Pepe J. Hernandez

The role of protein synthesis in memory consolidation: Progress amid decades of debate

A major component of consolidation theory holds that protein synthesis is required to produce the synaptic modification needed for long-term memory storage. Protein synthesis inhibitors have played a pivotal role in the development of this theory. However, these commonly used drugs have unintended effects that have prompted some to reevaluate the role of protein synthesis in memory consolidation. Here we review the role of protein synthesis in memory formation as proposed by consolidation theory calling special attention to the controversy involving the non-specific effects of a group of protein synthesis inhibitors commonly used to study memory formation in vivo. We argue that molecular and genetic approaches that were subsequently applied to the problem of memory formation confirm the results of less selective pharmacological studies. Thus, to a certain extent, the debate over the role of protein synthesis in memory based on interpretational difficulties inherent to the use of protein synthesis inhibitors may be somewhat moot. We conclude by presenting avenues of research we believe will best provide answers to both long-standing and more recent questions facing field of learning and memory.

Genomic analysis of sleep deprivation reveals translational regulation in the hippocampus

Sleep deprivation is a common problem of considerable health and economic impact in todays society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.

Aging impairs hippocampus-dependent long-term memory for object location in mice.

The decline in cognitive function that accompanies normal aging has a negative impact on the quality of life of the elderly and their families. Studies in humans and rodents show that spatial navigation and other hippocampus-dependent functions are particularly vulnerable to the deleterious effects of aging. However, reduced motor activity and alterations in the stress response that accompany normal aging can hinder the ability to study certain cognitive behaviors in aged animals. In an attempt to circumvent these potential confounds, we used a hippocampus-dependent object-place recognition task to show that long-term spatial memory is impaired in aged mice. Aged animals performed similarly to young adult mice on an object recognition task that does not rely on hippocampal function.

Reversal of Impaired Hippocampal Long-Term Potentiation and Contextual Fear Memory Deficits in Angelman Syndrome Model Mice by ErbB Inhibitors

BACKGROUND Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice. METHODS We determined the expression of neuregulin 1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10-16 weeks) and studied the effects of ErbB inhibition on long-term potentiation in hippocampal area cornu ammonis 1 and on hippocampus-dependent contextual fear memory. RESULTS We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in long-term potentiation, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice. CONCLUSIONS Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS.

Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A

It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories--signaling thought to proceed through protein kinase A (PKA). However, here we show that exchange protein activated by cAMP (Epac) is able to enhance the formation of long-term memory in the hippocampus and appears to do so independent of PKA, thus demonstrating the importance of Epac-mediated signaling in memory consolidation.

An open-source toolbox for automated phenotyping of mice in behavioral tasks

Classifying behavior patterns in mouse models of neurological, psychiatric and neurodevelopmental disorders is critical for understanding disease causality and treatment. However, complete characterization of behavior is time-intensive, prone to subjective scoring, and often requires specialized equipment. Although several reports describe automated home-cage monitoring and individual task scoring methods, we report the first open source, comprehensive toolbox for automating the scoring of several common behavior tasks used by the neuroscience community. We show this new toolbox is robust and achieves equal or better consistency when compared to manual scoring methods. We use this toolbox to study the alterations in behavior that occur following blast-induced traumatic brain injury (bTBI), and study if these behavior patterns are altered following genetic deletion of the transcription factor Ets-like kinase 1 (Elk-1). Due to the role of Elk-1 in neuronal survival and proposed role in synaptic plasticity, we hypothesized that Elk-1 deletion would improve some neurobehavioral deficits, while impairing others, following blast exposure. In Elk-1 knockout (KO) animals, deficits in open field, spatial object recognition (SOR) and elevated zero maze performance after blast exposure disappeared, while new significant deficits appeared in spatial and associative memory. These are the first data suggesting a molecular mediator of anxiety deficits following bTBI, and represent the utility of the broad screening tool we developed. More broadly, we envision this open-source toolbox will provide a more consistent and rapid analysis of behavior across many neurological diseases, promoting the rapid discovery of novel pathways mediating disease progression and treatment.

The clinical relevance of neuroplasticity in corticostriatal networks during operant learning

Dopamine and glutamate serve crucial functions in neural plasticity, learning and memory, and addiction. Contemporary theories contend that these two, widely-distributed neurotransmitter systems play an integrative role in motivational and associative information processing. Combined signaling of these systems, particularly through the dopamine (DA) D1 and glutamate (Glu) N-methyl-d-aspartate receptors (NMDAR), triggers critical intracellular signaling cascades that lead to changes in chromatin structure, gene expression, synaptic plasticity, and ultimately behavior. Addictive drugs also induce long-term neuroadaptations at the molecular and genomic levels causing structural changes that alter basic connectivity. Indeed, evidence that drugs of abuse engage D1- and NMDA-mediated neuronal cascades shared with normal reward learning provides one of the most important insights from contemporary studies on the neurobiology of addiction. Such drug-induced neuroadaptations likely contribute to abnormal information processing and behavior, resulting in the poor decision-making, loss of control, and compulsivity that characterize addiction. Such features are also common to many other neuropsychiatric disorders. Behavior problems, construed as difficulties associated with operant learning and behavior, present compelling challenges and unique opportunities for their treatment that require further study. The present review highlights the integrative work of Ann E. Kelley and colleagues, demonstrating a critical role not only for NMDAR, D1 receptors (D1R), and their associated signaling cascades, but also for other Glu receptors and protein synthesis in operant learning throughout a cortico-striatal-limbic network. Recent work has extended the impact of appetitive learning to epigenetic processes. A better understanding of these processes will likely assist in discovering therapeutics to engage neural plasticity-related processes and promote functional behavioral adaptations.