Effects of single cortical spreading depression on metabolic heat production in the rat

The effect of a single cortical spreading depression (CSD), elicited unilaterally by 10% KCI injection at the occipital cortex, was observed on the metabolic heat production in the rat with unilateral lesions in the preoptic and anterior hypothalamus (PO/AH). The metabolic rate increased by maximally 20% above its pre-CSD level for 7 min with a rise in rectal temperature when CSD entered the frontal cortex contralateral to the PO/AH lesion. By contrast, with the same onset, the increase in metabolic rate was lower (maximum 12%) and of shorter duration (3 min) in the ipsilateral CSD trial. Non-CSD trial with 0.9% NaCl injection had no effect on metabolic rate. The results provide further evidence to support the view that the frontal cortex of the rat is involved in the central thermoregulation.     

Effects of cortical spreading depression on behaviors elicited by hypothalamic stimulation in rats

Eating or drinking was elicited via electrical stimulation of the lateral hypothalamus of rats. To determine the effects of single waves of cortical spreading depression on elicited behavior, 1,1 animals were tested with 10 sec trains of stimulation at 20 sec intervals and administered 1–5 μl of 6% KCl through cannulae onto the frontal or occipital cortices of the contralateral or ipsilateral hemispheres. Under single waves of bilateral spreading depression the elicited consummatory behavior was blocked, but other signs of arousal were intact. Single waves of unilateral depression increased the onset-latencies and decreased the duration of elicited behavior, depending on the magnitude of the electrical stimulation. Anterior cortical injection blocked elicited behavior earlier than occipital injection. No differences were apparent between ipsilateral and contralateral injection of KCl. In some animals single waves of unilateral depression were accompanied by a reversible shifting from one elicited consummatory response to another, usually from eating to drinking. The results were interpreted to reflect cortico-hypothalamic interactions in the control of motivated behavior.     

Differential effects of cortical ablation and spreading depression on sensitivity to footshock: implications for the role of the cortex in learning.

Rats were tested for flinch and jump responses to shock under unilateral and bilateral spreading depression (USD and BSD) and unilateral cortical ablation (UCA). Some Ss were tested with insulating boots on the left or right limbs. Under USD and UCA the limbs contralateral to the depressed or ablated hemisphere were as insensitive as when under BSD, and the ipsilateral limbs were almost as sensitive as in the normal condition. The data indicate that lack of transfer typically found in the USD transfer paradigm can be attributed to stimulus factors and not to learning or memory deficits, especially since most studies have used a shock level which does not exceed the jump threshold for a depressed hemisphere.     

Learning of a single alternation concept under conditions of cortical spreading depression in rats

Sixteen rats were trained on a light-dark cued single alternation active avoidance task. Eight animals were trained under conditions of cortical spreading depression (CSD) and eight as operated controls. All animals reached criterion but animals trained CSD required significanlty more trials. Animals trained CSD showed fewer correct alternations on the first 10 trials of the last testing day but were indistinguishable in performance on the following 30 trials. However CSD animals showed continuing performance deficits in active avoidance. When operated controls were tested under conditions of CSD they had significantly greater performance deficits than CSD trained animals tested without elicitation of CSD. The results seem to reflect motoric and general metabolic effects of CSD rather than cognitive deficits or simple stimulus change effects.     

Prolonged slow potential variation associated with cortical spreading depression

Three methods of inducing cortical spreading depression in rats resulted in spreading depression and a prolonged negative slow potential change from subcortical and cortical areas of the brain. This prolonged potential has not been previously considered as a concomitant of cortical spreading depression.     

Facilitation of thermoregulatory heating behavior by single cortical spreading depression in the rat

Effects of single waves of unilateral cortical spreading depression (CSD) on skin-heating behavior were studied in the rat with the unilateral lesion in the preoptic and anterior hypothalamus (PO/AH). A single CSD contralateral to the PO/AH lesion significantly increased the number of heating for 4 min after CSD had entered the frontal cortex with a maximum facilitation rate 20% above the pre-CSD level. On the other hand, a single CSD ipsilateral to the PO/AH lesion slightly augmented the number of heating for 2 min with a maximum increase of 8% above the pre-CSD level. An injection of 0.9% NaCl (non-CSD trial) did not affect the skin-heating behavior. The present results, together with the changes in skin-cooling behavior during CSD reported previously, suggest the involvement of the frontal cortex in the central control of thermoregulation.     

Lateralization of learned taste aversion by cortical spreading depression

Male Sprague-Dawley rats which were taught a strong aversion to ingestion of lithium chloride under unilateral cortical spreading depression failed to show this aversion when spreading depression was changed to the opposite hemisphere. Control rats which learned the aversion with both hemispheres functional show a very strong aversion to LiCl in subsequent tests with either both hemispheres functional or one hemisphere under spreading depression. These results indicate that cortical participation is important for learning of a taste aversion.     

Learned taste aversion induced by cortical spreading depression.

Male albino rats were cannulated and placed on a 24 hr water deprivation schedule. The animals were allowed 10 min access to water in a large animal cage for 5 days. On the sixth day of deprivation the animals were randomly divided into 6 groups and given either 12 percent KCl, 25 percent KCl, or Ringers solution applied unilaterally or bilaterally to the cortex immediately after access to 8 percent sucrose. On the seventh day of deprivation, each rat was placed in a two-choice situation with the sucrose solution and water. Only the unilateral and bilateral 12 percent KCl groups developed an aversion to the sucrose. These results indicate that CSD has aversive as well as amnesic properties, there exists a gradient of amnesia, dependent on concentration, and that the cortex is not necessary for learning a taste aversion.     

Cortifugal influences on dorsal column nuclei: an electrophysiological study in the rat using the cortical spreading depression technique

Summary The sign and duration of corticofugal effects on the extracellularly recorded spontaneous activity of cuneate and gracile neurons were examined by means of the cortical spreading depresion technique (CSD). Among the 40 units studied 22 showed changes in their spontaneous firing rate during the passage of a CSD. Changes were of either short (5–20 s) or long (>20–140 s) duration. Increases and decreases in activity, as well as sequences of both types of alteration were observed. Short duration changes were more frequent and much more pronounced than those of long duration. From their time course and intensity the short duration effects seem to be related to the brief high frequency cortical neuron discharge that precedes the cortical silence due to CSD, whereas the long lasting effects seem related to the cortical block. It is concluded that the most important corticofugal effects on gracile and cuneate neurons are phasic in nature and the sensorimotor cortical regions were found to be responsible for these influences.During this work R. Giuffrida was supported by a fellowship from the European Science Foundation (1984)     

在体皮层扩散性抑制动物模型的建立

目的：用KCl和针刺分别在鼠皮层诱导皮层扩散性抑制（CSD），建立大鼠CSD动物模型，为进一步研究奠定基础。方法:采用Spangue-Dawley大鼠25只，随机分为针刺诱导组（n=10）、KCl诱导组（n=10）和NaCl对照组（n=5），在大鼠颅骨上分别钻磨出诱导窗口和观测窗口，分别在诱导窗口用针刺和滴加KCl诱导大鼠脑CSD，对照组在诱导窗口滴加NaCl，并用电生理记录和光学成像的方法来描记CSD的产生与传播，并分析其特点。结果:针刺诱导组和KCl诱导组在观测窗口均可以观察到向外周扩散的弧形波，观测窗口均可以观察到明暗相间的弧形波向远处扩散，针刺诱导的CSD波呈典型的同心圆样向四周均匀扩散，KCl诱导的CSD波则是呈不规则的圆弧形波向外周扩散，针刺组每次只诱发1次CSD波，而KCl组则可以诱导多次CSD波。在产生CSD波的同时，伴随着去极化电位的产生，而在NaCl对照组没有这一现象的发生。结论:用本方法制作CSD动物模型，简单易行，可以用OISI直观观测CSD的产生和发展，并与电生理观测到的去极化波一致，适于在体研究CSD，为进一步研究CSD的发生机制及其可能的作用提供了一种有效手段。     

Habituation to intense acoustic stimulation during cortical spreading depression in rats

Few investigations have focused on the effects of cortical spreading depression (CSD) on habituation. In the 2 experiments to be reported here long-term habituation to intense acoustic stimulation was investigated. Arrest of ongoing drinking behavior was used as an index of habituation. In the first experiment habituation training during bilateral CSD was compared to habituation training under nondepressed conditions; testing for long-term habituation took place under nondepressed conditions in both groups. In contrast to the control group the bilateral CSD group did not show long-term habituation. In the second experiment habituation training during CSD in one hemisphere did not result in long term habituation when testing took place during CSD in the contralateral hemisphere. Possible explanations of these results are discussed.     

Chronic neonatal exposure of rats to the opioid antagonist naloxone impairs propagation of cortical spreading depression in adulthood

Naloxone is an opioid receptor antagonist with effects on the EEG and behavior in animals and humans and has been used clinically in drug-abuse treatment. The goal of this work in the rat is to determine whether treatment with naloxone during the suckling period would influence the propagation of cortical spreading depression (CSD), both in weaned young and adult animals. From the 7th to the 28th postnatal day, male rat pups were treated daily with a single subcutaneous injection of either 10mg/kg/d naloxone (n=21 rats) or equivalent volume (10ml/kg) of saline (n=16). In both treatment conditions, when the pups were 30-40 days- (young groups; 9 Naloxone- and 10 saline-treated rats), or 90-120-days old (adult groups; 12 Naloxone- and 6 saline-treated rats), a 4h CSD recording session was performed with electrodes at two points at a fixed distance apart on the parietal cortical surface. CSD propagation velocity was calculated based on the time spent for a CSD-wave to pass between the electrodes. In both young- and adult groups, naloxone-treated animals displayed lower CSD velocities (P<0.05) than the corresponding saline injected animals. Our results demonstrate, for the first time, that chronic neonatal exposure of rats to the opioid antagonist naloxone results in an impairing propagation of the CSD that is long lasting, suggesting the existence of one or more opioid-mediated processes influencing CSD.     

Early malnutrition,but not age,modulates in the rat the l-Arginine facilitating effect on cortical spreading depression

Nutritional factors acting during brain development can permanently alter brain electrophysiology. l-Arginine is the precursor of nitric oxide synthesis, which can modulate brain function. Here we investigated the effect of early-in-life administration (during postnatal days 7–28) of l-Arginine (300 mg/(kg day)) on cortical spreading depression (CSD), recorded in well-nourished and malnourished (large litters technique) rats aged 30–40 days (young) and 90–110 days (adult). Compared to water-treated controls, well-nourished l-Arginine-treated rats, but not the malnourished ones, displayed higher CSD velocities (P < 0.05) at both ages. The mean ± S.D. CSD velocities (in mm/min) were: for water- and l-Arginine well-nourished rats, 3.78 ± 0.23 and 4.36 ± 0.19 (young groups), and 3.28 ± 0.16 and 4.09 ± 0.30 (adult); for the same conditions in the malnourished rats, 4.22 ± 0.09 and 4.27 ± 0.21 (young), and 4.11 ± 0.18 and 4.21 ± 0.33 (adult). l-Arginine treatment did not affect body and brain weights. It is concluded that early l-Arginine treatment long lastingly increased brain CSD-susceptibility and this effect is abolished by early malnutrition.     

Sleep-deprivation enhances in adult rats the antagonistic effects of pilocarpine on cortical spreading depression: A dose–response study

Conditions that facilitate epilepsy, such as sleep deprivation or the cholinergic muscarinic agonist pilocarpine (PILO), have been experimentally studied, as they are relevant for brain excitability control and could help in understanding the development of epilepsy in humans. In this work, following to 72 h deprivation (D) of sleep by the water tank technique, adult Wistar rats were anesthetized with a 1 g/kg urethane + 40 mg/kg chloralose mixture and cortical spreading depression (CSD) was recorded for a 1–2 h period in the parietal surface. CSD propagation velocity was calculated based on the time spent for a CSD-wave to pass the interelectrode distance. After this “baseline” recording, D-animals were divided in three groups and respectively injected with 45, 95 and 190 mg/kg of PILO, i.p., and the CSD recording continued for two more hours. Three groups of non-deprived (ND) rats were also injected with the three doses of PILO and studied regarding CSD features. D-animals presented higher baseline CSD velocities than the corresponding ND-controls, confirming previous observations that D-condition facilitates CSD propagation. After PILO, the ECoG amplitudes were markedly and lastingly reduced in all animals, at the three doses used. In the groups treated with 95 and 190 mg/kg PILO, the CSD velocity of propagation significantly (P < 0.05) decreased, and the incidence of PILO-associated CSD-propagation failure increased in the D rats, but not in the ND rats, as compared with the pre-drug values. The data suggest the existence of one or more cholinergic, muscarinic-mediated antagonistic processes influencing CSD, which are dose-dependent and are modulated by sleep-deprivation.     

Habituation of open field activity during cortical spreading depression in rats

Habituation of locomotor activity in an open field was investigated in a first experiment in 6 groups of rats which received different CSD treatments on 2 successive days. Both short-term habituation and long-term habituation were investigated. During bilateral CSD short-term habituation was slower and less negatively accelerated, whereas during unilateral CSD it was not different from control. Long-term habituation within treatments was significant for the control treatment and approached significance for the bilateral CSD treatment; for the unilateral CSD treatment no significant long-term habituation was found. The latter finding which was replicated in a second experiment was ascribed to neurological imbalance during unilateral CSD, leading to greater overall reactivity. Long-term habituation after treatment change revealed state dependent learning effects which were ascribed to retrieval failure, caused by the change in the functioning of the brain.     

Exposure of developing well-nourished and malnourished rats to environmental heating facilitates cortical spreading depression propagation at adulthood

Cortical spreading depression (CSD) is a brain electrical response related to neural activity and probably also related to diseases like migraine and epilepsy. Adverse conditions like malnutrition and exposure to a warm environment early-in-life can permanently alter brain development, changing electrophysiological features of the brain responses and rendering the brain prone to febrile seizures. Here we investigated the lasting effects of heat exposure on brain CSD propagation in well-nourished and malnourished developing rats. From postnatal days 10–29, rats were exposed to daily sessions (one session per day, five sessions per week during 3 weeks; total of 15 sessions) of a warm environment (40 ± 2 °C). At 30–40 days and 90–120 days of life (young and adult age-ranges, respectively), they were anesthetized (urethane + chloralose; 1000 + 40 mg/kg ip) and the electrocorticogram plus the slow potential change accompanying CSD were recorded on two parietal points for 4 h. Compared to controls (maintained on the normal environment temperature, 23 ± 2 °C), heat-exposed rats displayed higher CSD velocities of propagation (P < 0.05; ANOVA plus Tukey test) at both age-ranges and nutritional statuses. The mean ± S.D. CSD velocities (in mm/min) were: for control- and heat-exposed well-nourished rats, 3.75 ± 0.15 and 4.17 ± 0.19 (young groups), and 3.33 ± 0.06 and 3.88 ± 0.26 (adult); for the same control and heat exposure conditions in the malnourished rats, 4.30 ± 0.22 and 5.31 ± 0.46 (young), and 4.18 ± 0.20 and 4.88 ± 0.35 (adult). In contrast to early malnutrition, heat exposure did not affect body and brain weights. Data support the hypotheses that (1) early heat exposure long-lasting facilitates CSD propagation and (2) this effect is not modified by early malnutrition.     

Habituation and sensitization of the acoustic startle response during cortical spreading depression in rats

Habituation of the acoustic startle response was tested in 8 groups of rats which received different CSD-treatments on 3 successive days. Both short-term habituation and long-term habituation were investigated. Bilateral CSD did have a significant effect on short-term habituation, but not unilateral CSD. This effect was interpreted as a temporary increment of sensitization in the beginning of the session. Neither unilateral CSD nor bilateral CSD had an effect on long-term habituation as long as no treatment change took place. Treatment change resulted in an increased startle amplitude if it was a change from no CSD to unilateral or bilateral CSD. The reverse change had no such effect. These results were interpreted as evidence for a gradual compensation over sessions for the initial CSD-induced sensitization increment. The results were discussed in connection with the results of earlier experiments on CSD and habituation.     

Observations on the thermoregulatory effects of preoptic warming in rats

Experimental warming of the preoptic-anterior hypothalamic area was used to evaluate behavioral and autonomic thermoregulatory heat-loss responses. Hypothalamic warming was associated with reduced behavioral heat intake and decreased core and peripheral temperatures in rats working for radiant heat reward in a cold environment. Baseline rates of responding for external heat were determined by ambient temperature, but the magnitude of changes in core or peripheral temperatures during preoptic warming were not. Behavioral responses compensated for variations in ambient temperature so that the threshold hypothalamic temperature above which heat loss was activated by preoptic warming was not altered by changing ambient temperatures. Heat loss during hypothalamic warming was a function of both autonomic and behavioral thermoregulatory responses because the decrease in body heat content during preoptic warming could not be accounted for by the decreased behavioral heat intake alone. The threshold hypothalamic temperature for elicitation of tail vasodilation decreased systematically as ambient temperature increased when no behavioral option was available. In the rat, both behavioral and autonomic thermoregulatory responses cooperate to determine the magnitude of heat loss which is proportional to the magnitude of preoptic warming.     

The effect of cooling of the supplementary motor cortex and adjacent cortical areas

Summary The medial surface of the rostral part of frontal agranular cortex, largely corresponding to the supplementary motor area, was rapidly and reversibly cooled while a monkey was performing a trained motor task requiring a premovement selection process of determining sensory signals as movement triggering or non-triggering. During cooling, the motor task was poorly performed with grossly altered reaction times and variable amount of force, along with erroneous responses. Neuronal activity in the precentral motor cortex in response to sensory signals was also found to be altered.