Characterization of Motor and Non-Motor Behavioral Alterations in the Dj-1 (PARK7) Knockout Rat.

Parkinson's disease is a neurodegenerative disorder that encompasses a constellation of motor and non-motor symptoms. The etiology of the disease is still poorly understood because of complex interactions between environmental and genetic risk factors. Using animal models to assess these risk factors may lead to a better understanding of disease manifestation. In this study, we assessed the Dj-1 knockout (KO) genetic rat model in a battery of motor and non-motor behaviors. We tested the Dj-1 KO rat, as well as age-matched wild-type (WT) control rats, in several sensorimotor tests at 2, 4, 7, and 13 months of age. The Dj-1-deficient rats were found to rear and groom less, and to have a shorter stride length than their WT counterparts, but to take more forelimb and hindlimb steps. In non-motor behavioral tasks, performed at several different ages, we evaluated the following: olfactory function, anxiety-like behavior, short-term memory, anhedonia, and stress coping behavior. Non-motor testing was conducted as early as 4.5 months and as late as 17 months of age. We found that Dj-1 KO animals displayed deficits in short-term spatial memory as early as 4.5 months of age during place preference testing, as well as impaired coping strategies in the forced swim test, which are consistent with a parkinsonian-like phenotype. In some instances, effects of chronic stress were evaluated in the Dj-1-deficient rats, as an initial test of an environmental challenge combined with a genetic disposition for PD. Although some of the results were mixed with differential effects across several of the behaviors, the combination of the changes we observed indicates that the Dj-1 KO rat may be a promising model for the assessment of the prodromal stage of Parkinson's disease, but further evaluation is necessary.

Effects of Preweaning Manganese in Combination with Adult Striatal Dopamine Lesions on Monoamines, BDNF, TrkB, and Cognitive Function in Sprague-Dawley Rats.

Manganese (Mn) is an essential nutrient especially during development, but Mn overexposure (MnOE) produces long-term cognitive deficits. Evidence of long-term changes in dopamine in the neostriatum was found in rats from developmental MnOE previously. To examine the relationship between MnOE and dopamine, we tested whether the effects of developmental MnOE would be exaggerated by dopamine reductions induced by 6-hydroxydopamine (6-OHDA) neostriatal infusion when the rats were adults. The experiment consisted of four groups of females and males: Vehicle/Sham, MnOE/Sham, Vehicle/6-OHDA, and MnOE/6-OHDA. Both MnOE/Sham and Vehicle/6-OHDA groups displayed egocentric and allocentric memory deficits, whereas MnOE+6-OHDA had additive effects on spatial memory in the Morris water maze and egocentric learning in the Cincinnati water maze. 6-OHDA reduced dopamine in the neostriatum and nucleus accumbens, reduced norepinephrine in the hippocampus, reduced TH+ cells and TrkB and TH expression in the substantia nigra pars compacta (SNpc), but increased TrkB in the neostriatum. MnOE alone had no effect on monoamines or TrkB in the neostriatum or hippocampus but reduced BDNF in the hippocampus. A number of sex differences were noted; however, only a few significant interactions were found for MnOE and/or 6-OHDA exposure. These data further implicate dopamine and BDNF in the cognitive deficits arising from developmental MnOE.

4R-Cembranoid Improves Outcomes after 6-Hydroxydopamine Challenge in Both In vitro and In vivo Models of Parkinson's Disease.

(1S, 2E, 4R, 6R,-7E, 11E)-2, 7, 11-cembratriene-4, 6-diol (4R) is one of the cembranoids found in tobacco leaves. Previous studies have found that 4R protected acute rat hippocampal slices against neurotoxicity induced by N-methyl-D-aspartate (NMDA) and against the toxic organophosphorus compounds paraoxon and diisopropylfluorophosphate (DFP). Furthermore, in vivo, 4R reduced the infarct size in a rodent ischemic stroke model and neurodegeneration caused by DFP. The present study expanded our previous study by focusing on the effect of 4R in Parkinson's disease (PD) and elucidating its underlying mechanisms using 6-hydroxydopamine (6-OHDA)-induced injury models. We found that 4R exhibited significant neuroprotective activity in the rat unilateral 6-OHDA-induced PD model in vivo. The therapeutic effect was evident both at morphological and behavioral levels. 4R (6 and 12 mg/kg) treatments significantly improved outcomes of 6-OHDA-induced PD in vivo as indicated by reducing forelimb asymmetry scores and corner test scores 4 weeks after injection of 6-OHDA (p < 0.05). The therapeutic effect of 4R was also reflected by decreased depletion of tyrosine hydroxylase (TH) in the striatum and substantia nigra (SN) on the side injected with 6-OHDA. TH expression was 70.3 and 62.8% of the contralateral side in striatum and SN, respectively, after 6 mg/kg 4R treatment; furthermore, it was 80.1 and 79.3% after treatment with 12 mg/kg of 4R. In the control group, it was 51.9 and 23.6% of the contralateral striatum and SN (p < 0.05). Moreover, 4R also protected differentiated neuro-2a cells from 6-OHDA-induced cytotoxicity in vitro. The activation of p-AKT and HAX-1, and inhibition of caspase-3 and endothelial inflammation, were involved in 4R-mediated protection against 6-OHDA-induced injury. In conclusion, the present study indicates that 4R shows a therapeutic effect in the rat 6-OHDA-induced PD model in vivo and in 6-OHDA-challenged neuro-2a cells in vitro.

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring.

Activation of the maternal innate immune system, termed "maternal immune activation" (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14. Glutamic acid decarboxylase-67 (GAD67) mRNA expression was examined in male offspring at postnatal day (P)14, P30 and P60. At P60, GAD67 mRNA was elevated in hippocampus and thalamus and decreased in prefrontal cortex of MIA offspring. MIA-induced alterations in GAD expression could contribute to the pathophysiology of schizophrenia.

Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation.

Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases.

Stress, depression and Parkinson's disease.

In this review, we focus on the relationship among Parkinson's disease (PD), stress and depression. Parkinson's disease patients have a high risk of developing depression, and it is possible that stress contributes to the development of both pathologies. Stress dysfunction may have a role in the etiology of preclinical non-motor symptoms of PD (such as depression) and, later in the course of the disease, may worsen motor symptoms. However, relatively few studies have examined stress or depression and the injured nigrostriatal system. This review discusses the effects of stress on neurodegeneration and depression, and their association with the symptoms and progression of PD.

(±)3,4-methylenedioxymethamphetamine ("ecstasy") treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain.

(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment.