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Abstract: Scientists have systematically investigated the hereditary bases of behaviors since the 19th century, moved by either evolutionary questions or clinically-motivated purposes. The pioneer studies on the genetic selection of laboratory animals had already indicated, one hundred years ago, the immense complexity of analyzing behaviors that were influenced by a large number of small-effect genes and an incalculable amount of environmental factors. Merging Mendelian, quantitative and molecular approaches in the 1990s made it possible to map specific rodent behaviors to known chromosome regions. From that point on, Quantitative Trait Locus (QTL) analyses coupled with behavioral and molecular techniques, which involved in vivo isolation of relevant blocks of genes, opened new avenues for gene mapping and characterization. This review examines the QTL strategy applied to the behavioral study of emotionality, with a focus on the laboratory rat. We discuss the challenges, advances and limitations of the search for Quantitative Trait Genes (QTG) playing a role in regulating emotionality. For the past 25 years, we have marched the long journey from emotionality-related behaviors to genes. In this context, our experiences are used to illustrate why and how one should move forward in the molecular understanding of complex psychiatric illnesses. The promise of exploring genetic links between immunological and emotional responses are also discussed. New strategies based on humans, rodents and other animals (such as zebrafish) are also acknowledged, as they are likely to allow substantial progress to be made in the near future.

The Spontaneously Hypertensive Rats (SHR) strain was developed through selective breeding for high systolic blood pressure. In our laboratory, we established a congenic rat strain named SHR.Lewis-Anxrr16 (SLA16). The SLA16 rat strain is genetically identical to the SHR except for the inserted Anxrr16 region in chromosome 4. Our objective was to evaluate the influence of this genomic region on ethanol consumption and blood pressure. First, we exposed SHR and SLA16 male and female rats to ethanol consumption. Results showed that, regardless of strain, females consumed more ethanol than males during forced (10% v/v) and spontaneous ethanol consumption (SEC; 2.5-20% v/v). Then, females from both strains were used to evaluate sensitivity to ethanol. No strain differences in the loss of righting reflex were observed after ethanol treatment (3 g/kg, 20% w/v, intraperitoneal [i.p.]). But, in the triple test, female SHR rats presented lower sensitivity to the ethanol (1.2 g/kg, 14% w/v, i.p.). Surprisingly, female SHR rats also presented higher blood pressure after SEC (10% v/v). Finally, losartan treatment was effective in decreasing the blood pressure of female rats of both strains, but had specific effects on SHR ethanol consumption. Our data suggest that SLA16 female rats consume less ethanol (10%), are more sensitive to its effects, and present lower blood pressure than SHR female rats. We demonstrated that the Anxrr16 locus in chromosome 4 is a genetic candidate to explain high ethanol consumption and blood pressure, at least in females.

Attention Deficit Hyperactivity Disorder (ADHD) is a highly prevalent and disabling disorder that frequently persists into adulthood. Many patients are considered nonresponders to typical pharmacological treatments due to insufficient symptoms' reduction or the inability to tolerate the side effects of these medications. Agmatine is an endogenous neuromodulator with emotional- and cognitive-enhancing properties that arises as a promising agent to manage several Central Nervous System disorders. Here, we investigated the effects of chronic treatment with agmatine on behavioral impairments exhibited by adult Spontaneously Hypertensive Rats (SHR), an animal model for the study of ADHD. Adult male Wistar and SHR (3-4 months old) received intraperitoneal (i.p.) treatment with saline (NaCl 0.9%) or agmatine (30 mg/kg/day) during 20 consecutive days and were evaluated in a battery of behavioral tasks. Agmatine treatment improved olfactory and recognition memory impairments of SHR evaluated in the olfactory discrimination, object recognition, and social recognition memory tasks. In addition, agmatine administration improved the cognitive flexibility in the water maze test. Agmatine did not alter SHR's locomotor activity and hedonic-like behaviors observed in the open-field and splash tests, respectively. No changes were observed in SHR's systolic blood pressure following agmatine treatment. This study provides the first evidence that agmatine improves olfactory and cognitive impairments observed in an animal model of ADHD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A seleção genética de comportamentos relacionados a um componente emocional do tipo ansiedade, associada ao estudo das possíveis influências desse traço sobre outros componentes emocionais como o medo, impulsividade e tarefas de aprendizagem aversiva, podem contribuir para o entendimento da ansiedade, bem como, fornecer uma base sólida para investigações neurofisiológicas, bioquímicas e moleculares da mesma. Assim, o presente trabalho selecionou duas linhagens de ratos da linhagem Wistar: uma com característica de alta exploração dos braços abertos do labirinto em cruz-elevado (Filô-HE) e outra com baixa exploração desses braços (Filô-LE), e comparou os efeitos da seleção dessas duas linhagens sobre comportamentos associados à ansiedade, medo, impulsividade e aprendizagem aversiva. Para isso, um lote de animais fornecidos pelo Biotério Central da USP-RP foram distribuídos em dois grupos distintos: (1) os que apresentavam maior exploração dos braços abertos do Labirinto em Cruz Elevado (LCE) - (Filô-HE) e (2) os com menor exploração desses braços (Filô-LE) ao longo de doze gerações (de S1 a S12, sem contar o grupo inicial do qual derivam as gerações). Na sexta, nona e décima segunda gerações, os animais foram submetidos aos seguintes testes comportamentais: LCE, Campo Aberto (somente na décima segunda), esquiva passiva, labirinto aquático de Morris (somente na décima segunda), sobressalto (que avalia a resposta de medo), e gradiente de aversão elevado (desenvolvido em nosso laboratório para medir impulsividade). Os dados indicaram a seleção de duas linhagens de ratos Wistar com características distintas para a exploração dos braços abertos do LCE. De um lado, foi selecionada a linhagem Filô-HE, que possui como principal característica, altos índices de exploração de ambientes que geralmente são evitados por outros animais. De outro, foi selecionada (até a oitava geração), a linhagem Filô-LE, que explorava muito pouco ambientes potencialmente aversivos. Tais resultados podem ser interpretados, respectivamente, como (a) baixa e alta frequência de comportamentos associados à ansiedade e medo, (b) baixa e alta frequência de comportamentos associados à impulsividade, (c) altos e baixos níveis de dificuldade na aprendizagem relacionada a memórias emocionais, ou (d) até mesmo o efeito conjunto de todas essas características comportamentais. Porém, para um conhecimento mais confiável, é necessário que os estudos supracitados passem a explorar aspectos neurofisiológicos, psicofarmacológicos, bioquímicos e genéticos, ampliando a investigação dos componentes emocionais selecionados. Bem como, promovendo um controle mais rígido dos traços selecionados e de suas relações com outros componentes que possam interferir na seleção The genetic selection of behaviors related to an anxiety-like emotional component, associated to the study of the possible influences of this trait over other emotional components like fear, impulsivity and aversive learning, can contribute to the understanding of anxiety as well as supply a solid basis for its neurophysiological, biochemical and molecular investigation. Thus, the present work selected two strains of Wistar rats: one characterized by a high exploration of the open arms of an elevated plus-maze (Filô-HE) and another with a low exploration of these arms (Filô-LE), and compared the effects of such a selection on behaviors associated with anxiety, fear, impulsivity and aversive learning. For this, a batch of animals supplied by the animal house of the USP at Ribeirão Preto were distributed into two distinct groups: (1) one presenting more exploration of the open arms of an elevated plus-maze (EPM) Filô-HE and (2) one with less open arm exploration Filô-LE along twelve generations (from S1 to S12, not counting the initial group from which all generations derived). On the sixth, ninth and twelfth generations the animals were submitted to the following behavioral tests: LCE, open-field (only in the twelfth generation), passive avoidance, Morris aquatic maze (only in the twelfth generation), startle (which evaluates a fear response), and elevated aversion gradient (developed in our laboratory to measure impulsivity). The data indicated a selection of two Wistar rats strains with distinct characteristics concerning the exploration of the open arms of and EPM. On the one hand, the strain Filô-HE was selected exhibiting as the main characteristic high measures of exploration of environments which are usually avoided by other animals. On the other hand, the strain Filô-LE was selected (up to the eighth generation) exhibiting very little exploration of potentially dangerous environments. These results may be interpreted as, respectively, (a) low and high frequency of behaviors associated to anxiety and fear, (b) low and high frequency of behaviors associated to impulsivity, (c) high and low levels of difficulty in learning related to emotional memories, or (d) even the joint effect of all these behavioral characteristics. However, for a more reliable knowledge it is necessary that the studies above begin to explore neurophysiological, psychopharmacological, biochemical and genetic aspects, broadening the investigation ot hte selected emotional components, as well as promoting a more strict control of the selected traits and of its relations with other components that may interfere in the selection