Age- and Sex-Dependent Laterality of Rat Hippocampal Cholinergic System in Relation to Animal Models of Neurodevelopmental and Neurodegenerative Disorders

Abstract

Studies suggest age- and sex-dependent structural and functional patterns of human cerebral lateralization underlie hemisphere specialization and its alterations in schizophrenia. Recent works report sexual dimorphism of neurons in the hippocampal formation and specialization of hemispheres in rats. Our experiments indicate for the first time functional lateralization of the high-affinity choline uptake (HACU) system directly associated with a synthesis of acetylcholine in the hippocampus of Wistar rats. The markedly increased HACU activity was found in the left compared to the right hippocampus of adult male but not female animals. Lineweaver-Burk plot analysis revealed a statistically significant increase of Vmax in the left hippocampus of 14-day-old when compared to 7-day-old males. It appears that laterality of HACU occurs during late postnatal maturation, and its degree is markedly enhanced after puberty and attenuated during aging. Quinolinic acid (QUIN), an endogenous agonist of N-methyl-D-aspartate type glutamate receptors, was used in this study to evaluate the neurodevelopmental hypothesis of schizophrenia. It is known that elevated levels of QUIN accompany viral infections, increasing the risk of developing schizophrenia. Bilateral intracerebroventricular application of QUIN (250 nmoles/ventricle) to pups aged 12 days significantly impaired the cholinergic hippocampal system of adolescent male and female rats and reversed lateralization of male HACU. Morphological analysis indicated marked changes in brain lesion sizes (extensive 24 h and moderate 38 days after the operation). Asymmetry of lesions was observed in the majority of cases, but the left hemisphere was not generally more vulnerable to QUIN effects than the right side. Moreover, no lateral differences were found between lesioned hippocampi in the specific binding of [3H]hemicholinium-3 (10%-15% loss of binding sites when compared to sham-operated animals). In summary, our results indicate a symmetrical drop in the number of choline carriers of lesioned male rats but a asymmetrical decrease in the activity of remaing carriers, suggesting defects in processes of sexual brain differentiation, leading under normal conditions to the higher activity of carriers in the left hippocampus. The data demonstrate viral infection-mediated alterations in normal patterns of brain asymmetry and are discussed in relation to animal models of neurodevelopmental and neurodegenerative diseases.

Exposure of Postnatal Rats to a Static Magnetic Field of 0.14 T Influences Functional Laterality of the Hippocampal High-Affinity Choline Uptake System in Adulthood; In vitro Test with Magnetic Nanoparticles

“…of an attenuated left/right asymmetry in the activities of hippocampal choline carriers from 12-week-old control rats separated from nursing mothers for 60-120 min at postnatal days 7 or 14 (Table I) compared to intact animals from our previous work (14) and from this study (controls of Table II) should not be quite surprising. However, 3-10 min separations per day for the first three postnatal weeks are usually used in the above-mentioned studies in contrast to our longer single separation.…”

“…A comparison of both transport and binding data facilitates a more detailed determination of changes on presynaptic cholinergic nerve terminals. Our previous experiments have demonstrated that the HACU system is sexually dimorphic and functionally lateralized (14). We have observed an enhanced activity of the carriers in the left when compared to the right hippocampus of male but not female rats.…”

“…Our previous work showed age-and sex-dependent functional lateralization of the hippocampal HACU system (14). The highest asymmetry in the activity of hemicholinium-3 sensitive carriers between the right and left side was found in male rats older than 3 months.…”

“…Preparation of synaptosomal fractions and all subsequent experiments were carried out as previously described in more detail (14). Briefly, the hippocampi were homogenized (glassTeflon Potter's Braun homogenizer) in 10 volumes of 0.32 M sucrose (Serva) and the homogenates were centrifuged (centrifuge Universal 32R, 1000 · g for 10 min, 4°C).…”

“…It is suggested that global and metric aspects are associated with the right hemisphere, specific local aspects with the left hemisphere, on the contrary. The neurochemical (e.g., 14,20), volumetric (21,22) and some behavioural experiments (23) indicate structural and/or functional asymmetry and possible hemispheric specialization in rats, too.…”