Revealing past memories: proactive interference and ketamine-induced memory deficits

Abstract

Memories of events that occur often are sensitive to interference from memories of similar events. Proactive interference plays an important and often unexamined role in memory testing for spatially and temporally unique events ("episodes"). Ketamine (NMDA receptor antagonist) treatment in humans and other mammals induces a constellation of cognitive deficits, including impairments in working and episodic memory. We examined the effects of the ketamine (2.5-100 mg/kg) on the acquisition, retrieval, and retention of memory in a delayed-match-to-place radial water maze task that can be used to assess proactive interference. Ketamine (2.5-25 mg/kg, i.p.) given 20 min before the sample trial, impaired encoding. The first errors made during the test trial were predominantly to arms located spatially adjacent to the goal arm, suggesting an established albeit weakened representation. Ketamine (25-100 mg/kg) given immediately after the sample trial had no effect on retention. Ketamine given before the test trial impaired retrieval. First errors under the influence of ketamine were predominantly to the goal location of the previous session. Thus, ketamine treatment promoted proactive interference. These memory deficits were not state dependent, because ketamine treatment at both encoding and retrieval only increased the number of errors during the test session. These data demonstrate the competing influence of distinct memory representations during the performance of a memory task in the rat. Furthermore, they demonstrate the subtle disruptive effects of the NMDA antagonist ketamine on both encoding and retrieval. Specifically, ketamine treatment disrupted retrieval by promoting proactive interference from previous episodic representations.

Figure 1.

Delayed-match-to-sample radial water maze task. Each day (Day x, Session x) rats were given one forced-choice sample trial, with access to all but the start (S₁) and goal (G) arm blocked. The goal arm contained a submerged platform. On the test trial (typically 1 h later), all arms were open and a different start (S₂) arm was used to test memory for the spatial location of the current goal location. Typically only one sample and one test trial were given each day. Solid lines depict path to goal. The most common first errors are depicted in Test Trial on Day x + 1, Session x + 1. Once rats are well trained, the majority of first errors are to one of the arms on either side of the goal (adjacent; dashed line) or to the previous goal arm.

Figure 2.

Delay-dependent memory performance in a DMP radial water maze task. A, Effect of varying the retention interval (delay between sample and test trials). Means ± SEM represent five trial blocks at each delay. Control trials (CON) involved no sample trial with the goal moved to a new location (find the platform yourself). Horizontal gray band indicates range of 10 control trials. After a control trial, rats were returned to the maze within 2 min for a short-delay trial (2-MIN). Rats were tested on a series of long delays (4–48 h) at both 6 and 12 months of age. B, Effect of varying the intersession interval on mean ± SEM errors. Errors doubled when rats were tested on two sample-test sessions with different goal arms in the same day. Each ISI was tested four times. C, The distribution of first error by type for all long-delay trials is shown for each delay. The percentage of rats making no errors (first choice was correct goal) is presented at no error (dark gray). Note that, with increasing delays, more rats made an initial error and that the majority of first errors are to the arms adjacent to the goal (white). Thus, at 1 h delay ∼50% of rats made at least one error, with the majority being to the adjacent arm and a smaller percentage to the goal of the previous day or one of the three other arms. This distribution did not vary as a function of delay (compare 1HR–48HR and MIN-2). During control trials, the majority of errors are, as might be expected, to the previous goal arm (black). The distribution of previous, adjacent, and other errors during control trials was significantly different from all other distributions (*p < 0.001, χ² test). All of the other distributions (1HR–48HR and 2-MIN) were not different from each other. D, The distribution of first error by type for all ISI trials. The distribution of previous, adjacent, and other errors during 2 h ISI trials was significantly different from distribution during 24 and 72 h ISI trials (*p < 0.001, χ² test). Notably, the distribution of error types during 2 h ISI trials was similar to the distribution during control trials, with the majority of rats initially choosing the previous goal arm.

Figure 3.

Dose effects of ketamine (2.5–100 mg/kg) on encoding, retention, and retrieval. Top schematic (A) illustrates sequence of sample and test trials and the administration of ketamine on encoding (presample dose), retention (after-sample dose), and retrieval (pretest dose) using a 4 h retention interval. Mean errors (B) illustrate the dose-related effect of ketamine on encoding (left), retrieval (right), but not retention (center). Gray band illustrates the range of mean errors per day for all 1 h delay trials on the days after ketamine or saline treatments. *p < 0.05 compared with either presample or pretest saline (0) treatment. C, Effects of collapsed dose treatments on the distribution of first error by type. There were no differences in the distribution of first errors between saline, presample, or after-sample ketamine (p values > 0.2, χ² test). However, ketamine administered before the test session altered the distribution of first errors by reducing the number of errors to the adjacent arms and increasing the number of first errors to the previous goal position. The distribution of previous, adjacent, and other errors during pretest ketamine trials was significantly different from all other distributions (*p < 0.001, χ² test). Note that both presample ketamine and pretest ketamine increased the mean number of errors (B) and the number of rats making at least one error (C). However, presample ketamine resulted in more initial errors to the adjacent arm, whereas pretest ketamine resulted in more initial errors to the previous arm. The distribution of errors after pretest ketamine is analogous to that observed on control trials when rats have no knowledge of the new goal and navigate to the previous goal location (see Fig. 2C) or the condition of two sample-test trials in the same day evidencing proactive interference (see Fig. 2D). S₁, S₂, Start arms; G, goal arm.

Figure 4.

Lack of state-dependent effects of ketamine (6.25 or 12.5 mg/kg) on encoding and retention. A, Schematic illustrates presample dosing of saline or ketamine, followed by a pretest dosing of saline or ketamine. Each rat (n = 24) received each of seven treatment combinations [Sal–Sal, Ket(6.25)–Sal, Ket(12.5)–Sal, Sal–Ket(6.25), Sal–Ket(12.5), Ket(6.25)–Ket(6.25), and Ket(12.5)–Ket(12.5)] over the course of 7 weeks of testing (1 treatment per week). B, Effects of ketamine on encoding and retrieval, as well as the greater impairment when both the sample and test trials were run under the influence of ketamine. Gray band illustrates the range of mean errors per day for all 1 h delay trials the day after ketamine or saline treatments. *p < 0.05 compared with Sal–Sal treatment mean (Dunnett's t tests); **p < 0.05 compared with indicated ketamine dose (paired t test). C, Effects of collapsed dose treatments on first error by type. Note that ketamine administered before the test session or before both the sample and test session altered the distribution of first errors by reducing the number of errors to the adjacent arms and increasing the number of first errors to both the previous goal position and other arms. The distribution of previous, adjacent, and other errors during both pretest and presample/pretest ketamine trials was significantly different from all other distributions (*p < 0.001, χ² test). This distribution of errors is similar to that observed in Figure 3C (pretest ketamine doses) and further suggests that, under the influence of ketamine, rats are accessing the previously formed representation of the goal and not the newly formed representation. S₁, S₂, Start arms; G, goal arm.