M1 muscarinic receptor activation reverses age-related memory updating impairment in mice.

Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain.

Reactivation-dependent transfer of fear memory between contexts requires M1 muscarinic receptor stimulation in dorsal hippocampus of male rats.

Memory updating is essential for integrating new information into existing representations. However, this process could become maladaptive in conditions like post-traumatic stress disorder (PTSD), when fear memories generalize to neutral contexts. Previously, we have shown that contextual fear memory malleability in rats requires activation of M1 muscarinic acetylcholine receptors in the dorsal hippocampus. Here, we investigated the involvement of this mechanism in the transfer of contextual fear memories to other contexts using a novel fear memory updating paradigm. Following brief reexposure to a previously fear conditioned context, male rats (n = 8-10/group) were placed into a neutral context to evaluate the transfer of fear memory. We also infused the selective M1 receptor antagonist pirenzepine into the dorsal hippocampus before memory reactivation to try to block this effect. Results support the hypothesis that fear memory can be updated with novel contextual information, but only if rats are reexposed to the originally trained context relatively recently before the neutral context; evidence for transfer was not seen if the fear memory reactivation was omitted or if it occurred 6 h before neutral context exposure. The transferred fear persisted for 4 weeks, and the effect was blocked by M1 antagonism. These findings strongly suggest that fear transfer requires reactivation and destabilization of the original fear memory. The novel preclinical model introduced here, and its implication of muscarinic receptors in this process, could therefore inform therapeutic strategies for PTSD and similar conditions.

The Lysine Acetyltransferase PCAF Functionally Interacts with Estrogen Receptor Alpha in the Hippocampus of Gonadally Intact Male-But Not Female-Rats to Enhance Short-Term Memory.

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 ERß 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.

The evidence for and against reactivation-induced memory updating in humans and nonhuman animals.

Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of "reconsolidation" theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers' abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories.

Age-dependent attenuation of spatial memory deficits by the histone acetyltransferase p300/CBP-associated factor (PCAF) in 3xTG Alzheimer's disease mice.

Histone acetylation, catalyzed by histone acetyltransferases, 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.

Activation of cortical M1 muscarinic receptors and related intracellular signaling is necessary for reactivation-induced object memory updating.

Reactivated long-term memories can become labile and sensitive to modification. Memories in this destabilized state can be weakened or strengthened, but there is limited research characterizing the mechanisms underlying retrieval-induced qualitative updates (i.e., information integration). We have previously implicated cholinergic transmission in object memory destabilization. Here we present a novel rodent paradigm developed to assess the role of this cholinergic mechanism in qualitative object memory updating. The post-reactivation object memory modification (PROMM) task exposes rats to contextual information following object memory reactivation. Subsequent object exploratory performance suggests that the contextual information is integrated with the original memory in a reactivation- and time-dependent manner. This effect is blocked by interference with M1 muscarinic receptors and several downstream signals in perirhinal cortex. These findings therefore demonstrate a hitherto unacknowledged cognitive function for acetylcholine with important implications for understanding the dynamic nature of long-term memory storage in the normal and aging brain.

Modulation of object memory consolidation by heroin and heroin-conditioned stimuli: Role of opioid and noradrenergic systems.

There is recent evidence that cocaine, nicotine, and their conditioned stimuli have the ability to enhance memory consolidation. The present study compared the effects of post-training heroin and of a heroin contextual conditioned stimulus (CS+) on consolidation of object recognition memory and investigated the roles of opioid and beta-adrenergic receptors in heroin/CS+ memory modulation by co-administering the respective antagonists, naltrexone (NTX) and propranolol (PRO). Three experiments were performed in male Sprague-Dawley rats demonstrating that immediate, but not delayed, post-sample exposure to heroin (0.3, 1 mg/kg), or exposure (30 min) to a contextual CS+ paired with 1 mg/kg heroin (5 pairings, each 120 min), equally enhanced object memory. Importantly, while the memory enhancing effects of 1 mg/kg heroin and of the contextual CS+ were not altered by post-training co-administration of 3 mg/kg naltrexone, they were blocked by post-training co-administration of 10 mg/kg propranolol. Taken together, these data suggest that a context paired with heroin shares the memory enhancing effect of heroin itself and that these unconditioned and conditioned drug stimuli may modulate memory through the activation of beta-noradrenergic receptors.

Inhibition of 5α Reductase Impairs Cognitive Performance, Alters Dendritic Morphology and Increases Tau Phosphorylation in the Hippocampus of Male 3xTg-AD Mice.

Recent work has suggested that 5α-reduced metabolites of testosterone may contribute to the neuroprotection conferred by their parent androgen, as well as to sex differences in the incidence and progression of Alzheimer's disease (AD). This study investigated the effects of inhibiting 5α-reductase on object recognition memory (ORM), hippocampal dendritic morphology and proteins involved in AD pathology, in male 3xTg-AD mice. Male 6-month old wild-type or 3xTg-AD mice received daily injections of finasteride (50 mg/kg i.p.) or vehicle (18% ß-cyclodextrin, 1% v/b.w.) for 20 days. Female wild-type and 3xTg-AD mice received only the vehicle. Finasteride treatment differentially impaired ORM in males after short-term (3xTg-AD only) or long-term (3xTg-AD and wild-type) retention delays. Dendritic spine density and dendritic branching of pyramidal neurons in the CA3 hippocampal subfield were significantly lower in 3xTg-AD females than in males. Finasteride reduced CA3 dendritic branching and spine density in 3xTg-AD males, to within the range observed in vehicle-treated females. In the CA1 hippocampal subfield, dendritic branching and spine density were reduced in both male and female 3xTg-AD mice, compared to wild type controls. Hippocampal amyloid ß levels were substantially higher in 3xTg-AD females compared to both vehicle and finasteride-treated 3xTg-AD males. Site-specific Tau phosphorylation was higher in 3xTg-AD mice compared to sex-matched wild-type controls, increasing slightly after finasteride treatment. These results suggest that 5α-reduced neurosteroids may play a role in testosterone-mediated neuroprotection and may contribute to sex differences in the development and severity of AD.

Development of an "object category recognition" task for mice: Involvement of muscarinic acetylcholine receptors.

Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recognition (OCR) task. Based on the spontaneous object recognition paradigm, mice discriminated between two otherwise equally novel objects, one from a novel category and one from a studied category. During the sample phase, mice were exposed to two different exemplars from the same category. After a retention delay, they explored a third (i.e., novel) object from that sampled category and an object from a novel category in a choice phase. Mice preferentially explored the novel category object, taken as an index of category recognition, in this OCR task when a 30-min retention delay was used. Extensive preexposure to category exemplar objects also enhanced subsequent task performance across a longer (1-h) retention delay at which mice without preexposure did not demonstrate evidence for category recognition. Prechoice administration of the acetylcholine muscarinic receptor antagonist, scopolamine, disrupted OCR performance with or without preexposure, implicating acetylcholine in category recognition. The current study presents a valuable new rodent task for the study of the mechanistic basis of categorization-like processes and its potential relevance to common cognitive disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Dissociable involvement of estrogen receptors in perirhinal cortex-mediated object-place memory in male rats.

Estrogens and the estrogen receptors (ER) - ERα, ERß, and the G-protein coupled estrogen receptor (GPER) - are implicated in various forms of hippocampus (HPC)-dependent memory. However, the involvement of ER-related mechanisms in perirhinal cortex (PRh), which is necessary for object memory, remains much less clear. Moreover, there is a paucity of data assessing ER contributions to cognition in males,despite documented sex differences at the cellular level.We hypothesized that estrogens in PRh are important for object memory in males, assessingthe role of 17-ßestradiol (E2), ERα, ERß, GPER, and their downstream signaling pathways, in PRh-mediated object-in-place (OiP) memory in gonadally-intact male rats. Intra-PRh administration of E2 enhanced both long-term memory (LTM; 24 h) and short-term memory (STM; 20 min). Conversely, aromatase inhibition with letrozole impaired LTM and STM. The semi-selective ER inhibitor ICI 182780 impaired LTM, but not STM. This effect may be due to inhibition of ERß, as the ERßagonist DPN, but not ERαagonist PPT, enhanced LTM. GPER was also found to be necessary in PRh, as the antagonist G15 impaired both LTM and STM. Western blot analyses demonstrated that phosphorylation levels of the extracellular signal-related kinase (ERK2 isoform), awell-establisheddownstream signaling pathway activated by estrogens through ERα/ERß, was elevated in PRh 5 min following OiP learning.We also reportincreased levels of c-Jun N-terminal kinase (JNK; p46 and p54 isoforms) phosphorylation in PRh 5 min following learning,consistent with recent research linking GPER activation and JNK signaling in the HPC. This effect was abolished by intra-PRh administration of G15, but not letrozole, suggesting that JNK signaling is triggered via GPER activation during OiP learning, and is possibly E2-independent, similar to findings in the HPC. These results, therefore, reveal interesting dissociations between the roles of various ERs, possibly involving both estrogen-dependent and independent mechanisms, in PRh-mediated object-place learning in male rats.

Involvement of classical neurotransmitter systems in memory reconsolidation: Focus on destabilization.

When consolidated long-term memories are reactivated they can destabilize, rendering the memory labile and vulnerable to modification. This period of lability is followed by reconsolidation, a process that restabilizes the memory trace. Reactivation-induced memory destabilization is the gateway process to reconsolidation, but research in this area has focused primarily on the mechanisms underlying post-reactivation restabilization. As a result, our understanding of processes subserving destabilization have lagged behind those responsible for reconsolidation. Here we review the literature investigating the neural basis of reactivation-induced memory destabilization. We begin by reviewing memory destabilization broadly and the boundary conditions that influence the likelihood of reactivated memories to destabilize. We then discuss the fact that boundary conditions can be overcome in the presence of novelty, providing evidence for the theory that reconsolidation is a mechanism for memory updating. From here, we delve into a detailed review of the role of classical neurotransmitter systems, including dopamine, serotonin, noradrenaline, glutamate, GABA and acetylcholine, in reconsolidation, with a focus on their involvement in destabilization. Many of these neurotransmitters appear capable of promoting memory destabilization, and research investigating the cellular pathways through which they influence destabilization is a growing area. However, gaps remain in our understanding of how these neurotransmitters work in conjunction with one another to support destabilization across different types of memory and in different brain regions. Advances in the coming years within this research field should greatly contribute to our understanding of the neural mechanisms that influence the dynamic process of long-term memory storage and modification, information crucial to the development of potential treatments for disorders characterized by strong, maladaptive memories.