Anxiety disorders are commonly associated with increased generalization of fear from a stress- or trauma-associated environment to a neutral context or environment. Differences in context-associated memory in males and females may contribute to increased susceptibility to anxiety disorders in women. Here we examined sex differences in context fear generalization and its neural correlates. We observed stronger context fear conditioning and more generalization of fear to a similar context in females than males. In addition, context preexposure increased fear conditioning in males and decreased generalization in females. Accordingly, males showed stronger cFos activity in dorsal hippocampus during memory retrieval and context generalization, whereas females showed preferential recruitment of basal amygdala. Together, these findings are consistent with previous research showing that hippocampal activity correlates with reduced context fear generalization. Differential competition between hippocampus and amygdala-dependent processes may thus contribute to sex differences in retrieval of context fear and greater generalization of fear-associated memory.

Memories do not persist in a permanent, static state but instead must be dynamically modified in response to new information. Although new memory formation is typically studied in a laboratory setting, most real-world associations are modifications to existing memories, particularly in the aging, experienced brain. To date, the field has lacked a simple behavioral paradigm that can measure whether original and updated information is remembered in a single test session. To address this gap, we have developed a novel memory updating paradigm, called the Objects in Updated Locations (OUL) task that is capable of assessing memory updating in a non-stressful task that is appropriate for both young and old rodents. We first show that young mice successfully remember both the original memory and the updated information in OUL. Next, we demonstrate that intrahippocampal infusion of the protein synthesis inhibitor anisomycin disrupts both the updated information and the original memory at test, suggesting that memory updating in OUL engages the original memory. To verify this, we used the Arc CatFISH technique to show that the OUL update session reactivates a largely overlapping set of neurons as the original memory. Finally, using OUL, we show that memory updating is impaired in aging, 18-m.o. mice. Together, these results demonstrate that hippocampal memory updating is impaired with aging and establish that the OUL paradigm is an effective, sensitive method of assessing memory updating in rodents.

Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood–brain barrier–permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of “molecular memory” for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.

Agonists for neurotensin NTS1 receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS1 receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS1 agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, that suggest an ability of NTS1 receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS1 receptor activation on learning and memory consolidation in male Long Evans and Brown Norway rats using a delayed non-match to position radial arm maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following a 3, 7, and 24 hour delay, whereas Long Evans rats exhibited an increase in spatial memory errors following only a 7 and 24 hour delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hour delay. Administration of the NTS1/2 receptor antagonist SR142948 prior to the information trial did not affect retention trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, this study supports previous findings suggesting that NTS1 receptor agonists may improve some aspects of cognitive functioning.