Spatial Delayed Response Performance Research Articles

Chronic phencyclidine treatment impairs spatial working memory in rhesus monkeys.

Phencyclidine (PCP) could induce schizophrenia (Sz) like behavior in both humans and animals, therefore, has been widely utilized to establish Sz animal models. It induced cognitive deficits, the core symptom of Sz, mainly through influencing frontal dopaminergic function. Nonhuman primate (NHP) studies demonstrated impaired object retrieval detour (ORD) and spatial delayed response (SDR) task performance by acute or chronic PCP treatment. However, NHP investigations, continually monitoring SDR performance before, during and after PCP treatment, are lacking. Present study investigated the long-term influence of chronic PCP treatment on SDR performance and the possible increase of SDR deficit severity and duration by the incremental dosing procedure in rhesus monkeys. SDR task was performed repeatedly up to eight weeks after constant dosing procedure (i.m., 0.3 mg/kg, day 12-25), during which drug effects on locomotor activity and blood cortisol concentration were assessed. Incremental dosing procedure (starting dose 0.3 mg/kg, day 6-19) began five months later. Constant dosing procedure induced differential level of hyperactivity across testing days, without significant influence on blood cortisol concentration. It reduced SDR performance, until occurrence of the first and worst impairment on day 15 and 23 respectively. The impaired performance recovered to pretreatment level over one week after drug cessation. In contrast, incremental dosing procedure impaired SDR performance on the first treatment day, which recovered within treatment period. Results suggested increase of SDR deficit severity by repeated PCP administrations, whereas the incremental dosing procedure did not increase SDR deficit severity and duration.

Δ9Tetrahydrocannabinol impairs reversal learning but not extra-dimensional shifts in rhesus macaques

Expansion of medical marijuana use in the US and the recently successful decriminalization of recreational marijuana in two States elevates interest in the specific cognitive effects of Δ9tetrahydrocannabinol (Δ9THC), the major psychoactive constituent of marijuana. Controlled laboratory studies in nonhuman primates provide mixed evidence for specific effects of Δ9THC in learning and memory tasks, with a suggestion that frontal-mediated tasks may be the most sensitive. In this study, adult male rhesus monkeys were trained on tasks which assess reversal learning, extradimensional attentional shift learning and spatial delayed-response. Subjects were challenged with 0.1–0.5mg/kg Δ9THC, i.m., in randomized order and evaluated on the behavioral measures. Peak plasma levels of Δ9THC were observed 30min after 0.2mg/kg (69±29ng/ml) and 60min after 0.5mg/kg (121±23ng/ml) was administered and behavioral effects on a bimanual motor task persisted for up to 2h after injection. An increase in errors-to-criterion (ETC) associated with reversal learning was further increased by Δ9THC in a dose-dependent manner. The increase in ETC associated with extradimensional shifts was not affected by Δ9THC. Spatial delayed-response performance was impaired by Δ9THC in a retention-interval-dependent manner. Overall the pattern of results suggests a more profound effect of Δ9THC on tasks mediated by orbitofrontal (reversal learning) versus dorsolateral (extradimensional shifts) prefrontal mechanisms.

Reversal of Ketamine-Induced Working Memory Impairments by the GABA Aα2/3 Agonist TPA023

Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms. Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection. Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms. Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.

Motor asymmetry and substantia nigra volume are related to spatial delayed response performance in Parkinson disease

Studies suggest motor deficit asymmetry may help predict the pattern of cognitive impairment in individuals with Parkinson disease (PD). We tested this hypothesis using a highly validated and sensitive spatial memory task, spatial delayed response (SDR), and clinical and neuroimaging measures of PD asymmetry. We predicted SDR performance would be more impaired by PD-related changes in the right side of the brain than in the left. PD ( n = 35) and control ( n = 28) participants performed the SDR task. PD participants either had worse motor deficits on the right (RPD) or left (LPD) side of the body. Some participants also had magnetic resonance imaging for measurement of their substantia nigra (SN) volumes. The LPD group performed worse on the SDR task than the RPD and control groups. Right SN volume accounted for a unique and significant portion of the variance in SDR error, with smaller volume predicting poorer performance. In conclusion, left motor dysfunction and smaller right SN volume are associated with poorer spatial memory.

Frequency and Timing of Severe Hypoglycemia Affects Spatial Memory in Children With Type 1 Diabetes

Repeated severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes. Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure. Our goal was to determine whether the age at which severe hypoglycemia occurs modulates the impact of severe hypoglycemia frequency on long-term spatial memory. We combined data from three independent studies to obtain a sample of children aged 6-18 years with type 1 diabetes (n = 103) and nondiabetic control subjects (n = 60). Each study evaluated previous severe hypoglycemia and tested short (5 s)- and long (60 s)-delay spatial memory with the spatial delayed response task. Type 1 diabetic participants were categorized as having zero, one to two, or three or more severe hypoglycemic episodes and as having their first severe hypoglycemic episode before or after 5 years of age. Information on chronic hyperglycemia (HbA1c values) was also collected. We found that repeated severe hypoglycemia (more than three episodes) reduced long-delay spatial delayed response performance, particularly when severe hypoglycemic episodes began before the age of 5 years. Age of type 1 diabetes onset and estimates of chronic hyperglycemia did not influence performance. High frequency of and early exposure to severe hypoglycemia during development negatively affects spatial long-term memory performance.

Short- and Long-Term Spatial Delayed Response Performance Across the Lifespan

Delayed response paradigms have been used to examine the neural basis of short and long-term memory in humans. However, limited information exists on how delayed response performance changes across the lifespan. Using a well-validated spatial delayed response (SDR) task, we examined performance at short and long delays in over 300 control participants, 7 to 80 years old. We found a significant nonlinear relation between age and short delay performance (children and older adults worse than young adults) and a significant effect of delay length across the entire lifespan (long worse than short; largest in the youngest children, diminishing nonlinearly with age). This study compares short and long-term spatial memory and suggests that the relation between these systems may alter across the lifespan.

A prospective study of severe hypoglycemia and long-term spatial memory in children with type 1 diabetes.

In a previous retrospective study, severe hypoglycemia (SH) was associated with decreased long-term spatial memory in children with type 1 diabetes mellitus (T1DM). In this study, we tested the hypothesis that prospectively ascertained SH would also be associated with decreased spatial long-term memory over time. Children with T1DM (n = 42) and sibling controls (n = 25) performed a spatial delayed response (SDR) task with short and long delays and other neuropsychological tests at baseline and after 15 months of monitoring. Extreme glycemic events and other medical complications were recorded prospectively during follow-up. Fourteen T1DM children experienced at least one episode of SH during the follow-up period (range = 1-5). After controlling for long-delay SDR performance at baseline, age, gender, and age of onset, the presence of SH during the prospective period was statistically associated with decreased long-delay SDR performance at follow-up (semipartial r = -0.38, p = 0.017). This relationship was not seen with short-delay SDR or with verbal or object memory, attention, or motor speed. These results, together with previously reported data, support the hypothesis that SH has specific, negative effects on spatial memory skills in T1DM children.

Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective study.

Performance on long delays of delayed response tasks is associated with medial temporal function, a region of the brain affected by severe hypoglycemia. A previous study showed that children with type 1 diabetes mellitus (T1DM) with higher risk for severe hypoglycemia performed worse than controls on long delays of a spatial delayed response (SDR) task. We tested the more specific hypothesis that frequency of severe hypoglycemia would relate to long delay SDR performance. Children with T1DM (n = 51) and controls (n = 32) performed the SDR task with short and long delays. Information was collected on children's past severe hypoglycemia. In children with T1DM, number of past severe hypoglycemic episodes accounted for a significant portion of the variance in long delay SDR after controlling for age and age of onset. This relationship was not seen with short delay SDR or with other tasks (verbal or object memory, attention, motor speed). These results support the hypothesis that severe hypoglycemia has specific, negative effects on memory skills in children. If this relationship is extrapolated to children with higher frequency of severe hypoglycemia, due to longer duration of disease or poorer glucose control, it may affect daily functioning and thus need to be considered in treatment decisions.

6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Facilitation of Working Memory in Humans by a D2 Dopamine Receptor Agonist

Recent studies on the neurobiology of cognition have focused on the ability of the prefrontal cortex (PFC) to support processes of working memory, i.e, mnemonic processes by which information relevant for a correct response is temporarily maintained to be reevaluated or updated on a trial-by-trial basis. Of most recent interest is the role played by dopamine (DA) in spatial working memory processes of the principal sulcal region of the PFC. Although D1 DA receptors appear to modulate these mnemonic processes in monkeys, several lines of research suggest that D2 DA receptors could also be relevant to cognitive functions. Therefore, we assessed the effects of a specific D2 receptor agonist (bromocriptine) and placebo on visuospatial delayed response performance in human subjects. During delay periods of 0 or 8 sec, subjects were required to remember the spatial location of rapidly presented visual cues displayed in peripheral vision within a 360° circumference. The extent to which D2 receptor activation by bromocriptine facilitated working memory in the 8-sec delay condition relative to placebo performance was assessed. As a means of providing validation of bromocriptine's D2 receptor effect, maximum inhibition of prolactin (PRL) secretion, which is inhibited specifically by activation of D2 receptor sites, was determined. Additionally, tasks having no working memory component were administered to rule out nonspecific effects of bromocriptine on sensory, arousal, attentional, and motor factors. Results demonstrated a significant facilitatory effect of bromocriptine on spatial delayed response performance (i.e., 8-sec delay performance). Results could not be explained by nonspecific effects of bromocriptine. Thus, findings of this study suggest that spatial working memory is facilitated by D2 receptor activation. The role that DA may play in human cognitive processes is discussed within the larger theoretical framework of DA's general role in the facilitation of goal-directed behavior. In the case of cognition, DA may facilitate processes that serve to guide motivated behavior through complex environments.

Evidence against a specific effect of cholinergic drugs on spatial memory in primates

A scopolamine-like delay-dependent impairment in spatial delayed response performance in rhesus monkeys was induced by irrelevant interpolated activity or by using extended retention intervals. Physostigmine readily reversed the effects of scopolamine but had no effect on performance in young monkeys performing an irrelevant distractor task or in monkeys tested using extended retention intervals. Reducing stimulus control did not impair performance and did not alter the dose-response curve for induction of a deficit by scopolamine. Reducing the stimulus presentation time impaired performance across all retention intervals in a way which did not resemble the effect of scopolamine and which disappeared with practice. Our findings do not support the proposal that physostigmine interacts specifically with short-term spatial memory in primates.

Induction of cognitive impairment by scopolamine and noncholinergic agents in rhesus monkeys

In primates, treatment with scopolamine impairs performance of a spatial delayed response task in a way which mimics deficits seen spontaneously in aged primates and demented patients. Despite their efficacy in reversing scopolamine induced disruption, the effects of cholinergic agonists on cognition in aged primates and dements are unimpressive, suggesting that other neurotransmitter systems are also involved in this type of deficit. We have induced a scopolamine- like impairment of spatial delayed response performance in rhesus monkeys using phencyclidine (0.1–0.2 mg/kg i.m.), lorazepam (0.4–0.6 mg/kg s.c.) or tetrahydrocannabinol (1–4 mg/kg p.o.), but not amphetamine (0.1–0.4 mg/kg i.m.), yohimbine (0.1–1.0 mg/kg i.m.) or morphine (2–4 mg/kg i.m). Our findings suggest that disruption of specific neurotransmitter systems other than acetylcholine may contribute importantly to cognitive decline in aging and dementia.

Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models

Cognitive facilitation by physostigmine and tetrahydroaminoacridine (THA) was compared in two primate models. Disruption of spatial delayed response performance by scopolamine (0.03 mg/kg) was fully reversed by coadministration of 5 doses of physostigmine in the range 0.03–0.08 mg/kg, but by only one dose (4.0 mg/kg) of THA; partial reversal of some effects of scopolamine was observed at 1 and 3 mg/kg of THA. Visual recognition memory was enhanced following treatment with 4 doses of physostigmine in the range 0.001–0.03 mg/kg. The effect of THA across the group of animals was not significant but performance tended to improve using a dose of 0.8 mg/kg. Our findings indicate that THA does not have a superior profile to physostigmine as a cognitive enhancer in primates.

Sex as a factor in spatial delayed-response performance by rhesus monkeys.

Sex as a factor in spatial delayed-response performance by rhesus monkeys.