High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the Dorsal Striatum.

Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17ß-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80 µg/kg), or amphetamine (0.5 mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using in vivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias.

Changes in dendritic spine density on layer 2/3 pyramidal cells within the cingulate cortex of late pregnant and postpartum rats.

A rapid upregulation of astrocytic protein expression within area 2 of the cingulate cortex (Cg2) of the maternal rat occurs within 3h postpartum and persists throughout lactation. Previous studies have shown that similar changes in astrocytic proteins can signal changes in local synapses and dendritic spines. Thus, here we used the Golgi-Cox impregnation technique to compare spine density in layer 2 and 3 pyramidal cells of Cg2, the CA1 region of the hippocampus and the parietal cortex (ParCx) among metestrus, late pregnant (LP), 3-hour postpartum (3H PP) and 16-day postpartum rats (D16 PP). Rats in the 3H PP group had higher numbers of dendritic spines/10 µm on the apical dendrites of pyramidal neurons in both Cg2 and CA1 than the other groups, which did not differ. A similar pattern was observed in basilar dendrites but this failed to reach significance. In Cg2, Sholl analysis revealed that rats in the D16 PP group had a significantly greater extent of dendritic arborization in the basilar region than any other group. These data suggest that the changes in astrocytic proteins that occur in Cg2 in the postpartum period are associated with neuronal plasticity in pyramidal layers 2 and 3.

Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation.

Estrogens (E) and progestins regulate synaptogenesis in the CA1 region of the dorsal hippocampus during the estrous cycle of the female rat, and the functional consequences include changes in neurotransmission and memory. Synapse formation has been demonstrated by using the Golgi technique, dye filling of cells, electron microscopy, and radioimmunocytochemistry. N-methyl-d-aspartate (NMDA) receptor activation is required, and inhibitory interneurons play a pivotal role as they express nuclear estrogen receptor alpha (ERalpha) and show E-induced decreases of GABAergic activity. Although global decreases in inhibitory tone may be important, a more local role for E in CA1 neurons seems likely. The rat hippocampus expresses both ERalpha and ERbeta mRNA. At the light microscopic level, autoradiography shows cell nuclear [3H]estrogen and [125I]estrogen uptake according to a distribution that primarily reflects the localization of ERalpha-immunoreactive interneurons in the hippocampus. However, recent ultrastructural studies have revealed extranuclear ERalpha immunoreactivity (IR) within select dendritic spines on hippocampal principal cells, axon terminals, and glial processes, localizations that would not be detectable by using standard light microscopic methods. Based on recent studies showing that both types of ER are expressed in a form that activates second messenger systems, these findings support a testable model in which local, non-genomic regulation by estrogen participates along with genomic actions of estrogens in the regulation of synapse formation.

Novel target sites for estrogen action in the dorsal hippocampus: an examination of synaptic proteins.

Structural studies have shown that estrogens increase dendritic spine number in the dorsal CA1 field of rat hippocampus using Golgi impregnation as well as the number of dorsal CA1 synapses visualized via electron microscopy. The present study was carried out to further these findings by examining changes in the levels of pre- and postsynaptic proteins using radioimmunocytochemistry (RICC). In this study, 2 days of estradiol-benzoate treatment produced significant and comparable increases in synaptophysin, syntaxin, and spinophilin immunoreactivity (IR) in the CA1 region of the dorsal hippocampus of ovariectomized female rats. For spinophilin, IR was also increased in the hilar region of the dentate gyrus as well as CA3. In all cases, the nonsteroidal estrogen antagonist CI628, which has been previously shown to block spine formation, inhibited the effects of estrogen. However, these protein differences were not detected in whole hippocampus using Western blots. These findings add to a growing body of evidence that estrogens increase synapses in the CA1 region of hippocampus along with changes in previously unidentified sites. These results also suggest that RICC is a rapid and sensitive method for examining molecular changes in synaptic profiles in anatomically distinct brain regions.

Perinatal distress leads to lateralized medial prefrontal cortical dopamine hypofunction in adult rats.

Obstetric complications involving anoxia or prolonged hypoxia are suspected to increase the risk for such mental disorders as schizophrenia and attention deficit-hyperactivity disorder. In previous studies, we reported evidence of enhanced nucleus accumbens (NAcc) dopamine (DA) function in adult rats subjected to intrauterine anoxia during cesarean (C) section birth. In the present study, we used voltammetry and monoamine-sensitive electrodes to investigate the possibility that this functional hyperactivity of the meso-NAcc system is attributable to a loss of inhibitory control from the medial prefrontal cortex (PFC). We monitored the DA responses to repeated once-daily stress in the right or left PFC of adult male rats born vaginally (VAG) or by C-section, either with (C + 15) or without (C + 0) an additional 15 min of intrauterine anoxia. In C + 15 animals, we observed a pronounced and persistent blunting of stress-induced DA release in the right PFC but not in the left; with repeated testing, a similar pattern of dampened right PFC DA stress responses emerged in C + 0 animals. In addition, C + 15 animals were spontaneously more active than VAG and C + 0 animals and displayed an increase in PFC DA transporter density that was also lateralized to the right hemisphere. There was no evidence, however, that PFC D(1) and D(2) receptor levels differed between birth groups or hemisphere. These findings suggest a mechanism by which perinatal complications involving anoxia might contribute to the etiology of mental disorders that have been linked to disturbances in central DA transmission and lateralized PFC dysfunction.

Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex.

The medial prefrontal cortex modulates the nucleus accumbens dopamine response to stress and has been implicated in feedback regulation of hypothalamic-pituitary-adrenal axis activation by stress. Here we report on the effects of bilateral neonatal (postnatal day 7) ibotenate-induced lesions to the medial prefrontal cortex on nucleus accumbens dopamine and neuroendocrine function in adult rats. Voltammetry was used to monitor the dopamine response to each of five, once-daily exposures to tail-pinch stress whereas alterations in neuroendocrine function were determined from the plasma corticosterone response to a single 20-min episode of restraint stress. Potential lesion-induced deficits in sensory-motor gating were assessed by measuring prepulse inhibition of the acoustic startle response before and after repeated stress. Our data show that each daily stress episode elicited larger and longer-lasting dopamine increases in prefrontal cortex-lesioned animals than in sham-lesioned controls. Furthermore, greater stress-induced elevations in plasma corticosterone were seen in lesioned animals than in their sham-lesioned counterparts. However, while repeated stress potentiated startle responses in animals of both groups, there was no effect of lesion on the amplitude or on prepulse inhibition of the startle response.Together, these findings indicate that neonatal prefrontal cortex damage can lead to changes in mesolimbic dopamine and neuroendocrine function during adulthood. They also add to a growing body of experimental and clinical evidence implicating abnormal prefrontal cortex neuronal development in the pathophysiology of schizophrenia and other disorders linked to central dopamine dysfunction.

Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine response to stress: an electrochemical study in the adult rat.

Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA) transmission. In the present study, the effects of neonatal excitotoxic lesions to the VH on spontaneous locomotor activity and stress-elicited increases in extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats. Male pups received, on postnatal day 7, bilateral injections of either an ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4 months of age, animals were assessed during five daily sessions for changes in spontaneous locomotor activity associated with habituation to a novel environment. Voltammetry was used in separate groups of sham- and VH-lesioned animals to monitor the NAcc DA response to each of five once-daily exposures to tail-pinch stress. The results indicate that while VH-lesioned animals seem to habituate to novelty, they remain hyperactive relative to sham-lesioned controls. In contrast, however, stress consistently elicited in VH-lesioned animals smaller and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These data suggest that neonatal excitotoxic damage to VH leads to changes in DA function that persist into adulthood. The blunted response to stress seen in VH-lesioned animals indicates that one consequence of such damage is a functional hyporeactivity in meso-NAcc DA neurons. The fact that these animals are spontaneously more active suggests compensatory changes in DA function that are efferent to DA terminals in NAcc.

Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat.

Evidence from animal studies suggests that a period of anoxia to the fetus, a consequence common to many birth complications, results in long-term alterations in ventral mesencephalic dopamine function. Long-term functional changes in these dopamine neurons, in particular those that innervate the nucleus accumbens, also occur when animals are repeatedly stressed. In the present study, we examined the possibility that a period of anoxia during a Cesarean section birth can later alter the development of stress-induced sensitization of dopamine transmission in the nucleus accumbens. Dams were decapitated on the last day of gestation and the entire uterus was removed by Cesarean section. Pups were then delivered either immediately (Cesarean section group) or were immersed in a 37 degrees C saline bath for 3.5 or 13.5 min (Cesarean section+anoxia groups) before delivery of the pups. A fourth group of pups that were born vaginally served as controls (Vaginal group). Three to four months postnatally, animals from each group were implanted with monoamine-selective carbon-fiber electrodes into the nucleus accumbens. Voltammetry was used to monitor the dopamine response to each of five consecutive, once daily, 15-min exposures to tail-pinch stress. The results show that the first exposure to stress elicited dopamine signal increases of comparable amplitudes and durations in all animals. However, when compared to the initial stress response, the fourth and fifth exposures to tail-pinch elicited significantly longer-lasting dopamine responses in animals born by Cesarean section, either with or without added anoxia. In contrast, there was no significant day-to-day enhancement of the stress response in control, vaginally born animals. The findings reported here provide experimental support for the idea that birth complications may contribute to the pathophysiology of psychiatric disorders, in particular those that involve central dopamine dysfunction, such as schizophrenia. Specifically, our results suggest that subtle alterations in birth procedure may be sufficient to increase the sensitivity of mesolimbic dopamine neurons to the effects of repeated stress in the adult animal.

Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats.

We examined the possibility that anoxia at birth can alter behavioral sensitization to amphetamine during adulthood. Male rats born either vaginally or by Cesarean section with or without an additional 15-min period of anoxia received five once-daily injections of either d-amphetamine (2.0 mg/kg, i.p.) or vehicle or no pretreatment. One week later, all animals received a challenge injection of amphetamine (0.5 mg/kg, i.p.). The data indicate that all three birth groups of animals pretreated with amphetamine had sensitized equally to the drug's behavioral effect. Of animals pretreated with saline, however, only those born by Cesarean section with added anoxia displayed a sensitized response to amphetamine, suggesting that the stress of daily injection was sufficient to sensitize these animals to amphetamine. These findings provide experimental support for clinical evidence implicating obstetric complications, such as perinatal anoxia, in the pathophysiology of schizophrenia.

Hemicholinium-3 (HC3) blocks the effects of ethylcholine mustard aziridinium (AF64A) in the developing rat.

Two- to 3-day-old rat pups received bilateral intracerebroventricular (i.c.v.) injections of 2.0 nmol/microliters AF64A or vehicle. Half of the pups had been preinjected i.c.v. with hemicholinium-3 (HC3) and the other half with saline. The administration of AF64A impaired spatial learning/memory and caused brain damage characterized by marked loss of forebrain cortical/subcortical tissue and ventricular hypertrophy when these were assessed in adulthood. Neither the behavioral nor the histopathological effects of AF64A were observed in rats that had been pretreated with HC3. Since HC3 is a potent and relatively selective inhibitor of high affinity choline uptake (HACU), the results indicate that the toxic effects of AF64A in the neonatal rat are dependent upon its uptake via the HACU site. If as other research suggests, this site is primarily on Ach neurons in the neonatal rat, then the consequences of neonatal damage to cholinergic neurons are severe for forebrain development.

Event-related potential sensitivity to acoustic and semantic properties of terminal words in sentences.

This experiment was concerned with the effects of phonologically correct masking on the electrophysiological responses to terminal words of spoken sentences differing in contextual constraint. Two event-related potential (ERP) components, the N400 and N200, were recorded to the terminal words of high and low constraint sentences in four conditions. In the Control condition, subjects (Ss) simply attended to the sentences with no explicit task instructions. In the Semantic condition, Ss were required to listen to the stimuli in order to make semantic judgements about the terminal word of each sentence. The Control+Masking condition was identical to the Control condition except for the simultaneous presentation of a masking stimulus. The Semantic+Masking condition had Ss listening to sentences in the presence of masking with the task of making semantic judgements about the terminal word of each sentence. ERPs were recorded from Fz, Cz, Pz, T3, and T4 in 10 subjects. Amplitudes of both the N200 and the N400 were sensitive to contextual constraint with larger responses elicited by the terminal words of low constraint sentences. In addition to demonstrating the co-occurrence of the N200 and N400, this experiment highlighted a functional separation between the two components. Masking had no statistically significant effect on N200 latency but N400 latency was delayed in the masked conditions relative to those in the unmasked conditions. It is proposed that the N200 and N400 are manifestations of two different processes; the N200 reflects the acoustic/phonological processing of the terminal word while the N400 reflects the cognitive/linguistic processing. The relationship between the N200 recorded in this experiment and the discrimination N200 is discussed.