Ian Q. Whishaw

Generators and topography of hippocampal theta (RSA) in the anaesthetized and freely moving rat.

Spontaneous and hypothalamically induced hippocampal rhythmical slow activity (RSA or theta) was studied acutely in rats anaesthetized with urethane or immobilized with D-tubocurarine. Systematic tracking of microelectrodes showed two foci of hippocampal RSA, one located in the basal part (stratum oriens) of CAl (mean amplitude 1 mV) and the other located in stratum moleculare of the dorsal blade of the fascia dentata (mean amplitude 2 mV). The hippocampal RSA recorded from the lower blade of the fascia dentata was always smaller than that found in the upper blade (mean amplitude 1 mV). The whole dorsal hippocampal extent within each generator zone was shown to be in synchrony, and the respective generator zones of both hippocampi were synchronous with one another. A null zone in stratum radiation was found interposed between the two generators and a zone of large amplitude fast activity (30-50 Hz) was localized to the hilus of the fascia dentata. Wave form analysis showed that the RSA recorded from the two generators was approximately 180 degrees out of phase. Amplitude and analysis of phase changes of RSA recorded in brain areas outside of the two generator zones suggested that such activity was due to physical spread from the two generators, with the possible exception of a restricted portion of CA3. The existence of the two generators, 180 degrees out of phase, was demonstrated in freely moving rats. Behavioural observations showed that the two generators were related systematically to concurrent motor behaviour. Preliminary observations suggest that, of the two generators, the one located in CAl may be the more variable.

Proximal and distal impairments in rat forelimb use in reaching follow unilateral pyramidal tract lesions

Although it was once thought that the corticospinal (pyramidal) tract was the main substrate of voluntary movement, the extent to which it is involved in the control of proximal vs. distal musculature, independent finger movements, and movements characteristic of different species of animals now is unclear. The objective of this study was to examine the effects of pyramidal tract lesions on skilled forelimb use in rats. In addition, cell morphology in motor cortex following lesions was examined. Naive and trained rats received unilateral pyramidal sections just rostral to the pyramidal decussation. Performance was assessed and filmed on two reaching tasks. Measures of reaching consisted of success in obtaining food, kinematic analysis of limb trajectory and velocity, and qualitative evaluation of 10 movement components comprising a reach. Pyramidal tract lesions only impaired reaching for single food pellets. Almost all movements comprising a reach, except digit opening, were impaired, including lifting, aiming, pronating and supinating the limb, and releasing food. Although success in limb use was unchanged over the 180 day observation period, there were significant improvements in the qualitative features of limb use. Histologically, the morphology of pyramidal cells in the forelimb area ipsilateral to the lesion seemed normal. Rats with additional damage to adjacent structures, such as the medial lemniscus and olivary complex, were much more severely impaired on the reaching tasks, and displayed similar impairments as judged by qualitative and kinematic measures. The results demonstrate that a number of movements involved in independent limb use are chronically impaired by pyramidal tract lesions in the rat. Nevertheless, significant use of the limb is possible, due perhaps to both the contribution of extrapyramidal motor systems and the influence of the remaining pyramidal system through its extrapyramidal connections. The results not only show that the rat pyramidal tract supports functions very similar to those of primates and thus might provide a good model for some aspects of pyramidal tract dysfunctions, but also they argue that the pyramidal tract is involved in both proximal and distal limb movements.

Hippocampal formation is involved in movement selection: evidence from medial septal cholinergic modulation and concurrent slow-wave (theta rhythm) recording

Hippocampal rhythmical slow-wave field activity which occurs in response to sensory stimulation is predominantly cholinergic (atropine-sensitive theta rhythm), can precede movement initiation, and co-occurs during non-cholinergic theta rhythm associated with ongoing movement (atropine-resistant). This relationship suggests that theta rhythm plays some role in movement control. The present naturalistic experiments tested the idea that atropine-sensitive theta rhythm plays a role in sensory integration and planning required for initiating appropriate movements. One of a pair of hungry rats, the victim, implanted with hippocampal field recording electrodes, a septal injection cannula, and a posterior hypothalamic stimulating electrode, was given food which the other, the robber, tries to steal. Since the victim dodges from the robber with a latency, distance, and velocity dependent upon the size of the food, elapsed eating time, and proximity of the robber, the movement requires sensory integration and planning. Although eating behavior seemed normal, atropine-sensitive theta rhythm and dodging were disrupted by an infusion of a cholinergic antagonist into the medial septum. When the victim in turn attempted to steal the food back, Type 1 theta rhythm was present and robbery attempts seemed normal. Prior to cholinergic blockade, posterior hypothalamic stimulation produced theta rhythm and dodges, even in the absence of the robber, but following injections, atropine-sensitive theta rhythm and dodging were absent as the animals dropped the food and ran. The results provide the first evidence to link atropine-sensitive theta rhythm and hippocampal structures to a role in sensory integration and planning for the initiation of movement.

Behavioral deficits revealed by multiple tests in rats with ischemie damage limited to half of the CA1 sector of the hippocampus

Ischemia causes neuronal necrosis in the septal half of the CA1 sector of the hippocampus in rats and produces deficits in spatial and other tasks, but the impairments are not severe. CA1-damaged rats may perform at control levels on some tests and may overlap the performance of control animals on other tests. The present study examined the performance of CA1-damaged rats on a range of tests known to be sensitive to hippocampal damage and evaluated the size of the deficit using a composite test-battery score. The rats with CA1 damage were impaired on learning set, matching to place, and latent-learning spatial navigation in a swimming pool, delayed alteration, and pattern alternation on dry land, but not on amphetamine-induced locomotion or on negative patterning. The CA1-damaged rats impairments were mild, characterized by behavioral strategies similar to those of control rats, and their tests scores overlapped those of control rats. Nevertheless, a composite profile derived from the measures obtained from the different tests revealed a large overall impairment. The results confirm that rats with partial damage to CA1 display impairments, especially on tests that demand working memory, and suggest that the test-battery approach can be used to enhance group differences.

Bilateral impairments of skilled reach-to-eat in early Parkinson's disease patients presenting with unilateral or asymmetrical symptoms

Previous studies have described limb and hand movement abnormalities in a reach-to-eat task in advanced Parkinsons disease (PD) and animal models of PD. The present study was directed toward examining reach-to-eat movements in early PD patients untreated with medication, along with a follow-up examination of a PD patient sub-group who were treated with a symptomatically stable dosage of dopamine replacement. Analysis of the reach-to-eat movement was made using blinded assessment under a validated scoring system, and comparisons were made on the total reach score and reach sub-component scores. In both examinations, PD patients had unilateral deficits or significant deficit asymmetry, as indicated by Unified Parkinsons Disease Rating Scale (UPDRS) scores. UPDRS motor scores were higher for the most-affected side of the body (mean scores of 10.45 and 4.25 for more- and less-affected upper limbs, respectively), whereas reach scores were equivalently impaired for the two sides (median scores of 12.35 and 12.56 for more- and less-affected limbs, respectively). These differences between clinical and experimental assessments of motor impairments persisted among early PD patients treated with medication. Thus, functional reaching shows bilateral and symmetrical abnormalities in early PD patients, even when clinical assessment shows asymmetrical or even unilateral impairment. These findings suggest that functional qualitative reaching evaluation is a sensitive test in early PD, and that significant bilateral abnormalities in reach function are present even in pre-clinical stages of the disease.

Parkinsonian deficits in context-dependent regulation of standing postural control.

This study explored whether patients with Parkinsons disease alter the regulation of upright standing according to constraints imposed by the environmental context. The provision of context-dependent adaptations was inferred from the presence of adjustments to standing postural control that would serve to reduce fall risk when balance was challenged by a threatening environmental context. Participants were asked to stand as still as possible in two environmental context conditions that differed in the level of imposed postural threat: LOW threat and HIGH threat. Eight levodopa dependent patients with Parkinsons disease (PD) and eight age-matched control subjects (CTRL) provided the subject sample. PD patients were tested following a 12-h withdrawal of anti-Parkinsonian medications and approximately 1h post-medication. The CTRL group showed altered postural control in the HIGH threat condition, in a manner that was indicative of appropriate context-dependent regulation of standing. PD patients, in the non-medicated or medicated states, did not modify stance regulation when the environmental context heightened postural threat. Our results extend the current understanding of Parkinsonian deficits in the context-dependent regulation of postural control to include upright standing.

Strychnine and suppression of exploration

Abstract In Experiment I, rats under the influence of strychnine were given 20 trials on a very simple Hebb-Williams maze problem and six days later were given a further 20 trials on the same problem when they were not under the influence of the drug. On the drug day, the experimental animals made fewer errors than the control animals, but on the retention test without the drug, the difference was not upheld. These results were taken to mean that strychnine can suppress exploration in maze tasks. This was supported in Experiment II. Maze adapted rats were given an exploratory test which allowed them to take either a familiar route or a number of alternate routes to the goal. Animals injected with strychnine took the familiar route while control animals explored the maze.

Obstacle Avoidance amongst Parkinson Disease Patients Is Challenged in a Threatening Context

We examined whether people with Parkinson disease (PD) have difficulty negotiating a gait obstruction in threatening (gait path and obstacle raised above floor) and nonthreatening (gait path and obstacle at floor level) contexts. Ten PD patients were tested in both Meds OFF and Meds ON states, along with 10 age-matched controls. Participants completed 18 gait trials, walking 4.7u2009m at a self-selected speed while attempting to cross an obstacle 0.15u2009m in height placed near the centre point of the walkway. Kinematic and kinetic parameters were measured, and obstacle contact errors were tallied. Results indicated that PD patients made more obstacle contacts than control participants in the threatening context. Successful crossings by PD patients in the threatening condition also exhibited kinematic differences, with Meds OFF PD patients making shorter crossing steps, with decreased initiation and crossing velocities. The findings from this study lend support to the theory that PD patients rely on directed attention to initiate and control movement, while providing indication that the motor improvements provided by current PD pharmacotherapy may be limited by contextual interference. These movement patterns may be placing PD patients at risk of obstacle contact and falling.

Chapter 8 – Analysis of Behavior in Laboratory Rats1

Publisher Summary nThis chapter presents the analysis of behavior in laboratory rats. The three main ways of evaluating behavior are: end-point measures, kinematics, and movement description. Sensorimotor tests are undertaken to evaluate the sensory and motor abilities of animals. The tests evaluate the ability of animals to orient to objects in the environment in each sensory modality. Posture and locomotion are supported by independent neural subsystems. A condition of immobility in which posture is supported against gravity is the objective of a large number of local and whole-body reflexes. Thus, immobility should be viewed as a behavior with complex allied reflexes. Locomotor behavior includes all of the acts in which an animal moves from one place to another. It includes the acts of initiating movement, turning behavior, exploratory behavior, and a variety of movement patterns on dry land, water, or vertical substrates. Skilled movements in rodents and primates are quite comparable, which makes rodent models quite generalizable to humans. Two commonly used tests of skilled movement are beam walking and skilled reaching.