Changes in the plastic properties of hippocampal dendritic spines underlie the attenuation of place learning in healthy aged rats.

Normal aging is characterized by slight impairments in spatial memory, and the modification of some electrophysiological parameters that underlie place learning and associated reference memory. However, the morphological mechanisms underlying these impairments remain unknown. In the present study, we analyzed the spine density and the proportion of thin, mushroom, stubby, wide, branched and double spines on pyramidal neuron dendrites in the hippocampal CA1 field of young and aged rats. These parameters were assessed both before and after evaluating place learning and reference memory in the Morris water maze. Aged rats adopted an egocentric strategy to resolve the task, swimming slower and further, and taking longer to locate the sunken platform. While probe trials revealed that aged animals could recall the platform position, these animals spent more time exploring incorrect quadrants than young rats. An increase in spine density was observed after task performance in both young and aged rats, but aging provoked a decrease in the density of thin spines. In addition, there was an increase in the density of mushroom and wide spines in aged animals after task performance as compared with the untested aged counterparts. Moreover, in aged animals there were fewer thin spines and more wide spines after task performance than in the young tested animals. These findings support the view that aging attenuates but does not abolish spatial memory, a process that may be associated with plastic changes in the type of dendritic spines on aged hippocampal CA1 neurons.

Estradiol-mediated modulation of memory and of the underlying dendritic spine plasticity through the life span.

The morphophysiology of the nervous system changes and adapts in response to external environmental inputs and the experiences of individuals throughout their lives. Other changes in the organisms internal environment can also contribute to nervous system restructuring in the form of plastic changes that underlie its capacity to adapt to emerging psychophysiological conditions. These adaptive processes lead to subtle modifications of the organisms internal homeostasis which is closely related with the activity of chemical messengers, such as neurotransmitters and hormones. Hormones reach the brain through the bloodstream, where they activate specific receptors through which certain biochemical, physiological, and morphological changes take place in numerous regions. Fetal development, infancy, puberty, and adulthood are all periods of substantial hormone-mediated brain remodeling in both males and females. Adulthood, specifically, is associated with a broad range of life events, including reproductive cycles in both sexes, and pregnancy and menopause in women. Events of this kind occur concomitantly with eventual modifications in behavioral performance and, especially, in cognitive abilities like learning and memory that underlie, at least in part, plastic changes in the dendritic spines of the neuronal cells in cerebral areas involved in processing cognitive information. Estrogens form a family that consists of three molecules [17ß-estradiol (E2), estrone, estriol] which are deeply involved in regulating numerous bodily functions in different stages of the life-cycle, including the modulation of cognitive performance. This review addresses the effects of E2 on the dendritic spine-mediated synaptic organization of cognitive performance throughout the life span.

Selective estrogen receptor modulators regulate dendritic spine plasticity in the hippocampus of male rats.

Some selective estrogen receptor modulators, such as raloxifene and tamoxifen, are neuroprotective and reduce brain inflammation in several experimental models of neurodegeneration. In addition, raloxifene and tamoxifen counteract cognitive deficits caused by gonadal hormone deprivation in male rats. In this study, we have explored whether raloxifene and tamoxifen may regulate the number and geometry of dendritic spines in CA1 pyramidal neurons of the rat hippocampus. Young adult male rats were injected with raloxifene (1 mg/kg), tamoxifen (1 mg/kg), or vehicle and killed 24 h after the injection. Animals treated with raloxifene or tamoxifen showed an increased numerical density of dendritic spines in CA1 pyramidal neurons compared to animals treated with vehicle. Raloxifene and tamoxifen had also specific effects in the morphology of spines. These findings suggest that raloxifene and tamoxifen may influence the processing of information by hippocampal pyramidal neurons by affecting the number and shape of dendritic spines.

Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test.

The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway.

The motor learning induces plastic changes in dendritic spines of Purkinje cells from the neocerebellar cortex of the rat.

PURPOSE: The presynaptic stimulatory activity of parallel fibers on the dendritic spines of cerebellar Purkinje cells (PC) has a strong influence on the organization of motor learning. Motor learning has been shown to modify the synapses established on PC dendritic spines but the plastic changes of the different spine types, possibly underlying motor learning, have not been studied. METHODS: Adult male Sprague-Dawley rats were trained daily for 26 days using an acrobatic paradigm (AC), at the end of which dendritic spine density and the proportion of the different types of spines was assessed. RESULTS: The learning curves of AC rats reflected a robust decrease in the latency for resolution and in the errors committed during the first week of training, which subsequently stabilized until the end of training. Dendritic spine density was greater in these AC rats, reflected in a larger proportion of thin, mushroom and stubby spines. CONCLUSIONS: Since thin spines are associated with acquiring novel information whilst mushroom spines are associated with long-term information storage, there appears to be a strong relationship between AC motor learning and consolidation. The increase in stubby spines could be related to the regulation of excitatory stimulation underlying motor overactivity.

Cytoarchitectural characteristics of hippocampal CA1 pyramidal neurons of rats, four months after global cerebral ischemia and progesterone treatment.

PURPOSE: To analyze the cytoarchitectural characteristics of the remaining pyramidal neurons in the hippocampal CA1 subfield of rats, four months after global cerebral ischemia (GCI) and progesterone treatment. METHODS: Dendritic arborization, and density and shape of the dendritic spines of CA1 pyramidal neurons in brains of intact rats, or rats submitted 120 days earlier to GCI and treatment with progesterone (8 mg/kg) or its vehicle, at 15 min, and 2, 6, 24, 48, and 72 h after the onset of reperfusion, were analyzed in samples processed by a modified Golgi method. RESULTS: Few impregnated CA1 pyramidal neurons were identified in the ischemic vehicle-treated rats, with a short apical dendrite devoid of bifurcations and dendritic spines. In contrast, the remaining CA1 pyramidal neurons sampled from ischemic progesterone-treated rats showed sinuously branched dendrites with similar number of bifurcations and whole density of spines, and higher proportional density of mushroom spines than those in the intact group. CONCLUSIONS: These cytoarchitectural characteristics may underlie the long-term preservation of place learning and memory functions seen after ischemia and progesterone neuroprotective treatment, possibly compensating for the severe reduction in neuronal population.

Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer's disease.

SAMP8 is a strain of mice with accelerated senescence. These mice have recently been the focus of attention as they show several alterations that have also been described in Alzheimer's disease (AD) patients. The number of dendritic spines, spine plasticity, and morphology are basic to memory formation. In AD, the density of dendritic spines is severely decreased. We studied memory alterations using the object recognition test. We measured levels of synaptophysin as a marker of neurotransmission and used Golgi staining to quantify and characterize the number and morphology of dendritic spines in SAMP8 mice and in SAMR1 as control animals. While there were no memory differences at 3 months of age, the memory of both 6- and 9-month-old SAMP8 mice was impaired in comparison with age-matched SAMR1 mice or young SAMP8 mice. In addition, synaptophysin levels were not altered in young SAMP8 animals, but SAMP8 aged 6 and 9 months had less synaptophysin than SAMR1 controls and also less than 3-month-old SAMP8 mice. Moreover, while spine density remained stable with age in SAMR1 mice, the number of spines started to decrease in SAMP8 animals at 6 months, only to get worse at 9 months. Our results show that from 6 months onwards SAMP8 mice show impaired memory. This age coincides with that at which the levels of synaptophysin and spine density decrease. Thus, we conclude that together with other studies that describe several alterations at similar ages, SAMP8 mice are a very suitable model for studying AD.

Plastic changes in dendritic spines of hippocampal CA1 pyramidal neurons from ovariectomized rats after estradiol treatment.

Cognitive impairment or its recovery has been associated with the absence or reestablishment of estrogenic actions in the central nervous system of female experimental animals or women. It has been proposed that these cognitive phenomena are related to estrogen-mediated modulatory activity of synaptic transmission in brain structures involved in cognitive functions. In the present work a morphological study was conducted in adult female ovariectomized rats to evaluate estradiol-dependent dendritic spine sprouting in hippocampal pyramidal neurons, and changes in the presynaptic marker synaptophysin. Three or ten days after estradiol treatment (10 µg/day, twice) in the ovariectomized rats, a significant increase of synaptophysin was observed, which was coincident with a significant higher numerical density of thin (22%), stubby (36%), mushroom (47%) and double spines (125%), at day 3, without significant changes of spine density at day 10, after treatment. These results may be interpreted as evidence of pre- and postsynaptic plastic events that may be involved in the modulation of cognitive-related behavioral performance after estrogen replacement therapy.

Egocentric working memory impairment and dendritic spine plastic changes in prefrontal neurons after NMDA receptor blockade in rats.

Working memory may involve context-dependent allocentric or own movement-dependent egocentric strategies. While allocentric working memory can be disrupted by N-methyl-D-aspartate (NMDA) blockage, the possible effects of NMDA receptor manipulation on the egocentric strategy have not been studied. Because dendritic spine plasticity in part underlies working memory-related behavioral efficiency, egocentric working memory performance was evaluated in adult rats following NMDA receptor blockade with 10mg/kg of the NMDA-receptor antagonist CPP, i.p. Dendritic spine density and the proportion of different spine types (thin, stubby, mushroom, wide, branched and double) were assessed in third-layer pyramidal neurons of the dorsomedial prefrontal cortex, after behavioral testing. Working memory was evaluated by challenging the rats to resolve twelve trials per day in a single-day session over five consecutive days, in a "cross-arm" maze and according to a delayed match-to-sample procedure. In control animals, the dendritic spine density remained unchanged after behavioral testing, although the proportion of mushroom spines decreased while that of the branched spines increased. NMDA receptor blockade impaired the behavioral performance of rats and resulted in a decrease in dendritic spine density when compared to the control animals, and dendritic spine types were unchanged. These results suggest that behavioral efficiency of egocentric working memory is dependent on NMDA receptor activation, and that plastic changes in spine cytoarchitecture may play a key role in behavioral performance.