Joan F. Lorden

Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat

The genetically dystonic (dt) rat is a neurological mutant that displays a movement disorder characterized by repetitive twisting movements of the trunk and limbs. Previous work has identified the cerebellum of the dt rat as a site of biochemical, metabolic, and functional abnormality. In order to test the hypothesis that a cerebellar defect is critical to the expression of the motor syndrome, groups of dt rats and phenotypically normal littermates underwent cerebellectomy (CBX) at either 15 or 20 days of age. The performance of these animals on a battery of motor tasks was compared with their preoperative performance. Age-matched unoperated rats of the same phenotype and a group of dt rats with lesions in the entopeduncular nuclei (ENTO) served as controls. In dt rats, CBX permanently eliminated all motor signs of the disease except pivoting movements without reducing overall levels of activity. In the dt rats, CBX also caused significant improvement in several tests of motor function. The ENTO group, however, showed an increase in motor signs and no improvement in motor function. The results of this study provide the first evidence that the abnormalities detected in the cerebellum of the dt rat are causally related to the motor syndrome and suggest that abnormal cerebellar output may contribute to the expression of motor signs in some human dystonias.

Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat

The purpose of this study was to characterize neuronal activity in the deep cerebellar nuclei of the unanesthetized genetically dystonic rat during the neonatal period when the clinical signs of the dystonic syndrome first appear. Previous lesion studies have established cerebellar output as critical to the expression of the dystonic rats motor syndrome, a disorder that closely resembles generalized dystonia in humans. In the dystonic rat, both cerebellectomy and selective lesions of the deep cerebellar nuclei decrease the frequency of abnormal motor signs and improve performance on tests of motor function. Single-unit activity was recorded from the medial, interpositus and lateral cerebellar nuclei in awake normal (N=49) and dystonic (N=54) rats at postnatal days 12-26. One hundred and eighty-three cells were isolated, 91 from normal and 92 from dystonic rats. Interspike interval histograms, autocorrelations and ratemeter histograms were generated for each cells spike train. Interspike interval histograms were modeled with single and double gamma distributions. Cells from dystonic rats as young as 12 days of age showed bursting firing patterns, positively skewed or bimodal interspike interval histograms, and sinusoidal autocorrelations. Bursting activity increased linearly with postnatal age in dystonic rats. Cells from normal rats demonstrated non-sinusoidal autocorrelations and unimodal interspike interval histograms. Spike frequency increased linearly with postnatal age in both normal and dystonic rats. There were no statistically significant group differences in spike frequency between normal and dystonic rats. These findings show that functional neuropathology can be detected at the level of single neurons in the deep cerebellar nuclei at the earliest behavioral stages of the dystonic rats movement disorder. The degree of abnormality in spike train parameters correlates with the severity of the movement disorder. Independent of neuronal firing rates, abnormal neuronal firing patterns can serve as a guide to the localization of pathological cell populations within the central nervous system. These results provide additional evidence that abnormal cerebellar output plays a critical role in the pathophysiology of the dystonic rats motor syndrome.

Limbic lesions and the blocking effect

Abstract Rats with bilateral lesions to either the mamillary bodies, dorsomedial nucleus of the thalamus, dorsal hippocampus, or ventral hippocampus and sham-operated controls were tested on Kamins 2-stage blocking paradigm. When dorsal hippocampal, thalamic, and sham rats trained to a single auditory or visual cue prior to conditioning to a compound stimulus composed of the initial training cue and a novel, but redundant stimulus were later tested to the redundant element, they did not evidence learning to the redundant cue. Conditioning was blocked to the redundant cue. In contrast, blocking was attenuated in rats lesioned in either the ventral hippocampus or the mamillary bodies. The results suggest that different regions of the hippocampus and related structures comprise distinct systems, which mediate dissociably different behaviors. Moreover, it appears that the ventral hippocampus and mamillary bodies may be involved in “time-tagging” motivationally significant events.

Effect of paraventricular nucleus lesions on body weight, food intake and insulin levels

Lesions of the paraventricular nucleus of the hypothalamus (PVN) produce obesity and hyperphagia. However, the underlying mechanism is unknown. The connections of the PVN with brainstem centers for autonomic control suggest that a change in autonomic function could mediate the PVN obesity syndrome. We examined this hypothesis in a series of 3 experiments, searching specifically for changes in insulin secretion. Rats with PVN lesions were hyperphagic and hyperinsulinemic, when obese. However, hyperinsulinemia could not be detected prior to the onset of obesity or following weight reduction. Subdiaphragmatic vagotomy reversed the PVN obesity and lowered insulin levels below those of sham-vagotomized rats. Since noradrenergic innervation of the hypothalamus is implicated in feeding, hypothalamic norepinephrine (NE) was depleted by injection of 6-hydroxydopamine into the central tegmental tract, posterior to the hypothalamus. The effects of NE depletion was compared with those of PVN lesions. Loss of hypothalamic NE resulted in hyperphagia with no increase in body weight and no change in insulin. Histological analyses indicated that the posterior PVN was the most effective lesion focus for producing disturbances in body weight and food intake. Although the results of these experiments implicate the autonomic nervous system in PVN obesity, basal hyperinsulinemia does not appear to be a primary feature of the syndrome.

Stimulus processing and stimulus selection in rats with hippocampal lesions.

Rats with dorsal and ventral hippocampal lesions and sham-operated controls were either (a) trained to discriminate between two compound stimuli which contained a common element or (b) exposed to the same compounds under a condition in which each element was correlated with reinforcement 50% of the time. When each element was tested in isolation following training to condition (a), the partially reinforced cue, the element common to each compound, was overshadowed by elements more highly correlated with reinforcement among sham animals. However, no overshadowing was found with hippocampal rats: The common element was as effective in controlling behavior as elements more highly correlated with reinforcement. By contrast, hippocampal and sham rats assigned to condition (b) behaved similarly to the common element when it shared the same correlation to reinforcement as other elements. The data suggest that the attention-like deficit of hippocampal subjects may be due to an inability to encode stimuli properly. They appear deficient in forming appropriate internal representations of contingent events.

Enhancement of conditioned taste aversions by lesions of the midbrain raphe nuclei that deplete serotonin

Electrolytic lesions of the dorsal and median raphe nuclei enhanced the avoidance of a saccharin solution that had been paired with a single injection of the toxic drug, lithium chloride. A chemically specific lesion of the same nuclei by intracerebral infusion of 5,7-dihydroxytryptamine produced the same behavioral effect. Neither lesion group differed from control animals in the consumption of an unpaired novel fluid or of an unpaired familiar fluid. Both lesions caused a significant depletion of telencephalic serotonin. The data suggest that the enhanced suppression of saccharin intake was due to damage to serotonergic neurons. Rats with electrolytic lesions in the median raphe nucleus alone showed a significant enhancement of saccharin avoidance in the taste aversion paradigm. The addition of a dorsal raphe lesion increased serotonin depletion but did not produce a significant increment in saccharin avoidance. Thus, decreased hippocampal or septal serotonin, produced by the median lesions, may be responsible for the facilitation of the learned taste aversion. Furthermore, this facilitation may be due to the development of associations between the injection procedure and nongustatory aspects of the test situation.

Abnormal spontaneous and harmaline-stimulated Purkinje cell activity in the awake genetically dystonic rat

The genetically dystonic rat is an autosomal recessive mutant with a movement disorder that closely resembles the generalized dystonias seen in humans. Abnormal activity of neurons within the cerebellar nuclei is critical to the dystonic rat motor syndrome. Increased glutamic acid decarboxylase activity, increased glucose utilization, and decreased muscimol binding within the cerebellar nuclei of the dystonic rat suggests that Purkinje cell firing rates are increased in these animals. However, under urethane anesthesia, Purkinje cell simple spike firing rates in dystonic rats were less than half the rates seen in normal littermates. In this study, both spontaneous and harmaline-stimulated single-unit Purkinje cell recordings were obtained from awake normal and dystonic rats. In striking contrast to previous results obtained under urethane anesthesia, there was no statistically significant difference in average Purkinje cell spontaneous simple spike frequency between dystonic and normal rats. Similar to previous studies obtained under urethane anesthesia, Purkinje cell spontaneous complex spike frequency was much lower in dystonic than in normal rats. Many Purkinje cells from dystonic rats, particularly those from the vermis or older animals, exhibited rhythmic bursting simple spike firing patterns. Crosscorrelations showed that complex spikes produced less suppression of simple spikes in dystonic than in normal rats and harmaline-stimulated complex spike activity was, on average, faster and more rhythmic in normal than in dystonic rats. These findings indicate that olivocerebellar network abnormalities in the dystonic rat are not due to an inability of Purkinje cells to fire at normal rates and suggest that abnormal Purkinje cell bursting firing patterns in the dystonic rat are due to a defect in the pathway from the inferior olive to climbing fiber synapses on Purkinje cells.

Selective elimination of cerebellar output in the genetically dystonic rat

The genetically dystonic (dt) rat, an autosomal recessive mutant, exhibits a progressive motor syndrome that resembles the generalized idiopathic dystonia seen in humans. Even with supportive measures, dt rats die before reaching maturity. A total cerebellectomy that includes the dorsal portions of the lateral vestibular nuclei (dLV) eliminates the dystonic motor syndrome of the dt rats, greatly improves motor function, and prevents early death. The selective elimination of cerebellar nuclei was used to determine the cerebellar components critical to the mutants motor syndrome. Bilateral electrolytic and/or excitatory amino acid lesions of the medial cerebellar nucleus, nucleus interpositus, lateral cerebellar nucleus and dLV were created in separate groups of 15-day-old dt rats. Rats were observed for the presence of abnormal motor signs (falls, twists, clasps, pivots) and tested on several measures of motor performance (activity, climbing, righting, homing, hanging) before surgery and again on Postnatal Day 20. All nuclear lesions produced significant improvements in motor function and decreases in the frequency of abnormal motor signs. Electrolytic lesions of the dLV were associated with the greatest improvements.

Forebrain monoamines and associative learning: I. Latent inhibition and conditioned inhibition

Two experiments evaluated the effects of depletion of forebrain norepinephrine (NE) or serotonin (5-HT) on two forms of internal inhibition. Experiment 1 examined the role of NE and 5-HT depletion on latent inhibition: rats with dorsal bundle or raphe lesions or vehicle control rats were trained to one of two pre-exposure conditions (single vs multiple stimuli) or to a non-pre-exposure control prior to conditioning. The results of this experiment showed that latent inhibition was attenuated under either condition of pre-exposure following depletion of 5-HT but that attenuation was present in NE depleted rats only when pre-exposed to multiple stimuli. Experiment 2 assessed the rate at which a conditioned inhibitor was established following NE or 5-HT depletion. The results of Experiment 2 indicated that the formation of a conditioned inhibitor was unimpaired following depletion of either NE or 5-HT. The results of Experiment 1 demonstrate that 5-HT and NE have different effects on associative processes: 5-HT apparently affects a habituation-like process, whereas NE is an important influence on more complex mechanisms involving the comparison of new with previously acquired information. The findings of Experiment 2 are consistent with behavioral investigations which show that conditioned inhibition affects output processes rather than the salience of stimuli.

Forebrain monoamines and associative learning: III. The US pre-exposure effect

This experiment evaluated the effects of forebrain norepinephrine (NE) and serotonin depletion on the unconditioned stimulus (US) pre-exposure phenomenon. Rats with either dorsal bundle lesions, raphe lesions, or which served as vehicle controls were assigned to one of two training conditions. One-half of the animals in the 3 lesion groups received 30 episodes of a stimulus which later served as the US. The remaining rats experienced standard conditioning of CS-US pairing without US pre-exposure. The results indicate that while raphe-lesioned and vehicular rats exhibited the US pre-exposure effect, conditioning was unimpaired in NE-depleted rats following pre-exposure. These findings are consistent with a contextual blocking interpretation of the US pre-exposure effect.