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Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS ("MouseWAS") by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6-11%), and moderate genetic correlations (rg = 0.20-0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

Enrichment in rodents affects brain structure, improves behavioral performance, and is neuroprotective. Similarly, in humans, according to the cognitive reserve concept, enriched experience is functionally protective against neuropathology. Despite this parallel, the ability to translate rodent studies to human clinical situations is limited. This limitation is likely due to the simple cognitive processes probed in rodent studies and the inability to control, with existing methods, the degree of rodent engagement with enrichment material. We overcome these two difficulties with behavioral tasks that probe, in a fine-grained manner, aspects of higher-order cognition associated with deterioration with aging and dementia, and a new enrichment protocol, the 'Obstacle Course' (OC), which enables controlled enrichment delivery, respectively. Together, these two advancements will enable better specification (and comparisons) of the nature of impairments in animal models of complex mental disorders and the potential for remediation from various types of intervention (e.g., enrichment, drugs). We found that two months of OC enrichment produced substantial and sustained enhancements in categorization memory, perceptual object invariance, and cross-modal sensory integration in mice. We also tested mice on behavioral tasks previously shown to benefit from traditional enrichment: spontaneous object recognition, object location memory, and pairwise visual discrimination. OC enrichment improved performance relative to standard housing on all six tasks and was in most cases superior to conventional home-cage enrichment and exercise track groups.

Histone acetylation, catalyzed by e, has emerged as a promising therapeutic strategy in Alzheimer's disease (AD). By longitudinally characterizing spatial memory at 3, 6, and 9 mo of age, we show that acute activation and inhibition of the histone acetyltransferase PCAF remediated memory impairments in 3xTG-AD mice in an age-related bidirectional manner. At 3 and 6 mo of age, PCAF activation ameliorated memory deficits. At 9 mo of age, PCAF activation had no effect on spatial memory, whereas PCAF inhibition improved memory deficits in females. This work reveals a complex potential therapeutic role for PCAF in AD, initially benefitting memory but becoming detrimental as the disease progresses.

To test the hypothesis that drugs of abuse and their conditioned stimuli (CSs) enhance memory consolidation, the effects of post-training exposure to cocaine and nicotine were compared to the effects of post-training exposure to contextual stimuli that were paired with the effects of these drugs. Using the object recognition (OR) task, it was first demonstrated that both 10 and 20 mg/kg cocaine, and 0.2 and 0.4 mg/kg nicotine, enhanced recognition memory when administered immediately after, but not 6 h after the sample phase. To establish the drug CSs, rats were confined for 2 h in a chamber (the CS+) after injections of 20 mg/kg cocaine, or 0.4 mg/kg nicotine, and in another chamber (the CS-) after injections of vehicle. This was repeated over 10 d (5 drug/CS+ and 5 vehicle/CS- pairings in total). At the end of this conditioning period, when tested in a drug-free state, rats displayed conditioned hyperactivity in the CS+ relative to the CS-. More important, immediate, but not delayed, post-sample exposure to the cocaine CS+, or nicotine CS+, enhanced OR memory. Therefore, this study reports for the first time that contextual stimuli paired with cocaine and nicotine, like the drugs themselves, have the ability to enhance memory consolidation.

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF–ER interaction might exist as a male-specific mechanism supporting STM. [ABSTRACT FROM AUTHOR]

Reactivation can destabilize previously consolidated memories, rendering them vulnerable to disruption and necessitating a process of reconsolidation in order for them to be maintained. This process of destabilization and reconsolidation has commonly been cited as a means by which established memories can be updated or modified. However, little direct evidence exists to support this view. The present study addressed this issue by analyzing the influence of novel salient information present at the time of memory reactivation on the likelihood of the reactivated memory to become destabilized and vulnerable to disruption. Rats explored sample objects and, some time later, received systemic injections of the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 or saline prior to memory reactivation. When object memories were relatively young or weakly encoded, MK-801 significantly disrupted reconsolidation regardless of the reactivation conditions. However, increasing the amount of sample object exploration or the interval between the sample phase and reactivation abolished the effect of MK-801 on reconsolidation unless salient novel contextual information was present during memory reactivation. These results highlight the dynamic nature of memory storage and retrieval and indicate an important interaction between the age and strength of a memory, its probability of being destabilized upon reactivation, and the stimulus conditions during reactivation. The essential involvement of novel encoding in destabilizing certain memories supports the idea that the reconsolidation process enables modification of existing memories.

The perirhinal cortex (PRh) has a well-established role in object recognition memory. More recent studies suggest that PRh is also important for two-choice visual discrimination tasks. Specifically, it has been suggested that PRh contains conjunctive representations that help resolve feature ambiguity, which occurs when a task cannot easily be solved on the basis of features alone. However, no study has examined whether the ability of PRh to resolve configural feature ambiguity is related to its role in object recognition. Therefore, we examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus post-rhinal cortices) in the rat would cause deficits in a configural spontaneous object recognition task, and a configural simultaneous oddity discrimination task, in which the task could not be solved on the basis of features, but could only be solved using conjunctive representations. As predicted by simulations using a computational model, rats with PPRh lesions were impaired during a minimal-delay configural object recognition task. These same rats were impaired during a zero-delay configural object recognition task. Furthermore, rats with localized PRh lesions were impaired in a configural simultaneous oddity discrimination task. These findings support the idea that PRh contains conjunctive representations for the resolution of feature ambiguity and that these representations underlie a dual role for PRh in memory and perception.