Christina L. Williams

Organizational Effects of Early Gonadal Secretions on Sexual Differentiation in Spatial Memory

Neonatally castrated (MNC) and control male rats (MC) and female rats treated neonatally with estradiol benzoate (FNE) and female controls (FC) were studied. In Exp. 1 spatial memory was assessed using a 12-arm radial maze. During acquisition, MC and FNE groups were more accurate in choice behavior than FC and MNC groups. In Exp. 2 the discriminative control exerted by different types of cues was evaluated. Alteration of the geometry of the room but not movable landmarks disrupted performance of MC and FNE groups. For the FC and MNC groups, alteration of either geometry or landmarks did not disrupt performance. In Exp. 3 the effect of a 15-min delay was determined. MC and FNE groups were more disrupted by a delay than MNC and FC groups. Together, these data suggest that early exposure to gonadal steroids (probably estradiol) improves acquisition of spatial tasks by reorganizing and simplifying associational-perceptual processes that guide spatial ability.

THE ORGANIZATIONAL EFFECTS OF GONADAL STEROIDS ON SEXUALLY DIMORPHIC SPATIAL ABILITY

Numerous studies have provided evidence that both human and nonhuman males reliably outperform females on tasks that require spatial ability. Because most of the research on this topic has utilized hormonally normal adults as subjects, it is still not known to what extent, if any, sex differences in spatial ability can be attributed to hormonally organized dimorphisms in neural structures subserving cognitive function. The purpose of this paper is to address this critical issue in three areas: (1) Research that demonstrates that male rodents initially outperform females on maze tasks that utilize visuospatial representation will be reviewed. (2) New data which provide strong evidence for the organizational effects of gonadal steroids will be described. The timing of the sensitive period for hormone action, the specific hormones involved and their possible sites of action will be discussed. (3) The question of what behavioral processes hormones might be affecting to cause differential performance on spatial tasks will be examined. The studies described in this review suggest that gonadal steroids, probably the testosterone metabolite estradiol, cause organizational effects during perinatal development which have multiple effects on the associational-perceptual-motor biases that guide visuospatial navigation.

Memory retention is modulated by acute estradiol and progesterone replacement.

Ovarian hormones alter spine density of hippocampal granule and pyramidal cells in young adult and aging female rats (P. Miranda, C. L. Williams, & G. Einstein, 1999; C. S. Woolley, 1998). The present study used a delayed matching-to-place version of the water maze to investigate a behavioral correlate of these hormone-induced changes in hippocampal connectivity in 3- and 8-month-old female rats. When primed with 10-microg injections of estradiol 72 and 48 hr before testing, the memory retention of ovariectomized rats was improved compared with retention after priming with oil. A single injection of progesterone maintained this enhancement if testing occurred within 8 hr of the progesterone injection but not if testing occurred more than 24 hr after the progesterone injection. These findings indicate that estradiol and progesterone alter memory retention and suggest that these changes may be the result of hormone-induced increases in hippocampal connectivity.

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease

Increased levels of a 40–42 amino‐acid peptide called the amyloid β protein (Aβ) and evidence of oxidative damage are early neuropathological markers of Alzheimers disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from Aβ‐mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimers amyloidosis and monitored over time the effects of administering melatonin on brain levels of Aβ, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time‐dependent elevation of β‐amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.

Simultaneous temporal processing is sensitive to prenatal choline availability in mature and aged rats.

RATS were trained at 2–4 months and at 24–26 months of age on a peak-interval timing procedure in which auditory and visual stimuli signaled two different fixedinterval schedules of reinforcement (15 and 30 s) that were presented simultaneously in a hierarchical fashion. Compared with control rats, increases in the probability of attention to the 15 s signal were observed for both the choline-supplemented and the choline-deficient rats. In contrast, an increase in attention to the 30 s signal was only observed for the choline-supplemented rats, whereas choline-deficient rats exhibited a decrease in attention that increased with age. Proportional rightward shifts in the remembered times of reinforcement emerged for the 24–26-month-old rats in the cholinedeficient and control groups, but not in the cholinesupplemented group. These results indicate that prenatal choline supplementation facilitates cognitive function across the lifespan, whereas prenatal choline deficiency impairs divided attention and accelerates age-related declines in temporal processing.

Choline supplementation during prenatal development reduces proactive interference in spatial memory

Previous research has demonstrated that increasing dietary choline during early development can have long-lasting effects on cholinergic (Ch) function that are correlated with improvement of spatial memory ability in rats. The present study is designed to further our understanding of these organizational changes in brain and behavior by examining the effects of spaced vs. massed trials. A third of the rats (n=10) were supplemented with choline chloride prenatally by adding it to the drinking water of their dams. Another third were made deficient of choline during early development by removing choline from the dams diet. The remaining rats served as untreated controls. Postnatally, the offspring were maintained on a choline-sufficient diet and at 120 days of age they began 12-arm radial maze training. The maze data revealed two major effects of early choline availability: (1) Both choline-supplemented and choline-deficient rats performed more accurately than control littermates when trials were spaced. These differences in spatial ability did not appear to be a function of differential response or cue-use strategies. (2) Choline-supplemented rats showed little proactive interference when trials were massed; whereas control rats demonstrated moderate levels and choline-deficient rats exhibited high levels of proactive interference as a function of massed trials. These data suggest that the behavioral consequences of early dietary availability of choline may involve the modification of the discriminative abilities used to attend to stimuli that demarcate the end of one trial and the start of another as well as the capacity for remembering the locations that have been visited during a trial.

Organizational changes in cholinergic activity and enhanced visuospatial memory as a function of choline administered prenatally or postnatally or both.

This experiment was an examination of the effects of supplemental dietary choline chloride given prenatally (to the diet of pregnant rats) and postnatally (intubed directly into the stomachs of rat pups) on memory function and neurochemical measures of brain cholinergic activity of male albino rats when they became adults. The data demonstrate that perinatal choline supplementation causes (a) long-term facilitative effects on working and reference memory components of a 12-arm radial maze task, and (b) alternations of muscarinic receptor density as indexed by [3H]quinuclidinyl benzilate (QNB) binding and choline acetyltransferase (ChAT) levels in the hippocampus and frontal cortex of adult rats. An analysis of the relationship between these organizational changes in brain and memory function indicated that the ChAT-to-QNB ratio in the hippocampus is highly correlated with working memory errors, and this ratio in the frontal cortex is highly correlated with reference memory errors.

Spatial memory retention is enhanced by acute and continuous estradiol replacement.

Estradiol replacement to ovariectomized female rats causes dramatic changes in hippocampal structure and function as well as in performance on hippocampally dependent tasks. Using a delayed matching-to-place version of the water maze, the present study examines the time course of estradiol-induced enhancements in memory retention as well as the effectiveness of acute and continuous patterns of replacement. One 10-microg injection of estradiol administered on each of two successive days resulted in significant improvements in memory retention that persisted for approximately 4 days following the second injection. When estradiol administration continued for 10 consecutive days, these improvements in memory retention persisted. These findings indicate that estradiol replacement can improve memory retention and that these improvements can be maintained by continuous replacement for at least 10 days.

Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats

The effects of choline supplementation during two time-frames of early development on radial-arm maze performance and the morphology of basal forebrain neurons immunoreactive for the P75 neurotrophin receptor (NTR) in male and female Sprague-Dawley rats were examined. In the first experiment, rats were supplemented with choline chloride from conception until weaning. At 80 days of age, subjects were trained once a day on a 12-arm radial maze for 30 days. Compared to control littermates, supplemented rats made fewer working and reference memory errors; however, the memory enhancing effects of choline supplementation were greater in males than females. A morphometric analysis of NTR-immunoreactive cell bodies at three levels through the medial septum/diagonal band (MS/DBv) of these rats revealed that perinatal choline supplementation caused the somata of cells in the MS/DBv to be larger by 8-15%. In a second experiment, choline supplementation was restricted to embryonic days 12-17. A developmental profile of NTR immunoreactive cell bodies in the MS/DBv of 0-, 8-, 16-, 30- and 90-day old male and female rats again revealed that cell bodies were larger in choline-supplemented rats than controls. As in the behavioral studies, the effect of choline supplementation was greater in male than female rats. These data are consistent with the hypothesis that supplementation with choline chloride during early development leads to an increase in the size of cell bodies of NTR-immunoreactive cells in the basal forebrain and that this change may contribute to long-term improvement in spatial memory.

Activation and odor conditioning of suckling behavior in 3-day-old albino rats.

The circumstances under which a novel odor could elicit nipple attachment behavior in 3-day-old albino rats were investigated. In Experiment 1, rats suckled washed nipples scented with citral (a lemon odor) only if they either had received tactile stimulation (by stroking with a soft artists brush) or had been administered amphetamine in the presence of citral prior to the suckling test. Pups stimulated in citrals absence or simply exposed to citral without stimulation failed to suckle such nipples. In Experiment 2, rats stimulated in a benzaldehyde (an almond odor) ambience suckled washed nipples scented with benzaldehyde but not those with citral scent. The opposite held for rats stimulated in a citral-rich environment. The stimulus conditions that support this conditioning were investigated in Experiment 3. Simultaneously increasing citral concentration and raising ambient temperature markedly attenuated the phenomenon. Experiment 4 demonstrated that not all classes of stimulation produced conditioning. Caffeine, in a wide range of doses, did not allow citral to elicit suckling on washed nipples. These findings are discussed within a framework of higher order conditioning. They may provide a mechanism by which naturally occurring stimuli come to elicit the species- and age-typical behavior of suckling.