Personality Neuroscience Contribution of the Roman rat lines/strains to cambridge.org/pen personality neuroscience: neurobehavioral modeling of internalizing/externalizing psychopathologies Review Paper Cite this article: Fernández-Teruel A, Cañete T, Alberto Fernández-Teruel , Toni Cañete, Daniel Sampedro-Viana, Ignasi Oliveras, Sampedro-Viana D, Oliveras I, Torrubia R, and Tobeña A. (2023) Contribution of the Roman rat Rafael Torrubia and Adolf Tobeña lines/strains to personality neuroscience: neurobehavioral modeling of internalizing/ Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Faculty of Medicine & Institute of externalizing psychopathologies. Personality Neurosciences, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain Neuroscience. Vol 6: e8, 1–9. doi: 10.1017/ pen.2023.7 Abstract Received: 25 April 2023 The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established Revised: 28 July 2023 in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor Accepted: 4 August 2023 (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit Keywords: enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and externalizing disorders; internalizing disorders; increased sensitivity to frustration. Thus, RLA rats’ phenotypic profile falls well within the neurobiology; reward sensitivity; Roman high- “internalizing” behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs and low-avoidance rats; threat sensitivity present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/ Corresponding author: cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant Alberto Fernández-Teruel; sensitization and drug addiction. Thus, RHA rats’ phenotypes are consistent with a Email: albert.fernandez.teruel@uab.cat “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. Once upon a time, some rats left Rome – the many roads leading to it took them everywhere The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines were established in Rome through bidirectional selection and outbreeding of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task (TWAA; Figure 1) (Bignami, 1965). The two lines were then moved to Birmingham, UK (e.g., Broadhurst & Bignami, 1965). Two inbred strains were established in London (in 1974) and, derived from them, two inbred Roman sub-strains were established in Nijmegen (Durcan, Wraight & Fulker, 1984). Outbred sublines, from the Birmingham stock, were established in Canada (e.g., Satinder, 1971), France (e.g., Delacour, Houcine & Monmaur, 1978) and in Zurich, Switzerland, in 1972 (the RHA/Verh and RLA/Verh sublines; e.g., Driscoll & Bättig, 1982). Outbred sublines from the Zürich stock were established in Cagliari, Italy (e.g., Giorgi et al., 1994), Bordeaux, France (e.g., Castanon & Mormède, 1994), Geneva, Switzerland (Steimer & Driscoll, 2003) and in Germany (e.g., © Autonoumous University of Barcelona, 2023. Schwegler et al., 1997). Inbred RHA and RLA strains, generated through brother/sister mating of Published by Cambridge University Press. This the respective Swiss/Verh sublines, were established in Barcelona in 1995 (e.g., Driscoll et al., is an Open Access article, distributed under the 1998). Over 270 international articles have been published on the Roman rats (or using them as terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/ part of broader studies) during the past fifty-five years. They have been used for psychological, by/4.0/), which permits unrestricted re-use, neurobiological and genetic research purposes in over 20 different laboratories around the world distribution and reproduction, provided the (see Supplementary Table S1, in Fernández-Teruel et al., 2021), and continue to be very original article is properly cited. productive, as shown by the over 35 papers published in the past five years. In the TWAA task rodents can learn to escape/avoid an aversive stimulus (unconditioned stimulus, US; usually a foot shock) that is preceded by a warning signal (conditioned stimulus, CS; usually a tone, a light, or both) by shuttling between opposite compartments (Figure 1). After a few initial CS–US pairings, the TWAA generates approach-avoidance conflict, with the https://doi.org/10.1017/pen.2023.7 Published online by Cambridge University Press 2 A Fernández-Teruel et al. of RHA rats, as we will see below; see also reviews by Driscoll et al., 1998; Fernández-Teruel et al., 2021; Steimer & Driscoll, 2003; Giorgi et al., 2019). These trait differences generalize to many between-strain phenotype differences in conditioned and uncon- ditioned tests/tasks reflecting coping style of fear-, anxiety- and depression-related responses. For example, relative to RHA rats, RLAs present increased signs of anxiety in typical anxiety tests such as the Vogel’s punished-drinking, the elevated zero- and plus-maze and light-dark box tests among others; they also show enhanced frustration-related (Amsel, 1992) responding under reward devaluation, and heightened stress-linked endocrine and depres- sive-like responses (reviewed by Fernández-Teruel et al., 2021; Giorgi et al., 2019). Remarkably, RLAs also exhibit increased context- and cue-conditioned freezing and, like high trait-anxiety humans (Andión et al., 2013), RLAs display enhanced stress- and fear(cue)-potentiated startle (Aguilar, Gil, Tobeña, Escorihuela & Fernández-Teruel, 2000; López-Aumatell et al., 2009). From the perspective of the Research Domain Criteria (RDoC) framework (for Review, see Michelini, Palumbo, DeYoung, Latzman & Kotov, 2021) such a profile suggests that RLA rats are mainly driven by “negative valence” (e.g., Michelini et al., 2021) (see section A in Table 1). In fact, they have enhanced sensitivity to threat/distress and behavioral inhibition, which is compatible with a high “neuroticism” and low “extraversion” personality profile (see section C in Table 1) (e.g., Gray & McNaughton, 2000). In sum, RLAs’ behavioral profile seems to be dominated (and driven) by negative affectivity, which is a core characteristic of human Figure 1. Two-way active avoidance acquisition in the shuttle box (Medical Psychology Unit, Dept. Psychiatry & Forensic Medicine, Autonomous University of internalizing disorders (e.g., depression, anxiety- and stress-related Barcelona). The rat is crossing from the right compartment to the opposite one to disorders; see e.g., Michelini et al., 2021). Thus, RLA rats escape/avoid the shock but is also faced with the memory of having to escape from the phenotypes seem to fall within the domain of “Internalizing” left compartment on the previous trial. For further explanation see text. spectra and “Fear” and “Distress” sub-factors in terms of the “Hierarchical Taxonomy of Psychopathology” (HiTOP; Michelini et al., 2021) system (see section B in Table 1). appearance of context- and CS-conditioned freezing (e.g., Fernández-Teruel & Tobeña, 2020). This tendency to freeze (i.e., passive avoidance: Tendency to stay freezing in the present Neuroanatomical and neuro-functional profiles of Roman compartment, where they receive the CS) predominates in the low-avoidance rats initial trials, as the subject learns that the opposite compartment is At neurochemical and molecular levels, selection of outbred rats also threatening (i.e., approach-avoidance conflict), because in that for extremely divergent rates of acquisition of TWAA, or compartment he has also received a foot shock. As training and comparison of RLA vs RHA rats, has been shown to be associated CS–US associations progress, the subject learns that the US can be with differential expression of many genes related to neural and overcome by shuttling to the opposite compartment, first by synaptic function at the hippocampal and amygdala levels (Díaz- escaping (when the shock US is present) and later on by avoiding it Morán et al., 2013a, 2013b; Sabariego et al., 2013). In this regard, (i.e., by crossing to the opposite compartment when the CS is still and consistent with descriptions of the neuropsychology of anxiety on and the US has still not been presented). (Gray & McNaughton, 2000; McNaughton & Corr, 2004), relative The RLA rat line/strain presents high levels of freezing to the CS to RHA rats the RLAs display a more pronounced neural activation and the context (during the inter-trial intervals), and very low rate of the hippocampus (HPC) and amygdala (AMY), as reflected of active avoidance responses and inter-trial crossings. The RHA by increased c-Fos expression when exposed to different novelty- line/strain displays very low levels of freezing, very rapid active based approach-avoidance conflict situations (Meyza, avoidance acquisition and high levels of inter-trial activity Boguszewski, Nikolaev & Zagrodzka, 2009). In addition, the (Broadhurst & Bignami, 1965; Satinder, 1971; Driscoll & Bättig, activity of the phospholipase C signaling cascade is higher in 1982; Fernández-Teruel et al., 1991; Escorihuela et al., 1995; the HPC of RLA vs. RHA rats (Sallés et al., 2001). Accordingly, the reviewed by Fernández-Teruel et al., 2021; Giorgi et al., 2019). volume of the HPC and AMY is larger (Río-Álamos et al., 2019), and the neuronal density is higher in both brain areas of RLA vs. RHA rats (Gómez et al., 2009; Garcia-Falgueras, Castillo-Ruiz, Put, Selection for poor two-way active avoidance task Tobeña & Fernández-Teruel, 2012). acquisition led to behaviorally inhibited, high Authors from our group have studied the relationship between “neuroticism” and “internalizing” Roman functioning of Gray and McNaughton’s “Behavioural Inhibition low-avoidance rats System” (BIS; as measured by the “Sensitivity to Punishment” Thus, when facing different types of threatening situations, RLA scale; Torrubia, Ávila, Moltó & Caseras, 2001) and HPC and AMY rats are predominantly high freezers, displaying behavioral volumes in adult healthy human subjects. Consistent with the inhibition and a passive coping style (opposite to the trait profiles theory (Gray & McNaughton, 2000), and with the above findings https://doi.org/10.1017/pen.2023.7 Published online by Cambridge University Press Personality Neuroscience 3 Table 1. Overview of neurobehavioral traits of RLA and RHA rats, correspondence with RDoC domains, the HiTOP psychopathology spectra (Michelini et al., 2021) and the “Big Five” and “Eysenck-Gray” personality factors (B) HiTOP system (C) Personality Line/ (A) RDoC system (Spectra, sub-factors & (“Big Five” traits & “Eysenck-Gray”- (D) Main Neuroscience-based traits Strain (Domains) Symptom components) related factors) (RDoC domains) RLA Negative valence: “Internalizing” (þ) Neuroticism (þ) function of the hippocampus (HPC), (þ); Fear, Anxiety, Sub-factors: FEAR, DISTRESS -High “Sensitivity to punishment”/ amygdala (AMY) and prefrontal cortex Sustained threat Symptoms/phenotypes: high BIS activity (PFC), (depressive-like) (þ) Sensitivity to punishment (REFS: Gray & McNaughton 2000; Giorgi (þ) CRF expression in PVN of the effects, Frustrative (anxiety); Behavioral et al., 2019) hypothalamus, BNST and AMY. non-reward inhibition (-) Extraversion (þ) AMY-dependent HPA-axis (ACTH, Cognitive systems: (þ) Stress-induced helpless corticosterone) and prolactin (þ); Attention, (depression-like) behavior; responses to stress. Declarative (þ) Threat-induced freezing, (-) 5-HT function in FC memory, Working Passive avoidance; (-) BZR function in cortex memory (þ) Enhanced stress- and fear- (REFS: Giorgi et al., 1994, 2003, 2019; Arousal Systems: potentiated startle Bentareha et al., 1998; Carrasco et al., (þ); Threat-induced (þ) Enhanced reward- 2008; Meyza et al., 2009; Tapias- (anxious) Arousal devaluation-induced Espinosa et al., 2019, 2023) frustration RHA Positive valence: “Disinhibited Externalizing”: (þ) Extraversion (þ) mesolimbic DA activity, and altered (þ); Reward Sub-factors: -High “Sensitivity to reward”/high BAS striatal dopamine activity. Responsiveness, SUBSTANCE ABUSE activity (-) D2/3 receptors in Str Reward Valuation Symptoms/phenotypes: (REFS: Gray & McNaughton 2000; Giorgi (þ) D1 receptors in PFC and Str Cognitive systems: (þ) Impulsivity; Behavioral et al., 2019) (þ) Homer1 & Neuregulin1 expression in (-) Attention, Working disinhibition; -High “Impulsive-Sensation/Novelty PFC. Transcriptome analysis in the FC memory, Hyperactivity; Vulnerability to seeking” shows deficient maturation. Declarative drug addiction (REFS: Fernández-Teruel et al., 1992; (-) PFC, HPC and AMY function and memory (þ) Delay discounting; Risky Moreno et al., 2010; Giorgi et al., 2019; volume (-) Systems for decision-making in a rat Bellés et al., 2021a-b, 2023; Dimiziani (þ) 5-HT2A in PFC Social Processes: gambling task et al., 2021; Zuckerman et al., 1974; (-) mGlu2R in PFC, HPC, Str Detachment (þ) Schizophrenia spectrum Siegel & Driscoll 1996; Sampedro- Augmenting pattern of cortical VEPs Sensorimotor symptoms Viana et al., 2021; Oliveras et al., (REFS: Fernández-Teruel et al., 2021; Systems (altered) (-) Social interaction preference 2023) Siegel et al., 1993; Guitart-Masip (-) Prepulse inhibition & Latent et al., 2006; Meyza et al., 2009; inhibition Tournier et al., 2013; Klein et al., (-) performance in spatial and 2014; Fomsgaard et al., 2018; Elfving non-spatial working memory et al., 2019; Tapias-Espinosa et al., tasks, spatial reference 2019, 2023; Bellés et al., 2021a; learning/memory and Sánchez-González et al., 2021; cognitive flexibility Sønderstrup et al., 2023) (þ) Sensitivity to reward (þ) Habit (compulsive) learning (þ), (-); increased/improved, decreased/impaired, respectively. For reasons of space, the references are placed in columns C and D, but they also apply to columns A and B. See text for abbreviations. from RLA (vs. RHA) rats, the authors found that BIS scores were Table 1), seem to be consistent with theory (Gray & McNaughton, highly correlated with HPC and AMY gray matter volume, thus 2000) and with the behaviorally-inhibited and high threat- suggesting that behavioral inhibition (resulting from increased sensitivity profile of RLA rats (Giorgi et al., 2019) (sections A-B activity of the BIS) is associated with enhanced HPC and AMY in Table 1). function (Barrós-Loscertales et al., 2006, and references therein). Importantly also, the activation of the medial PFC (mPFC; as Selection for rapid two-way active avoidance task measured by c-Fos expression) following exposure to various acquisition led to behaviorally disinhibited, reward novelty tests or to a prepulse inhibition (PPI) session, as well as sensitive and “externalizing” Roman high-avoidance rats mPFC volume, is also enhanced in RLA rats relative to their RHA counterparts (Meyza et al., 2009; Río-Álamos et al., 2019; Tapias- Compared with RLA and other laboratory strains/lines, the RHAs Espinosa et al., 2019, 2023) (see section D in Table 1). On the other are behaviorally disinhibited, exhibiting a consistent low-anxious hand, alterations of the GABA-A/benzodiazepine receptor and profile in unconditioned and conditioned tests of anxiety or fear levels of endogenous benzodiazepine-like molecules have also been (Fernández-Teruel et al., 2021; Steimer & Driscoll 2003; Giorgi found in cortex and HPC of RLA (vs. RHA) rats (Giorgi et al., 1994; et al., 2019). They are hyperactive and highly exploratory, novelty/ Driscoll et al., 1995; Bentareha et al., 1998) (see section D in sensation seeking, impulsive and present impairments of attention, Table 1). sensorimotor gating (PPI), latent inhibition, startle habituation, In sum, the enhanced activity of HPC, mPFC and AMY, working memory and cognitive flexibility (see sections A-B in together with more stress-responsive hypothalamus (HPA-axis) Table 1). Remarkably, RHA rats exhibit increased locomotor and and bed nucleus of the stria terminalis (Steimer & Driscoll, 2003; nucleus accumbens (NAcc) dopaminergic (DA) sensitization to Carrasco et al., 2008; Río-Álamos et al., 2017; see section D in chronic psychostimulants and other abused drugs (morphine, https://doi.org/10.1017/pen.2023.7 Published online by Cambridge University Press 4 A Fernández-Teruel et al. ethanol), enhanced cocaine self-administration and reinstatement drug-seeking and schizophrenia-linked trait profiles (Fernandez- after extinction, enhanced preference for ethanol and natural Teruel et al., 2021; Giorgi et al., 2019). rewards and increased functional tone of the mesolimbic DA It has been known since the late 1990s that the reward-sensitive system (see sections B and D in Table 1). Vulnerability to drug and impulsive RHA rats are characterized by an enhanced addiction and schizophrenia are thought to share some core functional tone of the mesolimbic DA system, as shown, for features and/or mechanisms. In particular, for instance, the instance, by in vivo DA microdialisis in the NAcc following increased functional tone of the mesolimbic DA system is sensitization to psychostimulants (e.g., Giorgi et al., 2007; Tournier considered to be at the core of both schizophrenia and drug et al., 2013; Bellés et al., 2021a; reviewed by Giorgi et al., 2019; and addiction and is present in RHA rats relative to RLAs (Giorgi et al., Fernández-Teruel et al., 2021). Remarkably, these early findings 2019; Fernández-Teruel et al., 2021). are consistent with more recent findings obtained in healthy Collectively, the above profiles are consistent with RHA rats humans. Thus, reward sensitivity, as measured by the “Behavioural being driven by “positive valence” processes (see section A in Activation System” (BAS) trait scale (Carver & White, 1994; Gray Table 1) and characterized by high reward sensitivity (and & McNaughton, 2000), is positively correlated with activity impulsivity) and impairments in the cognitive domain, which are (measured through fMRI) of the dorsomedial and ventral striatum compatible with a personality dominated by “Impulsivity/ (equivalent to the NAcc in rats) during a gambling task involving Sensation seeking” traits (Zuckerman, Murtaugh & Siegel, 1974; reward-punishment conflict (Costumero et al., 2016). Hence, it is Siegel, Sisson & Driscoll, 1993; Gray & McNaughton, 2000; Giorgi noteworthy that the findings on DA function in RHA (vs. RLA) et al., 2019) (see section C in Table 1). Impulsivity, or impairment rats translate to humans. of behavioral control (i.e., behavioral inhibition deficit), is often a cause of both maladaptive behaviors directed toward an individual’s environment and interference in life functioning. Epigenetic and “genotype x environment” interaction These traits are typically associated with attention/cognition effects on personality/psychopathology impairments, impulsive choices/actions (i.e., premature responses or actions without foresight, often leading to adverse or Certain traumas, or stressful or positive events, particularly those maladaptive consequences) and hyperactivity. If combined with experienced at young ages, can lead to markers (e.g., DNA high reward/sensation seeking, they relate to risky behavior and methylation) being placed on genes, changing their functional vulnerability to substance use and abuse (e.g., review by Giorgi expression. These are the subject of study of epigenetics (e.g., et al., 2019, and references therein). All these aspects converge in Francis, Diorio, Liu & Meaney, 1999; Bahari-Javan et al., 2017). RHA’s behavioral profile (Fernández-Teruel et al., 2021; Giorgi Among other things, epigenetics deals with the study of “why”, et al., 2019). Hence, the RHA rats seem to fall within the “when” and “how” the markers that environmental life events place “Disinhibited Externalizing” spectra and “Substance Abuse” sub- on genes can lead to traceable changes in the development of the factor, and likely also within the “Thought disorder” spectra nervous system, biological and mental processes and behavior. (Michelini et al., 2021; see section B in Table 1), as they present Neonatal handling (NH; a neonatal stimulation treatment various schizophrenia-linked traits, such as, e.g., hyperactivity, administered to rats or mice during the first weeks of life) and relative asociality, and impairments of inhibitory control (impul- environmental enrichment (EE; administered for several months sivity) and attentional/cognitive processes (Fernández-Teruel from puberty to adulthood) induce stable long-lasting changes in et al., 2021; Giorgi et al., 2019) (see Table 1). the personality profile and HPA-axis stress responses in RLA as well as many other laboratory rats, so that treated rats become enduringly much less threat- and stress-sensitive (e.g., see Neurobiological and molecular profiles of Roman Fernández-Teruel, Escorihuela, Castellano, González & Tobeña, high-avoidance rats 1997; Fernández-Teruel et al., 2002a, 2002b; Río-Álamos et al., 2017, 2019, and references therein) than their non-handled Recent studies have shown that RHA rats present alterations of counterparts. NH treatment of offspring induces improved dams’ pre-/postsynaptic markers and trophic factors in the PFC and/or maternal behavior, which in turn induces epigenetic changes in the HPC (e.g., neuregulin1, homer1, synaptophysin and brain-derived HPC involving the nerve growth factor-inducible protein A neurotrophic factor/BDNF) that have been linked with glutama- (NGFI-A) transcription factor and glucocorticoid receptors, and tergic dysfunction, PFC maturation and schizophrenia (Elfving thus HPA-axis function (Francis et al., 1999; Weaver et al., 2007). et al., 2019; reviewed by Fernandez-Teruel et al., 2021). In addition, Importantly, neonatal handling leads to an enduring reduction of RHA rats exhibit increased DA D1 receptors in the PFC and the HPC and AMY volume in RLA rats, which correlates with the NH- NAcc, augmented NMDA2B receptors in the PFC, enhanced 5- decreased threat sensitivity and anxious/fear behavior (Río- HT2A receptors in PFC and HPC, a dramatic deficit of mGlu2 Álamos et al., 2017, 2019). receptors in PFC, HPC and striatum (Elfving et al., 2019), and Many “genotype x environment” interactions have been increased density of immature dendritic spines in the PFC reported for the effects of NH and/or EE treatments on RHA/ (Sánchez-González et al., 2021). This is overall consistent with the RLA rat behavior and neuroendocrine traits (for reviews, see evidence of lowered function and volume of the PFC and HPC in Fernández-Teruel et al., 2002a, 2021; and Río-Álamos et al., 2017, RHA rats (e.g., Meyza et al., 2009; Río-Álamos et al., 2019; Tapias- 2019, and references therein). NH and EE treatments also influence Espinosa et al., 2019, 2023). These molecular/synaptic markers and many aspects of personality of RHA rats. For example, NH neuro-functional profiles strongly suggest that RHA rats have improves attentional (PPI) and cognitive functions in this strain, immature (i.e., adolescent-like) PFC and (likely) HPC, which lead and NH and/or EE long-lastingly improve spatial cognitive to impaired top-down inhibitory control (e.g., of the mesolimbic processes of RHA rats and enhance novelty- and/or substance- DA system) (Sønderstrup et al., 2023). Collectively, these profiles seeking behavior in both Roman rat strains (e.g., Fernández-Teruel cohere with their behavioral/cognitive alterations, and with their et al., 1997, 2002b; Río-Álamos et al., 2019; Bellés, Dimiziani, https://doi.org/10.1017/pen.2023.7 Published online by Cambridge University Press Personality Neuroscience 5 Herrmann & Ginovart, 2021b; Bellés, Arrondeau, Urueña-Méndez It might be argued that the markedly enhanced capacity of RHA & Ginovart, 2023). rats to acquire TWAA learning might be due to the fact that they Regarding adverse early environmental events, we have found make better associations between the fear-eliciting CS and the that social isolation rearing (from pre-puberty to adulthood) aversive US (Mowrer & Lamoreaux, 1946). Studies of Pavlovian affects RHA/RLA rat behavior in a manner dependent upon the threat conditioning (i.e., classically-conditioned freezing) and strain (i.e., “genotype x environment” interactions). Thus, in RHA fear-potentiated startle seem to argue against that contention, since (but not RLA) rats this isolation enhances anxiety and hyper- in these paradigms RHAs exhibit both lowered conditioned freezing activity; and impairs PPI and PFC-/HPC-related reference and decreased potentiated startle responses (respectively) relative to memory, thus further increasing the schizophrenia-related impair- RLA rats (López-Aumatell et al., 2009; see further references in ments of RHA rats (Oliveras et al., 2016; Sánchez-González Fernández-Teruel et al., 2021). Importantly, also, the ability to et al., 2020). acquire one-way active avoidance responding does not differ in Still, in the context of adverse early events (i.e., early life stress), RHA vs. RLA rats when safety time is relatively long (30 s), i.e., when caregiving maltreatment produces epigenetic changes in the rat approach-avoidance conflict is low. Conversely, when safety time is adolescent brain (e.g., HPC, AMY), which could have relevance to drastically reduced (1 s), and thus approach-avoidance conflict is adolescent mental health and behavior (Doherty et al., 2016). In high, RHA rats acquire one-way active avoidance faster than RLA relation to psychopathology, Bahari-Javan et al., (2017) showed rats (Torres et al., 2007). These findings collectively suggest that fear- that (i) early life stress (ELS)-induced schizophrenia-like behav- eliciting CS–US associations are stronger in RLA than RHA rats, ioral and synaptic phenotypes in mice were associated with thus prompting the former strain to develop enhanced Pavlovian increased expression of histone-deacetylase-1 (Hdac1; one of the reactions (i.e., freezing, passive avoidance), which interfere with epigenetic processes) in PFC, possibly linked to DNA methylation active (escape/avoidance) responses, particularly when intensity of changes (another epigenetic process) and (ii) administration of an approach-avoidance conflict (and thus, threat) is high (Fernández- HDAC1 inhibitor reversed these schizophrenia-like phenotypes. Teruel & McNaughton, 2023). Importantly, Hdac1 blood levels were also increased specifically in In sum, the various processes involved in TWAA acquisition, as patients with schizophrenia who had been exposed to ELS as mentioned above, together (or in interaction) with parental strain compared with patients with schizophrenia who didn’t suffer ELS (Wistar) and individual genetic characteristics and/or vulnerabil- (Bahari-Javan et al., 2017). Thus, by using a translatable animal ities (e.g., threat sensitivity vs. reward sensitivity), have led to two model of induction of schizophrenia-relevant behavioral features, rat lines/strains that differ in a large number of stable neuro- it was suggested that a biological (epigenetic) factor might be a behavioural traits. These are not specific for two-way active relevant antecedent of at least some types of (environmentally- avoidance, nor are only related to defensive responses in the face of linked) schizophrenia, to the point that “ : : : analysis of Hdac1 threat (threat sensitivity) or approach-avoidance conflict, but expression in blood could be used for patient stratification and extend to changes in responses to positive reinforcers (reward individualized therapy” (Bahari-Javan et al., 2017, p. E4686). sensitivity, drug addiction), impulsivity and attentional/cognitive The above examples illustrate that both personality and processes (Fernández-Teruel et al., 2021; Giorgi et al., 2019). associated neurobiological and psychopathological processes can Hence, the threat-sensitive RLA rats present comorbidity with be enduringly influenced by environmental factors in a manner fear and distress, within the “Internalizing” spectra (see Table 1; dependent upon genetic background (“genotype x environment” Michelini et al., 2021). The extensive neurobiological and interactions). Epigenetics tells us that these environmental behavioral characterization carried out with RLA rats (e.g., influences on proneness to particular types of pathological Fernández-Teruel et al., 2021; Steimer & Driscoll, 2003; Giorgi symptom clusters will operate in many cases through environ- et al., 2019) makes them a very promising tool for personality mentally-induced changes in the epigenome. Thus, manipulating neuroscience and psychopathology research. They might be the environment in animal models, at different neurodevelop- particularly useful, for example, to study the neurobiological mental stages and in both (negative and positive) directions underpinnings of behavioral disinhibition (and top-down inhibi- (Fernández-Teruel, 2021), and exploring neurobiological and tory control) mechanisms (e.g., PFC, HPC), relations among top- epigenetic changes and their relation with variation of personality down inhibitory control and (good) cognitive performance, and psychopathology-linked phenotypes, might be crucial for a anxiety, stress-induced depression, anxious depression, reward- coherent/integrative and translatable development of personality devaluation-induced frustration, environmental influences on neuroscience and neuroscience-based psychopathology. these symptoms/phenotypes and epigenetic changes underlying these influences. The high reward-sensitive and behaviorally-disinhibited What more can the Roman rats tell us about personality RHA rats present comorbidity of symptoms associated with neuroscience and psychopathology? “Thought disorder” (i.e., schizophrenia-linked phenotypes) and Unlike selection of many other rat lines/strains for simpler innate “Disinhibited externalizing” (substance abuse, impulsivity) spectra behavioral traits, selection of the Roman rats for their (high/low) of the HiTOP system (Michelini et al., 2021; Table 1). Their ability to acquire the functionally complex two-way avoidance task behavioral/attentional/cognitive profile, combined with the exten- involves a variety of processes. Two-way avoidance involves (at sively characterized neurobehavioural and molecular schizophre- least) CS and context Pavlovian threat conditioning (related to nia- and drug-addiction-linked phenotypes make them a unique passive avoidance and freezing – i.e., passive coping- tendencies), tool to investigate comorbidity of schizophrenia-relevant features, instrumental escape conditioning, one-way active avoidance drug abuse (and addiction) and PFC-, HPC- and NAcc-linked conditioning, locomotor activity in a threat-conditioned context cognitive/behavioral alterations. As suggested by recent gene (e.g., inter-trial crossings) and flight responses (undirected active expression findings (e.g., Elfving et al., 2019; Sánchez-González responses searching alternative escape routes). et al., 2021; Sønderstrup et al., 2023), the RHA rats can be a useful https://doi.org/10.1017/pen.2023.7 Published online by Cambridge University Press 6 A Fernández-Teruel et al. tool for understanding the neural maturational trajectory leading enhanced functional tone of the mesolimbic dopaminergic to the behavioral and cognitive disturbances associated with pathway (including the NAcc) in the impulsive-sensation/ schizophrenia and perhaps comorbid traits/symptoms, such as novelty seeker RHA rats (see Giorgi et al., 2019). drug-seeking/abuse and impulsivity. In addition, this would allow 7. In RHA (but not RLA) rats there is a high positive correlation us to investigate whether early “therapeutic” interventions between cortical 5-HT2A receptor density and premature (e.g., infantile and/or juvenile enriched stimulation, such as NH (impulsive) responses in the “five choice serial reaction time” and EE treatments, combined or not with ELS) might modify these task. This is consistent with findings from studies in rodents neuro-molecular pathways (or factors) and phenotype expression. and humans in which the pharmacological blockade of the 5- In summary, some examples of the heuristic and translational HT2A receptor produces reductions of several types of potential of the Roman rat models are the following: impulsive responses, and with the notion that 5-HT2A receptors may facilitate some forms of impulsive behavior 1. In the RHA and RLA strains, HPC and AMY volume (reviewed by Klein et al., 2014, and Giorgi et al., 2019). positively correlate with behavioral inhibition in anxiety- 8. Similar to untreated patients with schizophrenia, RHA rats related tests (Río-Álamos et al., 2017), consistent with what exhibit enhanced cortical 5-HT2A receptor density and a has been reported between a BIS measure (Torrubia et al., dramatic deficit of mGlu2 receptors, which has been 2001) and volume of these two regions in humans (Barros- proposed to be a crucial factor for the neurodevelopmental Loscertales et al., 2006). alterations and the rich schizophrenia-related phenotypes of 2. Also, in line with human studies showing a positive this rat strain (Fernández-Teruel et al., 2021). association between a BAS-trait measure and activity of the 9. Both schizophrenia symptoms and drug addiction are related striatum during a gambling task (Costumero et al., 2016), to increased mesolimbic dopaminergic function in humans behavioral disinhibition (impulsivity) and novelty seeking in and in animal models (e.g., reviewed by Giorgi et al., 2019). Roman rats are predicted by striatal function (measured by Consistently, relative to the non-drug preferring RLA rats, amphetamine-induced DA release; Tournier et al., 2013; RHAs exhibit schizophrenia-related phenotypes and vulner- Bellés et al., 2021a; see Giorgi et al., 2019). ability to drug addiction, which are paralleled by enhanced 3. The anxious (and alcohol-non-preferring) RLA rats are more functional tone of the mesolimbic dopaminergic system in sensitive to reward loss-induced frustration than the low- RHAs (reviewed by Giorgi et al., 2007, 2019; Dimiziani anxious (and alcohol-preferring) RHA rats. Reward loss et al., 2019). (appetitive extinction) enhances ethanol preference in RLA (but not RHA) rats, similar to enhanced alcohol consumption A considerable number of pharmacological studies, with (i.e., emotion-induced “self-medication”) in humans experi- anxiolytic, antidepressant and anxiogenic drugs, or with psychos- encing sudden anxiogenic/stressful conditions. Pre-training in timulants, pro-psychotic and antipsychotic compounds, among a partial reinforcement (PR) instrumental program, a treat- others, have been carried out in the Roman rat lines/strains (e.g., ment that leads to development of resilience to (reward) loss- Oliveras et al., 2017; Sampedro-Viana et al., 2023; see reviews by induced anxiety, suppresses loss-induced ethanol preference in Fernández-Teruel et al., 2021, and Giorgi et al, 2019, and further RLAs in parallel to increasing their frustration tolerance references). While these studies globally give support to the (Cuenya et al., 2012; Manzo et al., 2015). This makes RLA (vs. predictive validity of RLAs as a model of anxiety (i.e., threat RHA) rats a translatable model to study innate differences in, sensitivity) and RHAs as a model of schizophrenia-relevant and mechanisms of “frustration tolerance”, vulnerability to phenotypes and drug-addiction vulnerability (i.e., reward sensi- negative emotion-induced self-medication (and substance use/ tivity), much more psycho- and neuro-pharmacological research is abuse) and neurobehavioral mechanisms mediating resilience still necessary. Future efforts should focus on (i) expanding the to loss-induced anxiety/frustration. number of relevant behavioral phenotypes affected by drugs in 4. Excessive anxiety of RLA rats in different tests/tasks is both rat strains, (ii) exploring neurobiological/molecular mech- attenuated by anxiolytic drugs and increased by known anisms affected by treatments shown to be effective in changing anxiogenic drugs (see Supplementary Table S2 in Fernández- particular phenotypes and, (iii) extending behavioral, pharmaco- Teruel et al., 2021). logical and neurobiological research to both sexes (Fernández- 5. Augmenting of cortical visual-evoked potentials (VEPs) is Teruel et al., 2021). considered a specific neurophysiological marker of high Collectively, the findings reviewed here provide an overview of sensation-novelty seeking (and disinhibited) personality in the major traits that distinguish RLA vs. RHA rats, from humans. Remarkably, similar to what has been observed in internalizing to externalizing spectra, from neuroticism- and disinhibited sensation-novelty seeker humans and cats, the threat-sensitivity-linked vulnerabilities (RLA) to impulsivity and RHA rats are cortical VEP augmenters, whereas RLA and reward sensitivity-related traits (RHA), from good attention/ Wistar rats are VEP-reducers like non-disinhibited humans cognitive capacities (RLA) to schizophrenia-linked phenotypes (Zuckerman et al., 1974; Siegel et al., 1993; Siegel & Driscoll, (RHA). Our aim has been to highlight (also giving several examples 1996). of translatability) that these two rat strains/lines may constitute 6. Novelty seeking in RHA/RLA rats is inversely associated with important tools for translational research on personality neuro- postsynaptic dopamine D2 receptor availability in striatum, science and neuroscience-based psychopathology. and similar findings have been reported in humans (reviewed by Giorgi et al., 2019). Consistently, in a large sample of Acknowledgments. The authors thank the anonymous reviewers and the editors of this Special Issue for their constructive comments, which importantly healthy and distressed humans the activity of the ventro- helped to improve the quality of this review article. lateral PFC and ventral striatum, during an ‘‘uncertain reward expectancy’’ paradigm, was positively related to Financial support. The authors receive support from grants PID2020– impulsive-sensation seeking. This is also in line with the 114697GB-I00 (ref. 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