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Sustained hyperactivity and lower blood pressure are influenced by the ANXRR16 chromosomic region in rats

Natalli GRANZOTTO1,3; Jéssica Cordeiro Oliveira SQUARIZ2,3; Eduardo Kuser1,3; Ariela Maína BOEDER1,3; Julia Fernandez Puñal ARAÚJO2,3; Pamela Ramborger ANJOS1,3, Guilherme Pasetto FADANNI1,3; Áurea Elizabeth LINDER1; André RAMOS3; Geison Souza IZÍDIO1,2,3#

1Graduate Program of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianopolis, Brazil.
2Graduate Program of Developmental and Cellular Biology, Center of Biological Sciences, Federal University of Santa Catarina, Florianopolis, Brazil
3Behavioral Genetics Laboratory, Federal University of Santa Catarina, Florianopolis, Brazil

*Corresponding author

*Izídio, G. S, *Graduate Program of Pharmacology, Center of Biological Sciences, Federal University of Santa
Catarina, Florianopolis, Brazil.
**Graduate Program of Developmental and Cellular Biology, Center of Biological Sciences, Federal University of Santa Catarina, Florianopolis, Brazil
***Behavioral Genetics Laboratory, Federal University of Santa Catarina, Florianopolis, Brazil

Abstract

Objectives: Quantitative Trait Locus (QTL) mapping is a virtuous strategy to find chromosomic regions related to behavioral traits in rats. We have mapped a QTL, on rat chromosome 4, called Anxrr16 (anxiety-related response 16) that modulates the central locomotion in the open-field (OF). To specifically study the Anxrr16 effects, we developed the congenic SLA16 (SHR.LEW-Anxrr16) rat strain.

Methods: Here, males and females from SLA16 and SHR (Spontaneously Hypertensive Rat) strain were (i) repeatedly evaluated in the OF throughout their entire lives (4 weeks to 24 months); (ii) evaluated for their systolic blood pressure; (iii) and repeatedly treated (from postnatal days 28 to 44) with methylphenidate (MPH, Ritalina®, 2 mg/kg) or vehicle, tested in OF and novel object recognition and retested 4 months later.

Results: SLA16 from both sexes presented more locomotor activity in non-classical repeated OF protocol and lower systolic blood pressure than SHR rats. MPH treatment administered during adolescence slightly improved recognition of the unfamiliar object in young SLA16, and adult females of both strains.

Conclusions: Our data highlight that SLA16 rats are naturally more hyperactive throughout their life and less hypertensive than SHR rats. We also put forward the involvement of a specific segment of rat chromosome 4 (Anxrr16) as a candidate to explain locomotor hyperactivity and low blood pressure, a potential outcome for basic ADHD research.

Keywords: SLA16; SHR; methylphenidate; ADHD; open-field.

INTRODUCTION

Many studies have shown that Quantitative Trait Locus (QTL) mapping is a virtuous strategy to find chromosomic regions related to behavioral traits in rats. The first QTLs for emotionality in rats were identified by Ramos et al. (1999), using the inbred strains Lewis (LEW) and SHR, which display high and low levels of anxiety/emotionality-related behaviors, respectively (Ramos et al., 1997). One major QTL, mapped on rat chromosome 4, modulated the central locomotion in the open-field (OF) test later named Anxrr16 (anxiety-related response # 16 QTL) by the Rat Genome Database (http://rgd.mcw.edu/). Subsequent studies confirmed Anxrr16 emotional effects in both male and female rats (Mormède et al., 2002; Hameister et al., 2008; Chiavegatto et al., 2009; Izídio et al., 2011) and extended its influences on learning/memory, locomotor behaviors, ethanol intake, cocaine sensitization and physiological stress response in rats (Vendruscolo et al., 2006, 2009; Anselmi et al., 2016).

One of the genetic approaches often used to identify genes underlying specific QTLs is the production of congenic strains. This approach allows the transfer of a chromosomal region, also called the differential locus (Bennett, 2000), from a donor strain to a receptor strain background. Using this strategy, our group has developed the SHR.LEW-Anxrr16 (SLA16) congenic rat strain, containing only part of chromosome 4 (Anxrr16) from the LEW strain (donor) on a genetic background from the SHR strain (receptor) (De Medeiros et al., 2013). The Anxrr16 genomic area has been suggested as important in the search of genes for human psychopathologies.

The Spontaneously Hypertensive Rat (SHR) strain is considered a standard animal model in Attention-Deficit/Hyperactivity Disorder (ADHD) research (Russell, 2011). These rats have been extensively studied because they exhibit innate hyperlocomotion, highly impulsive behavior, and poor performance on some learning/memory tasks (Sagvolden, 2000). The SHR rats also present dopaminergic disturbances and a genetic insertion in the noncoding region of the DAT (dopamine transporter) gene (Mill et al., 2005). Despite its utility, the use of SHR animals in this field has some limitations as they also exhibit spontaneous hypertension and inconsistent performance in discriminative tasks (Russell, 2011). Moreover, methylphenidate (MPH), the first-choice drug for ADHD in clinics, sometimes does not necessarily improve the SHR performances in learning/memory and impulsivity tasks and SHR rats are hyperactive compared to both Wistar-Kyoto, only at specific ages (van den Bergh et al., 2006).

Recently, our studies suggested that SLA16 animals are more hyperactive than SHR rats in a single OF trial (Anselmi et al., 2016), but no data is available about the consistency of these behavioral differences. Therefore, our main goal is to evaluate putative differences between SHR and SLA16 animals in locomotor, emotional, and blood pressure tests, either naïve or after MPH treatment (Ritalina®, Novartis). We hypothesize that SLA16 rats would show increased locomotion throughout their life, lower blood pressure and more consistent behavioral improvements after MPH treatment than SHR rats.

MATERIALS AND METHODS

Animals

The SHR (SHR/NCrlAnra) inbred rats were originally from Harvard University, Boston MA, and then they were bred at UNESP, Botucatu SP (https://rgd.mcw.edu/rgdweb/report/strain/main.html?id=6218997). The SLA16 (SHR.LEW-Anxrr16) congenic strain was developed at the Behavior Genetics Laboratory (in the Federal University of Santa Catarina) by backcrossing a portion of the Lewis chromosome 4 into the SHR genetic background (https://rgd.mcw.edu/rgdweb/report/strain/main.html?id=11528588). Both strains had been bred and maintained in the Behavior Genetics Laboratory for more than 40 generations under a system of brother-sister mating. The animals were housed in 5/6 per cage (polycarbonate white matte) with food and water ad libitum and under a 12h light/dark cycle (lights on 7:00 a.m.). The room temperature was automatically controlled (22 ± 2 °C). All procedures were performed following the animals’ guidelines for animal care from “Conselho Nacional de Controle de Experimentação Animal” (CONCEA, Brazil) following the local committee for Animal Care in Research (CEUA/UFSC).

Apparatuses

The open-field (OF) was the same as described in Anselmi et al. (2016). The apparatus for object recognition (OR) consisted of a transparent acrylic arena (approximately measures: 50-cm wide, 50-cm long, and 50-cm high) externally lined in gray material, completely opaque. The rats’ behavior was recorded by a camera placed above the OF and posteriorly analyzed by the Any-maze software (Stoelting Co., Illinois, USA). Behavior tests were performed under a light intensity of 12 lux.

Experimental design

First experiment

Males and females from the SHR and SLA16 strains (12/strain/sex) were submitted to 13 OF repeated sessions, beginning at 4 weeks and lasting up to 2 years of age (4, 5, 6, 7, 8, 9, 10, 12, 16 weeks, 5, 12, 18, 24 months). The animals were placed in the center, one at a time, and allowed to explore the apparatus for 5 min in each trial.

Second experiment

Male and female (8/strains/sex) adults (3.5-4.5 months old) from SHR and SLA16 strains had their blood pressure (BP) evaluated. Briefly, BP was measured by tail plethysmography (non-invasive method) after 30 min of habituation and in a room at 30ºC, between 10:00am and 3:00pm. All groups were subjected to three BP measurements by using a tail-cuff method (ML125 NIBP Controller, ADInstruments) coupled with the PowerLab® system (ADInstruments) and the average was used in the statistical analysis.

Third experiment

The protocol was based on Vendruscolo et al. (2008). Briefly, methylphenidate – (MPH, RITALINA®, Novartis) was dissolved in saline (SAL, 0.9% NaCl), which was used as a control solution. Males and females from SHR and SLA16 strains (12/strain/sex) were weighed once a day and treated with MPH (2 mg/kg) or SAL (gavage) twice a day (4 h apart) from postnatal days 28 to 44 (mid-late adolescence). Then, they were tested in the OF and OR tests (at 2.5 months of age). Four months later, the animals were resubmitted to the same tests.

In OR, the animals were habituated to the apparatus, on the day preceding the training session. Animals were individually placed in the center of the apparatus with two identical copies of an object (training session), placed on opposite sides, at 10 cm from the walls. The exploration of each of the objects was measured to verify if there was a preference for one of the copies. Thirty minutes later each animal was put back into the apparatus (test session) with a copy of the familiar object (identical to the training object) as well as a new object. The exploration of both objects was measured and expressed as a discrimination index (DI), where DI= (Time exploring new object-Time exploring familiar object)/(Total exploration time).

Statistical analyses and graphs

Data were evaluated using Statistica® software, version 10 (StatSoft Inc., Tulsa, USA). Normality was accessed by the Shapiro-Wilk method, and variance was evaluated with the Levene-test. ANOVA of repeated measures, separately for each sex, was used for the first experiment (independent variables: strain and repetition) and a two-way ANOVA for the second (independent variables: strain and sex) and third (independent variables: strain and treatment). For the OR test, a t-test was performed to compare each group’s discrimination index with the neutral value (DI=0). Whenever necessary, we performed a post hoc Duncan’s test. P values were considered significant when >0.05. Figures were produced with GraphPad Prism software, version 5 (GraphPad Software Inc., San Diego, California, USA).

RESULTS

First experiment: Repeated Open-field (OF)

            In males, a significant effect of strain [F(1,4)=107,84, p=0,005; SLA16>SHR] and time [F(12,48)=18,737, p<0,001] was observed for total locomotion. Duncan's post hoc test revealed that locomotion of both strains was higher in the 5th, 6th, 12th e 16th weeks and lower in 12, 18 e 24 months (Fig.1A).

In females, a significant effect of strain [F(1, 4)=21,050, p=0,005; SLA16>SHR] and time [F(12,48)=25,667, p=0,001] was observed for total locomotion. Duncan's post hoc test revealed that locomotion of both strains was lower at 12, 18 e 24 months (Fig.1B)

Second experiment: Blood pressure

The two-way ANOVA showed a significant effect for strain [F (1, 28)=8.791; p=0.006; SHR>SLA16] and for sex [F (1,28)=5.288; p=0.029; males>females; Fig.2] in the systolic arterial pressure of these animals.

Third experiment

Open-field after methylphenidate treatment

In naïve males, analyses showed a significant effect of strain for central [F (1,42)=4.190 p=0.046; SLA16>SHR; Fig.3A] and total [F (1,42)=17.925, p<0.001; SLA16>SHR; Fig.3C] locomotion.

In these same males, 4-months later, there was a significant strain effect for central [F (1,42)=23.097, p<0.001; SLA16>SHR; Fig.3B]; and total [F (1,42)=32.918; p<0.001; SLA16>SHR; Fig. 3D] locomotion. There was a treatment effect in time in center [F (1,42)=5.820, p=0.020; MPH>VEH; Fig.3F].

In naïve females, there was a significant strain effect for central [F(1,44)=9.707, p=0.003; SLA16>SHR; Fig.4A]; and total [F(1,44)=23.299, p<0.001; SLA16>SHR; Fig.4C] locomotion.

In the same females, 4-months later, there were a strain effect for central [F(1,41)=14.034; p<0.001; SLA16>SHR; Fig.4B]; and total [F (1, 41)=15.100; p<0.001; SLA16>SHR; Fig.4D] locomotion, and time in center [F (1,41)=4.816; p=0.034; SLA16>SHR; Fig.4F].

Object Recognition after methylphenidate treatment

In males, the t-test against “0” (Fig.5A) revealed differences in SHR MPH [t(11)=5.967, p<0.001], SHR saline [t(11)=5.516, p<0.001], SLA16 MPH [t(11)=9.309, p<0.001], and SLA16 saline [t(10)=3.418), p=0.007].

In the same males, 4 months after MPH treatment, the t-test ​​against “0” (Fig.5B) revealed differences in SHR MPH [t (11)=4.590, p<0.001], SHR saline [t (11)=4.105; p=0.002], SLA16 MPH [t (11)<0.001; p<0.001], and SLA16 saline [t (10)=5.688; p<0.001].

In females, the t-test against “0” (Fig.5C) revealed a specific difference in the SLA16 MPH group [t(11)=5.482, p<0.001].

In these same females, 4 months after MPH treatment, the t-test ​​against “0” (Fig.5D) revealed a difference in SLA16 females treated with MPH [t (11)=4.307; p=0.001], and SHR females treated with MPH [t (11)=4.025; p=0.002].

Figure 1- SHR and SLA16 rat strains submitted to the Open-Field repeated test (4 weeks to 24 months). (A) total locomotion in meters from males (B) and from females. Results are expressed as mean ± standard error of the mean. *Strain effect p<0.05. a=higher values; b=lower values. ANOVA with repeated measures and Duncan’s post hoc.

Figure 2:  Systolic Arterial Pressure of males and females from SHR and SLA16 rat strains. Results are expressed as mean ± standard error of the mean. **Strain effect p<0.01; @Sex effect p<0.05; Two-way ANOVA.

Figure 3: Males SHR and SLA16 rat strains submitted to open-field after methylphenidate treatment. 2.5 months old (A) central locomotion, (C) total locomotion, and (E) time in the center. 4 months after (B) central locomotion, (D) total locomotion, and (F) time in the center. Results are expressed as mean ± standard error of the mean. **Strain effect p<0.01, *p<0.05; #Repetition effect p<0.05; Two-way ANOVA.

Figure 4:  Females SHR and SLA16 rat strains submitted to open-field after methylphenidate treatment. 2.5 months old (A) central locomotion, (C) total locomotion, and (E) time in the center. 4 months after (B) central locomotion, (D) total locomotion, and (F) time in the center. Results are expressed as mean ± standard error of the mean. **Strain effect p<0.01, *p<0.05; #Repetition effect p<0.05; Two-way ANOVA.

Figure 5:  SHR and SLA16 rat strains submitted to object recognition after methylphenidate treatment. 2.5 months old (A) males and (B) females recognition index testing. 4 months after (C) males and (D) females recognition index testing. Results are expressed as mean ± standard error of the mean. ## significant values against the “0” p<0.01; Student t-test.

DISCUSSION

Currently, the SHR strain is still considered the gold standard model of ADHD in basic research (Sagvolden, 2000), although some criticisms on this proposition have already been published (Leffa et al., 2019, Regan et al., 2022). We have suggested that SLA16 rats are even more hyperactive than their SHR counterparts (Anselmi et al., 2016; Pértile et al., 2017) and, for the first time, we have shown that this characteristic remains even after long and repeated OF testing (4 weeks - 24 months of age). These results are suggesting that we have developed a strain that is naturally and consistently hyperactive, even when compared to SHR rats.

The sustained locomotion that was observed over the trials suggests that habituation has not occurred in the OF. Habituation is considered a form of learning in which the body learns to respond to non-significant stimuli (Groves & Thompson, 1970). Habituation observed within the same test session is often seen as a measure of adaptation, while the same phenomenon that occurs between sessions, performed on different days, can also be seen as a measure of memory from previous days (Müller et al., 1994). OF habituation seems to reflect a rather elementary form of learning, which is dependent on hippocampal processing (Thiel & Huston, 1998). For example, Wistar rats that had VTA or amygdala injured in childhood exhibited hyperlocomotion and did not habituate to OF under a repeated protocol (Daenen et al., 2001). Helmeste (1983) correlated the loss of habituation to OF to the high D2 receptor densities in the striatum and olfactory bulb, when comparing Fisher rats to the isogenic Buffalo strain. Another study also showed the loss of habituation in the OF in FIS rats when compared to LEW and associated this strain difference with the limbic system (Stöhr et al., 1998). Other studies indicate that OF exploration and habituation are closely related to cholinergic neurotransmission in the hippocampus (Carlton, 1968; Thiel & Huston, 1998). Furthermore, genetic influences are also evidenced in this process, since knocking out some genes, such as the one that encodes the dopamine transporter, has been shown to reduce the level of habituation to OF (Giros et al., 1996). Together, these data suggest an influence of some brain areas and the dopaminergic system on the habituation to the OF test, suggesting a correlation between dopaminergic hypoactivity and low OF habituation. Nonetheless, whether SLA16 animals exhibit dopaminergic hypoactivity is still a question that requires further investigation.

We observed for the first time a strain effect, for blood pressure (BP) measurements in naïve male and female animals, with SLA16 rats having lower systolic blood pressure than SHR rats. According to our data, SHR showed a mean BP of 188 mmHg for males and 169 for females, having thus a clear hypertensive profile. The SLA16, on the other hand, had a lower BP, with a reduction of 13 mmHg for males and 14 mmHg for females when compared to SHRs.

Sex BP differences were also observed in the original SHR development paper, with males showing higher BP than females (Okamoto & Aoki, 1963). This has been corroborated by further studies on the SHR strain (Iliescu et al., 2006). Normally, lower blood pressure levels in females compared to males are associated with higher levels of protection and vasodilator factors, but several studies show different underlying mechanisms regulating blood pressure in males and females (Tipton et al., 2012). It is known that in SHR males, hypertension is mediated by androgens, as castration reduces BP (Iliescu et al., 2006) while ovariectomy in females has no effects (Brinson et al., 2014). Levels of oxidative stress in males and females are similar, but the use of antioxidants is effective in controlling hypertension only in males (Fortepiani & Reckelhoff, 2005). In addition, there are sex differences in inflammation and immune profiles, with a lymphocyte contribution to the maintenance of hypertension in female SHR (Tipton et al., 2012).

The literature shows that hypertension can lead to cognitive impairment (Liu et al., 2018), which can be a confounding factor in some SHR studies. Instanes et al. (2018) reported that hypertension and vascular diseases are not more prevalent in ADHD patients than in controls. Notwithstanding, the high blood pressure of SHR rats and the difficulty of dissociating hypertension from hyperactivity are among the main drawbacks of their use as an ADHD model. Along with that, studies in humans demonstrate that children and adolescents with ADHD had significantly lower BP compared to a control group without ADHD, although this difference was no longer detectable in follow-up studies carried out ten years later (Schulz et al., 2021). In this context, SHR rats, due to their marked hypertension, are at a greater risk of developing other hypertension-related diseases, such as left ventricular hypertrophy, heart failure, metabolic abnormalities, kidney damage, and stroke (Bing et al., 2002; Hultström, 2012). This increases the limitations in the use of SHR as an ADHD model since we do not observe the same comorbidity profile in clinical practice. It is currently not possible to state that SLA16 rats are not hypertensive, but the fact that they present lower blood pressure than their SHR ancestors points to an important advance concerning ADHD rat model.

As herein results suggested that SLA16 animals were more hyperactive and with low blood pressure than SHR rats, we performed a final experiment trying to evaluate the validity of using SLA16 strain in ADHD basic research. But, when the animals were treated with MPH during adolescence, just small treatment effects were observed. Literature is controversial regarding the effects of MPH on hyperactivity in animals treated during adolescence. For instance, MPH could either increase (Carlezon et al., 2003), decrease (Gray et al., 2007; Wiley et al., 2009) or not affect (Valvassori et al., 2007) spontaneous locomotor activity. In another study, Somkuwar et al. (2016) reported a decrease in adult hyperactivity in SHR rats chronically treated with MPH in adolescence. Pointing in the opposite direction, a recent meta-analysis by Leffa and colleagues (2019) reported that MPH failed to reduce hyperactivity in SHR rats. Vendruscolo and colleagues (2008), showed that MPH during adolescence also induced emotional changes in SHR rats. Herein, we only observed an increase in the OF central area permanence after 4 months after the end of treatment. Such a delay, not described previously, might be due to our 6-day longer treatment.

However, in the OR test, the MPH SLA16 female group could discriminate the novel object, suggesting a slightly better performance in a short-term memory task. Pietrzak et al. (2006) mentioned improvements in short-term and long-term memory in 58% of studies after MPH treatment in humans. Weissenberger et al. (2001) reported that MPH administered to young rats resulted in altered levels of dopamine transporters that persisted into adulthood long after treatment termination. Somkuwar (2016) showed that discontinuation of treatment in adolescence produced a long-term reduction in hyperactivity in adult SHR, but the adverse consequence was increased impulsivity in these rats. Better characterizing the impulsivity and inattention of SLA16 rats, now appears to be imperative. In the same way, we need more studies that demonstrate the effectiveness of drugs used in the clinic for ADHD in these animals before we can recommend than to basic research in the ADHD field.

As all animals used in our experiments are raised in a strictly equal environment throughout their lives and their genetic differences are limited to the alleles of chromosome 4 in Anxrr16 region between the molecular markers D4Rat76 (85.2 Mbp) and D4Mgh11 (167.1Mbp), we suggest that the increased hyperactivity and lower blood pressure in SLA16 could be under the influence of these genes. The future investigation of this genome region in rats and its syntenic regions in humans strikes as a very promising endeavor because it contains numerous genes of interest involved in emotional and stress responses, immunity, ethanol consumption and gabaergic, dopaminergic and glutamatergic pathways (Ramos et al., in print). However, in special interest for the present results, some of the Anxrr16 genes have caught our attention for their functional relevance or because of previous data from rat strain studies. For example, based on the candidate-gene information from the Rat Genome Database, one might suggest that the most promising candidate gene for the Anxrr16 region is Tacr1. This gene is responsible for the neurokinin-1 receptor, whose main ligand is substance P, which is described in the literature to be involved in cardiovascular regulation (Mistrova et al., 2016). If different alleles of the Tac1r gene are involved in the differential systolic blood pressure and/or sustained hyperactivity from SHR and SLA16 animals should be further investigated shortly.

In conclusion, in the present study we showed for the first time that SLA16 animals did not habituate to the repeated OF, exhibited higher total locomotion throughout their life and low systolic blood pressure than SHR rats. SLA16 females slightly improved their performance in short-term memory tasks after MPH treatment. These effects were also present after 4 months in the SLA16 and SHR females. We also put forward the involvement of a specific segment of rat chromosome 4 (Anxrr16) as a candidate to explain locomotor hyperactivity and low blood pressure, a potential outcome for basic ADHD research. But at present, we also need more pharmacological validation of the SLA16 rats to show their usefulness in ADHD basic research.

ACKNOWLEDGMENTS

We disclose any possible conflict of interest in the conduct and reporting of research. We would like to thank Dra. Angela P. França and Rafaela Venturi Souza for technical contributions. We are grateful to the “Laboratório Multiusuário de Estudos em Biologia” (LAMEB/UFSC) for providing the infrastructure for carrying out the experimental tests. This work was supported by Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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