Phase-dependent molecular requirements for memory reconsolidation: differential roles for protein synthesis and protein kinase A activity

After consolidation, a process that requires gene expression and protein synthesis, memories are stable and highly resistant to disruption by amnestic influences. Recently, consolidated memory has been shown to become labile again after retrieval and to require a phase of reconsolidation to be preserved. New findings, showing that the dependence of reconsolidation on protein synthesis decreases with the age of memory, point to changing molecular requirements for reconsolidation during memory maturation. We examined this possibility by comparing the roles of protein synthesis (a general molecular requirement for memory consolidation) and the activation of protein kinase A (PKA) (a specific molecular requirement for memory consolidation), in memory reconsolidation at two time points after training. Using associative learning in Lymnaea, we show that reconsolidation after the retrieval of consolidated memory at both 6 and 24 h requires protein synthesis. In contrast, only reconsolidation at 6 h after training, but not at 24 h, requires PKA activity, which is in agreement with the measured retrieval-induced PKA activation at 6 h. This phase-dependent differential molecular requirement for reconsolidation supports the notion that even seemingly consolidated memories undergo further selective molecular maturation processes, which may only be detected by analyzing the role of specific pathways in memory reconsolidation after retrieval

A Bio-Logical Theory of Animal Learning

This article provides the foundation for a new predictive theory of animal learning that is based upon a simple logical model. The knowledge of experimental subjects at a given time is described using logical equations. These logical equations are then used to predict a subject’s response when presented with a known or a previously unknown situation. This new theory suc- cessfully anticipates phenomena that existing theories predict, as well as phenomena that they cannot. It provides a theoretical account for phenomena that are beyond the domain of existing models, such as extinction and the detection of novelty, from which “external inhibition” can be explained. Examples of the methods applied to make predictions are given using previously published results. The present theory proposes a new way to envision the minimal functions of the nervous system, and provides possible new insights into the way that brains ultimately create and use knowledge about the world

Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence.

The transition from recreational drug use to addiction involves pathological learning processes that support a persistent shift from flexible, goal-directed to habit behavioral control. Here, we examined the molecular mechanisms supporting altered function in hippocampal (HPC) and dorsolateral striatum (DLS) memory systems following abstinence from repeated cocaine. After 3 weeks of cocaine abstinence (experimenter- or self-administered), we tested new behavioral learning in male rats using a dual-solution maze task, which provides an unbiased approach to assess HPC- versus DLS-dependent learning strategies. Dorsal hippocampus (dHPC) and DLS brain tissues were collected after memory testing to identify transcriptional adaptations associated with cocaine-induced shifts in behavioral learning. Our results demonstrate that following prolonged cocaine abstinence rats show a bias toward the use of an inflexible, habit memory system (DLS) in lieu of a more flexible, easily updated memory system involving the HPC. This memory system bias was associated with upregulation and downregulation of brain-derived neurotrophic factor (BDNF) gene expression and transcriptionally permissive histone acetylation (acetylated histone H3, AcH3) in the DLS and dHPC, respectively. Using viral-mediated gene transfer, we overexpressed BDNF in the dHPC during cocaine abstinence and new maze learning. This manipulation restored HPC-dependent behavioral control. These findings provide a system-level understanding of altered plasticity and behavioral learning following cocaine abstinence and inform mechanisms mediating the organization of learning and memory more broadly

Effects of a Secretin Receptor Antagonist on Cerebellar Learning

Eyeblink conditioning (EBC) is an important procedure used to understand the neuronal plasticity that occurs with learning and memory. Delay EBC requires a brainstem-cerebellar circuit while the role of the cerebellum in trace EBC is not as well understood because it requires a more complex neural circuitry involving regions of the medial prefrontal cortex and hippocampus. Secretin is a neuropeptide that is found in high concentrations within the cerebellum. Previous work has shown that blocking secretin’s effects in the cerebellum with intra-cerebellar infusion of relatively large volume of a secretin receptor antagonist impairs delay EBC (Fuchs et al. 2014). Here we study the effect that intra-cerebellar infusion of 0.5 μL secretin receptor antagonist (5-27 secretin) or vehicle prior to training sessions 1 and 2 has on delay and trace EBC in rats. A 600-ms tone CS was used for the delay EBC paradigm and a 300-ms tone CS followed by a 300-ms trace interval was used for the trace EBC paradigm. For delay EBC, the delay vehicle and antagonist groups displayed similar acquisition of conditioned responses (CRs). There was a trend for the trace antagonist group to underperform compared to the trace vehicle group though not quite at a significant level. One explanation for why the results for the delay EBC do not support previous work is that slow learning occurred in the delay vehicle group that may have prevented the effects of secretin receptor antagonist from reaching significance. The trend for the trace antagonist group to display decreased acquisition of CRs suggests that the cerebellum does play an important role in trace EBC. However, in order to better understand the neural circuitry involved in trace EBC, future work should analyze the role that cerebellar secretin itself has on trace EBC

Historical response rates, reinforcement context, and behavioral persistence

In several studies, historically lower-rate responding has been found to be more persistent than historically higher-rate responding (e.g., Lattal, 1989; Nevin, 1974). In these studies, historical response-rate differences were generated by reinforcement schedules (e.g., fixed-ratio [FR] and differential-reinforcement-of-low-rates-of-responding [DRL]) that directly affect response rate. The current study was conducted with pigeons pecking keys to determine whether this finding would hold when response-rate differences were generated by the context of reinforcement, such as a concurrently available source of reinforcement or schedule of response-independent food. In each of 3 experiments, a history-building condition was followed by a history-testing condition. In Experiment 1, history building consisted of a multiple-concurrent (variable interval [VI] 40-s VI 20-s, VI 40-s VI 80-s) schedule, and history testing consisted of a multiple fixed interval (FI) 40-s, FI 40-s. It was expected that response rate would be lower on the VI 40-s schedule that was paired with the VI 20-s than the VI 40-s that was paired with the VI 80-s (cf. Belke, 1992), however, large differences in response rate on the two VI 40-s schedules were not obtained. The rate and temporal distribution of historically lower-rate responding initially changed more rapidly than did higher-rate responding in each of the four pigeons. In attempt to increase the difference in response rate across the two components of the multiple schedule, in Experiment 2, history building consisted of a multiple concurrent (VI 40-s Tandem VI FR, VI 40-s Tandem VI DRL), and history testing consisted of a multiple (FI 40-s, FI 40-s). Schedule values were adjusted in attempt to obtain response-rate differences, but the programmed rate of reinforcement was always equal on the VI 40-s alternative across the two components. Again, large differences in response rate on the two VI 40-s schedules were not obtained. The rate of historically lower-rate responding changed more rapidly in three of the four pigeons, and the temporal distribution of historically lower-rate responding changed more gradually than did higher-rate responding. In Experiment 3, history building consisted of a multiple mixed VI 30-s variable time (VT) 30-s, VI 30-s schedule, and history testing consisted of a multiple FI 30-s, FI 30-s. The VT schedule provided the contextual schedule designed to reduce response rate in the same component. In this case, larger response-rate differences across the two components were obtained. Lower-rate responding was less persistent, both in terms of rate and temporal distribution of responding. Results are discussed in terms of factors shown to determine resistance to change, and the importance of understanding relations between schedules of reinforcement and resultant response organization

Assessing the *discriminative properties of response -reinforcer relations using concurrent schedules of reinforcement

The discriminative properties of schedules of reinforcement have been assessed by making a choice response conditional upon some aspect of the schedule that produced the choice component. The discriminative properties of concurrent schedules of reinforcement and the effect of disruptions in the response-reinforcer relation were investigated using conditional-discrimination procedures. In the first experiment, choice components were produced by responding to one of two variable-interval (VI) schedules. Disruptions in the temporal contiguity between a VI response and a choice component were introduced by arranging a percentage of choice components according to a variable-time schedule. Choice responding was a function of the response that produced the choice component. Delays of up to 0.5 s resulted in responding that corresponded to the last VI response made.;In the second experiment, the delay between a VI response and choice component was controlled for by arranging choices according to concurrent VI and differential-reinforcement-of-other-behavior (DRO) schedules. Choice responding was a function of which schedule arranged the choice component. Varying the DRO value resulted in increased choice accuracy at shorter (0.25 to 2.00 s) delays and decreased accuracy at delays of greater than 2.00 s. These results indicate that concurrent schedules of reinforcement can serve a discriminative function and that the discriminative properties of response-reinforcer relations are a function of the temporal contiguity between a response and a stimulus change

Effects of Fixed and Mixed Delays on Responding under Variable-Interval Schedules

Delays to reinforcement are ubiquitous in the natural environment, where those delays often vary. Still, most research examining delayed reinforcement has focused only on fixed delays. Little research has examined the effects of variable delays. Nonresetting fixed and mixed delays to reinforcement were imposed on the responding of 4 pigeons previously maintained on a multiple variable-interval (VI) VI schedule of immediate reinforcement. Mixed delays consisted of two alternating delay values, the mean of which equaled the value of the fixed delay. A progressive delay procedure was used, in which delay durations increased across successive sessions. Conditions included using unsignaled (Mixed-Change) and signaled delays (Mixed-Signaled) in which both mixed delay values changed across sessions. A third condition (Mixed-Constant) involved using unsignaled delays in which one of the mixed delay values remained constant while the other progressively increased across sessions. Mixed delay components maintained higher rates of responding in some conditions. Response rates decreased more and changes in interresponse times were greater with unsignaled than signaled delays. With unsignaled delays, changes in responding were a function of the average obtained delay within each component of the multiple schedule, regardless of whether the delays were fixed or mixed. Obtained delays tended to be shorter in the mixed delay component, resulting in higher rates of responding

Dependência resposta-reforço, taxa de respostas e resistência à mudança

Dissertação (mestrado)—Universidade de Brasília, Instituto de Psicologia, Departamento de Processos Psicológicos Básicos, Programa de Pós-Graduação em Ciências do Comportamento, 2017.O efeito de diferentes porcentagens de dependência resposta-reforço sobre a resistência à mudança foi avaliado quando a diferença na taxa de respostas entre os componentes de um esquema múltiplo na Linha de Base (LB) foi manipulada. Na LB, ratos foram expostos a um esquema múltiplo com dois componentes. Em cada componente, intervalos entre reforços variáveis foram programados para igualar a taxa de reforços entre os componentes. Entre condições (i) a dependência foi 10%, em um componente (componente 10%), e 100%, no outro (componente 100%); e (ii) a diferença na taxa de respostas entre os componentes na LB foi manipulada. Nas condições em que as taxas de respostas foram iguais (condições A), um esquema tandem intervalo variável (VI) reforçamento diferencial de baixas taxas (DRL) esteve em vigor no componente 100%. Nessas condições, o valor do DRL foi acoplado ao intervalo entre respostas obtido no componente 10%. Nas condições em que o DRL foi retirado (condições B), apenas um VI esteve em vigor no componente 100%. O esquema tandem VI DRL voltou a ser utilizado no componente 100% em condições em que a taxa de respostas nesse componente foi 40-60% (condição C) ou 70-90% (condição D) maior que aquela no componente 10%. Em cada condição, extinção esteve em vigor em cada componente durante o Teste. Em geral, quando as taxas de respostas foram diferentes entre os componentes na LB (condições B, C e D), a resistência foi maior no componente com menor dependência e taxa de respostas mais baixa na LB. Entretanto, quando as taxas de resposta foram iguais (condições A), não houve diferenças sistemáticas na resistência à mudança entre os componentes. Esses resultados sugerem uma relação entre diferença na taxa de respostas entre os componentes na LB e a resistência à mudança diferencial e replicam aqueles de outros estudos que indicam a relevância da relação resposta-reforço na determinação da resistência à mudança.The effect of different percentages of the response-reinforcer dependency on resistance to change was assessed when the difference in response rates between components of a multiple schedule in Baseline (BL) was manipulated. In BL, rats were exposed to a two-component multiple schedule. In each component, variable interreinforcer intervals were programmed to equate reinforcement rate between components. Across conditions (i) the dependency was 10%, in one component (10% component) and 100% in the other (100% component); and (ii) the difference in response rates between components in BL was manipulated. In conditions in which response rates were equal (conditions A), a tandem variable interval (VI) differential reinforcement of low rate (DRL) schedule was in effect in the 100% component. In these conditions, the value of the DRL was yoked to the obtained interresponse time in the 10% component. In conditions in which the DRL was suspended (conditions B), only a VI was in effect in the 100% component. The tandem VI DRL was again in effect in the 100% component in conditions in which response rates in this component were 40-60% (condition C) or 70-90% (condition D) higher than that in the 10% component. In each condition, extintion was in effect in each component in the Test. In general, when response rates were different between components in BL (conditions B, C and D), resistance to change was greater in the component with lower dependency and lower response rate in BL. However, when response rates were equal (conditions A), there were no systematic differences in resistance to change between components. These results suggest a relation between the difference in response rates between components in BL and differential resistance to change, and replicate previous findings indicating the relevance of the response-reinforcer relation in determining resistance to change

Discrimination of Temporally Remote Causal Relations by Pigeons: Effects of Signals that Mediate the Temporal Gaps

The discriminative effect of the response-reinforcer relation may contribute to the change in response rates that occur when reinforcement is delayed. The present study investigated this possibility using a discrete-trials conditional discrimination procedure. Each trial began with a sample component where a variable-interval schedule was assigned either to a left or right key. The key peck that ended the schedule, which served as the sample response, in different conditions initiated delays with a signal fully mediating the delay interval, delays with a signal present only during the first second of the interval, or delays with the absence of signal. The delay in turn was followed by a choice component where one alternative was correct if the sample response had been a left-key response and the other alternative was correct if the sample had been a right-key response. Correct discrimination of the location of the sample response resulted in reinforcement. Accuracy was high with a full signal; slightly lower with a partial, relative to a full, signal; and lowest without a signal. Thus, responses producing delayed reinforcers were detected, but only when a stimulus change accompanied the response. The results parallel the way response rates change when behavior is maintained under a conventional reinforcement schedule as a result of adding delays prior to reinforcement at each type of delay. This suggests a possible role for the discriminative effect of the response-reinforcer relation in the control of behavior by (delayed) reinforcement