Ying-Jui Ho

Animal models of human psychopathology based on individual differences in novelty-seeking and anxiety

The role of individual factors in behavioural neuroscience is an important, but still neglected area of research. The present review aims to give, first, an outline of the most elaborated theory on animal behaviour, and second, an overview of systematic approaches of historic and present animal models of human psychopathology based on individual differences. This overview will be focused on animal models of unselected subjects (i.e. natural variance of a specific behaviour within a given population) and selected breeding for a specific behaviour. Accordingly, an outline of the personality model from Gray and McNaughton of individual behaviour in animals is given first. Then, a comprehensive overview of past and current animal models in novelty-seeking (i.e. psychomotor activation and exploration behaviour) based on systematic individual differences and its relationship to addiction is presented. Third, this will be followed by a comprehensive overview of individual differences in previous and present animal models for anxiety. Finally, critical aspects of such approaches in animal research are discussed, and suggestions are given where to go from here.

Effects of d-cycloserine on MPTP-induced behavioral and neurological changes: Potential for treatment of Parkinson's disease dementia

Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinsons disease (PD). Sub-chronic intraperitoneal injection with D-cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin-2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD.

Striatal glutamate release during novelty exposure-induced hyperactivity in olfactory bulbectomized rats

Striatal glutamate release during novelty exposure-induced hyperactivity was studied by microdialysis in freely-moving olfactory bulbectomized (OBX) rats. After collecting three 10 min basal striatal dialysate samples, the animals were transferred to an open-field apparatus (novelty) and locomotor activity recorded for 60 min. OBX rats showed significantly more locomotor activity (1210+/-270 cm) than sham-operated rats (420+/-70 cm), but only in the first 10 min after exposure to the novel environment. During the same period, striatal glutamate levels increased to 163+/-21% of the basal value in OBX rats, while no changes were seen in the striatum of sham-operated controls. These findings suggest that olfactory bulbectomy results in an increased response of the striatal glutamatergic system to novelty stress, and may consequently cause hyperactivity.

MPTP Lesion Causes Neuroinflammation and Deficits in Object Recognition in Wistar Rats

Animal models of Parkinsons disease with dementia would greatly facilitate research into the underlying causes of this disorder. Here, we showed that bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the substantia nigra pars compacta (SNc) of Wistar rats caused degeneration of nigrostriatal dopaminergic neurons, cell loss in the hippocampal CA1 area, as well as microglial activation and increase of interleukin-2 levels in several brain regions. In addition, increase of anxiety-like behavior and impairment of object recognition were observed in the MPTP-lesioned rats. These findings suggest that neuroinflammation may contribute to MPTP-induced neurodegeneration and behavioral deficits, which is suggested as an animal model of Parkinsons disease dementia.

Behavioral effects of d-cycloserine in rats: The role of anxiety level

It has been reported that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in stress responses and that anxiety is the primary response to stress. Although individual differences in anxiety levels of rats have been demonstrated by using the elevated plus-maze (PM) test, the role of NMDA receptor activity in such individuality of anxiety is not clear. Here, we examined whether low (LA) and high (HA) anxiety rats might respond differently to treatment with d-cycloserine (DCS), a partial agonist of the glycine binding site located on NMDA receptors. Male Wistar rats were screened by using the PM and divided into LA and HA subgroups. On the next day, these rats were again tested in the PM, 30 min after the treatment with DCS (5, 10, or 30 mg/kg ip). Five days later, the rats were subjected to a 2-day forced swim (FS) test, receiving the DCS treatment again 30 min before the second day session. The PM data showed that DCS had anxiogenic effects in LA but not HA rats. The immobility of LA or HA rats in the FS test was not affected by DCS. The results indicate that the behavioral effects of DCS depend on the anxiety level of rats and have task-dependent behavioral consequences, suggesting that glycine binding sites on NMDA receptors are involved in individual differences of anxiety level.

MPTP-induced dopaminergic degeneration and deficits in object recognition in rats are accompanied by neuroinflammation in the hippocampus

Emotional changes, impairment of object recognition, and neuroinflammation are seen in Parkinsons disease with dementia (PDD). Here, we show that bilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the rat substantia nigra pars compacta (SNc) of Wistar rats caused degeneration of nigrostriatal dopaminergic neurons, microglial activation in the SNc and hippocampus, and cell loss in the hippocampal CA1 area. With regard to behavior, an increase in anxiety-like behavior and impairment of object recognition were observed during the fourth week after MPTP lesioning. The behavioral changes were not caused by motor impairment, since the rats had already recovered from MPTP-induced catalepsy before the tests were performed. These findings show that MPTP-induced neuroinflammation and its consequences, for example, microglial activation and cell loss in the hippocampus, may be involved in dopaminergic degeneration-related behavioral deficits and suggest that, in addition to the dopaminergic system, the limbic system may also participate in the pathophysiology of PDD. MPTP-lesioned rats are therefore proposed as a useful tool for assessing the ability of pharmacological agents to prevent recognition deficits in PDD.

Relationship between striatal levels of interleukin-2 mRNA and plus-maze behaviour in the rat

Our previous experiments have shown that adult male Wistar rats can differ systematically in elevated plus-maze (EPM) behaviour, which was related to the neurotransmitter serotonin in the ventral striatum. The EPM serves as a model of anxiety-like behaviour, and there is evidence that interleukin (IL)-2 in the brain may be related to anxiety-like behaviour, and that IL-2 interacts with the striatal serotonergic system. We asked whether EPM behaviour may also be related to constitutive levels of cytokines in the striatum. Based on open arm time in the EPM, male Wistar rats were divided into sub-groups with either low or high anxiety-like behaviour. Then, IL-1beta, IL-2, IL-6, and tumour necrosis factor (TNF)-alpha cDNA levels were measured post mortem in striatal tissues using semi-quantitative, competitive, reverse transcription polymerase chain reaction. Rats with high anxiety-like behaviour in the EPM showed significantly higher levels of IL-2 mRNA compared to those with low anxiety-like behaviour, but did not differ significantly in expression of IL-1beta, IL-6, and TNF-alpha mRNA. These results provide new evidence indicating that specific cytokine patterns in the striatum may be associated with EPM behaviour in adult male Wistar rats.

Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinsons disease (PD). Metabotropic glutamate receptor subtype 5 (mGluR5) modulates glutamatergic transmission and thus has been proposed as a potential target for neuroprotective drugs. The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an mGluR5 antagonist, on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were stereotaxically injected with MPTP into the substantia nigra pars compacta (SNc). Starting 1 day after lesioning (day 1), the rats were treated daily with MPEP (2mg/kg/day, i.p.) for 14 days and rats underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test and both effects were prevented by MPEP treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all inhibited by MPEP treatment. These data provide support for a role of mGluR5s in the pathophysiology of PD and suggest that MPEP is a promising pharmacological tool for the development of new treatments for dementia associated with PD.

A Novel Elevated Plus-Maze Procedure to Avoid the One-Trial Tolerance Problem

The elevated plus-maze (EPM) test is one of the most commonly used behavioral assays to evaluate anxiety-related behavior in rodents. It is an economic test (5 min duration) without prior conditioning of the animals. The critical measure for anxiety is the time spent in the open arms of the maze. A confounding problem of the EPM is the so called one-trial tolerance (OTT), characterized by a marked decrease of open arm exploration in spite of treatment with anxiolytic acting benzodiazepines upon re-exposure to the EPM. This consistent finding is often raised as an evidence for the inappropriateness to re-test rodents in the EPM. However, a reliable re-test paradigm would broaden the usability and effectiveness of this test. Therefore, we tested how an extension of the inter-trial interval to 28 days (instead of the usual 24 h), and an additional change of the testing room would affect the open arm time and other behaviors on the EPM. In two experiments, drug-naive Wistar rats were exposed to the EPM on trial 1, and treated intraperitoneally with either vehicle or midazolam (0.25 mg/kg) 30 min before trial 2. Then, trial 2 (28 days after trial 1) was carried out in either the same testing room (Experiment 1) or in another unfamiliar room (Experiment 2). Twenty-eight days after trial 1 the open arm time of the rats in the vehicle treated control rats of both experimental groups was comparable to that of the first trial, independent of the testing room. Most importantly, we found that the treatment with the benzodiazepine midazolam had a significantly anxiolytic-like (i.e., increase of open arm time) effect in trial 2 only when conducted in the previously unfamiliar testing room (Experiment 2). We suggest that in order to reliably re-test the EPM and to prevent confounding effects due to the OTT, an inter-trial interval of 28 days and a change in testing rooms reinstates anxiolytic-like actions of benzodiazepines.

Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model.

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinsons disease (PD) and treatment with drugs modulating glutamatergic activity may have beneficial effects. Ceftriaxone has been reported to increase glutamate uptake by increasing glutamate transporter expression. The aim of this study was to determine the effects of ceftriaxone on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Then, starting the next day (day 1), the rats were injected daily with either ceftriaxone (200 mg/kg/day, i.p.) or saline for 14 days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test. The treatment of ceftriaxone decreased the above MPTP-induced cognitive deficits. Furthermore, this study provides evidence that ceftriaxone inhibits MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area. In conclusion, these data support the idea that hyperactivity of the glutamatergic system is involved in the pathophysiology of PD and suggest that ceftriaxone may be a promising pharmacological tool for the development of new treatments for the dementia associated with PD.