Norman L. Strominger

Responses of neurons of canine area postrema to neurotransmitters and peptides

Summary1.The responses of 122 neurons in the area postrema of anesthetized dogs to 17 common transmitters and peptides were determined. Recordings were made from one barrel of a seven-barrel ionophoretic electrode.2.All neurons were silent at rest, but most could be detected and excited by the application of glutamate. The glutamate response was a brief, high-frequency response of less than 1-sec duration.3.Excitatory responses were also found to histamine, norepinephrine, serotonin, dopamine, apomorphine, angiotensin II, neurotensin, leucine enkephalin, vasoactive intestinal polypeptide, thyrotropin releasing hormone, gastrin, vasopressin, and substance P. While most neurons tested were excited by dopamine and apomorphine, approximately half of those studied were also excited by each of the other substances. Inhibitory responses were found to norepinephrine (6 of 15 cells) and histamine (3 of 45 cells). No responses were found to acetylcholine, somatostatin, or cholecystokinin.4.The responses to all 13 excitatory substances other than glutamate were similar. Typically these responses had a latency of 2–20 sec and lasted for 30 sec to 5 min on their first application. The frequency of discharge was usually low (~0.5 Hz). Multiple applications of these agents often induced a maintained spontaneous discharge of low frequency. Each application also induced a transient incremental discharge at a frequency that rarely exceeded 2 Hz.5.The area postrema has been proposed to be the “chemoreceptor trigger zone” for emesis (Borison and Wang, 1953). All of the agents which excite area postrema neurons, with the exception of serotonin and norepinephrine, are emetic, while none of the three agents without excitatory effects is known to be emetic. Thus these results provide strong support for the central role of the area postrema in emesis.6.The similarity of response to so many substances on small neurons suggests a common ionic and/or metabolic mechanism underlying the response. The prolonged nature of the response to brief administration of these agents would seem to be appropriate for neurons which subserve a sensation and behavior such as nausea and vomiting.

An autoradiographic analysis of the tecto-olivary projection in primates

Autoradiographic tracing methods were used to demonstrate a well-defined projection from the superior colliculus to the inferior olivary complex in the monkey. This projection originates within the deep layers of the superior colliculus, descends within the contralateral tecto-spinal tract, and terminates within the caudal 1/3 of the medial accessory nucleus. The terminal field is restricted to a densely packed, darkly stained group of cells located in the most dorsal segment of subnucleus b. In one animal, another group of olivary afferents was identified. These fibers also descend within the contralateral tecto-spinal tract, and terminate within the dorsal cap of Kooy. While it was not possible to determine the origin of this projection, our data suggest that it arises within a region adjacent to the rostral pole of the superior colliculus. The present study further indicates that in the monkey relatively few axons which course within the classical tecto-spinal tract pass caudal to the medulla.

Peptide-induced emesis in dogs.

Systemic administration of apomorphine, angiotensin II, neurotensin and leucine-enkephalin induces emesis in dogs in a dose-dependent fashion. Receptors for Leu-enkephalin and angiotensin II but not apomorphine show receptor desensitization, such that a second systemic administration 5 min after the first is ineffective. Domperidone blocked the emetic response to apomorphine but not to Leu-enkephalin or angiotensin II. Naloxone selectively blocked the Leu-enkephalin response, while saralasin blocked responses to both angiotensin II and Leu-enkephalin, but not apomorphine. Chlorpromazine prevented the emetic response to all agents, suggesting a dopamine receptor in the emetic pathway on the brain side of the blood-brain barrier. In dogs with ablation of the area postrema the emetic response to apomorphine and all peptides was prevented.

Histopathology of the late-onset motor neuron degeneration (Mnd) mutant in the mouse

The motor neuron degeneration (Mnd) is characterized by a progressive deterioration of motor function (stiff-legged gait, abnormal limb placements and grasping, and finally paralysis; moving from rear to forelimbs). There is a dramatic degeneration of spinal cord motor neurons, more severe in the lumbosacral than in the other regions, as well as variable pathology in the lower cranial nerves. Upper motor neurons of the red nucleus, reticular formation of the pons and medulla, and restricted areas of the cerebral cortex are also affected. Degenerating motor neurons share many characteristics seen in the human disease amyotropic lateral sclerosis, including loss of Nissl substance, increases in lipofuscin and abnormal cytoplasmic inclusions. Additionally, Mnd, like ALS, is a disease of later life.

Neurotoxicity and protein binding of 2,5-hexanedione in the hen

Previous studies in this laboratory have demonstrated 2,5-dimethylpyrrole adduct formation during in vitro exposure of protein amino groups to the neurotoxic n-hexane metabolite 2,5-hexanedione (2,5-HD). The present investigation reports in vivo pyrrole adduct formation in neural and nonneural protein from 2,5-HD-treated animals. Adult, White-Leghorn hens were given daily doses of either 200 or 70 mg 2,5-HD/kg, po, for up to 55 or 135 days, respectively. Additional animals were given 70 mg/kg for 63 days and then allowed to recover for 72 more days. Protein separation by gel electrophoresis followed by staining with a pyrrole-specific reagent yielded evidence of widespread adduct formation in protein from serum, liver, kidney, brain, and purified myelin. Binding was particularly strong in serum albumin nd myelin basic protein. Quantitation of the adduct in these tissues revealed that its formation reached peak levels at 20 days in high dose and 30 days in low-dose animals. Levels subsequently declined, suggesting the presence of a clearance mechanism capable of removing altered protein during continuing 2,5-HD exposure. Protein from animals on the recovery regimen contained no detectable pyrrole adduct. Pyrrole adduct formation was also detected in neurofilament protein preparations, although protein yields were too low to allow assessment of clearance. Hens at both dosages displayed clinical signs indicative of CNS and PNS neuropathy. Histologic findings included axonal swelling and degeneration in peripheral nerve and some spinal cord nerve tracts. A hypothesis is proposed involving differential clearance of pyrrole adduct from neural vs nonneural tissue to explain the mechanism of action and target organ specificity of 2,5-hexanedione.

An experimental study of the efferent connections of the superior cerebellar peduncle in the rhesus monkey

Unilateral electrolytic lesions were made in the right superior cerebellar peduncle immediately lateral of its decussation or in the dentate nucleus of 6 monkeys. The course of the contralateral ascending and descending degenerated fibers and sites of preterminal degenerated fibers were studied in material stained by Fink-Heimer, Nissl and Weil methods. Major thalamic sites of preterminal degeneration were in the rostral part of VPLo, and in VPI, VLo, VApc, CL and PCn. In other thalamic nuclei or subdivisions, no preterminal was observed or was questionable. No degenerated fibers entered the internal capsule or corpus striatum. There was abundant preterminal degeneration in the rostral part of the nucleus ruber and adjacent reticular formation. The descending degenerated fibers of the superior cerebellar peduncle led to massive preterminal degeneration in the central part of the nucleus reticularis tegmentalis and in nuclei raphe pontis and magnus. The most caudal site of preterminal degeneration (minimal) was in the nucleus reticularis gigantocellularis adjacent to the median longitudinal fasciculus.

GRACILE, CUNEATE, AND SPINAL TRIGEMINAL PROJECTIONS TO INFERIOR OLIVE IN RAT AND MONKEY

In the cat, somatosensory nuclei send substantial projections to the inferior olive, where they terminate in a somatotopic fashion. Although the organization of the cat inferior olive has been used to interpret data from other species, published data suggest this organization may not occur universally. The present study investigated whether the inferior olive in albino rats and cynomolgus monkeys receives the same brainstem somatosensory inputs, whether these inputs are organized somatotopically and, if so, how the organization compares with that in the cat. Projections from the gracile, cuneate and spinal trigeminal nuclei were labeled with wheat germ agglutinin conjugated to horseradish peroxidase or with biotinylated dextran. The results were compared with data from cats (Berkley and Hand [1978] J. Comp. Neurol. 180:253‐264).

AUDITORY DISCRIMINATION BY THE CAT AFTER NEONATAL ABLATION OF TEMPORAL CORTEX.

Some auditory discriminations cannot be acquired by the cat after large bilateral ablations of auditory cortex at maturity. However, if such ablations are sustained during infancy, these discriminations are readily learned. The function of the cortex in auditory discrimination depends on the age of the nervous system at the time of injury.

Cross-modal innervation of primary visual cortex by auditory fibers in congenitally anophthalmic mice

Auditory-visual cross-modal innervation was examined in control (sighted, ZRDCT-N) and congenitally anophthalmic (eyeless, ZRDCT-AN) mice using electrophysiological recording and pathway tracing with carbocyanine dyes. Electrophysiological data demonstrate that the primary visual cortex of congenitally eyeless, blind, mice receives auditory stimuli. Neuroanatomical data demonstrate a direct connection between the inferior colliculus (IC) and visual cortex. Our experiments provide new information about how the brain adapts to the loss of sight.

Radiation-induced emesis in the dog: effects of lesions and drugs

Dogs exposed to 8 Gy 60Co gamma mid-abdominal irradiation exhibited emesis with an average latency of 102 min and an average of 7.4 episodes over 96 min. There were no significant changes in dogs subjected to a chronic bilateral subdiaphragmatic vagotomy, but emesis was prevented by ablation of the area postrema. Indomethacin pretreatment also prevented radiation-induced emesis in two of seven dogs and in the remainder reduced the average number of episodes. Domperidone pretreatment prevented radiation-induced emesis in all of four dogs tested. In electrophysiological studies recording from the area postrema the chemosensitive neurons were found to be normally silent in anesthetized preparations but excitable by a variety of emetic agents. After irradiation of the abdomen spontaneously active neurons were found with a discharge pattern that mirrored the behavioral pattern of postirradiation emesis. These studies are consistent with radiation-induced emesis being humorally mediated in the dog and implicate dopamine and/or prostaglandins as possible mediators.