Unraveling the Influence of Litter Size, Maternal Care, Exercise, and Aging on Neurobehavioral Plasticity and Dentate Gyrus Microglia Dynamics in Male Rats.

This study explores the multifaceted influence of litter size, maternal care, exercise, and aging on rats' neurobehavioral plasticity and dentate gyrus microglia dynamics. Body weight evolution revealed a progressive increase until maturity, followed by a decline during aging, with larger litters exhibiting lower weights initially. Notably, exercised rats from smaller litters displayed higher body weights during the mature and aged stages. The dentate gyrus volumes showed no significant differences among groups, except for aged sedentary rats from smaller litters, which exhibited a reduction. Maternal care varied significantly based on litter size, with large litter dams showing lower frequencies of caregiving behaviors. Behavioral assays highlighted the detrimental impact of a sedentary lifestyle and reduced maternal care/large litters on spatial memory, mitigated by exercise in aged rats from smaller litters. The microglial dynamics in the layers of dentate gyrus revealed age-related changes modulated by litter size and exercise. Exercise interventions mitigated microgliosis associated with aging, particularly in aged rats. These findings underscore the complex interplay between early-life experiences, exercise, microglial dynamics, and neurobehavioral outcomes during aging.

Taurine/Pilocarpine Interaction in the Malnourished Rat Brain: A Behavioral, Electrophysiological, and Immunohistochemical Analysis.

This study aimed to evaluate the possible protective role of taurine on anxiety-like behavior, brain electrical activity and glial cell immunoreactivity in well-nourished and malnourished rats that were treated with a subconvulsing dose of pilocarpine. Newborn Wistar rats were subjected to normal or unfavorable lactation conditions, represented by the suckling of litters with 9 or 15 pups, resulting in well-nourished and malnourished animals, respectively. Each nutritional group was split into five subgroups that were treated from postnatal day (PND) 35 to 55 with 300 mg/kg/day of taurine + 45 mg/kg/day of pilocarpine (group T + P), taurine only (group T), pilocarpine only (group P), vehicle control (group V), or not treated control (group naïve; Nv). At PND56-58, the groups were subjected to the elevated plus-maze behavioral tests. Glycemia was measured on PND59. Between PND60 and PND65, the cortical spreading depression (CSD) was recorded in the cerebral cortex, and the levels of malondialdehyde and microglial and astrocyte immunoreactivity were evaluated in the cortex and hippocampus. Our data indicate that treatment with taurine and pilocarpine resulted in anxiolytic-like and anxiogenic behavior, respectively, and that nutritional deficiency modulated these effects. Both treatments decelerated CSD propagation and modulated GFAP- and Iba1-containing glial cells. Pilocarpine reduced body weight and glycemia, and administration of taurine was not able to attenuate the effects of pilocarpine. The molecular mechanisms underlying taurine action on behavioral and electrophysiological parameters in the normal and altered brain remain to be further explored.

Pilocarpine/ascorbic acid interaction in the immature brain: Electrophysiological and oxidative effects in well-nourished and malnourished rats.

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.

Safflower (Carthamus tinctorius L.) oil during pregnancy and lactation influences brain excitability and cortex oxidative status in the rat offspring.

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.

Neonatal dexamethasone accelerates spreading depression in the rat, and antioxidant vitamins counteract this effect.

The use of dexamethasone (Dex) to treat chronic lung disease in preterm infants may produce adverse effects in the developing brain. Here, we evaluated the effects of neonatal Dex on the propagation of cortical spreading depression (CSD), and tested the action of vitamins C and E against the effect of Dex. Five groups of Wistar rats received, respectively: [1] no treatment (Naïve); [2] Vehicle (V); [3] tapering doses of Dex (Dex; 0.5mg/kg, 0.3mg/kg, and 0.1mg/kg) on postnatal day (PND) 1-3; [4] Dex plus 200mg/kg vitamin C and 100mg/kg vitamin E (DexCE); [5] only vitamins C and E (CE). Vehicle and vitamins were administered on PND 1-6. CSD was recorded after the pups reached maturity (PND 60-70). The Dex-treated group presented with higher CSD velocities (mean values ± SD, in mm/min: 4.14 ± 0.22, n=10) compared with the control groups (Naïve: 3.52 ± 0.13, n=8; V: 3.57 ± 0.18, n=10; CE: 3.51 ± 0.24, n=10; p<0.05 for all). Vitamins C and E antagonized this effect (DexCE group; CSD velocity: 3.43 ± 0.12, n=9). No intergroup difference was observed concerning P-wave amplitude and duration. In all groups, after the cortex underwent CSD, the electrocorticogram (ECoG) amplitude increased approximately 50% compared with the baseline amplitude for the same animal (CSD-induced ECoG potentiation); however, no intergroup difference was observed. Data suggest that coadministration of antioxidant vitamins with Dex may be a helpful therapeutic strategy to reduce brain adverse effects of dexamethasone.

Prooxidant versus antioxidant brain action of ascorbic acid in well-nourished and malnourished rats as a function of dose: a cortical spreading depression and malondialdehyde analysis.

Although ascorbic acid (AA) is an antioxidant, under certain conditions it can facilitate oxidation, which may underlie the opposite actions of AA on brain excitability in distinct seizure models. Here, we investigated whether chronic AA administration during brain development alters cortical excitability as a function of AA dose, as indexed by cortical spreading depression (CSD) and by the levels of lipid peroxidation-induced malondialdehyde. Well-nourished and early-malnourished rats received per gavage 30, 60, or 120 mg/kg/d of AA, saline, or no gavage treatment (naïve group) at postnatal days 7-28. CSD propagation and malondialdehyde levels were analyzed at 30-40 days. Confirming previous observations, CSD velocities were significantly higher in the early-malnourished groups than in the well-nourished groups. AA dose was important: 30 mg/kg/d AA decelerated CSD and reduced malondialdehyde levels, whereas 60 mg/kg/d and 120 mg/kg/d accelerated CSD and augmented malondialdehyde levels compared with the corresponding saline and naïve groups. Our findings reinforce previous suggestion that AA acts as an antioxidant in the brain when administered at low doses, but as a prooxidant at high doses, as indicated by CSD propagation and malondialdehyde levels.

Increased calcium influx triggers and accelerates cortical spreading depression in vivo in male adult rats.

Cortical spreading depression (CSD) is a depolarization wave associated with neurological disorders such as migraine, cerebral ischemia and traumatic brain injury. The mechanism of action of this phenomenon still remains unclear. Although it is suggested that extracellular K(+) accumulation contributes to CSD, other ions may play a relevant role in the mechanism of propagation of the wave. In this context, we hypothesize that Ca(2+) may play an important function in the wave propagation. Our results demonstrate that enhancing Ca(2+) influx into the cells by topical cortical application of the ionophore A23187 (10 µM, 50 µM and 100 µM solutions) increases the velocity of CSD propagation in a dose-dependent manner, and a much higher dose of this compound (2 mM) triggers CSD. In conclusion, increased Ca(2+) influx can be a key element in the induction mechanism of the CSD, and should be assessed in further experimental strategies targeting brain disorders related to CSD.

Aging-dependent brain electrophysiological effects in rats after distinct lactation conditions, and treadmill exercise: a spreading depression analysis.

Aging-related neurophysiological alterations are a matter of growing concern in gerontology. Physical exercise has been therapeutically employed to ameliorate aging-associated deleterious neurological changes. The aging process, as well as the effects of treadmill exercise on brain excitability, can be influenced by nutritional demands during lactation. In this study we investigated whether physical exercise, lactation conditions, and aging interact and modulate brain electrophysiology as indexed by the excitability-related phenomenon known as cortical spreading depression (CSD). Wistar male rats were suckled in litters of 12 or 6 pups (constituting two groups named L12 and L6), with different lactation conditions. Each group was subdivided into exercised (treadmill) and sedentary. CSD was recorded immediately after the exercise period for young, adult, and aged groups (respectively 45-60, 120-130, and 600-700 days old). In L6 groups, the mean CSD velocity (in mm/min) ranged from 2.57±0.24 in aged rats to 3.67±0.13 in young rats, indicating an aging-related CSD deceleration. The L12 condition accelerated CSD (velocities ranging from 3.11±0.21 to 4.35±0.16 in aged and young rats, respectively) while treadmill exercise decelerated it in both L6 groups (range: 3.02±0.19 to 2.57±0.24) and L12 groups (3.32±0.16 to 3.11±0.21), with an observed interaction between factors in the aged group. Furthermore, aging led to a significant failure of CSD propagation. These results contribute to the understanding of underlying mechanisms by which exercise and aging influence brain electrophysiological functioning, previously associated with distinct lactation conditions during the period of brain development.