F. Colin

The olivocerebellar system. II. Some ultrastructural correlates of inferior olive destruction in the rat.

Short- and long-term ultrastructural changes induced in rat inferior olivary nucleus (ION) and cerebellum by a single injection of 3-acetylpyridine (3-AP) were investigated. Evidence of perikaryal and dendritic alterations was already present in numerous ION neurons at 3 h after injection. All ION neurons were affected at 6 h. Complete destruction of the entire ION was achieved within 8-10 h. Time-course and cytological features of this degeneration were described. Total absence of axonal termination degeneration in the ION or at its periphery ruled out the existence of recurrent olivary axons in these locations. Climbing fiber (CF) terminal degeneration in the cerebellar cortex apparently was restricted to the molecular layer, which cast serious doubts on the existence of glomerular collaterals of CFs. Evidence of axonal terminal degeneration was observed within all cerebellar nuclei at 24 and 26 h after 3-AP treatment, but degenerating profiles were unexpectedly infrequent. Consequential to CF deafferentation, Purkinje cells (P.cells) underwent both precocious and delayed ultrastructural changes. Delayed and long-range changes involved mainly dendrites and perikarya. Axon terminals underwent precocious but prolonged alterations which were interpreted as evidence supporting enhanced synaptic activity of P. cells deprived of CFs.

Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice

Arylsulfatase A (ASA)-deficient (-/-) mice and ASA(+/+) controls were constructed as a transgenic model for the lysosomal storage disease, metachromatic leukodystrophy (MLD). One-year-old ASA(-/-) mice showed impaired rotarod performance and altered walking pattern characterized by a shorter pace, later evolving into more severe ataxia with tremor in 2-year-old mice. Examination of cerebellar histology showed that 2-year-old ASA(-/-) mice have lost most of the calbindin immunoreactivity from their Purkinje cell dendrites and show simplified dendritic architecture. Additionally, ASA-deficient mice lost a substantial proportion of their Purkinje cells. Recordings of unitary potentials and stimulation of climbing fibers on cerebellar slices from 2-year-old mice indicated that, although the main cerebellar synapses seem to be present and functioning physiologically, the climbing fibers of ASA-deficient mice may have enhanced effects on Purkinje cell activity. It is concluded that ambulatory dysfunctions in ASA(-/-) mice might be explained by an imbalance in the consequences of climbing fiber signals upon Purkinje cell activity due to selective neurodegeneration within the cerebellum.

N-methyl-D-aspartate receptor activation by guanidinosuccinate but not by methylguanidine: behavioural and electrophysiological evidence.

Levels of methylguanidine (MG) and guanidinosuccinate (GSA) are known to be highly increased in uraemic patients. In the present work, the effects of these uraemic guanidino compounds on the excitatory amino acid system were investigated in vivo and in vitro. It was found that convulsions induced by intracerebroventricular GSA injection in mice were antagonized by N-methyl-D-aspartate (NMDA) receptor blockade, whereas those induced by MG were not significantly altered. Application of GSA (between 25 and 10,000 microM) to mouse spinal cord neurones in primary dissociated cell cultures, evoked depolarizing, inward whole-cell currents in a dose-dependent fashion and with reversal potential at 0 mV; MG did not produce such effects. GSA-induced whole-cell currents were caused by NMDA receptor activation since NMDA receptor antagonists (2-amino-5-phosphonovalerate, Mg2+ and ketamine) blocked GSA-evoked whole-cell currents completely and reversibly, whereas co-application of a non-NMDA receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione) did not affect GSA-induced current. Evoked field potentials in CA1 region of rat hippocampal slices were completely abolished by GSA, and this effect was antagonized by NMDA receptor blockade. All data were consistent with selective agonist action of GSA upon the NMDA-type glutamate receptor. In view of the results presented here, it should be examined whether NMDA receptors contribute to the neurological complications of renal failure through GSA-induced inappropriate or excessive activation of NMDA receptors.

Formalin-induced central sensitization in the rat: somatosensory evoked potential data

Cortical somatosensory evoked potentials were used to measure secondary hyperaesthesia resulting from subcutaneous 1 and 5% formalin in unanesthetized rats with permanently implanted electrodes. Near field responses were evoked by contralateral non-noxious electrical stimulation of the middle third of the tail. 0.05 ml 5% formalin injected subcutaneously at the base of the tail increased the amplitude of P1-N1 a maximum of 158.5+/-10.91% and N2 a maximum of 150.4+/-21.40% compared to controls (P<0.05 and P<0.01). Amplitudes were increased from 5 min after injection to the end of the 70 min test period. The effect of 1% formalin was equivalent to 5% formalin. This increase was prevented by pretreatment with 5 mg/kg ketamine or 5 mg/kg morphine, in agreement with behavioral and electrophysiological data. Cortical somatosensory evoked potentials are objective measures of central sensitization which may usefully complement current behavioral models for the evaluation of analgesic drugs.

Properties of the Spontaneous Fluctuations in Cortical Oxygen Pressure

In previous publications (Manil et al., 1978; 1981; Bourgain et al., 1980) the spontaneous fluctuations of the cortical tissue pressure in oxygen (Po2) in the awake rabbit were described in detail. The mean amplitude of these irregular oscillations was 5% of the normal local Po2 where 100% is defined as the value recorded in normal control conditions and 0% as the value recorded when death occurred after sustained pure nitrogen breathing. Analysis of the frequency domain demonstrates that in control conditions the power of the spectrum decreased from 0.06 to 0.5 Hz.

Naloxone-reversible opiate-sensitivity of a nociceptive cortical component of the somesthetic evoked potential (SEP) in the rat

NALOXONE-REVERSIBLE OPIATE-SENSITIVITY OF A NOCICEPTIV CORTICAL COMPONENT OF THE SOMESTHETIC EVOKED POTENTIAL (SEP {m IN THE RAT. C. Van Laere*, J. Manil*. M. Vervaeck’, Ph. Lebrun*. M Sosnovski. A. Soebert* and F. Cohn*. Physiological Laboratories of the Free Universities of Brussels, B-1090 Brussels, Belgium Aim of the Investigation: We firstly defined the cortical SEP of the rat after electrical stimulation of its tail-base, with an intensity of 1.5 x motor threshold (MT). Secondly, we evidenced a nociceptive component using noxious stimuli, and analyzed its naloxonereversible sensitivity to fentanyl, in order to define an electrophysiological index for pain and opiate-analgesia evaluation. Methods: The SEPs were recorded extradurally at the parietal region, referred to the nostril (frequency bandpass: 0.1 to 700 Hz; sampling frequency for digitization: 2000 Hz). After 256 stimulations, the averaged raw data were sent to a VAX 11/75 (DEC) computer for further analysis and display. Fentanyl(15 microg/kg) and naloxone (0.12 mg/kg) were injected intramuscularly (IM). Results: Stimulation at 1.5 x MT elicited an early positive component (P), followed by a larger negative one (N). with peak-latencies of 10 and 15.5 msec, respectively, (PlON15.5). A number of rats showed a W-shaped early component (P6PllN15.6). The peak to peak amplitude was in the range of 100 microV. Noxious stimuli (10 x MT or more) increased the amplitude of these components until saturation occurred, and evoked a supplementary late negative component of longer duration, peaking at 26 msec. This nociceptive wave disappeared within 10 min after IM injection of fentanyl. The effect of fentanyl lasted for 15 mm. The plateau then gradually reappeared and reached its initial value 45 min after fentanyl injection. The IM injection of naloxone reversed the opiate-analgesia within 3 min: the animal displayed again an exacerbated nociceptive behaviour, and the late negative plateau in the SEP reappeared. Conclusions: We have evidenced a negative, nociceptive, opiate-sensitive and naloxone-reversible plateau in the SEP of the rat. It constitutes a new objective assessment for pain measurement and opiate analgesia evaluation.

Relations between local microflow and tissue pressure in oxygen of the cerebral cortex in the awake rabbit (1 figure)

AbstractPrevious experiments (Manil et al., 1983) have revealed spontaneous oscillations of the cortical tissue pressure in oxygen (CTpO2) in a frequency band going from 0.03 to 0.33 Hz. No correlation could be found with the fluctuations of the systemic blood pressure except in stress situation. These oscillations were still present even after the spontaneous electrocortical activity had completely disappeared as a result of deep barbiturate anaesthesia. It was shown that these oscillations had to be attributed to circumscribed areas of the cerebral cortex of about 2 mm. Maximal vasodilation induced by breathing 5% CO2 increased and stabilized the CTpO2. Pharmacological analysis showed that alpha-blocking agents tremendously enhanced this otherwise spontaneous phenomenon. It was thus tempting to attribute this phenomenon to some vasomotor mechanisms. However, it remained to be shown that the oscillations of the CTpO2 were linked to fluctuations of the local microflow.

ABOUT THE FUNCTION OF THE TONIC ACTIVITY OF CEREBELLAR CLIMBING FIBERS

Publisher Summary This chapter presents the study of Purkinje cell (PC) activity in rats by a microelectrode lowered into vermal lobule VI. Either climbing fibers (CFs) were surgically severed at their crossing on the midline or the inferior olivary nucleus (ION) was destroyed by administration of 3-acetylpyridine (3-AP). Thus, suppressed CF activity could be restored by juxtafastigial (JF) stimulation. The acute suppression of the tonic CF activity was followed within few minutes by a tremendous change in the firing pattern of the PC—The frequency about doubled and the firing became much more regular. To study this interaction, a quantitative relationship between simple spike (SS) and complex spike (CS) firing rates was established by restoring a calibrated CS rate through JF stimulation. Beside CF axons, the JF electrode also stimulated PC axons and mossy fibers (MFs). When the intensity of the JF stimulus was increased, antidromic and MF-induced responses of the PC were frequently elicited before the CF response.