Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala.In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.

Mice with cytotoxic lesions of the dorsal hippocampus (DH) underestimated 15 s and 45 s target durations in a bi-peak procedure as evidenced by proportional leftward shifts of the peak functions that emerged during training as a result of decreases in both ‘start’ and ‘stop’ times. In contrast, mice with lesions of the ventral hippocampus (VH) displayed rightward shifts that were immediately present and were largely limited to increases in the ‘stop’ time for the 45 s target duration. Moreover, the effects of the DH lesions were congruent with the scalar property of interval timing in that the 15 s and 45 s functions superimposed when plotted on a relative timescale, whereas the effects of the VH lesions violated the scalar property. Mice with DH lesions also showed enhanced reversal learning in comparison to control and VH lesioned mice. These results are compared with the timing distortions observed in mice lacking δ -opioid receptors (Oprd1 ^−/− ) which were similar to mice with DH lesions. Taken together, these results suggest a balance between hippocampal–striatal interactions for interval timing and demonstrate possible functional dissociations along the septotemporal axis of the hippocampus in terms of motivation, timed response thresholds and encoding in temporal memory.

Cognitive reappraisal is a widely utilized emotion regulation strategy that involves altering the personal meaning of an emotional event to enhance attention to emotional responses. Despite its common use, individual differences in cognitive reappraisal techniques and the spontaneous recovery, renewal, and reinstatement of negative responses across varying contexts may limit its effectiveness. Furthermore, detached reappraisal could cause distress for clients. According to Gross’s theory, cognitive reappraisal is an effortless process that can occur spontaneously. When guided language triggers cognitive reappraisal as an emotion regulation strategy in laboratory or counseling settings, clients experience improved emotional states, but this induced strategy may not necessarily guide them in regulating emotions in similar future situations. Therefore, effectively applying cognitive reappraisal techniques in clinical practice to help clients alleviate emotional distress in daily life remains a significant concern. Exploring the mechanism of cognitive reappraisal reveals that reconstructing stimulus meaning is akin to extinction learning, which entails fostering cognitive contingency that the original stimulus provoking negative emotions will no longer result in negative outcomes in the current context. However, extinction learning is a new learning process rather than an elimination process. The activation of new learning relies on the presentation of critical cues, with contextual cues often playing a vital role, such as a safe laboratory or consulting room environment. We propose a new understanding of cognitive reappraisal based on the schema theory and the dual-system theory, emphasizing the significance of environmental interaction and feedback in constructing new experiences and updating schemata. This approach ultimately enriches the schema during training and integrates the new schema into long-term memory. Bottom-up behavioral experiences as schema enrichment training provide the foundation for top-down regulation to function. This method can assist clients in activating more suitable schemata probabilistically when encountering stimuli in real life, forming stable emotions, and achieving transfer and application across diverse contexts.

Exploring the 4th Dimension: Hippocampus, Time, and Memory Revisited