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Sensory development is a complex process that can influence physiological and pathological factors. In laterally-eyed mammals, monocular enucleation (ME) during development and the subsequent lack of external sensory stimuli can result in permanent morphological and physiological changes. Malnutrition, especially in early life, also can cause permanent morphofunctional changes due to inadequate nutrient intake in both hemispheres. This study investigated the effects of early (postnatal day 7) ME and malnutrition during the suckling period on cortical excitability in adulthood (110-140 days of life). For this, we compared the speed propagation of cortical spreading depression in the occipital and parietal cortex of malnourished and well-nourished adult rats, previously suckled small-sized litters with three pups (L3/dam) medium-sized litters with six pups (L6/dam), and large-sized litters with twelve pups (L12/dam). The CSD velocity was augmented by the ME in the contralateral side of the removed eye in the parietal and occipital cortex. These findings suggest that visual sensory input deprivation is associated with permanent functional changes in the visual pathways, which can alter cortical excitability and lead to modifications in CSD propagation.

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Objectives: Maternal physical activity may impact behavioral and electrophysiological aspects of brain function, with short- and long-term effects on pre- and postnatal neurodevelopment of the offspring. This study evaluated in the rat the effects of maternal voluntary physical activity (MVPA) on food intake and weight gain in the dams, as well as anxiety-like behavior, short-term memory and the brain excitability-related phenomenon known as cortical spreading depression (CSD) on the mother-pup dyad.Methods: Female Wistar rats (n=33) were individually housed in cages containing a running wheel for a 30-days adaptation period before mating. Rats were classified as inactive (I); active (A) or very active (VA) according to the distance spontaneously travelled daily. During gestation, the dams continued to have access to the running wheel. Mothers and their respective pups (1 pup per mother) were evaluated in the open field test (OFT), object recognition test (ORT), elevated plus maze test (EPMT) and the CSD propagation features.Results: MVPA was directly associated with increased food intake and weight gain during gestation, and maternal anxiolytic-like behavioral responses in the OFT. Pups from VA mothers showed a high discrimination index for shape recognition memory (ORT) and decreased propagation velocities of CSD, when compared with the inactive group.Discussion: The data suggest that MVPA during the gestational period induces neuroplasticity and may modulate the brain functions in the mother-infant dyad in the rat.

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Objectives: Unfavorable lactation influences brain excitability and behavioral reactions in adults. Administration early in life of the cholinergic agonist, pilocarpine, even at non-convulsive doses, alters the brain excitability-related phenomenon known as cortical spreading depression (CSD), and produce anxiogenic-like behavior. However, the influence of unfavorable lactation on the CSD- and memory-effects of pilocarpine administration late in life has not been investigated. Herein, we analyzed the ponderal, electrophysiological (CSD), and behavioral effects of chronic treatment with a non-convulsive dose of pilocarpine, in adult rats suckled under favorable and unfavorable conditions.Methods: Wistar rats were suckled in litters with 9 or 15 pups (groups L9 and L15, respectively). A very low dose of pilocarpine (45/mg/kg/day) was chronically administered in mature rats from postnatal day (PND) 69-90. Behavioral tests occurred at PND91 [elevated plus maze (EPM)], PND93 [open field (OF)], and PND94-95 [object recognition memory (ORM)]. CSD was recorded between PND96-120.Results: Pilocarpine-treated rats performed worse in the anxiety and memory tests, and displayed lower CSD propagation velocity when compared with saline-treated controls. In addition, L15 rats showed an increase in the distance traveled and a decrease in the immobility time in the EPM, impaired ORM, and accelerated CSD propagation when compared with L9 rats (p ≤ 0.05).Discussion: These data suggest that sub-convulsive pilocarpine treatment in adult rats can affect behavioral and excitability-related reactions. In addition, unfavorable lactation increases the ambulatory effects of pilocarpine. Further studies should investigate the possible cholinergic molecular mechanisms involved in these effects.

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INTRODUCTION: Cortical spreading depolarization (SD) describes pathological waves characterized by an almost complete sustained depolarization of neurons and astrocytes that spreads throughout the cortex. In this study, we carried out a qualitative review of all available evidence, clinical and preclinical, on the use of ketamine in SD. METHODS: We performed a systematic review of Medline, with no restrictions regarding publishing date or language, in search of articles reporting the use of ketamine in SD. The search string was composed of "ketamine," "spreading," "depolarization," and "depression" in both (AND) and (OR) combinations. RESULTS: Twenty studies were included in the final synthesis. Many studies showed that ketamine effectively blocks SD in rats, swine, and humans. The first prospective randomized trial was published in 2018. Ten patients with severe traumatic brain injury or subarachnoid hemorrhage were enrolled, and ketamine showed a significant, dose-dependent effect on the reduction of SD. CONCLUSION: The available evidence from preclinical studies is helping to translate the role of ketamine in blocking spreading depolarizations to clinical practice, in the settings of migraine with aura, traumatic brain injury, subarachnoid hemorrhage, and hemorrhagic and ischemic stroke. More randomized controlled trials are needed to determine whether interrupting the ketamine-blockable SDs effectively leads to an improvement in outcome and to assess the real occurrence of adverse effects.

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Sepsis is a clinical syndrome with high morbidity and mortality. It is characterized by acute inflammatory response and oxidative stress, which is implicated in cerebral dysfunction. Murici (Byrsonimacrassifolia (L.) Kunth) is a fruit rich in antioxidant compounds, which could be an alternative to prevent damage to tissues induced by sepsis . Here, we evaluated the effects of sepsis on the propagation of cortical spreading depression (CSD) and oxidative stress, and tested the action of murici antioxidant extract in prevention against the effect of sepsis. Male Wistar rats (90-210 days, n = 40) were previously supplemented, orogastrically, with murici extract (150 mg/kg/day or 300 mg/kg/day), or an equivalent volume of the vehicle solution, for fifteen days. Then the animals were subjected to experimental sepsis through cecal ligation and perforation (CLP). Subsequently, CSD recordings were obtained and brain oxidative stress was evaluated. Sepsis decelerated CSD and increased the malondialdehyde (MDA) levels in the brain cortex of the animals. In contrast, septic rats that had been previously supplemented with murici antioxidant extract in doses of 150 and 300 mg/kg/day showed an increase in CSD propagation velocity, low levels of MDA and GSH/GSSG ratio and an increase of superoxide dismutase (SOD) activity, regardless of the dose tested. Our results demonstrate that sepsis affects brain excitability and that this effect can be prevented by murici antioxidant extract. The effects of sepsis and/or murici extract on CSD may be due to the oxidative state of the brain.

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Objectives: Pyridoxine plays a key role in the development of the human nervous system. Several reports suggest that administration of high doses of pyridoxine can be helpful in improving disturbances such as anxiety and pyridoxine-dependent epilepsy, although it has also been associated with a proconvulsive action. In this study, we investigated in developing rats the effects of repeated administration of various doses of pyridoxine on anxiety-like behavior and the brain excitability-related phenomenon known as cortical spreading depression (CSD).Methods: From postnatal day (P) 7 to P27, Wistar rat pups received per gavage pyridoxine hydrochloride (1 mg/kg/day, or 5 mg/kg/day, or 10 mg/kg/day). On P60-70, the animals were tested in the elevated plus maze (EPM) to evaluate anxiety-like behavior. On P71-80, we recorded the CSD (4-hour recording session).Results: Compared with naïve (gavage-free) and saline-treated controls, pyridoxine-treated groups displayed a significant (p < 0.001) increase in CSD propagation velocity and amplitude of the CSD negative direct-current (DC)-shift, and a decrease in the CSD DC-shift duration. These effects were long-lasting and dose-dependent. In the EPM, no significant pyridoxine-associated effect was observed.Discussion: Our data demonstrate a novel action of pyridoxine on an electrical activity-related phenomenon (CSD) in the developing brain, confirming the hypothesis that the chronic treatment with pyridoxine early in life modulates CSD. Data on CSD propagation suggest that pyridoxine at a high dose might act as a prooxidant agent in the developing brain, a hypothesis that deserves further testing.

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Astrocytes can protect neurons against oxidative stress and excitability-dependent disorders, such as epilepsy. Valeriana officinalis has been used as anticonvulsant and can exert an antioxidant effect, which may underlie its opposing action against the toxic effects of the pesticide rotenone. We investigated the V. officinalis /rotenone interaction in the cortical spreading depression (CSD), a phenomenon that depends upon brain excitability (in vivo model). In addition, we analyzed the protective action of V. officinalis against the cytotoxic effects of rotenone in cultures of rat C6 glioma cells (in vitro model). For the CSD study, Wistar rats received either V. officinalis (250 mg/kg/day via gavage for 15 days; n = 8) or 10 mg/kg/day rotenone via subcutaneous injections for 7 days (n = 7), or they received both substances (n = 5). Two control groups received either saline (vehicle for V. officinalis; n = 8) or 1% Tween-80 aqueous solution (vehicle for rotenone; n = 9). After treatment, CSD was recorded for 4 h. The rotenone- and V. officinalis-treated groups presented, respectively, with lower (2.96 ± 0.14 mm/min), and higher CSD propagation velocity (3.81 ± 0.10 mm/min) when compared with the controls (Tween-80, 3.37 ± 0.06 mm/min and saline, 3.35 ± 0.08 mm/min; p < 0.05). The rotenone plus V. officinalis-treated group displayed a CSD velocity (3.38 ± 0.07 mm/min) that was similar to controls. In line with these results, in vitro experiments on rat glioma C6 cells revealed a protective effect (MTT assay) of V. officinalis against rotenone-induced cytotoxicity. These results suggest the therapeutic potential of V. officinalis for treating neurological diseases involving redox imbalance and astrocyte dysfunction.

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Objectives - Clinical and experimental evidence indicates that both ovarian hormones and nutritional condition can affect several brain functions, including those depending on excitability mechanisms. Nutritional deficiency, on the other hand, is capable of disturbing brain structure and function of mammals. We have previously demonstrated that ovariectomy decelerates [Accioly NE, Benevides R, Costa B, Guedes RCA. Ovariectomy in the developing rat decelerates cortical spreading depression in adult brain. Internat J Develop Neurosci. 2012;30:405-410.], whereas systemic hormone administration accelerates the excitability-dependent phenomenon known as cortical spreading depression (CSD; [Accioly NE, Guedes RCA. Neonatal treatment with ovarian hormones and suckling among distinct litter sizes: Differential effects on recognition memory and spreading depression at adulthood. Nutr Neurosci. 2017;1-11. doi:10.1080/1028415X.2017.1358472.]). In this study we investigated the interaction between topical cortical treatment with ovarian hormones and malnutrition during lactation on CSD parameters. Methods - Female Wistar rats were suckled in litters with 6-9 or 12-15 pups (L9 and L15 groups; normal size- and large size litters, respectively). At postnatal days 90-120, estradiol (5, 10 and 20 mg/ml solutions) and progesterone (66 mg/ml, 132 mg/ml and 264 mg/ml solutions) were topically applied during a CSD recording session. CSD parameters (propagation velocity, and amplitude and duration of the CSD DC-shift) were calculated before and after CSD. Results - Topical applications of estradiol and progesterone reversibly and dose- dependently accelerated CSD, and decreased duration and increased amplitude of the CSD DC-shift (p < 0.05); furthermore, unfavorable lactation (L15) accelerated CSD in adulthood. Discussion - In support of our previous studies with systemic hormone treatment, topical cortical application of ovarian hormones modulates CSD in the adult brain, suggesting a cortically-based mechanism for this effect, which might be related to the hormonal action on synaptic transmission with consequent modulation of brain excitability.

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Objectives: This investigation studied whether physical exercise could modulate cortical spreading depression (CSD) propagation velocity in adult rat offspring from dams that had received a high-fat (HF) diet during lactation. Methods: Wistar male rats suckled by dams fed either control (C) or HF diet ad libitum. After weaning, pups received standard laboratory chow. From 40 to 60 days of life, half of the animals exercised on a treadmill (group E); the other half remained sedentary (group S). Two additional HF groups (E and S) received fluoxetine (F; 10 mg/kg/day, orogastrically) from 40 to 60 days of life (groups HF/EF and HF/F). Results: At 40 days of life, rats from the maternal HF diet presented higher weight, thoracic circumference, and Lee Index than C animals and remained heavier at 60 days of life. Physical exercise decreased abdominal circumference. HF diet increased CSD propagation velocity (mean ± SD; mm/min) in sedentaries (HF/S 3.47 ± 0.31 versus C/S 3.24 ± 0.26). Treadmill exercise decelerated CSD propagation in both groups C/E (2.94 ± 0.28) and HF/E (2.97 ± 0.40). Fluoxetine alone decreased CSD propagation (HF/F 2.88 ± 0.45) compared with HF/S group. The combination of fluoxetine + exercise under HF condition (2.98 ± 0.27) was similar to HF/E group. Discussion: Physical exercise is able to reduce CSD propagation velocity in rat adult brains even when they have suffered over-nourishing during lactation. The effects of exercise alone or fluoxetine alone on CSD were similar to the effects of fluoxetine + exercise, under the HF condition. Data reinforce malnutrition during lactation modifies cortical electrophysiology even when the HF condition no longer exists.

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Early growth response-1 (Egr-1), defined as a zinc finger transcription factor, is an upstream master switch of the inflammatory response, and its expression can be used to investigate the spatial and temporal extent of inflammatory changes in the brain. Cortical spreading depression (CSD) is characterized as a slowly propagating (2-5 mm/min) depolarization wave through neurons and astrocytes in humans that contributes to migraines and possibly to other brain pathologies. In rodents, CSD can be induced experimentally, which involves unilateral depolarization that is associated with microglial and astrocyte responses. The impact of CSD on structures beyond the affected hemisphere has not been explored. Here, we used an optical fractionator method to investigate potential correlations between the number of and period of the eletrophysiologic record of CSD phenomena and Egr-1 expression in ipsilateral and contralateral hemispheres. CSD was elicited by the restricted application of a 2% KCl solution over the left premotor cortex. Electrophysiological events were recorded using a pair of Ag/AgCl agar-Ringer electrodes for 2 or 6 h. An optical fractionator was applied to count the Egr-1 positive cells. We found that CSD increased Egr-1 expression in a time- and event-dependent manner in the ipsilateral/left hemisphere. Although CSD did not cross the midline, multiple CSD inductions were associated with an increased number of Egr-1 positive cells in the contralateral/right hemisphere. Thus, repeated CSD waves may have far reaching effects that are more global than previously considered possible. The mechanism of contralateral expression is unknown, but we speculate that callosal projections from the depolarized hemisphere may be related to this phenomenon.

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ABSTRACT Objective: This study aimed to analyze whether exposure to environmental enrichment (EE) during the juvenile phase of life interferes with the electrical activity of the adult rat brain. In addition, the present research also investigated whether this putative effect on brain electrical activity could be affected by prior overnutrition during lactation. Electrophysiology was measured through cortical spreading depression (CSD), a phenomenon related to brain excitability. Methods: Wistar rats were suckled in litters of either nine or three pups, forming the nourished (N) or overnourished (ON) groups, respectively. At 36 days old, half of the animals from each nutritional condition were exposed to EE. The other half was kept in the standard environment (SE). At 90-120 days of life, each animal was anesthetized for CSD recordings. Results: Overnutrition during lactation caused increases (p < 0.05) in body and brain weights. The EE decelerated CSD propagation velocity regardless of nutritional state during lactation (p < 0.001). The CSD deceleration in the N-EE group was 23.8% and in the ON-EE group was 15% in comparison with the N-SE and ON-SE groups, respectively. Conclusion: Our data demonstrated that EE exposure in the juvenile phase of the rat's life reduced brain excitability, and this effect was observed even if animals were overnourished during lactation. An EE could be considered an adjuvant therapeutic resource to modulate brain excitability.

RESUMO Objetivo: Este estudo analisou se a exposição ao ambiente enriquecido durante a fase juvenil da vida interferiria na atividade elétrica do cérebro de ratos adultos. Além disso, a presente pesquisa também investigou se esse provável efeito na atividade elétrica cerebral poderia ser afetado pela hipernutrição durante a lactação. A eletrofisiologia foi medida através da depressão alastrante cortical, um fenômeno relacionado à excitabilidade cerebral. Métodos: Ratos Wistar foram amamentados em ninhadas de nove ou três filhotes, formando os grupos nutridos ou hipernutridos, respectivamente. Aos 36 dias, metade dos animais de cada condição nutricional foram expostos ao ambiente enriquecido. A outra metade foi mantida na condição de ambiente padrão. Aos 90-120 dias de vida, foram obtidos os registros da depressão alastrante cortical. Resultados: A hipernutrição durante a lactação causou incrementos (p < 0,05) nos pesos corporal e cerebral.O Ambiente Enriquecido desacelerou a velocidade de propagação da depressão alastrante cortical independentemente do estado nutricional durante a lactação (p < 0,001). A desaceleração da depressão alastrante cortical no grupo nutrido/ambiente enriquecido foi de 23,8% e no grupo hipernutrido/ambiente enriquecido foi de 15% em comparação com os grupos nutrido/ambiente padrão e hipernutrido/ambiente padrão, respectivamente. Conclusão: Nossos dados demonstram que a exposição ao ambiente enriquecido na fase juvenil da vida do rato reduz a excitabilidade cerebral, e esse efeito pode ser observado mesmo se os animais estiverem hipernutridos durante a lactação. O ambiente enriquecido pode ser considerado um recurso terapêutico adjuvante para modular a excitabilidade cerebral.

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Guanosine (GUO) is a guanine-based purine that has been extensively described in the literature as an endogenous nucleoside with participation in brain cell signalling pathways. Here, we evaluated whether chronic treatment with exogenous guanosine during brain development altered behavioral and electrophysiological parameters in adulthood. Rat pups received a daily intraperitoneal injection of 10, 50 or 100 mg/ kg/day GUO, or saline solution or no treatment (naive group) from postnatal (P) day 7 to P27. At P 60-65 the animals were behaviorally tested in the Elevated Plus-Maze (EPM). On P90-100, the electrophysiological phenomenon known as cortical spreading depression (CSD) was recorded on the right cortical surface for 4 h. With the EPM task, GUO treatment was associated with a significant increase in rearing behavior and a non-significant trend towards anxiogenic behavior. In a dose-dependent manner, GUO significantly (p < 0.01) increased weight gain on P90, and reduced the CSD propagation velocity from 3.42 ±â€¯0.10 and 3.43 ±â€¯0.10 mm/min in the Naive and Vehicle controls, respectively, to 3.05 ±â€¯0.12 mm/min, 2.87 ±â€¯0.07 mm/min and 2.25 ±â€¯0.25 mm/min in the groups treated with 10, 50 and 100 mg/kg/d GUO, respectively. The results confirmed the hypothesis that the chronic treatment with GUO early in life modulates CSD and body weight. Data on CSD propagation suggest that, besides its suppressing action on glutamatergic transmission (via enhancement of astrocytic glutamate uptake), GUO might act as an antioxidant in the brain, a hypothesis that deserves further exploration.

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OBJECTIVE: Analyze the hypothesis that swimming exercise, in rats suckled under distinct litter sizes, alters behavioral parameters suggestive of anxiety and recognition memory, and the electrocorticogram potentiation that occurs after the excitability-related phenomenon that is known as cortical spreading depression (CSD). METHODS: Male Wistar rats were suckled in litters with six or 12 pups (L6 and L12 groups). Animals swam at postnatal days (P) 8-23, or P60-P75 (early-exercised or late-exercised groups, respectively), or remained no-exercised. Behavioral tests (open field - OF and object recognition - OR) were conducted between P77 and P80. Between P90 and P120, ECoG was recorded for 2 hours. After this 'baseline' recording, CSD was elicited every 30 minutes over the course of 2 hours. RESULTS: Early swimming enhanced the number of entries and the percentage of time in the OF-center (P < 0.05). In animals that swam later, this effect occurred in the L6 group only. Compared to the corresponding sedentary groups, OR-test showed a better memory in the L6 early exercised rats, and a worse memory in all other groups (P < 0.05). In comparison to baseline values, ECoG amplitudes after CSD increased 14-43% for all groups (P < 0.05). In the L6 condition, early swimming and late swimming, respectively, reduced and enhanced the magnitude of the post-CSD ECoG potentiation in comparison with the corresponding L6 no-exercised groups (P < 0.05). DISCUSSION: Our data suggest a differential effect of early- and late-exercise on the behavioral and electrophysiological parameters, suggesting an interaction between the age of exercise and the nutritional status during lactation.

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OBJECTIVES: The route of administration is an important factor in determining the action of some drugs. We previously demonstrated that subcutaneous monosodium glutamate (MSG) accelerated cortical spreading depression (CSD) in the rat and that treadmill exercise attenuated this effect. This study evaluated whether other routes of administration exert the same action by testing orogastric (gavage) and topical cortical MSG administration in treadmill-exercised and sedentary rats. Additionally, in the orogastric treatment we tested anxiety-like behavior. METHODS: Exercised and sedentary rats received per gavage water or MSG (1 or 2 g/kg) daily from postnatal (P) day 7 to 27. Behavioral tests (open field and elevated plus-maze) occurred at P53 ± 3. At P56 ± 3, we analyzed CSD parameters (velocity, amplitude, and duration of the negative potential change). Other three groups of rats received an MSG solution (25, 50 or 75 mg/ml) topically to the intact dura mater during CSD recording. RESULTS: MSG-gavage increased anxiety-like behavior and the CSD velocities compared with water-treated controls (P < 0.05). Exercise decelerated CSD. In contrast to gavage, which accelerated CSD, topical MSG dose-dependently and reversibly impaired CSD propagation, reduced CSD amplitude and increased CSD duration (P < 0.05). CONCLUSIONS: The exercise-dependent attenuation of the effects of MSG confirms our previous results in rats treated subcutaneously with MSG. CSD results suggest two distinct mechanisms for gavage and topical MSG administration. Additionally, data suggest that exercise can help protect the developing and adult brain against the deleterious actions of MSG.

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OBJECTIVES: Ovarian hormones (OH) and early malnutrition may affect the developing brain, with repercussions on behavioral and excitability-dependent processes. However, the possible synergistic effects of both factors have not been analyzed. In this study, we investigated the effect of treatment in early life with OH and suckling among distinct litter sizes on recognition memory, anxiety behavior, and the excitability-dependent phenomenon known as cortical spreading depression (CSD). METHODS: Female Wistar rats were suckled under favorable and unfavorable lactation, corresponding to litters with 9 and 15 pups (L9 and L15 groups, respectively). From postnatal days (P) 7 to 21, the animals received 50 µg/kg of ß-estradiol or progesterone. From P80 to P84, we tested behavioral reactions. From P90 to P120, we analyzed CSD parameters. RESULTS: Compared with the corresponding L9 groups, the OH-treated L15 groups performed worse in recognition memory tasks. No intergroup difference in the anxiety parameters was observed. Compared with naive and vehicle-treated controls, OH-treated groups displayed higher CSD velocities and amplitudes and shorter CSD durations. DISCUSSION: Early treatment with OH facilitates recognition memory and CSD, and in association with unfavorable lactation (L15) impaired recognition memory, but not anxiety behavior, in the adult brain. OH treatment and L15 lactation condition seem to interact regarding OH action on memory, but not on CSD. Data suggest a long-lasting differential effect that might be related to the lasting hormonal action on brain excitability. We postulate and discuss the possibility that these findings may be implicated in human neurological diseases.

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Ascorbic acid (AA) administration has been associated with neuroprotection against oxidative stress, although at high doses it can facilitate oxidation and acts like a proconvulsing drug. The pilocarpine-induced epilepsy model has been widely studied. However, less is known about the effects of sub-convulsive doses of pilocarpine on brain activity in immature animals under normal or deficient nutritional conditions. Herein, we investigated the effects of chronic pilocarpine administration in a sub-convulsive dose, with or without AA, on the excitability-related phenomenon denominated as cortical spreading depression (CSD) and levels of lipid peroxidation-induced malondialdehyde in well-nourished and malnourished rats. At postnatal days 7-28, rats received no gavage treatment (naïve group), saline (vehicle group), 45 mg/kg/d of pilocarpine and/or 120 mg/kg/d of AA. CSD propagation and malondialdehyde levels were analyzed at 34-40 days. The pilocarpine group presented with lower CSD velocities, while AA groups exhibited higher CSD velocities and augmented malondialdehyde levels compared with controls. The co-administration of AA partially antagonized the pilocarpine CSD effects, but did not revert it to control levels. Malnutrition increased CSD amplitude and velocity in comparison to the well-nourished condition. The electrocorticogram (ECoG) amplitude increased after CSD (ECoG potentiation) when compared with the baseline amplitude before CSD. However, no intergroup difference was observed in this CSD-related ECoG potentiation. The results support the hypothesis of a pilocarpine/ascorbic acid interaction in the immature rat brain and might help further the understanding of this interaction on neuronal electrical activity and oxidative stress.

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Spreading depolarization in cerebral cortex is associated with swelling of neurons, distortion of dendritic spines, massive ion translocation with a large change of the slow electrical potential, and silencing of brain electrical activity. The term spreading depression represents a wave of spontaneous activity of the electrocorticogram that propagates through contiguous cerebral gray matter at a characteristic velocity. Spreading depression is a consequence of cortical spreading depolarization. Therefore, spreading depolarization is not always accompanied by spreading depression and the terms are not synonymous.

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OBJECTIVES: To evaluate how safflower oil (SFO) influences brain electrophysiology and cortical oxidative status in the offspring, mothers received a diet with SFO during brain development period. METHODS: Beginning on the 14th day of gestation and throughout lactation, rats received safflower (safflower group - SG) or soybean oil (control group - CG) in their diet. At 65 days old, cortical spreading depression (CSD) and cortex oxidative status were analyzed in the offspring. RESULTS: SG presented reduction of the CSD velocity as compared to the CG (SG: 3.24 ± 0.09; CG: 3.37 ± 0.07 mm/min). SFO reduced levels of lipid peroxidation by 39.4%. SG showed the following increases: glutathione-S-transferase, 40.8% and reduced glutathione, 34.3%. However, SFO decreased superoxide dismutase by 40.4% and catalase by 64.1%. To control for interhemispheric effects, since CSD was recorded only in the right cortex, we evaluated the oxidative status in both sides of the cortex; no differences were observed. DISCUSSION: Data show that when SFO is consumed by the female rats during pregnancy and lactation, the offspring present long-term effects on brain electrophysiology and cortical oxidative state. The present study highlights the relevance of understanding the SFO intake of pregnant and lactating mammals.

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Spreading depolarization in cerebral cortex is associated with swelling of neurons, distortion of dendritic spines, massive ion translocation with a large change of the slow electrical potential, and silencing of brain electrical activity. The term spreading depression represents a wave of spontaneous activity of the electrocorticogram that propagates through contiguous cerebral gray matter at a characteristic velocity. Spreading depression is a consequence of cortical spreading depolarization. Therefore, spreading depolarization is not always accompanied by spreading depression and the terms are not synonymous.

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In mammals, L-glutamine (Gln) can alter the glutamate-Gln cycle and consequently brain excitability. Here, we investigated in developing rats the effect of treatment with different doses of Gln on anxiety-like behavior, cortical spreading depression (CSD), and microglial activation expressed as Iba1-immunoreactivity. Wistar rats were suckled in litters with 9 and 15 pups (groups L 9 and L 15; respectively, normal size- and large size litters). From postnatal days (P) 7-27, the animals received Gln per gavage (250, 500 or 750 mg/kg/day), or vehicle (water), or no treatment (naive). At P28 and P30, we tested the animals, respectively, in the elevated plus maze and open field. At P30-35, we measured CSD parameters (velocity of propagation, amplitude, and duration). Fixative-perfused brains were processed for microglial immunolabeling with anti-IBA-1 antibodies to analyze cortical microglia. Rats treated with Gln presented an anxiolytic behavior and accelerated CSD propagation when compared to the water- and naive control groups. Furthermore, CSD velocity was higher (p < 0.001) in the L 15 compared to the L 9 condition. Gln treatment increased Iba1 immunolabeling both in the parietal cortex and CA1 hippocampus, indicating microglial activation. The Gln effect was dose-dependent for anxiety-like behavior and CSD in both litter sizes, and for microglial activation in the L 15 groups. Besides confirming previous electrophysiological findings (CSD acceleration after Gln), our data demonstrate for the first time a behavioral and microglial activation that is associated with early Gln treatment in developing animals, and that is possibly operated via changes in brain excitability.

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