NR4A Transcription Factor Family: Key Regulators of Memory Formation

Memory formation is one of the most important functions of the brain regarding individual identity and survival, as well as propagation of a species. Decades of research at numerous levels has begun to elucidate the complex molecular, cellular, circuit, and brain-wide mechanisms underlying learning and memory. One of the key mechanisms involves gene expression required for changes in cellular structure and function, which ultimately give rise to long-lasting changes in behavior. Here, we review a unique transcription factor family, called the nuclear orphan receptor 4a (NR4A). The Nr4a gene family is involved in the development of the dopaminergic signaling system, and dynamically regulated in the adult brain with regard to memory formation. Intriguing results from studying how epigenetic mechanisms modulate synaptic plasticity and long-term memory formation also highlight the pivotal role the Nr4a genes may have in pushing the boundaries of memory formation. We review the discovery of the Nr4a gene family, the complex nature of their activity in transcriptional regulation, and the evidence suggesting they may be one of the most important set of immediate early genes and transcription factors involved in memory, age-related memory impairments, and neurological disease related cognitive dysfunction.

Neuronal Excitability in Memory Allocation: Mechanisms and Consequences

Throughout the brain, sparse ensembles of neurons, termed “engrams,” are responsible for representing events. Engrams are composed of neurons active at the time of an event, and recent research has revealed how these active neurons compete to gain inclusion into a subsequently formed engram. This competitive selection mechanism, called “memory allocation,” is the process by which individual neurons become components of the engram. Memory allocation is crucially influenced by neuronal excitability, with more highly excitable neurons outcompeting their neighbors for inclusion into the engram. The dynamics of this excitability-dependent memory allocation process have important consequences for the function of the memory circuit, including effects on memory generalization and linking of events experienced closely in time. Memory allocation arises from cellular mechanisms of excitability, governs circuit-level dynamics of the engram, and has higher-order consequences for memory system function.

Emotional Memory in the Human Brain

Across a lifetime, people tend to remember some experiences better than others, and often these biases in memory are fueled by the emotions felt when initially encoding an event. The neuroscientific study of emotional memory has advanced considerably since researchers first detailed a critical role for the amygdala in enhancing memory consolidation for arousing experiences. It is now known that the influence of emotion on memory is both a more selective and multifaceted process than initially thought. Consequently, the neural mechanisms that govern emotional memory involve an expansive set of distributed connections between the amygdala and other medial temporal lobe structures, along with prefrontal and sensory regions, that interact with noradrenergic, dopaminergic, and glucocorticoid neuromodulatory systems to both enhance and impair items in memory. Recent neurocognitive models have detailed specific mechanisms to explain how and why the influence of emotion on memory is so varied, including arousal-based accounts for the selective consolidation of information based on stimulus priority, as well as top-down cognitive factors that moderate these effects. Still other lines of research consider the time-dependent influence of stress on memory, valence-based differences in neural recapitulation at retrieval, and the mechanisms of emotional memory modification over time. While appreciating these many known ways in which emotions influence different stages of memory processing, here we also identify gaps in the literature and present future directions to improve a neurobiological understanding of emotional memory processes.

Alzheimer’s Disease: Causes, Mechanisms, and Steps Toward Prevention

Alzheimer’s disease (AD) is the most common form of dementia in the elderly; it is clinically characterized by progressive memory loss and catastrophic cognitive dysfunction. Neuropathologically, the brains of AD patients are characterized by abundant beta-amyloid plaques, neurofibrillary tangles, and neuroinflammation. To date, this fatal disease ranks as the sixth leading cause of death; 5.8 million people in the United States are estimated to have the disease, and the total incidence of AD-related dementia is projected to grow to 16 million by 2050. Currently, there is no cure or any reliable means for pre-symptomatic diagnosis of AD. AD is a genetically heterogenous and multifactorial disease, and a variety of molecular mechanisms have been suggested to underlie its etiology and pathogenesis. A better understanding of pathogenic mechanisms underlying the development of AD pathology and symptoms would accelerate the development of effective therapeutic strategies for preventing and treating AD. Here, we present a comprehensive overview of the pathogenetic and molecular mechanisms underlying AD along with current therapeutic and lifestyles interventions being investigated for the prevention and treatment of this devastating neurological disorder.

Insights into Cognitive Disorders in Aging and Mental Illness: Molecular Influences on Circuits of the Prefrontal Cortex

The newly evolved prefrontal cortex underlies our highest order cognitivewe functions yet is remarkably vulnerable to dysfunction in most mental disorders. The prefrontal cortex subserves working memory and top-down control, operations that are weakened in both cognitive and affective disorders. Prefrontal microcircuits contain extensive recurrent excitatory connections that allow representation of information in the absence of sensory stimulation, the foundation of abstract thought and goal-directed behavior. Basic research has discovered that the strength of these prefrontal cortical synaptic connections is governed by unique molecular mechanisms, where both neurotransmission and neuromodulation differ from those in classical circuits. These include exceptionally powerful regulation by the arousal systems, which magnify calcium-cAMP signaling to open or close ion channels near the synapse to rapidly alter synaptic strength, a process called Dynamic Network Connectivity. The magnification of intracellular calcium actions renders these synapses particularly vulnerable to degeneration in schizophrenia, aging, and Alzheimer’s disease.