Improvement In Spatial Working Memory Research Articles

REVIEW: Cognitive effects of nicotine: genetic moderators

Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, beta2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. alpha7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine.

Nitric-Oxide Synthase Mediates the Ability of Darbepoetin Alfa to Attenuate Pre-Existing Spatial Working Memory Deficits in Rats Subjected to Transient Global Ischemia

Erythropoietin has been reported to improve the behavioral performance of healthy mice in tests thought to depend on synaptic plasticity in the CA1 region of the hippocampus. We show here for the first time that a single injection of the erythropoietin analog darbepoetin alfa reverses pre-existing cognitive deficits in adult rats that had been subjected to transient global ischemia produced by four-vessel occlusion (4-VO). Quantification of neuronal density demonstrated that 12 min of 4-VO selectively killed more than 90% of CA1 neurons in the dorsal hippocampus. Rats that had sustained a bilateral loss of hippocampal CA1 neurons in this range (4-VO rats) displayed more errors and longer escape latencies in the Barnes maze compared with sham-operated controls. A single injection of darbepoetin alfa (5000 U/kg i.p.) 4 h before behavioral testing decreased deficits in escape latency for 4-VO rats but not sham-operated controls. This improvement in spatial working memory performance was correlated with increased levels of nitric-oxide metabolites in the ventral hippocampus. Systemic administration of the nitric-oxide synthase inhibitor N(G)-nitro-L-nitro-arginine methyl ester reversed the increase in nitric-oxide metabolites and improvements in spatial working memory produced by darbepoetin alfa (5000 U/kg, i.p.) at a dose (10 mg/kg, i.p.) that did not impair the spatial working memory performance of intact rats. Taken together, these findings suggest that darbepoetin alfa reverses pre-existing spatial working memory deficits resulting from transient global ischemia by increasing the activity of nitric-oxide synthase, an enzyme implicated in synaptic plasticity.

Preferential enhancement of working memory in mice lacking adenosine A2A receptors

There is evidence that adenosine acting at A2A receptors (A2AR) can influence striatal plasticity and cognitive functions. We examined spatial working memory in wild-type (WT) and A2A receptor knock-out (KO) mice using two assessments: the eight arm radial maze and a repeated trial Morris water maze (MWM) paradigm. Compared to WT littermates, A2AR KO mice displayed enhanced working memory as evidenced by a decrease in escape latency in trial 2 compared to trial 1 in the repeated trial MWM, and by a reduction in working memory errors in the radial arm maze. Both MWM and radial maze results indicated that this enhancement of working memory in A2AR KO mice was selective for this specific short-term memory. The decrease in escape latency in MWM was detected with an inter-trial interval of 15 s but not with intervals of 10 or 60 min. In the radial maze, spatial reference memory and memory retention after prolonged training (15 days but not 6 days) were not affected by the A2AR KO. These results demonstrate preferential improvement in spatial working memory by genetic inactivation of the A2AR and support a modulatory role of the A2AR in spatial working memory in mice.

Transient early postnatal corticosterone treatment of rats leads to accelerated aquisition of a spatial radial maze task and morphological changes in the septohippocampal region

In the present study new-born rats were treated with corticosterone (CORT) between postnatal days 1 and 12. At the age of 16–20 weeks, these animals were tested for spatial learning capacity using an eight-arm radial maze. After behavioral testing, density of cholinergic fibers and sizes of the mossy fiber terminal fields in the hippocampus and number of cholinergic and GABAergic neurons in the septal area were quantified. In the radial arm maze CORT-treated animals initially showed better working memory performance than controls. However, control animals showed a significant improvement of spatial working memory in the last trials and reached similar working memory scores as compared to treated animals. At neither day of training differences in reference memory errors were found between groups. In the diagonal band of Broca, both numbers of cholinergic and GABAergic neurons were increased after corticosterone treatment. The fiber systems in hippocampus showed no significant differences between groups. In conclusion, early postnatal stress induced by CORT administration in neonatal rats results in mild, yet significant morphological and behavioral changes in later life.

Mice Lacking Dopamine D2and D3Receptors Have Spatial Working Memory Deficits

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D(1) agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D(2) mutants but remained submaximal in METH-pretreated D(3) mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.

Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D(1) agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D(2) mutants but remained submaximal in METH-pretreated D(3) mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.

Chronic nicotine-induced improvement of spatial working memory and D2 dopamine effects in rats

Nicotine improves working memory function in a variety of different testing situations. In a series of studies, we have found that chronic nicotine infusion improves working memory performance of rats in the win-shift version of the radial-arm maze. In the current studies, we examined the interaction of chronic nicotine effects in the radial-arm maze with dopamine D2 agonist and antagonist drugs, since we have previously found significant interactions of acute nicotinic agonist and antagonist effects with D2 systems. Replicating our earlier results, significant nicotine-induced improvements in working memory performance were seen. Chronic co-infusion of raclopride, a D2 antagonist, or quinpirole, D2/D3 agonist, were not found to significantly interact with the choice accuracy improvement caused by nicotine. Acute challenge with a range of quinpirole doses also did not affect the facilitating effect of chronic nicotine. This stands in contrast to the significant interactions of D2 systems with acute nicotine effects. Acute and chronic nicotine administration have similar effects of facilitating memory performance in the radial-arm maze. However, these effects appear to have differential interactions with D2 systems. Drug Dev. Res. 39:29–35. © 1997 Wiley-Liss, Inc.