Comparative effects of stressors on behavioral and neuroimmune responses of fawn-hooded (FH/Wjd) and Wistar rats: Implications for models of depression.

Patients with depression and rodent models of depression show increased cytokines and activated microglia. Fawn Hooded (FH/Wjd) rats have long been used as a model of depression based on their depressive-like behaviors, high basal corticosterone levels and altered serotonergic levels, but little is known about the neuroimmune function in this model. To test whether depressive-like behaviors relate to dysfunction of the neuroimmune system, depressive-like behaviors in the forced swim test (FST) and corticosterone (CORT) response to the swim test were compared in male Fawn Hooded versus Wistar rats, and cytokine levels in plasma and brain and plasma CORT in response to lipopolysaccharide (LPS, an endotoxin that activates the neuroimmune system) or 1 h restraint were measured. Fawn Hooded rats had more depressive-like behaviors in the FST (decreased swim time and increased immobility) and increased overall plasma CORT compared with Wistar rats. Additionally, Fawn Hooded rats exhibited blunted brain and plasma cytokine response to LPS compared with Wistar rats, an effect that might be related to the blunted plasma CORT response to LPS. No strain differences were found on these measures in response to restraint stress. These results suggest that Fawn Hooded rats have a depressive-like phenotype potentially more closely associated with serotonin dysregulation and a dysregulated HPA axis and remain a relevant model for further defining the role of these systems in depressive conditions.

Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral-regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral-regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral-regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral-regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders.

Coping style and stress hormone responses in genetically heterogeneous rats: comparison with the Roman rat strains.

The purpose of the present study was to evaluate for the first time the stress-induced hypothalamus-pituitary-adrenal (HPA), adrenocorticotropic hormone (ACTH), corticosterone and prolactin responses of the National Institutes of Health genetically heterogeneous rat stock (N/Nih-HS rats) in comparison with responses of the relatively high and low stress-prone Roman Low- (RLA-I) and High-Avoidance (RHA-I) rat strains. The same rats were also compared (experiment 1) with respect to their levels of unconditioned anxiety (elevated zero-maze test), novelty-induced exploratory behavior, conditioned fear and two-way active avoidance acquisition. In experiment 2, naive rats from these three strains/stocks were evaluated for "depressive-like" behavior in the forced swimming test. N/Nih-HS and RLA-I rats showed significantly higher post-stress ACTH, corticosterone and prolactin levels than RHA-I rats. N/Nih-HS rats also presented the highest context-conditioned freezing responses, extremely poor two-way avoidance acquisition and very low novelty-induced exploratory behavior. Experiment 2 showed that, compared to RHA-I rats, N/Nih-HS and RLA-I rats displayed significantly less struggling (escape-directed) and increased immobility responses in the forced swimming test. Factor analysis of data from experiment 1 showed associations among behavioral and hormonal responses, with a first factor comprising high loadings of elevated zero-maze variables and lower loadings of conditioned fear, two-way avoidance acquisition and hormonal measures, while a second factor mainly grouped conditioned fear and two-way avoidance acquisition with novelty-induced exploration and post-stress prolactin. Thus, regarding their anxiety/fearfulness, passive coping style, "depressive-like" and stress-induced hormonal responses the N/Nih-HS rats resemble the phenotype profiles of the relatively high-anxious and stress-prone RLA-I rat strain.

Comparison of SHR, WKY and Wistar rats in different behavioural animal models: effect of dopamine D1 and alpha2 agonists.

Spontaneously hypertensive rats (SHR) and its counterpart, the Wistar-Kyoto rats (WKY), are probably the most often used animal model of ADHD. However, SHR as model of ADHD have also been criticised partly because of not differing to outbred rat strains. In the present study, adolescent SHR, WKY and Wistar rats from Charles River were tested in open-field, elevated plus maze and novel object recognition and on gastrointestinal transport to more intensively evaluate the strain characteristics. Non-habituated SHR and Wistar rats were more active than WKY rats but contrary to Wistar rats SHR stay hyperactive in a familiar environment. SHR were more sensitive to the alpha2-adrenoceptor agonist guanfacine and the dopamine D1 agonist A-68930 than WKY and Wistar rats, whereas amphetamine, the D1/D5 agonist ABT431 and the D2 agonist quinpirole, similarly affected open-field activity in all strains. In the elevated plus maze, SHR and Wistar rats showed less anxiety-related behaviour than WKY rats. Guanfacine and amphetamine induced an anxiolytic-like activity in SHR but not in WKY and Wistar rats. SHR showed the highest long-term memory in the novel object recognition. Gastrointestinal transport was similar and comparably affected by guanfacine in all rat strains. The present study shows clear differences in the behaviour of SHR and Wistar rats but also of WKY and Wistar rats. The use of SHR as animal model of ADHD is supported.

The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected].

A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comorbidity of depression. WAG/Rij rats, originally developed as an animal model of human absence epilepsy, share many EEG and behavioral characteristics resembling absence epilepsy in humans, including the similarity of action of various antiepileptic drugs. Behavioral studies indicate that WAG/Rij rats exhibit depression-like symptoms: decreased investigative activity in the open field test, increased immobility in the forced swimming test, and decreased sucrose consumption and preference (anhedonia). In addition, WAG/Rij rats adopt passive strategies in stressful situations, express some cognitive disturbances (reduced long-term memory), helplessness, and submissiveness, inability to make choice and overcome obstacles, which are typical for depressed patients. Elevated anxiety is not a characteristic (specific) feature of WAG/Rij rats; it is a characteristic for only a sub-strain of WAG/Rij rats susceptible to audiogenic seizures. Interestingly, WAG/Rij rats display a hyper-response to amphetamine similar to anhedonic depressed patients. WAG/Rij rats are sensitive only to chronic, but not acute, antidepressant treatments, suggesting that WAG/Rij rats fulfill a criterion of predictive validity for a putative animal model of depression. However, more and different antidepressant drugs still await evaluation. Depression-like behavioral symptoms in WAG/Rij rats are evident at baseline conditions, not exclusively after stress. Experiments with foot-shock stress do not point towards higher stress sensitivity at both behavioral and hormonal levels. However, freezing behavior (coping deficits) and blunted response of 5HT in the frontal cortex to uncontrollable sound stress, increased c-fos expression in the terminal regions of the meso-cortico-limbic brain systems and greater DA response of the mesolimbic system to forced swim stress suggest that WAG/Rij rats are vulnerable to some, but not to all types of stressors. We propose that genetic absence epileptic WAG/Rij rats have behavioral depression-like symptoms, are vulnerable to stress and might represent a model of chronic low-grade depression (dysthymia). Both 5HT and DAergic abnormalities detected in the brain of WAG/Rij rats are involved in modulation of vulnerability to stress and provocation of behavioral depression-like symptoms. The same neurotransmitter systems modulate SWDs as well. Recent studies suggest that the occurrence and repetition of absence seizures are a precipitant of depression-like behavior. Whether the neurochemical changes are primary to depression-like behavioral alterations remains to be determined. In conclusion, the WAG/Rij rats can be considered as a genetic animal model for absence epilepsy with comorbidity of dysthymia. This model can be used to investigate etiology, pathogenic mechanisms and treatment of a psychiatric comorbidity, such as depression in absence epilepsy, to reveal putative genes contributing to comorbid depressive disorder, and to screen novel psychotropic drugs with a selective and/or complex (dual) action on both pathologies.

The Roman High- and Low-Avoidance rat strains differ in fear-potentiated startle and classical aversive conditioning.

The Swiss sublines of Roman High-(RHA/Verh) and Low-(RLA/Verh) Avoidance rats have been genetically selected (and outbred) since 1972 because of their good versus extremely poor acquisition of two-way, active avoidance. Inbred strains (RHA-I and RLA-I), derived from those two lines, have been maintained at our laboratory since 1997. The RLA line/strain shows increased stress-induced endocrine responses and enhanced anxiety/fearfulness in a variety of unconditioned behavioural variables and tests. Thus far, however, the Roman rat strains have not been compared in procedures involving classical fear conditioning to cues or contexts. Therefore, the present work was aimed at comparing RHA-I and RLA-I rats in 1) two different procedures of fear-potentiated startle and 2) in a classical fear conditioning (i.e., conditioned freezing) paradigm. The results indicate that, compared to RHA-I rats, RLA-I animals display higher levels of conditioned fear (as measured either by startle responses or freezing behavior) across those different tasks.

Efeitos da radiação ionizante sobre a polidpsia induzida por esquema de reforçamento / Effects of ionizing radiation on schedule-induced polydipsia

O objetivo do presente trabalho consistiu em explorar e avaliar os efeitos da radiação ionizante sobre a polidipsia induzida por esquema de reforçamento. Cinco ratos albinos foram utilizados como sujeitos e divididos em dois grupos: dois sujeitos foram expostos a um esquema de liberação de alimento em tempo fixo de 60 segundos (FT 60 s) e três foram expostos a um esquema de reforçamento em intervalo fixo de 60 segundos (FI 60 s). Depois de estabelecida a polidipsia, quatro foram expostos a uma dose de radiação de 4,5 Gy. Uma segunda exposição à radiação ionizante de 6,0 Gy foi realizada para três sujeitos trinta e seis dias após a primeira exposição. Os resultados demonstraram que, para a dose de 4,5 Gy, tanto a resposta de pressão à barra quanto a polidipsia sofreram decréscimo na sessão realizada 2 horas após a exposição. Para a dose de 6,0 Gy houve uma intensificação dos efeitos da radiação ionizante sobre a resposta de pressão à barra e sobre a polidipsia na sessão realizada 48 horas após a exposição. Os sujeitos sob esquema de reforçamento Fl 60 s sofreram maiores decréscimos em ambas as medidas que aqueles sob esquema FT 60 s. Os dados obtidos replicam dados existentes na literatura, em relação a comportamentos operantes, e estendem para comportamentos adjuntivos os efeitos da radiação ionizante. Os resultados sugerem ainda a interação entre o comportamento operante e o comportamento induzido modulando os efeitos da radiação ionizante(AU)

Efeitos da radiação ionizante sobre a polidpsia induzida por esquema de reforçamento / Effects of ionizing radiation on schedule-induced polydipsia

O objetivo do presente trabalho consistiu em explorar e avaliar os efeitos da radiação ionizante sobre a polidipsia induzida por esquema de reforçamento. Cinco ratos albinos foram utilizados como sujeitos e divididos em dois grupos: dois sujeitos foram expostos a um esquema de liberação de alimento em tempo fixo de 60 segundos (FT 60 s) e três foram expostos a um esquema de reforçamento em intervalo fixo de 60 segundos (FI 60 s). Depois de estabelecida a polidipsia, quatro foram expostos a uma dose de radiação de 4,5 Gy. Uma segunda exposição à radiação ionizante de 6,0 Gy foi realizada para três sujeitos trinta e seis dias após a primeira exposição. Os resultados demonstraram que, para a dose de 4,5 Gy, tanto a resposta de pressão à barra quanto a polidipsia sofreram decréscimo na sessão realizada 2 horas após a exposição. Para a dose de 6,0 Gy houve uma intensificação dos efeitos da radiação ionizante sobre a resposta de pressão à barra e sobre a polidipsia na sessão realizada 48 horas após a exposição. Os sujeitos sob esquema de reforçamento Fl 60 s sofreram maiores decréscimos em ambas as medidas que aqueles sob esquema FT 60 s. Os dados obtidos replicam dados existentes na literatura, em relação a comportamentos operantes, e estendem para comportamentos adjuntivos os efeitos da radiação ionizante. Os resultados sugerem ainda a interação entre o comportamento operante e o comportamento induzido modulando os efeitos da radiação ionizante

Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F(2) intercross of Roman rat strains.

Anxiety-related behaviours were evaluated across various tests in a 800 F(2)-intercross of the Roman high- and low-avoidance inbred rats. These tests either evoke unlearned (open field [OF]; plus-maze [PM]; hole-board [HB]; spontaneous activity [A]; and acoustic startle reflex [ASR]) or learned (classical fear conditioning [CFC]; and shuttlebox avoidance conditioning [SAC]), anxious/fearful responses. Using factor analysis (oblique rotation), we obtained a six-fold solution with 14 variables derived from all tests. These six factors represented SAC, CFC, PM anxiety, PM and OF activity, ASR anxiety, plus a mixed whole of anxious and activity variables (from OF and A), respectively. In searching for a smaller number of meaningful factors, we applied a three-factor solution that coherently corresponded with differentiated facets of fearfulness, rather than with the tests. Results showed that (1) measures of SAC and CFC strongly loaded onto Factor 1, labelled as "Learned Fear"; (2) a blend of almost all variables loaded onto Factor 2, called "Emotional Reactivity"; and (3) open arm behaviour in the PM loaded onto Factor 3, called "Fear of Heights." After discussing limitations of this apparently consistent behavioural map of anxiety, we advance some connections between those factors with quantitative trait loci candidates (genetic markers) as detected in the same sample.

Fear-potentiated startle in rats.

Fear-potentiated startle measures the increase in the startle reflex elicited by a sudden noise in the presence of a cue that has previously been paired with footshock. It involves an initial training session in which a cue, such as a light, is paired with footshock, and then a later test session in which startle is elicited in the presence or absence of the cue. It thus involves associative learning, memory for that association measured during the retention test, and conditioned fear in the presence of the cue. Drugs that interfere with learning, memory, or fear and anxiety can alter fear-potentiated startle depending on when they are given with respect to training and testing.

WKHA rats with genetic hyperactivity and hyperreactivity to stress: a review.

WKHA rats are a homozygous strain of hyperactive rats developed by successive selected inbreedings, starting from a cross of spontaneously hypertensive (SHR) rats with their normotensive control strain, WKY. WKHA express hyperactivity in a novel environment, as do SHRs, however their blood pressure is normotensive, thus they are potentially a more promising model of hyperactivity than the SHR. WKHA became homozygous in 1990 (20 strict brother/sister inbreedings), and they are currently in the F36 generation. Studies in collaboration with numerous colleagues have allowed us to describe a limited behavioral and neurochemical profile of WKHA rats. Their most prominent behaviors include hyperactivity in a novel environment, and a marked hyperreactivity to stress, both of which are also characteristic of SHRs. They differ from SHRs in other respects: WKHA are less aggressive, habituate more readily to a novel environment, and are less exploratory in a familiar environment than the SHR. Neurochemical studies have revealed changes in brain monoamine function in WKHA rats, particularly in frontal cortical norepinephrine and dopamine uptake, and they show marked changes in neuroendocrine responses in the hypothalamic/pituitary/adrenal axis, as well as altered POMC peptides in the pituitary anterior and posterior lobes. Molecular genetic studies by colleagues in Bordeaux have identified a quantitative trait locus for the hyperactivity/hyperreactivity trait of WKHA rats.

Strain difference in behavioral response to a new environment in rats.

Locomotor activity in rats throughout a 24-hour period in a new environment was examined for strain differences and for the capacity for adaptation to that environment. Fischer 344 rats (F344), spontaneously hypertensive rats (SHR) and Wistar normotensive Kyoto rats (WKY) were used. The horizontal locomotor activity of individual rats was measured by photocell-utilizing activity-recording devices. The locomotor activity counts on the second day, after 1 day of adaptation, were compared with those after 5 days of adaptation (on the sixth day). In WKY, there was no difference in activity at any period of the day between the second and sixth days. In SHR, the locomotor activity on the second day between 6:00 h and 9:00 h (in the light phase) and between 24:00 h and 3:00 h (in the dark phase) was higher than on the sixth day. In F344, the locomotor activity on the second day between 18:00 h and 2:00 h was higher than on the sixth day. The capacity for adaptation in SHR and F344 was thus poorer than in WKY. The poor adaptation in SHR and F344 was similar to that in depressive patients induced by moving house. These findings suggested that SHR or F344 were suitable for depression research.

Neuroendocrine correlates of emotional reactivity and coping in male rats from the Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance lines.

The Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance rats, originally selected and bred for rapid vs. poor acquisition of a two-way active avoidance response, differ in emotional reactivity and sensitivity to stressors in various other test situations. These behavioral differences are associated with particular neuroendocrine and neurochemical characteristics. The aim of this short review is to present data currently available on the neuroendocrine profiles of RHA/Verh and RLA/Verh rats, together with more recent findings which suggest that differences in peripheral and central hormonal responses, and in hormone action on the brain, may be closely related to emotional reactivity and coping ability. Although genetic factors certainly play a major role, there is also evidence that epigenetic factors, e.g., early environmental influences, can modulate the phenotypic expression of the basic behavioral and neuroendocrine traits characterizing these lines. These psychogenetically selected lines can therefore be used as a model to investigate interactions between genes and the environment in determining each individual's sensitivity to stress and coping abilities ("vulnerability" model). This model may prove particularly useful for studies on the etiology and pathophysiology of anxiety and affective disorders and their neuroendocrine correlates.

Neonatal handling and environmental enrichment effects on emotionality, novelty/reward seeking, and age-related cognitive and hippocampal impairments: focus on the Roman rat lines.

Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats are selected and bred for extreme divergence in two-way active avoidance acquisition. In addition, compared to RLA/Verh rats, RHA/Verh rats are (behaviorally and physiologically) less anxious or reactive to stressors, show increased novelty (sensation)-seeking behavior as well as a higher preference for rewarding substances, and are usually less efficient in learning tasks not involving shock administration. The present article reviews evidence showing that neonatal handling and/or environmental enrichment leads to enduring effects (their magnitude frequently depending upon the rat line) on those behaviors. For example, it has been found that neonatal handling reduces most of the (behavioral and physiological) signs of emotionality/anxiety in RLA/Verh rats, while environmental enrichment increases their novelty seeking (also the case with RHA/Verh rats), saccharin and ethanol intake, and sensitivity to amphetamine. Finally, initial results (currently being further elaborated upon) support a preventive action of both environmental treatments on age-related impairments in learning a spatial, water maze task as well as on hippocampal neuronal atrophy.

Augmenting and reducing of visual evoked potentials in high- and low-sensation seeking humans, cats, and rats.

High- and low-sensation seeking behaviors in human and cat are shown to be correlated with visual evoked potential (VEP) augmenting and reducing, respectively. Demonstration of this relationship in RHA/Verh and RLA/Verh rats provides a heuristic animal model with which to investigate the physiological and genetic basis of this relationship. Recent work is described which shows that VEP augmenting and reducing is a true cortical phenomenon and not merely a reflection of differences occurring at the thalamus. Recent evidence is discussed that suggests the role of diffuse subcortical monoaminergic projections to the cortex as the neurochemical basis for sensation seeking behaviors controlled by prefrontal and limbic cortex and perhaps the correlated VEP augmenting/reducing responses recorded from the posterior cortex.

Labyrinth exploration, emotional reactivity, and conditioned fear in young Roman/Verh inbred rats.

An inbreeding program has been carried out with the Swiss sublines of Roman high- and low-avoidance rats since 1993. The present study reports the first experiments conducted with young animals of those inbred strains (RHA-I/Verh and RLA-I/Verh, respectively) from the sixth and seventh inbreeding generations. The results confirmed expected behavioral profiles. Compared to the RHA-I/Verh strain, RLA-I/Verh rats showed decreased entries into the illuminated central arena of an hexagonal tunnel maze, as well as decreased spontaneous locomotor activity and increased defecations, in two independent experiments. Young RLA-I/Verh females explored less than did their RHA-I/Verh counterparts during session 1 of a conditioned-fear experiment preceding shock administration, and in session 2 (conducted 24 h after the application of three footshocks), they showed greater conditioned behavioral inhibition (i.e., reduced amount of rearing), as well as higher defecation scores, than did RHA-I/Verh females.

The acoustic startle response in inbred Roman high- and low-avoidance rats.

To investigate the emotional reactions of two rat strains selectively bred for good and poor two-way avoidance acquisition (RHA/Verh and RLA/Verh), male animals of both strains were tested in an acoustic startle response test. They received 40 acoustic stimuli followed by 10 electric foot shocks and another 30 acoustic stimuli. RLA/Verh rats showed a significantly higher startle response compared to RHA/Verh animals, indicating a stronger emotional reaction to acoustic stimuli. In addition, the former showed a stronger response to foot shocks. Combined with earlier findings, we conclude that selection for two-way avoidance learning does not result in cognitive defects in the RLA/Verh strain but, rather, in stronger emotional reactions to fearful stimuli.

Clorgyline effect on pineal melatonin biosynthesis in Roman high- and low-avoidance rats.

Pineal melatonin and related indoles levels were higher in Roman high- than in Roman low-avoidance rats, while 5-HIAA/5-HT ratio, as an index of MAO activity was higher in low- than in high-avoidance rats. Clorgyline stimulated pineal melatonin biosynthesis in both lines of rats. However, melatonin and N-acetylserotonin levels remained higher and 5-HIAA levels remained lower in the high avoidance rats treated with low dose (0.5 mg/kg) while treatment with 1.0 mg/kg of clorgyline eliminated the differences in melatonin production between high- and low-avoidance rats.