The significance of occult skeletal metastases, detected by skeletal scintigraphy, in patients with otherwise apparently 'early' mammary carcinoma.

Fifty patients with apparently 'early' mammary carcinoma on clinical, radiological and biochemical grounds had a skeletal scintigram carried out when they first presented. Twelve (24 per cent) of the patients had a positive scintigram. All these patients have developed metastatic disease in the first 5 years following mastectomy, and at least 9 (75 per cent), and probably 10 (83 per cent), have died from mammary carcinoma during this period. This compares with 10 (26 per cent) of the patients with a negative scintigram who have developed recurrent or metastatic disease, of whom 8 (21 per cent) have died from their disease. Five years following mastectomy none of the patients with a positive scintigram was alive and free from disease, compared with 25 (66 per cent) of the patients with a negative scintigram. It would appear that skeletal scintigraphy is the most sensitive method of detecting skeletal metastases and of staging breast carcinoma at the moment. Where practicable, this investigation should be carried out before embarking upon treatment for any particular patient, and this certaily should become part of any clinical trial comparing different therapeutic regimens. However, before some of the newer bone-seeking isotopes are used in this way, further studies are required to determine their false positive rate.


Acute cholecystitis.

One hundred and fifty-six successive patients have been admitted with the clinical diagnosis of acute cholecystitis and have been treated by operation on the next operating list. The diagnosis was correct in 154 and a diagnostic pathway has been determined. The clinical features, investigations, bacteriology and pathology are discussed. There is an increased need for choledochotomy in acute cholecystitis and this bile is more commonly infected than in the elective patient. It is suggested that those with infection can be identified prior to operation and should be treated with antibiotics on admission. The morbidity of operation on patients with uninfected bile is no greater than in those receiving elective surgery, and operative treatment is recommended for both groups of patients.


Prognosis after portocaval anastomosis: a 15-year follow-up.

A 15-year follow-up of 57 patients who underwent portocaval anastomosis is reported. Twenty-seven patients were still alive and the progress of these and of those who died is followed. The young cryptogenic cirrhotic with no encephalopathy, normal liver function tests and absence of portal vein mural thrombus at the time of operation is best benefited. The only factor from the series to suggest a poor prognosis is deterioration in liver function in the post-jaundice cirrhotic, and the development of encephalopathy in cryptogenic cirrhotics suggests a poor long term prognosis, but its onset is not related to the time before death.


The effect of acute ethanol administration on the exocrine pancreatic secretion of the pig.

The acute effect of intravenous and intragastric alcohol on exocrine pancreatic secretion was studied in pigs with chronic pancreatic and gastric fistulas. A new H-type pancreatic cannula was designed for the study. With intravenous alcohol and the gastric fistula open, increased gastric acid secretion occurred but pancreatic enzyme output was inhibited. When acid was allowed to inter the duodenum by closing the gastric fistula, intravenous alcohol produced a secretin-like effect of increased pancreatic volume and bicarbonate secretion. Intragastric alcohol caused an increase in volume, bicarbonate and enzyme output. This was probably due initially to direct gastroduodenal stimulation as the same response occurred following intragastric mannitol of similar volume, pH and osmolality. The subsequently sustained increase in volume and bicarbonate was possibly a secondary secretin-like response following absorption of alcohol. It is concluded that the pig pancreas responds to alcohol as has been described in other animals. The use of a single model has allowed clarification of various phases of response invoking the effects of secretin, gastric and glucagon.


Cause and management of high volume output salt-depleting ileostomy.

Ileostomy function was studied in 12 patients with an established ileostomy following proctocolectomy, in 6 of whom minimal amounts (less than 9 cm) and in 6 significant amounts (30-120 cm, mean 60 cm) of terminal ileum had been removed. Patients who had undergone significant ileal resection had daily faecal volumes considerably greater than those with minimal ileal resection (1202 +/- 284 ml versus 401 +/- 92 ml, P less than 0.001), and also greater daily outputs of sodium (146 +/- 53 mEq versus 43 +/- 12 mEq) and potassium (12.7 +/- 9.0 mEq versus 4.0 +/- 0.99 mEq). The percentage water content of the ileostomy fluid was greater in patients who had had the ileum resected (93.1 +/- 1.8% versus 89.8 +/- 2.5%). In addition, the sodium/potassium ratio in the urine in patients with a properly acting ileostomy after ileal resection was low. It is concluded that when recurrent inflammatory bowel disease, partial small bowel obstruction and intraperitoneal sepsis have been excluded there remains a number of patients whose high ileostomy output is due entirely to the amount of ileum resected. The management of patients with a high output ileostomy with codeine phosphate, Lomotil and oral administration of sodium chloride tablets is discussed.


Factors influencing local recurrence after abdominoperineal resection for cancer of the rectum and rectosigmoid.

One hundred and fifty-two patients who underwent abdominoperineal resection for cancer of the rectum and rectosigmoid are reviewed. Six physicians were selected to predict which of these patients would have a local recurrence. All information available at the end of the operation was duplicated and submitted to the observers. None of the physicians was able to predict local recurrence significantly better than random. There were 31 local recurrences, i.e. an incidence of 20-4 per cent. Low level of tumour in the rectum, local spread into perirectal fat or serosa, lymph node involvement and age below 60 years at time of operation were the only factors that were statistically related to local recurrence. The strategy for careful follow-up of patients at risk is outlined and a plea is made for a controlled trial of postoperative radiotherapy.


The transdiaphragmatic approach to the heart.

A modification of the transdiaphragmatic approach to the heart is described. The technique has been used successfully in both adults and children, the youngest child being 8 years of age. The approach has advantages over others in gaining access to the heart for purposes of internal cardiac massage and drainage of suppurative pericarditis and is also a suitable manaeuvre in the surgical treatment of acute tamponade. Clinical experience in the use of this approach is summarized. The transdiaphragmatic approach is recommended as a standard technique for internal cardiac massage.


False abdominal aortic and iliac aneurysms.

A case of late postoperative false abdominal aortic an iliac aneurysms complicated by malposition of the inferior vana cava is presented and attention is drawn to its presentation, diagnosis and management. Several factors assumed to be responsible for the formation of the false aneurysms 7 years after the previous grafting operation are discussed.


Collagen biosynthesis in normal and hypertrophic scars and keloid as a function of the duration of the scar.

The rates of collagen biosynthesis and the tissue concentrations of collagen in normal scar, hypertrophic scar and keloid were determined as a function of the duration of the lesions. The rate of collagen synthesis in normal scar was approximately constant between 6 months and 20 years after the initial wounding, but in both hypertrophic scar and keloid the rate was initially approximately twice that in normal scar, and 2-3 years after wounding it fell to approximately the same level as in normal scar. The tissue concentration of collagen appeared to be relatively constant in normal scar with respect to the time elapsed after wounding, but in both types of abnormal scar it was initially somewhat lower than normal scar and then rose to values higher than in normal scar after about 2-3 years. Since similar results were obtained for both types of abnormal scar in terms of the rates of collagen biosynthesis with respect to the time elapsed after wounding and also in terms of the tissue concentrations of collagen, this may indicate that the events in the pathogenesis of both abnormal scar types are similar. The results also raise the possibility that the formation of both types of abnormal scar may occur in two phases: an initial phase characterized by abnormally high rates of collagen biosynthesis and a later phase characterized by essentially normal rates of collagen biosynthesis.


A technique for re-exploration of the saphenofemoral junction for recurrent varicose veins.

A safe and simple method is described for re-exploration of the saphenofemoral junction in patients with recurrent varicose veins following incomplete 'Trendelenburg operation'.


Selective surgery for abdominal stab wounds.

The value of selective surgery for abdominal stab wounds was assessed in a prospective study of 226 patients admitted over an 18-month period. Two died soon after admission and before operation, the indications for which were signs of peritoneal irritation or haemorrhage, evisceration of bowel and omental protrusion. Of the 226 patients, 113 were selected for immediate surgery, which was carried out within 3 hours of admission. There were 12 deaths (10-6 per cent). Of the 111 patients initially selected for observation, 47 (42-3 per cent) underwent delayed operation with 4 deaths (8-5 per cent), but in only 1 (2-1 per cent) of these patients could the delay have influenced the adverse result. There were no deaths in the 64 patients treated conservatively. The overall mortality rate of patients who were initially selected for observation was 3-9 per cent. One hundred and fifty patients underwent laparotomy, positive findings justifying operation being present in 134 (89 per cent). Six patients required thoractomy for concomitant thoracic injuries, including 2 patients who required cardiorraphy. Four other patients required combined thoracic and abdominal exploration. The selection of patients for either conservative or operative management was based entirely on clinical criteris; abdominal X-rays were not helpful in the early diagnosis of visceral lesions. The indications for operation were evident within 12 hours of admission in 156 of the 160 patients who were treated surgically. A substantial reduction in the incidence of 'negative laparotomy' can be made by this process of selection, and without an associated increase in the morbidity and mortality rates.


Response of fibrinolytic activity to venous occlusion.

Resting fibrinolytic activity and the response of the fibrinolytic system to venous occlusion were studied in a group of healthy middle-aged men. All subjects showed increased fibrinolytic activity but of varying degrees. There was a linear relationship between resting and occluded levels of fibrinolytic activity but many subjects with lower levels of fibrinolytic activity showed an anomalous response. Responses over the expected level were more common than unexpectedly low levels of response. Fibrinogen and plasminogen concentrations were inversely correlated with fibrinolytic activity.


Register of newly diagnosed diabetic children.

In November 1972 the British Diabetic Association sponsored a register to which notification was invited of all new cases of diabetes occurring in children aged 0-15 years in Great Britain and Ireland. More than 2000 cases were notified in the first two years. Notification suggested that there was a minimum yearly incidence of 7-67 cases per 100 000, though incidences varied from year to year and by geographical area. Several reports of simultaneous onset of diabetes in sibs of different ages provided evidence of clustering. A seasonal variation in incidence was found in children aged 5-15 years with peaks in the autumn and winter. The age distribution was bimodal with a main peak at about 11 years and a secondary peak at about 5 years. The sex ratio showed a male excess from 0-4 years and from 11-15 years and a female excess from 5-10 years. Overall there were slightly more male cases. Altogether 11% of patients had a first-degree relative with diabetes. The register and several investigations based on it will continue.


Community participation in primary health care.

A two and a half year's experience of a community participation group has shown that this can have a valuable role in suggesting practicable improvements in a group practice. Topics discussed by the group (which is composed of one representative from every known organization in the area) have included problems of receptionists; the role of the individual ancillary worker; and teaching in general practice. The high attendance rate at the group's meetings testifies to the community's interest in primary health care services.


Relation between lung cancer, chronic bronchitis, and airways obstruction.

Since cigarette smoking is an important cause of lung cancer and chronic bronchitis both conditions should occur together more often in cigarette smokers than would result from chance. If they do commonly occur together then severe airways obstruction, which is often associated with chronic bronchitis, should also be often associated with lung cancer. To discover whether this were so three groups of patients were studied at the London Chest Hospital. Two hundred men and 43 women who presented with lung cancer provided information on the prevalence of defined chronic bronchitis and airways obstruction in those suffering from lung cancer. The third group consisted of 233 men presenting with defined chronic bronchitis who were kept under observation to discover how many would die from lung cancer. The results suggested that simple bronchitis and lung cancer often occur together but that obstructive bronchitis and lung cancer do not often occur together. The lack of association between lung cancer and severe airways obstruction requires an explanation.


Whooping-cough vaccine. Statement by Joint Committee on Vaccination and Immunization of the Central Health Services Council and the Scottish Health Service Planning Council.

In 1974 it was recommended that pertussis vaccine should continue to be offered in a triple vaccine together with diphtheria and tetanus vaccines. Further data on the prevalence of whooping cough and the incidence of adverse reactions have shown no reason to change this policy; the hazard of whooping cough remains greater than that of immunization.


Tuberculosis among immigrants related to length of residence in England and Wales. Report from the British Thoracic and Tuberculosis Association.

Between 1965 and 1971 the notifications of tuberculosis among lifetime residents of the British Isles declined, but among those born in India, Pakistan, and new Commonwealth countries in Africa tuberculosis notifications increased appreciably. Furthermore, the long-held suspicion that among these immigrants the most recent arrivals in England and Wales have higher rates of tuberculosis than those who have lived here longer was confirmed.


Moorgate tube train disaster. Part 1-Response of medical services.

Experience of the medical staff at a major subterranean accident scene showed that there appeared to be a substantial advantage in using site medical teams that could offer anaesthetic facilities. The need for adequate communication from the accident site to the hospital is emphasized.


Moorgate tube train disaster. Part II. Clinicopathological review.

A review of the injuries sustained by the 113 casualties of the Moorgate tube train disaster has shown the need for rapid evacuation of casualties. Recognition of the "crush syndrome" and its early consequence, hyperkalaemia, is important and a radical surgical approach is suggested. Chest injuries were common and contributed to many of the deaths.


Retinoblastoma: a study of natural history and prognosis of 268 cases.

The natural history and prognosis of retinoblastoma were analysed using data relating to the 268 cases registered during 1962-8 in England, Scotland, and Wales. The children were followed up for a minimum of four years; the proportion surviving for four years was 86%. The most important factors affecting survival rate were the stage of the tumour at diagnosis and the hospital of treatment. Of children surviving for three years after treatment only three died during the subsequent period of follow-up, which varied from one to seven years. Among children with retinoblastoma treated between 1949 and 1968 nine died between seven and 13 years later of other cancers: seven from osteosarcomas, one from angiosarcoma, and one from fibrosarcoma.


Colonic carcinoma: clinicopathological correlation with immunoreactivity.

The relation between tumour spread, histological differentiation, and in-vitro antitumour immunoreactivity was studied in 132 cases of carcinoma of the large bowel. Positive correlations were found between blood lymphocyte antitumour cytotoxicity and both tumour differentiation and absence of recurrence or metastatic spread.


Suicide and "The Befrienders".

The short-term effect of "The Befrienders"--an 11-episode weekly series on B.B.C. 1 portraying the Samaritans as a suicide prevention service--on suicide and undetermined deaths was monitored in Edinburgh. No preventive effect was observed though the series was associated with a dramatic rise in new client referrals to the Edinburgh branch of the Samaritans.


Fibreoptic bronchoscopy today: a review of 255 cases.

An analysis of 255 fibreoptic bronchoscopies showed that the major indication for bronchoscopy was suspected bronchial carcinoma (93% of cases). Of the 183 patients finally shown to have bronchial carcinoma 83% had abnormal bronchoscopy findings and 65% had bronchial biopsy specimens diagnostic of malignancy. These figures were superior to those obtainable with rigid bronchoscopy, particularly with upper lobe and peripheral tumours. Brush biopsy and bronchography were useful supplementary techniques. Sputum cytology gave poorer results than fibreoptic bronchoscopy, but enabled diagnosis in some otherwise undiagnosed cases. The complication rate was low and the claim of this new technique to be the investigation of choice in bronchial carcinoma seemed to be justified in clinical practice.


Needling renal cysts and tumours: cytology and radiology.

Renal masses found by intravenous urography, ultra-sound scanning, and arteriography were needled in 102 patients. Simple renal cysts containing clear fluid and no cytological abnormalities were found in 85 patients. Two unsuspected renal cell carcinomas were found on puncture; cytological examination showed malignant cells in the aspirate. Another five renal tumours were needled deliberately before nephrectomy, and a firm preoperative diagnosis of renal cell carcinoma was made on aspiration cytology in three. Benign cysts which had bled were particularly hard to diagnose. With care, radiology and cytology in combination can provide the firm diagnostic base needed for sound clinical management. The radiology-cytology team must be alert to the unusual finding that indicates a complex lesion, such as an unsuspected renal tumour.


Regular short haemodialysis in end-stage renal failure.

A study was made of thrice weekly haemodialysis of 3-3 1/2 hours' duration using a large surface area dialyser in patients with end-stage renal failure. Body water, potassium, and blood pressure control were satisfactory and comparable with the more widely used long dialysis schedules (6-9 hours thrice weekly). Patient rehabilitation was improved overall and the regimen enabled the dialysis unit to treat more patients despite a reduction in technical and nursing staff. The technique proved inadequate, however, in two patients with an intercurrent infection, and more intensive dialysis in recommended in such cases.


Transport of newborn infants for intensive care.

During the three years 1972-4 222 newborn infants were transported to this hospital for intensive care. They were collected by trained staff using a specially modified transport incubator with an in-built mechanical ventilator and facilities for monitoring body temperature, heart rate, and inspired oxygen concentration. Two of the infants came from home and the rest from 41 hospitals from half a mile (0-8 km) to 50 miles (80-5 km) (median eight miles (12-9 km)) away. The mean birth weight of the infants was 1702 g (range 520-4040 g) and their mean gestational age was 32 weeks (range 24-42 weeks). The principal reasons for referral were low birth weight and severe respiratory illnesses. Altogether 109 (49%) of the infants needed mechanical ventilation in transit and another 38 (17%) needed it later. During the journey the condition of 88 (40%) of the infants was thought to improve, in 125 (56%) it was static and in nine (4%)--four of whom died--it deteriorated. A total of 142 infants (64%) survived the neonatal period. There was no correlation between the distance travelled and the survival rate. Seriously ill newborn infants may be transported safely to a referral centre within a radius of 50 miles, and the risks of the journey are negligible compared with the risks of leaving the infant in a hospital that is not staffed or equipped for neonatal intensive care.


Aminocaproic acid and menstrual loss in women using intrauterine devices.

A controlled study of the effect of aminocaproic acid 3 g six-hourly taken by mouth during menstruation was carried out on 56 women for eight months from the time of insertion of a Lippes D intrauterine device (IUD). Thirty-five women presenting with menorrhagia in association with an IUD were also treated during three out of six consecutive menses. A highly significant reduction in menstrual loss was observed during treatment in both groups.


Vitamin E deficiency and platelet functional defect in a jaundiced infant.

A 16-month-old infant with hepatic fibrosis, cholestasis, and chronic jaundice had signs of vitamin E deficiency, including mild acanthocytosis, thrombocytosis, increased peroxide haemolysis, and absent serum vitamin E. Abormal prothrombin consumption and platelet restocetin aggregation suggested the presence of defective platelet function, and correction studies indicated that this was due to a plasma defect. The abnormality was corrected by treatment with vitamin E, and the findings suggest a possible role of this vitamin in platelet reactions.


Survey of dietary policy and management in British diabetic clinics.

Questionnaires about dietary policy were sent to 471 physicians in diabetic clinics throughout the United Kingdom, and usable replies were received from 281. Insulin-dependent patients were mostly taught to use carbohydrate-exchange units in regulating their diets; this method was used less often for maturity-onset diabetics. Restriction of sucrose and foods containing concentrated sugars was more rigorous in clinics in teaching hospitals than elsewhere; paediatric clinics were the most liberal. Maturity onset diabetics were generally advised to restrict their fat intake, but most clinics did not restrict fat for their insulin-dependent patients. Again teaching-hospital clinics were the most restrictive. Patients were rarely encouraged to weigh their food. In general physicians thought that insulin-dependent patients adhered to their diets but maturity-onset patients did not. There is uncertainty about the ideal dietary policy for diabetics and the best way of helping patients to follow the regimen prescribed.


Notes on the hypothesis of columnar organization in somatosensory cerebral cortex.

The five principles that make up the hypothesis of columnar organization for somatosensory cerebral cortex are considered in relation to their experimental foundations. Several important implications that flow from these principles are examined, and the requirements for their experimental evaluation are elaborated. A number of specific measurements are found to be lacking in necessary precision: the total amount of somatosensory cerebral tissue in each area, the sizes, shapes and degree of overlap of aggregate excitatory receptive fields, the number of distinct modalities and the modality equivalences in our different linguistic categories, the sizes and shapes of the columns and, finally, the number of columns for each modality and the total number of columns. Some possible columnar arrangements are set up, and their experimental detectability is assessed, using optimal conditions and values. It is shown that if a columnar structure exists, it defies clear detection by current neurophysiological techniques and experimental approaches. The concept of an 'elementary functional unit' is found to need clear definition; taken at face value, it is shown to yield some rather unusual predictions. The conditions under which the hypothesis of columnar organization can be distinguished from its rival, the hypothesis of topographic organization, are also reviewed.


Development of air righting in rats.

Rats aged between 13 and 18 days were dropped from different heights in order to establish the height at which 50% of the animals were able to perform complete air righting. The proportion of animals showing complete air righting abruptly increased at 16 days of age indicating maturation of the response at this age. No necessary relationship was observed between eye opening and air righting. At 15 days of age, when normally only a minority of the rats are able to display complete air righting, a marked effect of training was observed.


Eye movements evoked by electrical stimualtion of the brain in anesthetized fishes.

Several eye movements were evoked by electrical stimulation of the brain in anesthetized sunfish and goldfish. Conjugate lateral rolling movements, similar to eye movements observed when an unoperated fish is rotated about its long axis, were evoked from the acoustico-lateral area of the medulla and the eminentia granularis and an adjacent medial portion of the cerebellum. Bilateral and unilateral backward rotations, similar to the eye movements observed when unoperated fish are rotated forward about the interpupillary axis, were evoked from the medial longitudinal fasciculus and areas related to the oculomotor nerve. Bilateral forward rotations, comparable to the eye movements resulting when unoperated fish are rotated backward about the interpupillary axis, were elicited by stimulation near the trochlear nerve roots in the valvula of the cerebellum; unilateral responses resulted from stimulation near the exiting trochlear nerves. Convergence was elicited by stimulation in the midline near the oculomotor complex and the medial longitudinal fasciculus while unilateral vergence responses were triggered by stimulation in the medial longitudinal fasciculus and areas lateral to the oculomotor nucleus. Conjugate eye movements in the horizontal plane were frequently evoked but were not studied in detail.


Ontogeny of behavioral sensitivity to strychnine in the chick embryo: evidence for the early onset of CNS inhibition.

The development of behavioral sensitivity to strychnine has been studied in the chick embryo between day 7 of incubation and 1 day posthatching. The earliest response to systemically applied strychnine was a marked depression of spontaneous motility at high concentrations of the drug. Lower concentrations had no effect at this time (6-7 days). About 2 days later, on day 81/2 or 9, strychnine induced a statistically reliable increase in spontaneous motility (hyperactivity). This consisted of a brief (i.e. 1-2 min) excitatory response which was followed by a return to baseline activity levels in the case of low drug concentrations, or a depression of activity in the case of low drug concentrations, or a depression of activity in the case of higher concentrations. By 11 days of incubation the brief excitatory response following strychnine had increased in duration to about 4 min. This was also the case for 13-day embryos. At no time between 7 and 13 days were convulsions produced by strychnine, even at concentrations several times greater than that required to induce hyperactivity. For the first time at 16 days myoclonic convulsions were observed following strychnine. These usually began soon after the initial hyperactivity and frequently lasted for as long as 30 min. At the same time the sensitivity of the embryo to strychnine increased, compared to earlier stages. By 18 days strychnine most often induced an immediate convulsive response without the preceding brief hyperactivity. This was also typical of newly hatched chicks. The systemic application of glycine at 9 and 13 days of incubation produced a slight, but statistically reliable, depression of ongoing spontaneous motility, consistent with what one might expect if glycine were acting as an inhibitory neurotransmitter. It typically took between 3 and 4 min following injection for this glycine response to occur. Biochemical, electrophysiological and neuroanatomical evidence was reviewed in an attempt to support the suggestion that the strychnine and glycine data summarized above may reflect the presence of strychnine-sensitive postsynaptic inhibitory processes in the chick spinal cord. Additionally, comparative data on the relative onset of excitatory and inhibitory  processes in the developing spinal cord were discussed. It was concluded that, although the data are still imcomplete concerning the question of whether, developmentally, inhibition is a primary or secondary acquisition, inhibitory mechanisms nevertheless appear rather early during vertebrate neurogenesis.


Changes in the size and organisation of the brain in man and his ancestors.

Changes in brain size are described during the evolution of man's ancestors and during man's development. It is shown that differences in size are accompanied by changes in the proportions of the brain, and that selection pressures have been greater for some parts than others.


Interhemispheric projections of the optic tectum in pigeon.

The anatomical patterns of intertectal pathways in pigeon (Columba livia) were studied with modifications of the Nauta-Gygax silver technique following discrete unilateral tectal lesions. No homotopic connections between the two optic tecta were found. The data do not support an anatomical basis for the behavioral observation of interhemispheric reversal of left-right mirror-image patterns in monocularly trained pigeons. Degenerated fibers of passage were identified in the tectal commissure, the posterior commissure, the ventral tegmental decussation and the supraoptic decussations. Preterminal fields were identified in the contralateral substantia grisea perinventricularis of the tectum, lateral mesencephalic reticularnuclei, area pretectalis, nucleus linearis caudalis, nuclues posteroventrialis, and lateral geniculate nucleus, pars ventralis. The possible significance of these findings is discussed with reference to behavioral, electrophysiologic and neuroanatomic studies.


Retinal afferents to the pigeon optic tectum: discharge characteristics in response to whole field illumination.

Responses of pigeon retinotectal afferents to changes in whole field illumination are quantitatively analyzed for 313 units recorded in the stratum opticum. One hundred per cent of these units were responsive in unanesthetized birds and 92.9 percent in urethane anesthetized preparations. Of the responsive units, 92.4 percent (anesthetized) and 100 percent (unanesthetized) gave on-responses whose discharge characteristics showed an orderly relationship to stimulus intensity. Following the on-response, discharge generally ceased during sustained illumination. At stimulus termination off-responses frequently occurred, their probability being a function of stimulus intensity and duration. This probability, as well as specific response characteristics, could be predicted to a large extent from on-response characteristics. Anesthesia and level of background illumination predictably affected these response characteristics quantitatively but did not alter them qualitatively. It is hypothesized that with respect to whole field illumination the pigeon's retinotectal afferents constitute a homogeneous population continuously distributed according to threshold for intensity change.


The subfrontal lobe and touch learning in the octopus.

Octopuses with the supraoesophageal lobes of the brain divided longitudinally can be taught to discriminate using the arms on either side. If there is no further lesion the two sides behave alike. Lesions limited to one side did not affect the performance of the contralateral, "control" side. Lesions made in the vertical (n=7) lobes led to a slight drop in the quality of performance in training to take a smooth sphere, in discrimination training (rough vs. smooth spheres) and in subsequent extinction and transfer tests. After removal of the median inferior frontal lobe (n = 10) there were somewhat greater effects in the same direction. Much larger effects followed interference with the subfrontal lobe (n = 20). Removal of parts from this always led to a marked loss of capacity for touch learning, broadly dependent on the amount of tissue removed. Removal of the whole of the subfrontal lobe (n = 6) produced animals that showed, at best, only very slight signs of learning. Such animals can adjust their overall level of response as a result of training but they seem incapable of adjusting response levels to two objects independently. These results are discussed in relation to the function of the subfrontal lobe as a memory store.


The effect of intravenously administered gamma-aminobutyric acid on afferent fiber polarization.

(1) The effect of intravenously administered gamma-aminobutyric acid (GABA) on afferent fiber polarization in the feline spinal cord was ascertained from fluctuations induced in the DC level of dorsal root filaments. (2) A dose-related depolarization of the filament, with a concomitant reduction in the magnitude of the dorsal root potential, was observed after 50 and 100 mg/kg GABA. (3) GABA also depolarized filaments of preparations in which interneuronal activity was suppressed by pretreatment with tetrodotoxin. Since the magnitude of the depolarization induced in these preparations was equal to that observed in nonpretreated animals, it is likely that the depolarization in the latter preparations reflects a direct effect on afferent terminals or fibers rather than an action on interneurons. (4) GABA failed to depolarize filaments in animals pretreated with bicuculline. This suggests that intravenously administered GABA interacted with receptors that are identical with or similar to those involved in neurally evoked primary afferent depolarization (PAD). (5) The direct depolarization of afferent fibers by intravenous GABA and the blockade thereof by bicuculline are characteristics compatible with those of the endogenous axo-axonic transmitter operating in pathways mediating neurally evoked PAD. These data, therefore, support the involvement of GABA at this synapse in the mammalian spinal cord.


CNS depressants: effects on post-synaptic pharmacology.

(1) The effects of 5 anesthetics (chloralose, chloroform, ethanol, pentobarbital and urethane) and one anticonvulsant (diphenylhydantoin) were studied on the membrane properties and post-synaptic responses of crustacean neuromuscular junction preparations and molluscan neurons to putative transmitters and peptides. (2) In crustacean preparations pentobarbital selectively depressed, in a dose-dependent, reversible manner, post-synaptic, Na+-dependent, depolarizing responses to the putative transmitter glutamate without altering post-synaptic, Cl(-)-dependent inhibitory responses to the putative transmitter gamma-aminobutyric acid. (3) The effects of all the agents on post-synaptic pharmacology of a molluscan neurosecretory cell were studied either by causing the cell to hyperpolarize to about--100mV through repeated application of acetylcholine (ACh) in a K+-free, Ca++-containing solution or by hyperpolarization through injection of intracellular current in a K+-free solution. Effects of these agents on post-synaptic responses on other molluscan neurons were studied using intracellular current injection to manipulate membrane potential. (4) All of the agents tested selectively depressed the depolarizing Na+-K+-dependent post-synaptic responses of the neurosecretory cell to ACh in a dose-dependent reversible manner without appreciably altering the membrane properties of the cell (over the potential range of the ACh responses). (5) Pentobarbital did not alter the inversion potential of the ACh response. (6) Reciprocal plot analysis of all of the agents tested revealed that the antagonism of the ACh response was primarily non-competitive. (7) None of the agents tested altered hyperpolarizing, K+-dependent responses to dopamine and glutamate on the neurosecretory cell, nor did they affect either the induction or enhancement of BPP activity by the vertebrate peptide vasopressin on this cell.


DNA, ganglioside and sulfatide in brains of rats given corticosterone in infancy, with an estimate of cell loss during development.

Evidence of a postnatal loss of cerebral cells has been presented, based on counts of the activity of cerebral DNA following labeling with [3H]thymidine on embryonic day 14. In otherwise untreated rats, the loss was about 15 percent of the labeled cells between postnatal days 3 and 15. There was no further loss of activity thereafter. Littermates given corticosterone at day 3 showed little additional loss of labeled cells. Ganglioside NANA (N-acetylneuraminic acid) was reduced in proportion to the reduction in cerebral weight in the corticosterone treated rats. Sulfatide was reduced more, so that the concentration was 11 percent below that of the controls; It is concluded that the deficit in DNA after postnatal corticosterone treatment must be due primarily to an irreversible suppression of DNA synthesis, involving mainly glia. The reduction in gangliosides may represent a deficit in the growth of neuronal processes, leading to a reduction in the amount of neuropil, and perhaps contributing to a decrease in the number or size of myelinated axons.


Low molecular weight specific proteins in identified molluscan neurons. I. Synthesis and storage.

Low molecular weight specific proteins in phenotypically distinct, identified neurons of Aplysia californica, have been detected using a high resolution acid-urea polyacrylamide gel system, and the molecular weight of these proteins labeled by in vitro incubation in [3H]leucine were determined by two different methods. The relative mobilities of these proteins on the acid-urea gel differed significantly, even though they appeared to co-electrophorese on SDS gelss. These identified neurons, and the specific proteins that they synthesize and store represent excellent model systems for the study of specific protein regulation in neurons.


Computer simulation of the metabolism of guinea pig brain slices, and how they differ from the intact brain.

A computer model of the metabolism of glutamate, glutamine, gamma-aminobutyrate and the Krebs cycle in guinea pig cortex slices has been constructed in terms of 98 reactions among 38 unlabeled species. Fitting the data from slices required the addition of a third small compartment to previous 2-compartment models based on whole brain experiments. This third compartment corresponds to the tissue damaged during the slicing process, and dominates the metabolism of 14C-labeled substrates at early times. The times required for equilibration between this additional compartment and the bulk of the slice are no longer than expected. Interpretation of short-term slice experiments may be subject to appreciable error owing to the presence of this additional compartment.


Effects of exposure to an imprinting stimulus on the activity of enzymes involved in acetylcholine metabolism in chick brain.

One-day-old chicks were exposed for 60 min to either an imprinting stimulus or a dark-box. They were killed at 0, 1, 6 or 12 h after the end of this treatment, and the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAc) assayed in the forebrain roof, forebrain base and midbrain. The activity of AChE increased by 11% in the roof of stimulus-exposed birds 1 h after exposure and in base (by 13%) and midbrain (by 8%) 6 h after exposure. At 12 h the only difference was a lowered AChE (14%) activity in midbrain of stimulus-exposed animals. By contrast only one difference was found in ChAc activity between the two types of birds: an elevation of 10% immediately after the end of treatment (0 h) in the midbrain of the stimulus-exposed birds.


Changes in chick brain RNA polymerase associated with an imprinting procedure.

The specific activity of RNA polymerase was measured in nuclei from 3 brain regions of 1-day-old chicks which had been exposed for different periods to either an imprinting stimulus or diffuse light and compared to that in birds kept in the dark. Several differences were observed, all of which were short-lived. After 15 min treatment there was a decrease in enzyme activity in the forebrain base of both stimulus- and diffuse light-exposed birds as compared to dark birds, which disappeared by 30 min treatment. After 30 min treatment there was increased activity of the enzyme in the forebrain roof of the stimulus-exposed as compared to both diffuse light-exposed and dark-maintained birds. There were no differences in activity in any region from 45 min up to 120 min of treatment. These changes in RNA polymerase activity were in general accord with the altered uracil incorporation into RNA measured in previous experiments where birds were exposed to 38 or 76 min of treatment, and also with our earlier report on RNA polymerase activity after 30 min treatment.


A study of the de- and regenerative changes in the sympathetic nervous system of the adult mouse after treatment with the antiserum to nerve growth factor.

In the adult mouse, the antiserum to nerve growth factor (NGF) induced marked atrophic changes of the ganglionic cell bodies in the superior cervical ganglion (SCG) and a disappearance of adrenergic nerve terminals in several peripheral tissues. By fluorescence histochemistry a lower-than-normal content of the noradrenaline (NA) transmitter was observed within the entire adrenergic neurone only 1 day after a single injection of NGF-antiserum (0.1 ml/g body weight). An atrophy of adrenergic nerve cell bodies and a disappearance of adrenergic nerve terminals were observed after 3 days, but the antiserum-induced effects did not appear maximally developed until 7 days after treatment. These fluorescence histochemical findings were paralleled by a gradual decrease of the endogenous NA levels in peripheral tissues and also of the weight of the SCG. A gradually proceeding restoration towards normal of the adrenergic innervation apparatus was observed fluorescence histochemically following a 5-day treatment with NGF-antiserum (0.1 ml/g body weight each dose), and after 6 weeks to 3 months a normal or close to normal fluorescence microscopical appearance was regained in the peripheral tissues and also in the SCG. These findings were parelleled by the results of the determinations of endogenous NA in peripheral tissues and by the results of weighing the SCG. We discuss some important differences between NGF-antiserum and 6-hydroxydopamine with respect to their mode of action on the mature sympathetic nervous system. Finally, we suggest that a decreased availability of NGF in a terminal area, due to an interference with endogenous NGF by NGF-antibodies, may temporarily result in an impaired function of the supplying adrenergic neurone, including a degeneration of nerve terminals.


Secondary effects of fetal eye damage in rats on intact central optic projections.

Lesions have been made damaging the whole or part of the retina of one eye in a series of rats from fetal days 16 through 20. The projection from the unlesioned eye when tested at postnatal times fills the visual centers contralateral to the lesioned eye either completely (after total eye lesions) or partially (after subtotal retinal lesions). In no case is the density or distribution of the aberrant ipsilateral retinotectal pathway greater than after comparable lesions made at birth. The suggestion is offered that a particular population of ganglion cells contributes the aberrant ipsilateral pathway and that the stimulus for the pathway is effective close to birth and depends on damaging optic axons from one eye some time before then.


Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine.

By means of single unit recording techniques it was found that a small systemically administered (intravenous) dose of the alpha-adrenergic agonist clonidine inhibited the spontaneous firing of brain norepinephrine (NE)-containing neurons in the locus coeruleus. In addition, the NE neurons were consistently inhibited by the direct (microiontophoretic) application of minute amounts of NE or clonidine. Intravenous clonidine also inhibited the firing of the great majority of (5-HT) neurons in the midbrain dorsal raphe nucleus. However, this action does not appearto be a direct one since clonidine (and NE) had relatively weak or variable effects when applied microiontophoretically to raphe neurons. The clonidine-induced depression of raphe firing may be secondary to an impairment in adrenergic transmission since (1) the depression could be reversed by the NE-releasing agents D- and L-amphetamine, (2) high doses of clonidine itself (which have been reported to have postsynaptic alpha-agonistic activity) reversed the depression produced by a low dose of clonidine and (3) prior destruction of NE neurons by 6-hydroxydopamine (7-12 days) rendered raphe neurons insensitive to the depressant effect of i.v. clonidine. Dopaminergic (substantia nigra, zona compacta) neurons did not respond to either low or high doses of clonidine. These results are consistent with previous data showing that clonidine decreases NE and 5-HT but not dopamine turnover. We conclude that systemically administered clonidine inhibits the firing of brain NE neurons by acting directly upon adrenergic receptors located on or near the soma of these neurons but that the concomitant inhibition of 5-HT neurons is an indirect effect (possibly secondary to an impairment in noracrenergic transmission).


Divalent cations: effects on post-synaptic pharmacology of invertebrate synapses.

(1) The effects of divalent cations (Ca++, Mg++, Sr++ and Co++) were studied on the post-synaptic responses of crustacean neuromuscular junctions and identified molluscan neurons to bath and iontophoretic application of putative transmitters. (2) The glutamate response of the crustacean muscle was parabolically dependent on [Ca++]0, while the ACh response of an identified molluscan neuron was inversely dependent on[Ca++]0. Elevated [Ca++]0 depressed both glutamate and ACh depolarizations in a concentration-dependent, reversible manner. Low concentrations of Co++ also depressed both depolarizations in a concentration-dependent, reversible manner. (3) Double-reciprocal plot analyses of the Ca++ and Co++ depressions indicate that these agents were apparently not acting to reduce the affinity of the receptor for the agonist. Elevated concentrations of both Ca++ and Co++ shifted the inversion potential of the ACh response in a hyperpolarizing direction, suggesting a preferential block of the receptor-coupled Na+ conductance. (4) Neither Ca++ nor Co++ depressed Cl- or K+-dependent responses coupled to the putative transmitters GABA, glutamate, dopamine or ACh. (5) The selective inhibition of the ACh and glutamate responses by the general anesthetic pentobarbital was examined as a function of[Ca++]0. Decreasing [Ca++]0 by 5-fold decreased the pentobarbital inhibition by about 50% while increasing [Ca++]0 by 5-fold produced an insignificant increase in the inhibition. (6) The data indicate that divalent cations, like general anesthetics, selectively depress post-synaptic excitatory responses that are primarily Na+-dependent. This selective depression by Ca++ could contribute to its anesthetic and anticonvulsant properties when present in elevated concentrations in the ventricular fluid. The mechanism by which divalent ions and general anesthetics selectively depress receptor-coupled conductances appear to be different: divalent ions preferentially attack the Na+ component while anesthetics block Na+ and K+ conductance equally (possibly by affecting the kinetics of the mechanism).


An autoradiographic study of the projections from the lateral geniculate body of the rat.

The projections from the lateral geniculate body of the rat were followed using the technique of autoradiography after injections of [3H] proline into the dorsal and/or ventral nuclei of this diencephalic structure. Autoradiographs were prepared from either frozen or paraffin coronal sections through the rat brain. The dorsal nucleus of the lateral geniculate projected via the optic radiation to area 17 of the cerebral cortex. There was also a slight extension of label into the zones of transition between areas 17, 18 and 18a. The distribution of silver grains in the various layers of the cerebral cortex was analyzed quantitatively and showed a major peak of labeling in layer IV with minor peaks in outer layer I and the upper half and lowest part of layer VI. The significance of these peaks is discussed in respect to the distribution of geniculocortical terminals in other mammalian species. The ventral nucleus of the lateral geniculate body had 5 major projections to brain stem structures both ipsilateral and contralateral to the injected nucleus. There were two dorsomedial projections: (1) a projection to the superior colliculus which terminated mainly in the medial third of the stratum opticum, and (2) a large projection via the superior thalamic radiation which terminated in the ipsilateral pretectal area; a continuation of this projection passed through the posterior commissure to attain the contralateral pretectal area. The three ventromedial projections involved: (1) a geniculopontine tract which coursed through the basis pedunculi and the lateral lemniscus to terminate in the dorsomedial and dorsolateral parts of the pons after giving terminals to the lateral terminal nucleus of the accessory optic tract, (2) a projection via Meynert's commissure to the suprachiasmatic nuclei of both sides of the brain stem as well as to the contralateral ventral lateral geniculate nucleus and lateral terminal nucleus of the accessory optic tract, and (3) a medial projection to the ipsilateral zona incerta. The results obtained in these experiments are contrasted with other data on the rat's central visual connections to illustrate the importance of these connections in many subcortical visual functions.


Muscle receptors with group IV afferent fibres responding to application of bradykinin.

In 60 anaesthetized cats the discharge characteristics of single group IV afferent fibres from skeletal muscle at rest, during local mechanical stimulation of the muscle, and in response to injections of bradykinin have been studied. 250 group IV fibres from the gastrocnemius-soleus muscle have been identified by their conduction velocity. Of these fibres 121 have been recorded from the dorsal root and 129 from the muscle nerve. A resting discharge was present in 52% of the dorsal root fibres and in 57% of the fibres recorded peripherally. Out of 203 units subjected to local mechanical stimulation of the muscle 9 responded to light, innocuous pressure; 129 fibres required strong, presumably noxious stimulation to be excited. The rest of 65 fibres could not be activated by the mechanical stimuli used. Intraarterial injection of bradykinin excited 88 out of 184 group IV fibres. Intramuscular injection of bradykinin was also found to be an effective stimulus. External application of bradykinin to the intact and to the dissected muscle nerve regularly had no excitatory effect on fibres being sensitive to intraarterially administered bradykinin. Injections of vasoactive drugs (nylidrine, noradrenaline) failed to affect the activity of group IV fibres responding to bradykinin. It is concluded that bradykinin is a potent stimulant for the intramuscular endings of afferent group IV fibres; the effective concentration lying within the range observed in pathologically altered tissues. This sensitivity to bradykinin together with a high mechanical threshold suggests that muscular group IV afferent units participate in the reception of muscular pain.


Elaboration of a conditioned reflex in a single experiment with simultaneous recording of neural activity.

In 18 of 20 experiments with click CS, and in 5 of 10 experiments with flash CS, we have elaborated a conditioned EMG response in a single session (less than 60 pairings). The US was direct electrical stimulation of the rabbit's motor cortex that evoked a movement of the forelimb. Electrical stimulation of the lateral hypothalamus was used as reinforcement. Parameters for this reinforcement were chosen to evoke a feeding reaction or self-stimulation in the freely behaving animal. The elaborated EMG response satisfied most of the required characteristics of a conditioned reflex. These included spontaneous recovery after extinction, savings of long duration, specificity to stimulus pairing, and weak efferent and afferent generalization. In most experiments with click CS, the elaborated phasic response had an amplitude of 0.1-6 mV with a latency of 12-16 msec. In form and latency the conditioned response was similar to the unconditioned startle reaction of the same animal under chloralose anesthesia, or to its unanesthetized response to a loud sound. However, the conditioned response differed from the startle reaction in that it was localized. Extracellular recordings of 2-5 neurons were simultaneously made from sensory motor cortex near the point at which the US was applied. In 7 experiments 17 neurons were followed through the entire cycle of elaboration and extinction of the conditioned response. Seven neurons showed a statistically significant (P less than 0.05) increase of the response to CS during conditioning. Latencies were 20-140 msec. Interactions between neurons were studied by computing cross-correlograms and joint PST scatter diagrams. These measures were less informative than we had hoped because of the low level of spontaneous and evoked activity, and because of the small numbers of stimulus presentations that were needed for elaboration and extinction of the conditioned reflex. In isolated presentations of the CS after elaboration of the CR, we sometimes observed neural responses to click with a latency less than 6 msec. We propose that at least one of the pathways involved in the localized conditioned startle reflex reported here goes through the sensory motor cortex.


Behavioral changes in 2-month-old rats following prenatal exposure to antibodies against synaptic membranes.

Two-month-old male offspring of rats injected intravenously on day 19 of gestation with antiserum to synaptic membrane fraction showed marked behavioral deficits on a DRL (differential reinforcement at low rates) training paradigm. These behavioral deficits included perseveration, slow acquisition rates, and poor retention. Offspring of pregnant rats injected with antiserum to galactocerebroside or isotonic saline did not show these behavioral effects.


Tolerance of protein and lipid synthesis to mild hyperphenylalaninemia in developing rat brain.

Chronic injection of low levels (1.5-2.5 mg/g body wt./day for 6-8 days) of L-phenylalanine which did not significantly affect body weight or brain to body weight ratios also did not significantly affect myelin accumulation or synthesis in developing rat brain. A single injection of L-phenylalanine (1 mg/g body wt.) significantly reduced in vivo protein synthesis by 10% in cerebral cortex of 7-day-old rats. Although transient reductions in protein synthesis are produced during low level daily injections, cumulative effects are not expressed in significant reductions in brain to body growth ratios. It is concluded that myelination is significantly inhibited in hyperphenylalaninemia only when other parameters of brain growth and development are affected.


A study of so-called 'retrograde fine-grain' degeneration in the thalamus.

Following lesions of the neocortex a uniform dust-like silver deposit may appear in certain thalamic nuclei stained with the Nauta or Fink-Heimer methods. Because this deposit lacks the characteristic morphology of axons undergoing Wallerian degeneration and often appears in regions of retrograde cell degeneration, it has been interpreted as a retrograde reaction7,15. The present study, however, employing reduced silver and autoradiographic techniques, suggests that this silver deposit is an anterograde rather than a retrograde phenomenon. In cats with lesions of the posterior cingulate and presubicular cortex the Fink-Heimer method showed the fine-grain silver deposit in the lateralis dorsalis (LD) and the anteroventral nucleus (AV). The 'dust' was densest in the dorsomedial zones of the anteroventral nucleus. After the survival times used (6-8 days) no retrograde perikaryal changes were seen in these nuclei. In other cats, 3 weeks after injections of radioactive proline in the posterior cingulate cortex, the distribution of the label in the LD and AV nuclei was almost identical to the distribution of the 'dust' in the Fink-Heimer sections. Since the autoradiographic method reveals anterograde transport, it appears that both methods are demonstrating corticofugal axons. Thus it is suggested that the 'fine-grain' degeneration arises from an anterograde not a retrograde reaction.


Structural organization of 'callosal' OBg in human corpus callosum agenesis.

The structural organization of the 'callosal' OBg was studied in Nissl and Weil stained sections of two human brains completely lacking in the corpus callosum. OBg of the normal brain contains a set of distinctive large pyramidal cells in layer III. By contrast, in the brains with absence of the corpus callosum, layer III of OBg contained a slightly reduced number of smaller pyramidal cells than normal, and the characteristic large pyramidal cells were scarsely detectable. Other layers of OBg were not definitely changed. Furthermore, 'acallosal' striate cortex revealed no specific changes. From these observations, it was suggested that the large layer III pyramids of OBg might be closely related to callosal connections.


Catecholamines in mutant mouse cerebellum: fluorescence microscopic and chemical studies.

Catecholamine-containing fibers have been examined in the cerebella of normal and hypocerebellar mutant mice using Falck-Hillarp and glyoxylic acid histofluorescence techniques. The amounts of norepinephrine and dopamine were also determined chemically in the same mutants. Green fluorescent fibers in cerebella of normal mice are similar in size and distribution to those described in the rat. Weanling and adult weaver, reeler and staggerer mice all manifest greatly increased specific catecholamine fluorescence per unit area in cerebellar cortex, but the patterns of fluorescent fibers are distinctive. In weaver, the fibers are of normal diameter, surround Purkinje cell bodies and appear to climb along major dendrites. In reeler, similar fibers form a plexus around cortical and non-cortical Purkinje cells; relatively normal fluorescent fiber patterns are present in well-organized cortical regions, while stouter disoriented fibers course through the shallow molecular layer in disorganized regions. Staggerer cerebellar cortex exhibits the greatest fluorescence with most terminals appearing as matted tangles adjacent cell bodies. Clearly defined fibers, however, can be distinguished in the molecular layer running perpendicular to the pia or for long distances in the coronal plane parallel to the pia. The major catecholamine determined chemically is norepinephrine. Reeler cerebella contain normal absolute levels and a doubled concentration of norepinephrine. In contrast, and despite the fluorescence findings, the total norepinephrine content of weaver and staggerer cerebella is significantly reduced and concentrations are not significantly different from normal.


The dependence of the blood to brain passage of radioactive sodium on blood pressure and temperature.

Brain sodium uptake (BSU) was calculated from estimated radioactivities of brain and blood, collected from rats which were given [24Na]sodium chloride 30 min and [22Na]sodium chloride 1 min before killing. The calculated BSU values, when plotted against the average blood pressure of the animal during the survival time of 30 min, showed a linear dependence of BSU on blood pressure. In another series of animals, in which in addition to variation of the blood pressure as in the former series, the brain was cooled to 15 degrees C, the resulting regression line showed the same slope, but a significantly lower intercept than at normal temperature. The results indicate the existence of a blood pressure-dependent component of sodium passage, reflecting the exchange of fluid at the blood-brain interface as governed by the Starling hypothesis, and an additional component which being temperature dependent, presumably constitutes an active transport mechanism.


Magnocellular nuclei of the basal forebrain project to neocortex, brain stem, and olfactory bulb. Review of some functional correlates.

Horseradish peroxidase was injected into the neocortex of squirrel monkeys, rats, tree shrews and one opossum, in the brain stem of one squirrel monkey and rats, and in the olfactory bulb, the corpus vitreum or the vascular system of rats. Following the cortical, brain stem and bulbar injections labeled cells were found (predominatly ipsilaterally) in the magnocellular nuclei of the basal forebrain: nucleus of the diagonal band, the magnocellular preoptic nucleus and nucleus basalis. These nuclei may, therefore, be classified together hodologically as well as cytologically and histochemically. The number of labeled cells was proportional to the size of the injected region. It is uncertain whether the same cells project to all target regions. Large labeled cells were found scattered among pallidal and entopeduncular neurons in rats with cortical or brain stem injections. These neurons may be the equivalent to the nucleus basalis in other species.


Responses of pontocerebellar neurones to stimulation of the parietal association and the frontal motor cortices.

The corticopontine projections from the parietal association cortex (the anterior portion of the middle suprasylvian gyrus) were electrophysiologically investigated and compared with those from the frontal motor cortex (the anterior sigmoid gyrus) in cats under light Nembutal anaesthesia. It was indicated by field potential study that the pontine nucleus (PN) neurones receive a significant amount of the direct corticopontine fibres from both the parietal and frontal cortical areas. In extracellular unitary study, out of 107 PN neurones identified by antidromic activation due to the brachium pontis stimulation, 33 responded with firings to stimulation of the parietal association area and 64 to the frontal motor area. Only 10 of them were excited by both parietal and frontal stimulations, but they were not estimated to receive the dual monosynaptic projections from both cortical areas. There were found data suggesting that the pontocerebellar neurones with faster conduction velocities respond at shorter latencies to the cortical stimulation and those with slower conduction velocities fire at longer latencies on the cortical stimulation. No remarkable difference was observed between the topographical localization of the PN neurones receiving the projection fibres from the parietal association and the frontal motor cortical areas. It was concluded that a vast majority of the pontocerebellar neurones possibly receive monosynaptic contacts differentially with the corticopontine fibres originating from the parietal association and the frontal motor areas.


Rhythmic firing of Deiters' neurons and synchronization by cerebellar inhibition in lidocaine-treated cats.

Cerebellar inhibition of spontaneous or homocysteic acid-induced activity of dorsal Deiters' neurons was studied in cats anesthetized with chloralose-urethane. Following intravenous lidocaine (5-10 mg/kg), cerebellar inhibition was not reduced but postinhibitory peaks (PIPs) appeared in the poststimulus histograms. The number of PIPs increased as variability in firing rate decreased after lidocaine. The frequency of PIPs observed in the histograms approximated the monitored firing rates of the cells. The peaks observed in autocorrelograms constructed after lidocaine had the same frequency, structure and variability as the PIPs. In 'dot diagrams', only one spike per corresponding PIP was observed. Similar PIPs were observed in poststimulus histograms constructed during inhibition of crayfish stretch receptor neurons which fired regularly in the absence of lidocaine. These studies indicate that the postinhibitory peaks and silent periods were due to synchronized firing of Deiters' neurons induced by cerebellar inhibition, which was detectable only after lidocaine regularized the firing of Deiters' neurons.


Tryptophan metabolism in developing chick brain.

The normal patterns of the occurrence of tryptophan, 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and monoamine oxidase (MAO) activity in chick brain during development were investigated. Tryptophan level in the brain on the 7th day of embryonic development was rather high and decreased gradually until the 17th day, but increased markedly from the 17th day to hatching, then increased slightly from hatching to the 14th day after hatching. 5-HT, 5-HIAA and MAO were already present on the 7th day of incubation, increased gradually with a temporary peak on the 14th day, and increased remarkably from the 17th day to hatching, after which they reached a plateau and remained unchanged from the 7th to the 14th day after hatching. Since the increase between the 17th day and hatching was observed in the patterns of tryptophan, 5-HT, 5-HIAA and MAO activity, the critical period of tryptophan metabolism in the brain during development seems to exist in this period. In order to examine the formation of 5-HT from tryptophan in vivo, newly hatched chicks and chicks 2 weeks after hatching were injected intraperitoneally with L-tryptophan and brain 5-HT was measured. 5-HT was increased markedly, even in newborn chick brain. This might indicate that the activity of tryptophan hydroxylase in newborn chick brain would be as high as that in adult chick brain.


Anatomical organization of retinotectal afferents in the cat: an autoradiographic study.

The distribution of retinotectal afferents has been studied by autoradiography in 4 adult cats. The findings suggest that crossed and uncrossed retinal fibers terminate in a striking cluster-and-sheet pattern that varies systematically with respect to the retinotopic map of the colliculus. Following unilateral eye injection, labelling was most pronounced in the contralateral colliculus but a suprising volume of label appeared on the ipsilateral side in all cases in the form of dense clumps of silver grains separated by sparsely labelled zones. The contralateral projection appeared densest in the most superficial of the 3 laminae of the stratum griseum superficiale; appreciable labelling was present also in the middle lamina at all survival times used (23-72 h). Near the area centralis representation labelling in both contralateral tiers weakened markedly and local gaps appeared densest in the more dorsal band. Elsewhere, labelling in this dorsal band was generally dense, though sharply interrupted at the optic disc representation and in a curious, elongated lateral zone at mid-collicular levels. In the caudal half of the binocular zone rarefications or 'holes', about 200 mum wide, appeared in the more ventral tier between more densely labelled zones of roughly similar width. On the ipsilateral side, labelling was sparse or absent at the rostral and caudal collicular poles, and was also weak in the region of the area centralis representation save for occasional very superficial grain-clusters. Farther caudally, however, prominent approx. 200 mum wide 'puffs' of label marked the middle lamina of the superficial gray layer. The puffs were most regular in shape in the caudal half of the ipsilateral zone and these were spaced at roughly 200 mum intervals. Puffs lateral to the horizontal meridian representation tended to lie more dorsal than those medial to this line and some of the most lateral puffs at mid-collicular levels invaded the upper lamina of the superficial gray layer. The optic disc representation was marked by a column of label extending through the upper and middle laminae. Similar experiments in cat fetuses suggest that these staggered--and possible even complementary--patterns of crossed and uncrossed retinotectal projection are innate: ipsilateral 'puffs' of labelling and contralateral 'holes' appear in the superior colliculus at least one week before term, as does the ipsilateral filling-in and contralateral gap at the optic disc representation. These observations suggest that in the cat, a vertical as well as horizontal organization may characterize the superficial layers of the superior colliculus. The additional finding of a similar, interrupted puff-like pattern of labelling in the stratum griseum medium following injections in the region of the substantia nigra makes it likely that a somewhat comparable cluster-and-sheet organization may exist also in the deep collicular layers.


Interaction of cerebellar mutant genes. II. Mice doubly affected by 'reeler' and 'weaver' conditions.

An an extension of a study of the mode of ineraction of mutant genes that affect motor activities and cerebellar cytoarchitectonics, mice doubly affected by both the 'reeler' and 'weaver' conditions were produced. The cerebellum of the double mutant showed both reeler and weaver characteristics. Anomalies present in both mutants were greatly accentuated in the double mutant. In addition to the paucity of fissures and general cerebellar disorganization observed in reeler and the extreme scarcity of granule cells seen in weaver, double mutants showed an additional decrease in the cerebellar size and the molecular layer, and a further loss of external granule cells. These observations were interpreted as indicating that the effects of the reeler and weaver genes upon altering the cytoarchitectonics of the cerebellum were additive.


GABA metabolism and cerebral protein synthesis.

Glutamate decarboxylase (GAD) activity and [14C)leucine incorporation into brain protein in vivo were measured in mice injected with L-glutamic acid-gamma-hydrazide and 60 min later with pyridoxal-5'-phosphate; this combined treatment produces a decrease in GAD activity and an increase in GABA levels. Under such conditions, protein synthesis was inhibited to the same extent as GAD activity. A parellelism between the decrease in GAD activity and that in protein synthesis was also observed in brain cortex slices treated with GAD inhibitors. This treatment did  not affect leucine incorporation into protein in liver slices. The results support the previously suggested hypothesis that a certain pool of GABA may have a role in the regulation of protein synthesis in brain, and further suggest that the synthesis of GABA may be more important in this respect than its total concentration.


Effects of nerve growth factor administration of N-ethyl-N-nitrosourea carcinogenesis.

We attempted to determine whether the sympathetic nervous system in rodents is susceptible to co-carcinogenesis, employing murine salivary nerve growth factor (NGF) as a co-carcinogenic agent. NGF had no co-carcinogenic effect with either methylcholanthrene or ethylnitrosourea (ENU) on the sympathetic nervous system of the mouse, whether administered transplacentally, postnatally, or both transplacentally and postnatally. At a dose of ENU of 30 mug/g body weight, NGF did not shorten the latent period for tumor induction of BD-IX rats. In contrast, a 25% reduction in latent period was brough about by NGF for tumor appearance in BD-IX rats receiving 90 mug/g ENU. In both cases the frequency of urogenital tumors in rats was increased as a result of NGF administration, at the apparent expense of neural tumors.


The effect of trauma on the formaldehyde-induced fluorescence of noradrenaline in the hypothalamus and brain stem of the rat.

Noradrenaline (NA) fluorescence in the hypothalamus and brain stem of the rat has been examined during and up to 1.5 h after a 4-h period of bilateral hind-limb ischaemia. A decrease in the fluorescence of the NA terminals in the n. supraopticus and n. paraventricularis was seen during the second half of the period of limb ischaemia and became more marked 1.5 h after removal of the tourniquets. Changes in the preoptic-anterior hypothalamic (POAH) area and n. dorsomedialis occurred more slowly and depletion was best seen after the limb ischaemia. Measurements of the fluorescence with a microphotometer confirmed the changes seen in the POAH area, the n. supraopticus and the n. dorsomedialis 1.5 h after 4 h bilateral hind-limb ischaemia but suggested that the visual gradings of changes in the n. paraventricularis, which normally has a high NA content, could be unreliable. No changes were seen at any of the times studied in the ventral part of n. striae terminalis. The cells of origin of the affected terminals could not be identified since no changes were detected in the fluorescence of the cells in the NA nuclei of the brain stem. alpha-Methyl-p-typrosine, given at the start of the experiment to inhibit tyrosine hydroxylase, reduced the fluorescence  of these cells but still no difference could be discerned between those in the control and injured rats. These results confirm the previous chemical findings of a fall in the NA concentration in the hypothalamus after injury with little change in that of brain stem. The results are discussed in relation to the effects of the injury on the homoeostatic functions of the hypothalamus.


Incorporation of sialic acid into gangliosides and glycoproteins of the optic pathway following an intraocular injection of [N-3H]acetylmannosamine in the chicken.

Following an intraocular (i.o.) injection of [N-3H]acetylmannosamine, low molecular soluble radioactive label is distributed rapidly along the optic pathway.  At the same time glycoproteins and gangliosides were found radioactively labelled in the distal parts of the optic pathway. Negligible amounts of radioactivity were incorporated into the same structures via the blood. The present data confirm, that glycoproteins are transferred in the retinal ganglion cells by a rapid axonal transport mechanism towards the nerve endings. Unlike glycoproteins labelled gangliosides accumulated in the optic nerves up to 4 days after the precursor injection. Simultaneously radioactive material, soluble in TCA/PTA, disappeared from the optic nerves. The specific radioactivities (disint./min/mug NeuNAc) of the single ganglioside fractions of the optic lobes, which contain the nerve endings of the retinal ganglion cells, differed considerably. Especially one fraction, moving on TLC plates identically to 'GD1a', was up to 20 times higher labelled than the other gangliosides. After an intracerebral injection of the same precursor, radioactivity was incorporated into the ganglioside fractions of the optic lobes to the same extent.


Cysteine oxidase in brain.

Cysteine oxidase, which catalyzes the oxidation of cysteine to the neuroexcitatory and neurotoxic compounds cysteine sulfinic and sulfonic acids, previously has not been studied successfully in brain. Here we report optimal conditions for measuring cysteine oxidase activity in rat brain, describe its regional and subcellular distribution and compare activity during several stages of development. Employing NAD+ as cofactor, substantial activity was measurable in whole brain homogenate, 70% of which was localized to the microsomal fraction. Appreciable activity was present throughout brain with a 3-fold difference being detected between pons-medulla and cerebral cortex, the regions with the highest and lowest levels respectively. Cysteine oxidase activity in adult rat brain was approximately 5 times higher than that measured at birth. For the first 6 days of life there was very little change in activity; thereafter, a steady increase occurred with adult levels being reached between the 25th and 50th days.


Self-stimulation and noradrenaline: evidence that inhibition of synthesis abolishes responding only if the "reserve" pool is dispersed first.

Although noradrenaline (NA) is thought to play a critical role in electrical self-stimulation, suppression of NA synthesis by injection of the dopamine-beta-hydroxylase inhibitor, FLA-63 (Hässle) (25 mg/kg), had little or no effect on response rates. But 3 or 5 days after prior reserpinisation, FLA-63 in the same dosage suppressed or profoundly depressed self-stimulation without eliciting signs of general incapacity. Suppression of self-stimulation could be reversed by intraventricular injection of NA, indicating that the depressant effect depended specifically on NA depletion. These findings support the view that NA may play a necessary role in self-stimulation and indicate that the NA available for this purpose included intraneuronal NA in a reserpine-sensitive reserve pool.


Effect of stimulation of prefrontal cortex and amygdala on diencephalic neurons.

Extracellular unit recordings were obtained from the nucleus medialis dorsalis (MD) and adjacent thalamic nuclei and from the hypothalamus of anesthetized cats. Electrical stimulation of the prefrontal cortex produces suppression of unit activity and rebound excitation in MD. In addition antidromic and short latency excitation was found which was followed by prolonged suppression of firing. This suppression was also followed by a strong postinihibitory activation of unit firing which was, in some cases, again followed by a second phase of inhibition. Amygdala stimulation produced similar results except that antidromic responses were found only in the intralaminar nuclei, and short-latency transynaptic excitation occurred somewhat later. The results are in consonance with the hypothesis that the same interneuronal mechanism is engaged by both afferent sources to MD. In the hypothalamus, fewer units responded to cortical and amygdalar stimulation and alternating sequences of excitation-inhibition-excitation were not found.


Patterns of cortical projection to hindlimb muscle motoneurone pools.

This study was undertaken to examine the organization of the hindlimb area of the motor cortex. Two specific questions were posed. The first was: are the cortical neurones which control the excitability of a given motoneurone pool localized in a small zone of corjex or are they diffuse? The second question was: does microstimulation in the hindlimb area of the motor cortex activate spinal motoneurones in a reciprocal fashion, i.e., is cortically elicited facilitation of a muscle accompanied by inhibition of the antagonist? Intracortical microstimulation was used to condition monosynaptic reflexes of the cat hindlimb to study the organization of a cortical projection to lumbar motoneurone pools. Cortical neurones which produced facilitation or inhibition of a given monosynaptic reflex were localized within a small zone of the cortex. Facilitatory and inhibitory effective zones were found to have similar shape and size. Intracortical microstimulation elicited facilitation or inhibition of individual monosynaptic reflexes without eliciting reciprocal effects on the antagonists. The pyramidal tract was shown to play an important role in the mediation of cortically elicited facilitation as well as inhibition of the monosynaptic reflexes in the lumbar cord.


Response patterns to noxious and non-noxious stimuli in rostral trigeminal relay nuclei.

Postimulus time histogram analysis of second-order neuron responses in rostral trigeminal relay nuclei of cat demonstrated characteristic firing patterns after noxious (tooth pulp) and non-noxious (tooth tap) stimuli. The response to noxious stimulation was prolonged and frequently bimodal while the response to non-noxious stimulation was brief. The same neurons were fired by electrical stimuli applied directly to nucleus caudalis but with longer latencies suggesting a contributory role of nucleus caudalis to the characteristic prolonged bimodal response pattern to noxious stimuli. Interacting noxious and non-noxious stimuli using condition-test sequences demonstrated further stimulus mode-related changes in firing patterns. Electrical conditioning stimuli in nucleus caudalis reduced some responses while strychnine sulfate applied into nucleus caudalis augmented the responses evoked in rostral nuclei by both noxious and non-noxious peripheral stimuli. Nucleus caudalis appeared to contain elements which may modulate activity in rostral trigeminal nuclei by either augmenting or reducing specific firing patterns of second-order neurons in rostral relay nuclei.


Slow potentials of the turtle olfactory bulb in response to odor stimulation of the nose.

Odor stimulation of the nose in the box turtle and the gopher tortoise produced a characteristic series of slow potentials in the olfactory bulb which were referred to as the odor evoked response. When recorded with direct coupling, the odor evoked response had 3 components: wave I, a short duration monophasic event; wave II, a long duration variation in the DC potential; and wave III, an oscillatory potential superimposed on wave II. Waves I and II were negative at bulbar surfaces receiving olfactory input and positive deep within the bulb. This series of potentials could be evoked by 3 methods of odor stimulation: (1) large puffs delivered from odorant test bottles, (2) small puffs delivered from a syringe and (3) continuous flow with concentration and nasal flow rate parameters controlled by an olfactometer. When the odor evoked response was recorded at a bulbar locus, these potentials were seen in response to each stimulation and the amplitudes of each wave were reproducible with the same stimulus. The amplitudes of the 3 waves were compared in the gopher tortoise and differed with the 3 odorants tested--high purity geraniol, technical grade geraniol and amyl acetate. Odorant concentration also directly affected the response amplitudes of all 3 wave components. The amplitudes of waves I and III markedly decreased with closely spaced stimulations recovering to near the initial values when the interstimulus interval was increased severalfold. This series of sensory evoked potentials is considered to reflect the processing of odor information from the olfactory receptors by the olfactory bulb.


The effect of passive eye movement on unit discharge in the superior colliculus of the cat.

The effects of passive eye rotation on unit discharge in the superior colliculus has been examined in the chloralose anaesthetized cat. Providing that velocity exceeded 50 degrees/sec, passive eye movement led to brief-burst discharges in the superior colliculus. This discharge occurred as the eye traversed a fixed point. The displacement of this point from the primary position has been defined as the displacement threshold for that unit. Displacement thresholds range from 3 to 30 degrees and are consistent over a wide range of velocities but become larger at the velocity threshold for the unit. Conduction times to the superior colliculus ranged from 7 to 108 msec.


Purkinje cell dendritic alterations after transient developmental injury of theexternal granular layer.

To examine the influence of granule cell axons on morphogenesis of their major synaptic target, the Purkinje cell dendrites, a transient injury of the external granular layer of developing rat cerebellum was induced by injecting 10 mg/kg methylazoxymethanol acetate on postnatal days 1, 2, 3 and 4. The antiproliferative action of the drug resulted in a diminution of the mitotic population which slowed the expansion of the internal granular and molecular layers. This was followed by a reconstitution of a thicker than normal external granular layer and a late phase of extensive growth. Perturbations of Purkinje cell dendritic morphology induced by this altered timing of granule cell accumulation were studied with Golgi-Cox impregnation techniques. Systematic observation were made of a number of defined abnormalities of Purkinje cells which included somas positioned below the normal monolayer; elongated dendrites; multiple somatic dendrites; S-shaped dendrites; dendrites disoriented away from the radial direction; and portions of dendrites below the soma of origin. The results indicated that most of these 'abnormalities' occur to a small extent in normal cerebellum but that these experimental conditions induced a bias in favor of their appearance. Some dendritic abnormalities, i.e., dendrites tilted out of the sagittal plane, dendrites directed toward the white matter, and apical dendrites growing vertically between cells of the external granular layer, were not noted in normal cerebellum and we attribute these particular changes to unique developmental possibilities occuring only after a more or less severe injury. This analysis of bias in dendritic morphology subsequent to subtle developmental injury provides informat on on processes of normal development and on the genesis of phylogenetic variants of Purkinje cell morphology.


Time-dependent changes in commissural field potentials in the dentate gyrus following lesions of the entorhinal cortex in adult rats.

Previous neuroanatomical work has shown that lesions of the entorhinal cortex in adult rats cause the commissural projections to spread from their normally restricted locus in the inner molecular layer approximately 40-50 mum into the outer molecular layer (that is, into the zone deafferented by the lesion). In the present study we measured the effects of the entorhinal lesion on the distribution of short-latency potentials elicited by commissural stimulation in the molecular layer. Studies with animals tested at various times after the lesion and with a preparation that permitted recording from the same rat at several post-lesion intervals both indicated that the commissural response spread 100-150 mum towards the deafferented outer molecular layer, while the maximum response spread 50-100 mum. These effects were first detectable by 9 days after the lesion and were fully developed by 15 days post-lesion. These findings suggest that the growth of the commissural system seen after entorhinal lesions results in the rapid formation of functional terminals and are discussed in relationship to the behavioral consequences of brain lesions.


In vivo effects of glycine on retinal ultrastructure and averaged electroretinogram.

Glycine, when injected intravitreally, has an inhibitory action on the electroretinogram (ERG) of the rabbit resulting in a transient loss of the oscillatory potentials of the b-wave. This inhibitory action is reversible within 24 h after glycine injection. In autoradiographs, after [3H] glycine administration, the radioactive label is mainly found over the inner nuclear layer (INL) and inner plexiform layer (IPL) without predilection of specific cell types and/or synapses. Electron microscopy reveals cytopathological changes in amacrine cells, in particular their cell membranes. These changes are conspicuous especially 1-2 h after the injection and the cells become normal again within 24 h. It is concluded that glycine has an inhibitory action upon the rabbit ERG in vivo. This action, on the basis of our morphological observations under our experimental conditions, may be due to an overall somatic membrane action rather than to an action as inhibitory neurotransmitter at the synaptic level. The reversible cellular lesions of amacrine cells after glycine administration with a concomitant, transient loss of oscillatory potentials (OP) supports the hypothesis that the cellular origin of OP is situated in amacrine cells.


Further evidence for cholinergic habenulo-interpeduncular neurons: pharmacologic and functional characteristics.

Placement of high frequency lesions in the medial habenular area results in a large depletion of acetylcholine (ACh) levels, choline acetyltransferase (ChAc) activity, and high affinity choline uptake in the interpeduncular nucleus area (IPN) at 1, 3 and 7 days post-lesion. Areas adjacent to the IPN did not have a reduction in ChAc activity. The reduction in high affinity choline uptake was selective in that there was no change in the uptake of L-[3H]tyrosine or L-[3H]glutamic acid. Unlike the cholinergic septal-hippocampal neurons, there was no rise in ACh levels in the IPN 1 h after placement of lesion, or 30 min after administration of pentobarbital. While the IPN probably has a much denser cholinergic innervation than the hippocampus (as evidenced by much higher ACh levels, ChAc activity and choline uptake levels), it has only one-fourth as many [3H]QNB binding sites (a measure of cholinergic muscarinic receptors). This, some of the habenulo-interpeduncular neurons are probably cholinergic, and they may have pharmacologic and functional differences compared to the septal-hippocampal neurons.


Interaction of glycine with brain-cortex membrane fragments: kinetics, ionic requirements and amino acid specificity.

The binding of [14]glycine to rat brain-cortex membrane fragments, incubated in artificial cerebrospinal fluid, was studied in vitro by means of a nitrocellulose filter assay. The membranes were obtained from the large granule fraction (P2) of a brain-cortex homogenate, which was osmotically shocked and the larger membrane fractions isolated by centrifugation. Initial binding velocity lasts for about 2 min and equilibrium is reached in 10 min. The binding reaction is reversible, and [14C]glycine can de displaced by an excess of [12C]glycine or by dilution. Binding is strongly dependent on temperature and on sodium ions. The latter activate the binding process in a cooperative manner. Two binding components may be discerned: one with high affinity for glycine (Km = 40 +/- 8 muM) and one with lower affinity. Lowering the sodium concentration to 60 mM increases the Km of the high-affinity component to 59 muM, with no change in Vmax. The bound product is, after incubating the membranes at 37 degrees C for 10 min, 85% glycine. A large fraction of it may released by hypo-osmotic media.


Rapid transport of proteins in the sonic motor system of the toadfish.

A pure cholinergic, motor system of a marine fish has been utilized to study the kinetics and characteristics of proteins rapidly transported from the sonic motor nucleus to the musculature enveloping the swim bladder. Following microinjection of [3H]leucine, [3H]lysine, [35S]methionine, or [3H]fucose into the nucleus a wave of radioactivity was observed moving along the sonic motor nerves with an apparent rate of 96-120 mm/day. Analysis of the rapidly transported methionine-labeled protein using SDS gel electrophoresis revealed at least 9 major peaks of activity. Eight of these proteins were found to incorporate fucose, suggesting that most of the rapidly transported material consists of glycoproteins. These results are consistent with the previously suggested hypothesis relating the function of rapid transport to synaptic vesicles and the maintenance of pre-synaptic terminal membranes.


Circling behaviour produced by unilateral lesions in the region of the locus coeruleus in rats.

Rats with unilateral lesions in the region of the locus coeruleus circled tightly to the opposite side when given apomorphine or amphetamine. This turning behaviour was transient and disappeared within some 30 days after surgery. It was seen most obviously in animals with severe unilateral destruction of the locus coeruleus, which caused on average a 55% reduction in the level of noradrenaline in the ipsilateral cerebral cortex. It was not marked in animals with partial unilateral lesions of the locus coeruleus, which caused only an average fall in cortical noradrenaline of 22%. It was not seen in sham operated animals or animals in which lesions were placed into adjacent structures such as the cerebellum above, superior cerebellar peduncle laterally, and brain stem ventrally. A clue to the mechanism of this phenomenon may lie in the observation that dopamine in the ipsilateral striatum was increased 5 days after operation, when circling occurred, but had returned to normal by 30 days when circling had ceased. It is suggested that the lesion causes a reduction in impulse traffic in the ipsilateral nigrostriatal pathway, and that circling is due to preferential stimulation of the ipsilateral striatal dopamine receptors by both drugs; apomorphine directly, amphetamine by release of endogenous dopamine.


Effect of activation and adaptation on the sensitivity of slowly adapting cutaneous mechanoreceptors.

The effect of adaptation on the sensitivity of type I and type II cutaneous mechanoreceptors was evaluated with test stimuli applied before, during and after a persistent indentation (offset) of the skin. It was found that the offset initially lowered the threshold to both high (100-200 Hz) and low (1-20 Hz) frequency sinusoidal stimuli, as compared with the preoffset condition. This lowered threshold increased for both stimuli as adaptation progressed. When adaptation was nearly complete, there was an appreciable residual reduction of threshold, as compared with preoffset values, for the low frequency stimuli but not for high frequency stimuli. For a time after the offset was removed, the threshold was increased above preoffset levels for both stimuli. Suprathreshold ramp displacements superimposed on an offset caused higher maximal frequencies and a larger change in frequency than before the offset was applied. This difference often was considerable (20-40 impulses/sec) even though the discharge produced by the offset had adapted to only 2-4 impulses/sec above the preoffset level. Shortly after removal of the offset, the ramp responses typically were less than before the offset was applied. Thus, these receptors are not "reset" to the preoffset condition by adaptation nor is their sensitivity reduced. On the contrary, they respond more vigorously to superimposed stimuli except for near threshold displacements that are brief and rapid.


Anatomical, physiological and biochemical studies of the cerebellum from mutant mice. I. Electrophysiological analysis of cerebellar cortical neurons in the staggerer mouse.

An electrophysiological analysis of cerebellar cortical neurons was performed in staggerer mutant mice on postnatal days 18 to 22, and data were compared with cerebellar activities in normal mice of the same age. Bioelectrical activities were elicited through local (LOC) and juxtafastigial (JF) stimulation. In staggerer mice, parallel fibers (PF) exhibited no major alterations, i.e. they conducted impulses and they activated most of the cerebellar cortical units encountered, but some minor differences existed in comparison with normal mice, i.e. their excitability was reduced, as tested by their refractory period and conduction velocity. On the contrary, Purkinje cell (PC) responses presented marked abnormalities. (1) Depth profiles during antidromic invasion of PC and unitary antidromic responses revealed a lower safety factor than normal in the invasion of the somatodendritic region of PC. In particular, a marked IS-SD delay or block occurred in about 60% of unitary antidromic responses of the mutant mouse. (2) Spontaneous or evoked typical climbing fiber responses (CFR) were never recorded in staggerer mice, despite functional synapses between climbing fibers (CF) and PC disclosed with harmaline injections. Activation of PC via CF under harmaline consisted of rhythmical trains of simple spikes, Finally, most of the PC studies in the staggerer mice were certainly activated via PF but with a low efficacy. The results suggest that PC are directly affected by the mutation.


Properties of motor units in the first deep lumbrical muscle of the cat's foot.

Isometric contractions of single motor units were studied in the first deep lumbrical muscle of the cat's hind-foot. Motor units with short twitch contraction times (15-20 msec) generally differed from those with longer ones (23-50 msec; contraction time measured in unpotentiated twitches) in showing (1) a greater maximum tetanic tension, (2) a smaller resistance to fatigue, (3) more post-tetanic potentiation of twitch tension, and (4) no post-tetanic occurrence of repetitive activity in response to single nerve stimuli (such "post-tetanic repetitive activity" was seen in several of the slower units). The ratio between unpotentiated twitch tension and maximum tetanic tension was similar for units with brief and long contraction times. The peak-to-peak amplitude of a single motor unit spike, recorded with gross electrodes, tended to be directly proportional to the maximum tetanic tension of the same motor unit.