Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice.

Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation.

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.

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area.

During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

Home-field advantage of litter decomposition: from the phyllosphere to the soil.

Plants often associate with specialized decomposer communities that increase plant litter breakdown, a phenomenon that is known as the 'home-field advantage' (HFA). Although the concept of HFA has long considered only the role of the soil microbial community, explicit consideration of the role of the microbial community on the foliage before litter fall (i.e. the phyllosphere community) may help us to better understand HFA. We investigated the occurrence of HFA in the presence vs absence of phyllosphere communities and found that HFA effects were smaller when phyllosphere communities were removed. We propose that priority effects and interactions between phyllosphere and soil organisms can help explain the positive effects of the phyllosphere at home, and suggest a path forward for further investigation.

Aging mice show impaired memory updating in the novel OUL updating paradigm.

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.

Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity.

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.

A Dynamic Memory Systems Framework for Sex Differences in Fear Memory.

Emerging research demonstrates that a pattern of overlapping but distinct molecular and circuit mechanisms are engaged by males and females during memory tasks. Importantly, sex differences in neural mechanisms and behavioral strategies are evident even when performance on a memory task is similar between females and males. We propose that sex differences in memory may be best understood within a dynamic memory systems framework. Specifically, sex differences in hormonal influences and neural circuit development result in biases in the circuits engaged and the information preferentially stored or retrieved in males and females. By using animal models to understand the neural networks and molecular mechanisms required for memory in both sexes, we can gain crucial insights into sex and gender biases in disorders including post-traumatic stress disorder (PTSD) in humans.

Examining the contribution of histone modification to sex differences in learning and memory.

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.

Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval.

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.

The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.

Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs.

Systemic administration of the neurotensin NTS1-receptor agonist PD149163 improves performance on a memory task in naturally deficient male brown Norway rats.

Agonists for the 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, which 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 nonmatch-to-position task radial arm-maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following 3-, 7-, and 24-hr delay, whereas Long-Evans rats exhibited an increase in spatial memory errors following only a 7-, and 24-hr delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hr delay. Administration of the NTS(1/2)-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, the results of this study support previous findings suggesting that NTS1-receptor agonists may improve some aspects of cognitive functioning.

Nitrogen uptake and preference in a forest understory following invasion by an exotic grass.

Plant-soil interactions have been proposed as a causative mechanism explaining how invasive plant species impact ecosystem processes. We evaluate whether an invasive plant influences plant and soil-microbe acquisition of nitrogen to elucidate the mechanistic pathways by which invaders might alter N availability. Using a (15)N tracer, we quantify differences in nitrogen uptake and allocation in communities with and without Microstegium vimineum, a shade-tolerant, C(4) grass that is rapidly invading the understories of eastern US deciduous forests. We further investigate if plants or the microbial biomass exhibit preferences for certain nitrogen forms (glycine, nitrate, and ammonium) to gain insight into nitrogen partitioning in invaded communities. Understory native plants and M. vimineum took up similar amounts of added nitrogen but allocated it differently, with native plants allocating primarily to roots and M. vimineum allocating most nitrogen to shoots. Plant nitrogen uptake was higher in invaded communities due primarily to the increase in understory biomass when M. vimineum was present, but for the microbial biomass, nitrogen uptake did not vary with invasion status. This translated to a significant reduction (P < 0.001) in the ratio of microbial biomass to plant biomass nitrogen uptake, which suggests that, although the demand for nitrogen has intensified, microbes continue to be effective nitrogen competitors. The microbial biomass exhibited a strong preference for ammonium over glycine and nitrate, regardless of invasion status. By comparison, native plants showed no nitrogen preferences and M. vimineum preferred inorganic nitrogen species. We interpret our findings as evidence that invasion by M. vimineum leads to changes in the partitioning of nitrogen above and belowground in forest understories, and to decreases in the microbial biomass, but it does not affect the outcome of plant-microbe-nitrogen interactions, possibly due to functional shifts in the microbial community as a result of invasion.