Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice.

Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. We report that aging impairs the expression of Gadd45γ in the hippocampus of cognitively impaired male mice. Mimicking this decrease in young adult male mice led to age-like memory deficits in hippocampus-dependent memory tasks. Gadd45γ reduction impaired the activity of key components of the mitogen-activated protein kinase (MAPK) pathway (p38 and JNK) in mouse hippocampal cultures. Furthermore, we found that activation of downstream targets, such as ATF-2, c-Jun, and CREB (cAMP response element-binding protein), was disrupted. Finally, we showed that Gadd45γ is required for induction of key early- and late-response genes that have been associated with aging. Together, these findings indicate that Gadd45γ expression regulates cognitive abilities and synapse-to-nucleus communication and suggest Gadd45γ dysfunction as a potential mechanism contributing to age-related cognitive impairments.SIGNIFICANCE STATEMENT A high percentage of subjects experience age-related memory loss that burdens daily performance. Although many advances have been made, the precise changes in the brain governing these deficits are unclear. Identifying molecular processes that are required for cognition and are altered during old age is crucial to develop preventive or therapeutic strategies. Here, we show that baseline and learning-induced expression of the growth arrest DNA damage (Gadd45) γ is selectively impaired in the hippocampus of aged mice with cognitive deficits. Next, we show that modeling this impairment in young adult mice with normal cognitive performance disrupts long- and short-term memories in an age-like manner. Finally, we demonstrate that Gadd45γ regulates synapse-to-nucleus communication processes that are needed for plasticity-associated gene expression.

Diagnostic Value of Cholinesterase Activity for the Development of Postoperative Delirium after Cardiac Surgery.

BACKGROUND: Depression of cholinesterase (CHE) activity has been reported to lead to an amplified neuroinflammatory response, which clinically manifests as postoperative delirium (PD). This observational study investigates the association between CHE activity and the development of PD following elective cardiac surgery. METHODS: Patients with preexisting neurologic deficits or carotid artery disease as well as patients undergoing reoperations or procedures under circulatory arrest have been excluded from this study. The Mini-Mental State Examination, the Confusion Assessment Method for the Intensive Care Unit, and the Intensive Care Delirium Screening Checklist were performed at regular intervals. CHE activity was estimated pre- and postoperatively until postoperative day (POD) 5 and at discharge. RESULTS: A total of 107 patients were included. PD was diagnosed in 34 (31.8%) patients, who have been compared with those without PD. Time on ventilator, length of ICU, and hospital stay were longer in patients with PD (p = 0.001, p < 0.001, and p = 0.004, respectively). MMSE scores were lower in patients with PD (p < 0.001; p = 0.015). CHE activity on POD 1 to 4 as well as at discharge were lower in the delirium group (p = 0.041; p = 0.029; p = 0.015; p = 0.035; p = 0.028, respectively). A perioperative drop of CHE activity of more than 50% and a postoperative CHE activity below 4,800 U/L (on POD 0) were independently associated with an increased risk of development of PD (p = 0.038; p = 0.008, respectively). CONCLUSION: In addition to the established functional tests, routine estimation of CHE activity may serve as an additional diagnostic tool allowing for the timely diagnosis and treatment of PD in cardiac surgery patients.

Norepinephrine and glucocorticoid effects on the brain mechanisms underlying memory accuracy and generalization.

Stressful and emotionally arousing experiences activate hormonal and brain systems that create strong memories. Extensive evidence indicates that this strengthening effect involves the synergistic action of both norepinephrine and glucocorticoid hormones. This tight regulation of emotional memories is normally highly adaptive and pivotal for survival; yet, aberrant memory processing of stressful events is a major risk factor for the development of stress-related psychopathology. It remains unclear, however, to what extent these two stress hormone systems also affect the quality of such strengthened memories. In this Review, we discuss recent advances in the understanding of norepinephrine and glucocorticoid effects on the accuracy and generalization of contextual or episodic-like aspects of memory in rodents. We will argue that norepinephrine and glucocorticoids exert opposite effects on accuracy and generalization of memory through distinct effects on systems consolidation processes underlying the time-dependent reorganization of memory. Norepinephrine improves memory accuracy by boosting basolateral amygdala-hippocampal connectivity, hereby creating long-lasting hippocampus-dependent episodic-like memories. In contrast, glucocorticoids contribute to memory generalization by promoting integration of new memories into neocortical networks, decreasing hippocampal dependence. We discuss possible implications of these conceptual insights for understanding inter-individual differences in stress resilience and risk for psychopathology.

MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function.

Methyl CpG binding protein 2 (MeCP2) was first identified as a nuclear protein with a transcriptional repressor role that recognizes DNA methylation marks. MeCP2 has a well-established function in neurodevelopment, as evidenced by the severe neurological impairments characteristic of the Rett syndrome (RTT) pathology and the MeCP2 duplication syndrome (MDS), caused by loss or gain of MeCP2 function, respectively. Research aimed at the underlying pathophysiological mechanisms of RTT and MDS has significantly advanced our understanding of MeCP2 functions in the nervous system. It has revealed, however, that MeCP2 has more varied and complex roles than previously thought. Here we review recent insights into the functions of MeCP2 in neurodevelopment and the less explored requirement for MeCP2 in adult brain function. We focus on the emerging view that MeCP2 is a global chromatin organizer. Finally, we discuss how the individual functions of MeCP2 in neurodevelopment and adulthood are linked to its role as a chromatin regulator.

Adult hippocampal MeCP2 preserves the genomic responsiveness to learning required for long-term memory formation.

MeCP2 is required both during postnatal neurodevelopment and throughout the adult life for brain function. Although it is well accepted that MeCP2 in the maturing nervous system is critical for establishing normal development, the functions of MeCP2 during adulthood are poorly understood. Particularly, the requirement of hippocampal MeCP2 for cognitive abilities in the adult is not studied. To characterize the role of MeCP2 in adult neuronal function and cognition, we used a temporal and region-specific disruption of MeCP2 expression in the hippocampus of adult male mice. We found that MeCP2 is required for long-term memory formation and that it controls the learning-induced transcriptional response of hippocampal neurons required for memory consolidation. Furthermore, we uncovered MeCP2 functions in the adult hippocampus that may underlie cognitive integrity. We showed that MeCP2 maintains the developmentally established chromatin configuration and epigenetic landscape of CA1 neurons throughout the adulthood, and that it regulates the expression of neuronal and immune-related genes in the adult hippocampus. Overall, our findings identify MeCP2 as a maintenance factor in the adult hippocampus that preserves signal responsiveness of the genome and allows for integrity of cognitive functions. This study provides new insight into how MeCP2 maintains adult brain functions, but also into the mechanisms underlying the cognitive impairments observed in RTT patients and highlights the understudied role of DNA methylation interpretation in adult cognitive processes.

Multimodal interventions (chewing gum, early oral hydration and early mobilisation) on the intestinal motility following abdominal gynaecologic surgery.

AIMS AND OBJECTIVES: To determine the effects of chewing gum, early oral hydration and early mobilisation on the time of first bowel sounds, first passage of flatus and first defecation following abdominal gynaecologic surgery. BACKGROUND: A major complication of abdominal surgical procedures is paralytic ileus which results in patient discomfort, prolonged length of hospital stay and increased cost of treatment. DESIGN: Prospective randomised case-control study. METHODS: Women who underwent abdominal gynaecological surgery for benign disorders under general anaesthesia were randomised into eight groups according to different combinations of interventions consisting of chewing gum, early oral hydration and early mobilisation. The effects of these interventions on the time of first bowel sounds, first passage of flatus and first defecation following abdominal gynaecologic surgery were investigated. The data were analysed using chi-square tests, t-test for independent samples, Tukey's HSD test, pairwise comparison test, one-way analysis of variance. RESULTS: It was found that the time when bowel sounds were heard was shorter, the time first passage of flatus was shorter and first defecation occurred earlier in the 1st group of women who chew gum, were hydrated orally and were mobilised early after surgery than the other groups. It was also determined that these periods were longest in the women who did not receive any intervention and received the routine hospital care when compared with other groups. Duration of hospital stay was shorter in the women who chew gum, were hydrated orally and were mobilised early than the other groups. CONCLUSIONS: Early oral feeding, early mobilisation and chewing gum are effective methods in terms of preventing paralytic ileus following abdominal gynaecological surgery, improving patient comfort and shortening the duration of hospitalisation. RELEVANCE TO CLINICAL PRACTICE: Nurses may cause early recovery, improve the patient comfort, prevent paralytic ileus and shorten the duration of hospitalisation after gynaecologic abdominal surgery by recommending gum chewing, early mobilisation and early hydration.

Regulation of neuronal plasticity by the DNA repair associated Gadd45 proteins.

Neurons respond rapidly to extracellular stimuli by activating signaling pathways that modulate the function of already synthetized proteins. Alternatively, signal transduction to the cell nucleus induces de novo synthesis of proteins required for long-lasting adaptations. These complementary strategies are necessary for neuronal plasticity processes that underlie, among other functions, the formation of memories. Nonetheless, it is still not fully understood how the coupling between different stimuli and the activity of constitutively and/or de novo expressed proteins gate neuronal plasticity. Here, we discuss the molecular functions of the Growth Arrest and DNA Damage 45 (Gadd45) family of proteins in neuronal adaptation. We highlight recent findings that indicate that Gadd45 family members regulate this function through multiple cellular processes (e.g., DNA demethylation, gene expression, RNA stability, MAPK signaling). We then summarize the regulation of Gadd45 expression in neurons and put forward the hypothesis that the constitutive and neuronal activity-induced pools of Gadd45 proteins have distinct and complementary roles in modulating neuronal plasticity. Therefore, we propose that Gadd45 proteins are essential for brain function and their dysfunction might underlie pathophysiological conditions such as neuropsychiatric disorders.

Molecular and cellular mechanisms of engram allocation and maintenance.

Understanding how we learn and remember has been a long-standing question in neuroscience. Technological developments of the past 15 years have allowed for dramatically increased access to the neurons that hold the physical representation of memory, also known as a memory trace or engram. Such developments have tremendously facilitated advancement of the memory field, since they made possible interrogation of the cellular and molecular mechanisms underlying memory formation with unprecedented cellular specificity. Here, we discuss the studies that have investigated rules governing neuronal recruitment to a particular memory engram. Furthermore, we provide an overview of the evidence that functional and structural changes associated with memory consolidation occur in engram neurons. Moreover, we summarize the expanding literature showing that transcriptional regulatory factors such as transcription factors and epigenetic mechanisms play an important role in the maintained allocation of behaviorally-selected neurons to an engram. Together, these studies have begun elucidating how neuronal networks are selected and modified in order to support memory formation and storage.

Engram reactivation during memory retrieval predicts long-term memory performance in aged mice.

Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labeled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population during long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus.

Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice.

Aging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted cAMP response element-binding protein signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

Neuronal ensemble-specific DNA methylation strengthens engram stability.

Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.