Using Extinction-Renewal to Circumvent the Memory Strength Boundary Condition in Fear Memory Reconsolidation

Reconsolidation is a process by which memories are destabilized, updated, and then restabilized. Strong memories are resistant to undergoing reconsolidation. Here, we addressed whether an overtrained fear memory could be made susceptible to reconsolidation by first extinguishing, and then renewing, the memory. Rats were trained with ten tone-footshock pairings, followed by eight days of tone extinction in the training context. The next day, rats were placed into a second context and memory for the tone was renewed/reactivated with a single tone presentation. Immediately following reactivation, rats received an injection of midazolam or vehicle. Rats were then tested for freezing to the tone in a third context. Midazolam had no effect in rats that did not undergo tone extinction, but significantly attenuated freezing to the tone in extinguished rats. Thus, rats that received tone extinction underwent tone memory reconsolidation following its renewal. In a second experiment, we administered the reactivation session and midazolam injections prior to extinction. Midazolam had no effect and rats extinguished at a rate similar to controls. These data suggest that strong emotional memories are capable of updating following weakening of memory expression through extinction.

Thyroidectomy- And Ptu-Induced Hypothyroidism: Effect of L-Thyroxine on Suppression of Spatial and Non-Spatial Memory Related Signaling Molecules

The calcium/calmodulin protein kinase II (CaMKII) signaling cascade is crucial for hippocampus-dependent learning and memory. In adult rats, Hypothyroidism impairs hippocampus-dependent learning and memory, which can be prevented by simple replacement therapy with L-thyroxine (thyroxine, T4) treatment. In this study, we compared animal models of hypothyroidism induced by thyroidectomy and treatment with propylthiouracil (PTU). Our findings show that thyroidectomy and PTU models are equally effective as indicated by the identical plasma levels of thyroid stimulating hormone (TSH) and T4. The two model produced identical degree of inhibition of synaptic plasticity as indicated by depression of LTP. We then investigated the effect of thyroidectomy hypothyroidism and thyroxine treatment on the underlying molecular mechanism of spatial and non-spatial types of memory. To generate spatial memory, we used training in the radial arm water maze (RAWM) where rats had to locate a hidden platform. For non-spatial memory, rats were trained to swim to a clearly visible platform in an open swim field. Western blot analysis of hippocampal area CA1 revealed that training, on both mazes, of control and thyroxine-treated hypothyroid rats produced significant increases in the P-CaMKII, PKCγ, calcineurin and calmodulin protein levels, but the training failed to induce such increases in untreated thyroidectomized rats. As expected, we show that thyroxine therapy prevented the deleterious effects of hypothyroidism at the molecular level.

'Online' integration of sensory and fear memories in the rat medial temporal lobe

How does a stimulus never associated with danger become frightening? The present study addressed this question using a sensory preconditioning task with rats. In this task, rats integrate a sound-light memory formed in stage 1 with a light-danger memory formed in stage 2, as they show fear when tested with the sound in stage 3. Here we show that this integration occurs ‘online’ during stage 2: when activity in the region that consolidated the sound-light memory (perirhinal cortex) was inhibited during formation of the light-danger memory, rats no longer showed fear when tested with the sound but continued to fear the light. Thus, fear that accrues to a stimulus paired with danger simultaneously spreads to its past associates, thereby roping those associates into a fear memory network.

Multiple memory systems

Multiple memory systems describes how memories can be declarative or non-declarative; incentive learning produces one type of non-declarative memory. Patients with bilateral hippocampal damage have declarative memory deficits (amnesia) but intact non-declarative memory; patients with striatal dysfunction, for example, Parkinson’s patients who lose striatal dopamine have impaired incentive learning but intact declarative memory. Rats with lesions of the fornix (hippocampal output pathway), but not lesions of the dorsal striatum, have impaired spatial (declarative) memory; rats with lesions of the dorsal striatum, but not fornix, have impaired stimulus–response memory that relies heavily on incentive learning. These memory systems possibly inhibit one another to control responding: in rats, a group that received fornix lesions and had impaired spatial learning did better on an incentive task; in humans, hippocampus damage was associated with improvement on an incentive learning task and striatal damage was associated with increased involvement of the hippocampus in a route-recognition task.