The medial prefrontal cortex (mPFC) is known to be critical for specific forms of long-term recognition memory, however the cellular mechanisms in the mPFC that underpin memory maintenance have not been well characterized. This study examined the importance of phosphorylation of cAMP responsive element binding protein (CREB) in the mPFC for different forms of long-term recognition memory in the rat. Adenoviral transduction of the mPFC with a dominant-negative inhibitor of CREB impaired object-in-place memory following a 6 or 24 h retention delay, but no impairment was observed following delays of 5 min or 3 h. Long-term object temporal order memory and spatial temporal order memory was also impaired. In contrast, there were no impairments in novel object recognition or object location memory. These results establish, for the first time, the importance of CREB phosphorylation within the mPFC for memory of associative and temporal information crucial to recognition.

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.

The basolateral complex of amygdala (BLA) processes emotionally arousing aversive and rewarding experiences. The BLA is critical for acquisition and storage of threat-based memories and the modulation of the consolidation of arousing explicit memories, that is, the memories that are encoded and stored by the medial temporal lobe. In addition, in conjunction with the medial prefrontal cortex (mPFC), the BLA plays an important role in fear memory extinction. The BLA develops relatively early in life, but little is known about the molecular changes that accompany its development. Here, we quantified relative basal expression levels of sets of plasticity, synaptic, glia, and connectivity proteins in the rat BLA at various developmental ages: postnatal day 17 (PN17, infants), PN24 (juveniles), and PN80 (young adults). We found that the levels of activation markers of brain plasticity, including phosphorylation of CREB at Ser133, CamKIIα at Thr286, pERK1/pERK2 at Thr202/Tyr204, and GluA1 at Ser831 and Ser845, were significantly higher in infant and juvenile compared with adult brain. In contrast, age increase was accompanied by a significant augmentation in the levels of proteins that mark synaptogenesis and synapse maturation, such as synaptophysin, PSD95, SynCAM, GAD65, GAD67, and GluN2A/GluN2B ratio. Finally, we observed significant age-associated changes in structural markers, including MAP2, MBP, and MAG, suggesting that the structural connectivity of the BLA increases over time. The biological differences in the BLA between developmental ages compared with adulthood suggest the need for caution in extrapolating conclusions based on BLA-related brain plasticity and behavioral studies conducted at different developmental stages.

The epigenome serves as a signal integration platform that encodes information from experience and environment that adds tremendous complexity to the regulation of transcription required for memory, beyond the directions encoded in the genome. To date, our understanding of how epigenetic mechanisms integrate information to regulate gene expression required for memory is primarily obtained from male derived data despite sex-specific life experiences and sex differences in consolidation and retrieval of memory, and in the molecular mechanisms that mediate these processes. In this review, we examine the contribution of chromatin modification to learning and memory in both sexes. We provide examples of how exposure to a number of internal and external factors influence the epigenome in sex-similar and sex-specific ways that may ultimately impact transcription required for memory processes. We also pose a number of key open questions and identify areas requiring further investigation as we seek to understand how histone modifying mechanisms shape memory in females.

The laterodorsal thalamic nucleus (LD) is believed to play roles in learning and memory, especially spatial tasks. However, the molecular mechanism that underlies the cognitive process in the LD remains unclear and needs to be investigated. So far, there is plenty of evidence indicating that plasticity has been in some of the cortical or subcortical regions closely related to the LD, particularly stimulated by external learning tasks. Therefore, the present study aimed to test the hypothesis that similar effect exists in the LD. The transcription factor, cAMP-response element binding protein (CREB), works essentially in brain plasticity by tightly regulating the transcriptional level of memory-related target genes, and the increase of activated CREB (phosphorylated CREB, p-CREB) could facilitate memory consolidation. In this study, the siRNA against CREB was synthesized to down-regulate the CREB mRNA in the LD. After Morris water maze behavioral training, CREB siRNA rats exhibited a memory deficiency, significantly diverging from the control groups. In subsequent detection, the expression of p-CREB of these memory impairment rats attenuated. These results support the hypothesis that CREB-mediated plasticity contributes to memory facilitation and consolidation in the LD.

It is tempting to equate the automatization of an action sequence with the formation of a habit. However, the term “habit” specifically implies a failure to evaluate future consequences to guide behavior. To test if automatized sequences become habitual, we trained rats on an action sequence task for either 20 or 60 d and then conducted reward devaluation tests. While both groups showed equivalent goal-directed performance of the trained action sequence on a global measure of behavior, sequence initiation and completion times were differentially sensitive to outcome devaluation in moderately and extensively trained rats.

Declarative memory performance is superior for items that were encoded in temporal proximity to reward delivery or expectancy. How reward-predicting contexts affect subsequent declarative memory formation in those contexts are, however, unknown. Using an ecological experimental setup in the form of a naturalistic driving simulator task, we examined the effect that previously rewarded environments may have on incidental memory formation. After driving in two distinct environments, one of which associated with monetary reward, participants drove again in the environments, which were embedded with unique images on billboards. A recognition test 24 h later demonstrated that incidental memory was superior for items presented in the reward-associated environment. These findings suggest that environmental cues imbued with incentive salience promote memory processes even in the absence of reward.

Multiple lines of evidence suggest that glucocorticoid hormones enhance memory consolidation of fearful events. However, most of these studies involve male individuals. Since anxiety, fear, and fear-associated disorders present differently in male and female subjects we investigated in mice whether male and female mice perform differently in a mild, auditory fear conditioning task and tested the modulatory role of glucocorticoid hormones. Using an auditory fear conditioning paradigm with different footshock intensities (0.1, 0.2, and 0.4 mA) and frequencies (1× or 3×), we find that intraperitoneal injections with corticosterone (2 mg/kg) immediately after training, altered freezing behavior when repeated footshocks were applied, and that the direction of the effects were opposite in male and female mice. Effects were independent of footshock intensity. In male mice, corticosterone consistently increased freezing behavior in response to the tone, whereas in female mice, corticosterone reduced freezing behavior 24 h after training. These effects were not related to the phase of the oestrous cycle. In addition, corticosterone enhanced extinction learning for all tones, in both male and female mice. These results emphasize that glucocorticoid hormones influence memory consolidation and retrieval, and underscore sex-specific effects of glucocorticoid hormones in modulating conditioned fear responses.

We have shown previously that male rats develop a conditioned ejaculatory preference (CEP) for females scented with a neutral odor like almond or lemon that is paired with the male's post-ejaculatory reward state during their first and subsequent early sexual experiences. However, preexposing males to the neutral odor alone prior to its pairing with sexual reward results in latent inhibition. Here, we examined the phenomenon of unconditioned stimulus (US) preexposure, in which male rats were preexposed to the ejaculatory reward state either one or five times with scented (ScF) versus unscented (UnScF) females prior to multiple ejaculatory trials with females in the opposite condition (e.g., ScF preexposure received 10 subsequent ejaculatory trials with UnScF, whereas UnScF preexposure received 10 subsequent ejaculatory trials with ScF). As before, mate and partner preference was evaluated in an open field where each male had access to two females, one ScF and the other UnScF. Males that underwent five trials of preexposure did not display a CEP for either female. Conversely, males preexposed once to a ScF, and later trained with UnScF developed a preference for the latter, whereas males preexposed once to the UnScF, and then trained with ScF did not show a preference for any of the females. Subsequent exposure to the odor cue alone revealed different patterns of brain activation in areas related to sexual behavior that depended on the animal's group membership. Altogether, these findings demonstrate the pivotal role of first sexual experiences in the establishment of future sexual partner preference in the male rat, and suggest an innate preference for estrous odors over neutral odors that can become conditioned subsequently as predictors of sexual reward.

When discrete localizable stimuli are used during appetitive Pavlovian conditioning, “sign-tracking” and “goal-tracking” responses emerge. Sign-tracking is observed when conditioned responding is directed toward the CS, whereas goal-tracking manifests as responding directed to the site of expected reward delivery. These behaviors seem to rely on distinct, though overlapping neural circuitries, and, possibly, distinct psychological processes as well, and are thought to be related to addiction vulnerability. One currently popular view is that sign-tracking reflects an incentive motivational process, whereas goal-tracking reflects the influence of more top-down cognitive processes. To test these ideas, we used illness-induced outcome-devaluation and Kamin blocking procedures to determine whether these behaviors rely on similar or distinct underlying associative mechanisms. In Experiments 1 and 2 we showed that outcome-devaluation reduced sign-tracking responses, demonstrating that sign-tracking is controlled by reward expectancies. We also observed that post-CS goal-tracking in these animals is also devaluation sensitive. To test whether these two types of behaviors rely on similar or different prediction error mechanisms, we next tested whether Kamin blocking effects could be observed across these two classes of behaviors. In Experiment 3 we asked if sign-tracking to a lever CS could block the development of goal-tracking to a tone CS; whereas in Experiment 4, we examined whether goal-tracking to a tone CS could block sign-tracking to a lever CS. In both experiments blocking effects were observed suggesting that both sign- and goal-tracking emerge via a common prediction error mechanism. Collectively, the studies reported here suggest that the psychological mechanisms mediating sign- and goal-tracking are more similar than is commonly acknowledged.