Jerome S. Cohen

Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10

BackgroundParkinsons disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance.ResultsHere we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats.ConclusionOur data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.

A behavior analysis of absolute pitch: sex, experience, and species.

Absolute pitch (AP) perception refers to the ability to identify, classify, and memorize pitches without use of an external reference pitch. In tests of AP, several species were trained to sort contiguous tones into three or eight frequency ranges, based on correlations between responding to tones in each frequency range and reinforcement. Two songbird species, zebra finches and white-throated sparrows, and a parrot species, budgerigars had highly accurate AP, they discriminated both three and eight ranges with precision. Relative to normally reared songbirds, isolate reared songbirds had impaired AP. Two mammalian species, humans and rats, had equivalent and weak AP, they discriminated three frequency ranges to a lackluster standard and they acquired only a crude discrimination of the lowest and highest of eight frequency ranges. In comparisons with mammals even isolate songbirds had more accurate AP than humans and rats.

Effects of varying trial distribution, intra- and extramaze cues, and amount of reward on proactive interference in the radial maze

Rats are typically less accurate in their arm selections in the radial maze over successive trials in a session (Roberts & Dale, 1981). In the present study, rats’ choice accuracy declined when such trials were separated by 2-min (massed) but not by 2-h (spaced) intertriai intervals. Changing intramaze visual/tactile arm stimuli (Experiments 1 and 3) or extramaze landmark stimuli (Experiment 4) between trials weakened the massed-trials effect, but changing the number of food pellets per arm, either alone or in conjunction with changes in intramaze cues (Experiments 2 and 3), did not. The rats also tended to avoid the spatial locations of their last four choices on a previous trial during their first four choices on a current trial, and more so with massed than with spaced trials. These findings indicate that intertriai proactive interference (PI) occurred only with massed trials and was weakened by changing intra- and extramaze cues between such trials.

Retrospective and prospective short-term memory in delayed response tasks in rats

Separate groups of rats were trained and tested on asymmetrically and symmetrically reinforced successive delayed matching-to-sample (DMTS) or delayed discrimination (DD) tasks in Experiment 1. Each rat received training and testing on symmetrically reinforced DMTS and DD tasks in Experiment 2. The only difference between each task was that the rats had to respond correctly to a light or tone test stimulus, S2, if it matched a light or tone sample stimulus, S1, in DMTS, but could respond to either S2 if S1 had been a particular stimulus in DD. Only correct leverpresses were reinforced in the asymmetrically reinforced version of each task. Both correct presses and correct omissions were reinforced in the symmetrically reinforced version of each task. Response biases to leverpress during tests for delayed responding to S1 were reduced in both symmetrically reinforced tasks, but only in the DD task did such contingencies produce consistently poorer performance in responding to either S, in Experiment 1. Declines in accuracy of performance that occurred in both experiments were greater to the visual than to the auditory S1 only in the DMTS tasks with increased intervals between S1 and S2. A third experiment, in which rats had to respond to S2 if it matched S1 (DMTS) or if S2 mismatched S, (DMmTS), was carried out. Modality of S1 similarly affected accuracy of delayed responding in each task, as in the first two experiments. Methodological and theoretical implications of these results are discussed in terms of Honig and Thompson’s (1982) dual-process theory of working memory.

Effect of drive level on habit strength in a discrimination task

Effects of drive level on habit strength of a brightness discrimination were determined for male albino rats. Habit strength was assessed by measuring response strength of the old stimulus, compared with a newer trained redundant positive cue. Only in one type of test trial was a drive effect on habit strength found. Moderately water-deprived Ss (MOD), regardless of drive level during redundant cue training or testing, preferred the redundant cue to the positive stimulus. Highly deprived Ss (HI) showed no preference, but responded more to the older positive stimulus than did MOD Ss. These results support the hypothesis that habit strength is directly related to drive level. The specific conditions under which drive level effects on learning could be most easily observed were discussed.

Rats form cognitive maps from spatial configurations of proximal arm cues in an enclosed 4-arm radial maze☆

Abstract Rats were trained to select a final, remaining baited arm following a 6- to 10-min delay following their entries into three experimenter-selected baited arms in an enclosed 4-arm radial maze containing different proximally cued arms. Rats’ accuracy in selecting the remaining baited arm was disrupted when the spatial configuration of arm cues was randomly varied over trials following initial training with one configuration in Experiment 1. In Experiment 2, the same rats acquired this task with the original and a new configuration of the same arm cues when each consistently occurred at a specific time of day (one in the morning, the other in the afternoon). Randomly varying the temporal presentations of these configurations following acquisition disrupted rats’ choice accuracy more within the new than the original configuration. Other rats in Experiment 3 learned this task with two configurations containing different types of arm cues (full arm inserts, objects at the arm entrances). When required to relearn this task with recombined configurations of pairs of arm cues from of each configuration, only rats presented pairs of arms arranged differently from that in their original configurations were unable to reacquire the task. Together these results support a cognitive map hypothesis more than a proximal arm cue list hypothesis. These findings were discussed in terms of recent versions of cognitive map theory ( Benhamou, 1998 ; Poucet, 1993 ) and the possible limits of such processing ( Roberts, 2001 ).

Response perseveration in the hippocampal lesioned rat

Hippocampal lesions were found to affect a rat’s relearning a previously learned correct arm from a new starting position in a T-maze situation. Hippocampal-damaged rats (HIPP group) perseverated turning responses by entering into the opposite arm from the correct one more than did sham-operated rats (SHAM group). This perseveration phenomenon was seen only for HIPP rats that were required to choose between two similar choice arms. When side arms were differentiated by brightness cues, no differences in relearning the correct arm were found between groups. Greater resistance to extinction of the position habit was also found in HIPP rats, but only in the situation with both side arms similar in color.

The role of trial tracking in rats’ working memory

The experiments reported in the present study tested whether decreasing intertrial intervals (ITIs) intensifies the disruptive effects of increasing retention intervals (RIs) in a delayed conditional discrimination by decreasing the animal’s trial tracking accuracy (Cohen & Armstrong, 1996; Cohen & Roberts, 1996). Rats responded on a fixed ratio (FR) 1 or fixed interval (FI) 10-sec reinforcement schedule at a second light or tone stimulus, S2, when the first light or tone stimulus, S1, had signaled an FI 10-sec or FR 1 schedule, respectively. RIs between S1 and S2 were increased from 3 to 24 sec and never exceeded ITIs that were reduced from 24 to 6 sec. For some rats, the trials were separated from each other by extending the lever at S1 and retracting it at the end of S2 (ITI lever-retracted group). For other, control rats, the lever remained extended throughout the session (lever-extended group, Experiment 1) or was extended and retracted with the onset and offset of each stimulus (RI/ITI lever-retracted group, Experiment 2). The rats under all trial conditions learned to delay leverpressing on the FI 10-sec schedule. Latency to begin leverpressing on the FI 10-sec schedule declined as RIs were increased, but this effect was attenuated in the ITI lever-retracted groups in both experiments, as would be predicted by thetrial tracking hypothesis. Decreasing ITIs from 24 to 6 sec intensified the disruptive effects of increasing RIs from 3 to 6 sec in the RI/ITI lever-retracted group (Experiment 2), as would be predicted by the trial tracking hypothesis.

Intratrial proactive interference in rats’ serial alternation performance in the radial maze

Rats acquired a serial alternation task in an eight-arm radial maze that was partitioned into four pairs of arms. Each pair was associated with a different distal stimulus. Rats were initially forced to the left or right arm in each pair (the study segment) before being exposed to both arms in each pair (the free-choice or test segment). Only the previously blocked arm of each pair remained baited. Following initial training, proactive interference (PI) was induced by presenting rats with a forced-choice (prestudy) segment containing arm positions opposite those in the subsequent study segment. Such trials generated poorer free-choice accuracy than did trials without a prestudy segment. Forcing rats to both arms in the pair in a prestudy segment produced only transient PI. A slight improvement in rats’ free-choice performance was obtained by forcing them to the same arm position, but only when the test segment was delayed by 30 min. Increasing the interval between the prestudy and study segments from 2 to 30 min eliminated PI, but only when free-choice testing was delayed by 2 min rather than by 30 min. These results suggest that intratrial PI in this preparation was primarily due to confusion about which arm position in each pair had been visited during the last forced-choice segment.

Genetic Susceptibility Model of Parkinson's Disease Resulting from Exposure of DJ-1 Deficient Mice to MPTP: Evaluation of Neuroprotection by Ubisol-Q 10

INTRODUCTION Parkinsons disease arises from a combination of environmental and genetic risk factors. At present neither the curative nor preventative therapies are available; hence, there is an urgent need to develop reliable animal models to facilitate their development. Water soluble nanomiceller formulation of CoQ10 (Ubisol-Q10) has shown neuroprotection against neurotoxin on human neuronal cells. We have combined the genetic deficiency of DJ-1/PARK7 mice with MPTP exposure and develop a genetic susceptibility model of PD and evaluated the neuroprotective efficacy of (Ubisol-Q10). METHODS Transgenic mice with DJ-1 deficiency (DJ-1/PARK7) were given either water or Ubisol-Q10 prophylactically at a dose of 6 mg/kg/day added directly to a drinking water for one month followed challenged with MPTP injections while keeping the same drinking water regiments. Four weeks after the last injection we evaluated neuroprotective efficacy of Ubisol-Q10 in DJ-1/MPTP model of PD using histochemical and behavioral readouts. RESULTS We confirmed genetic susceptibility to MPTP and showed that prophylactic oral treatment with Ubisol-Q10 significantly offset the neurotoxicity and ameliorated motor dysfunction, otherwise correlated with the MPTP injury. CONCLUSION Ubisol-Q10 protects against MPTP-induced neurodegeneration and motor dysfunction in DJ-1 deficient mice. Ubisol-Q10 might be a treatment prospect for people genetically predisposed to PD as well as with sporadic PD.