contribution of the Roman rat lines/strains to personality neuroscience: neurobehavioral modeling of internalizing/externalizing psychopathologies

Abstract

The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats’ phenotypic profile falls well within the “internalizing” behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats’ phenotypes are consistent with a “disinhibiting externalizing” profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

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“…Fernández-Teruel et al ( 2023 ) also focused on avoidance learning but, more specifically, on its relation more to stress in general than anxiety in particular. The Roman high- and low-avoidance rat lines/strains (RHA/LHA, respectively) were bidirectionally selected for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task.…”

“…Fernández-Teruel et al ( 2023 , p. 2) propose: “From the [translational] perspective of the Research Domain Criteria framework such a profile suggests that RLA rats are mainly driven by ‘negative valence’. …They have enhanced sensitivity to threat/distress and behavioural inhibition, which is compatible with a high ‘neuroticism’ and low ‘extraversion’ personality profile ….…”

“……They have enhanced sensitivity to threat/distress and behavioural inhibition, which is compatible with a high ‘neuroticism’ and low ‘extraversion’ personality profile …. Thus, RLA rats phenotypes seem to fall within the domain of ‘Internalizing’ spectra and ‘Fear’ and ‘Distress’ sub-factors in terms of [HiTOP].” Fernández-Teruel et al ( 2023 )…”

“…According to them, the behaviorally inhibited and high threat-sensitivity profile of RLA rats is linked to “the enhanced activity of [hippocampus, medial prefrontal cortex and amygdala], together with more stress-responsive hypothalamus (HPA-axis) and bed nucleus of the stria terminalis” (Fernández-Teruel et al, 2023 , p. 3).…”

“…In contrast, “the RHAs are behaviorally disinhibited, exhibiting a consistent low-anxious profile in unconditioned and conditioned tests of anxiety or fear. They are hyperactive and high exploratory, novelty/sensation seeking, impulsive, and present impairments of attention, sensorimotor gating (PPI), latent inhibition, startle habituation, working memory and cognitive flexibility” (Fernández-Teruel et al, 2023 , p. 3). Due to these characteristics, the authors link RHA to an “externalizing” domain of human personality: “Collectively, the above profiles are consistent with RHA rats being driven by ‘positive valence’ processes, and characterized by high reward sensitivity (and impulsivity) and impairments in the cognitive domain, which are compatible with a personality dominated by ‘Impulsivity/Sensation seeking’ traits … Hence, the RHA rats seem to fall within the ‘Disinhibited Externalizing’ spectra and ‘Substance Abuse’ sub-factor, and likely also within the ‘Thought disorder’ spectra; as they present various schizophrenia-linked traits, such as, e.g., hyperactivity, relative asociality, and impairments of inhibitory control (impulsivity) and attentional/cognitive processes.” Fernández-Teruel et al ( 2023 , p. 4) …”