Variable Decay of Memory and Its Recovery in Cycloheximide-Treated Mice

Abstract

Mice were trained in an automated visualdiscrimination task. When injected with cycloheximide before training, mice showed: (a) some impairment of memory within minutes after the beginning of training, (b) gradual development of total amnesia in less than 3 hr or in more than 6 hr after training, depending on the extent of training, and (c) spontaneous recovery of memory within 3 days after training. The results are consistent with the operation of three processes of memory storage: (i) a short-term process that is independent of protein synthesis, (ii) a long-term process that is dependent on protein synthesis, and (iii) a slow-developing memory storage that becomes apparent during the days after training.Previous studies on effects of cycloheximide and acetoxycycloheximide on learning and memory in mice given brief training have repeatedly demonstrated normal acquisition in the presence of these potent inhibitors of cerebral protein synthesis, normal retention for about 3 hr, and then marked and permanent amnesia by 6 hr after training (1, 2). These experiments suggested a simple view of learning and memory in mice. Since acquisition and retention for at least 3 hr were normal during marked inhibition of cerebral protein synthesis, it seemed reasonable to postulate a "short-term" memory storage process that is independent of protein synthesis, with a fixed lifetime of 3-6 hr. Since long-term retention was impaired only if the drug were given shortly before or very shortly after training, a "long-term" memory storage process that is dependent on protein synthesis was also postulated that is normally initiated during training or within minutes there-FIG. 1. The Deutsch Carousel for training a discrimination habit in mice. Mice are placed in the apparatus while facing position A. The mouse is then rotated to position B for trial one, and then to adjacent positions for subsequent trials. At each position, the mouse must touch the small object to escape shock. Once the mouse has been secured in the apparatus, the entire training procedure is controlled by a PDP/8L computer.after. With decline of the proposed "short-term" process after 3 hr, absence of the "long-term" process is detectable and amnesia is observed.Recent experiments in a multiple-trial, automated discrimination task and the work of others suggest that the situation is somewhat more complex. In the present report, we describe studies indicating that (a) cycloheximide impairs the gradual acquisition of a discrimination task when training is continued beyond 20-30 trials, although it does not affect acquisition up to this point, (b) memory is detectable for less than 3 hr after training when cycloheximide-treated mice are given brief training, but considerable memory is detectable for more than 6 hr after training when cycloheximide-treated mice are given more extended training, and (c) once amnesia has developed, it may persist for only several days, followed by complete, spontaneous recovery of memory. We will present an interpretation of thes...

Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation

“…Gold 2006). For example, in studies using cycloheximide or anisomycin to inhibit protein synthesis, the range of times to onset of amnesia range from ∼1 h to 24 h for memory (Quartermain and McEwen 1970;Squire and Barondes 1972) and for decay of long-term potentiation range from ∼10 min to 4 h (Huang et al 1994;Tang et al 1999;cf. Gold 2006).…”

The influence of duration of protein synthesis inhibition on memory

“…Three injections of Ani produced significant amnesia in all four training conditions; nearly all animals were amnestic under Conditions I and II. (13) " "…”

“…The discrepancy in the relative effectiveness of the two drugs, pretraining versus posttraining, suggests that Cyclo when administered prior to training caused some impairment of acquisition in addition to blocking memory formation. Squire and Barondes [ 13] have reported that Cyclo impaired acquisition of an active avoidance task in mice. The amnesia caused by a posttraining injection of Cyclo (when it could not have interfered with training) demonstrated that Cyclo is a powerful amnestic agent (Experiment 4).…”

Relation of memory formation to controlled amounts of brain protein synthesis

“…While the,agents Cycloheximide (2,4,7,8,9) and Acetoxycycloheximide (1,3) have frequently been employed in such studies, we have found Anisomycin (5,6) to be particularly useful for b/o reasons: (a) the duration of inhibition of protein synthesis in mouse brain can be controlled by giving successive injections of Anisomycin (Ani) at 2-hr intervals (5), and (b) an injection that produces about 2 hrs of in --hibition at 80% or greater --or even a series of such injections --is far below the lethal dose of the drug (5). The degree of amnesia has been found to depend upon both the duration of inhibition and several parameters of the passive-avoidance training situation (shock intensity and latenci~s to enter and to escape the training box)j…”