281 research outputs found
Formation and adaptation of memory. Neurobiological mechanisms underlying learning and reversal learning
Full text linkThe hippocampus is a brain region that plays a critical role in memory formation. In addition, it has been suggested that this brain region is important for ‘updating’ information that is incorrect or outdated. The main goal of this thesis project was to investigate which neurobiological processes underlie these processes.
In the majority of the experiments the following method was used: by means of training in a spatial maze, mice learned to visit a specific location to obtain a food reward. After training, the mice were confronted with a modified situation: the food reward was now at a novel location, with no food reward at the previously learned location. To associate the new location with the food reward, mice had to modify the previously formed memory for the original location of the food reward.
We show that within the hippocampus, the protein calcineurin, which has been suggested to suppress the formation of memories, plays a crucial role in modifying previously formed memories. In addition, we reveal that the protein PKA plays a crucial role in the detection of changes in a well-known environment or situation and is involved in the processes required for updating outdated memories.
We also show that sleep loss attenuates the functioning of PKA in the hippocampus. As a result, updating of previously formed memories is delayed. This study gives new insight into the role of sleep in memory processes and shows which proteins play a key role in changing previously stored memories.
The tired hippocampus: The molecular impact of sleep deprivation on hippocampal function
Full text linkMemory consolidation, the process by which information is stored following training, consists of synaptic consolidation and systems consolidation. It is widely acknowledged that sleep deprivation has a profound effect on synaptic consolidation, particularly for memories that require the hippocampus. It is unclear, however, which of the many molecular changes associated with sleep deprivation directly contribute to memory deficits. In this review, we highlight recent studies showing that sleep deprivation impairs hippocampal cAMP and mTOR signaling, and ultimately causes spine loss in CA1 neurons in a cofilin-dependent fashion. Reversing these molecular alterations made memory consolidation resistant to the negative impact of sleep deprivation. Together, these studies have started to identify the molecular underpinnings by which sleep deprivation impairs synaptic consolidation
Impacts of sleep loss versus waking experience on brain plasticity:Parallel or orthogonal?
Full text linkRecent studies on the effects of sleep deprivation on synaptic plasticity have yielded discrepant results. Sleep deprivation studies using novelty exposure as a means to keep animals awake suggests that sleep (compared with wake) leads to widespread reductions in net synaptic strength. By contrast, sleep deprivation studies using approaches avoiding novelty-induced arousal (i.e., gentle handling) suggest that sleep can promote synaptic growth and strengthening. How can these discrepant findings be reconciled? Here, we discuss how varying methodologies for the experimental disruption of sleep (with differential introduction of novel experiences) could fundamentally alter the experimental outcome with regard to synaptic plasticity. Thus, data from experiments aimed at assessing the relative impact of sleep versus wake on the brain may instead reflect the quality of the waking experience itself. The highlighted work suggests that brain plasticity resulting from novel experiences versus wake per se has unique and distinct features.</p
Electrocorticographic recording of cerebral cortex areas manipulated using an adeno-associated virus targeting cofilin in mice
Full text linkThe use of electrocorticographic (ECoG) recordings in rodents is relevant to sleep research and to the study of a wide range of neurological conditions. Adeno-associated viruses (AAVs) are increasingly used to improve understanding of brain circuits and their functions. The AAV-mediated manipulation of specific cell populations and/or of precise molecular components has been tremendously useful to identify new sleep regulatory circuits/molecules and key proteins contributing to the adverse effects of sleep loss. For instance, inhibiting activity of the filamentous actin-severing protein cofilin using AAV prevents sleep deprivation-induced memory impairment. Here, a protocol is described that combines the manipulation of cofilin function in a cerebral cortex area with the recording of ECoG activity to examine whether cortical cofilin modulates the wakefulness and sleep ECoG signals. AAV injection is performed during the same surgical procedure as the implantation of ECoG and electromyographic (EMG) electrodes in adult male and female mice. Mice are anesthetized, and their heads are shaved. After skin cleaning and incision, stereotaxic coordinates of the motor cortex are determined, and the skull is pierced at this location. A cannula prefilled with an AAV expressing cofilinS3D, an inactive form of cofilin, is slowly positioned in the cortical tissue. After AAV infusion, gold-covered screws (ECoG electrodes) are screwed through the skull and cemented to the skull with gold wires inserted in the neck muscles (EMG electrodes). The animals are allowed three weeks to recover and to ensure sufficient expression of cofilinS3D. The infected area and cell type are verified using immunohistochemistry, and the ECoG is analyzed using visual identification of vigilance states and spectral analysis. In summary, this combined methodological approach allows the investigation of the precise contribution of molecular components regulating neuronal morphology and connectivity to the regulation of synchronized cerebral cortex activity during wakefulness and sleep.</p
Genetic manipulation of cyclic nucleotide signaling during hippocampal neuroplasticity and memory formation
Full text linkDecades of research have underscored the importance of cyclic nucleotide signaling in memory formation and synaptic plasticity. In recent years, several new genetic techniques have expanded the neuroscience toolbox, allowing researchers to measure and modulate cyclic nucleotide gradients with high spatiotemporal resolution. Here, we will provide an overview of studies using genetic approaches to interrogate the role cyclic nucleotide signaling plays in hippocampus-dependent memory processes and synaptic plasticity. Particular attention is given to genetic techniques that measure real-time changes in cyclic nucleotide levels as well as newly-developed genetic strategies to transiently manipulate cyclic nucleotide signaling in a subcellular compartment-specific manner with high temporal resolution.</p
Differential involvement of hippocampal calcineurin during learning and reversal learning in a Y-maze task
Full text linkThe regulation and function of the calcium-dependent phosphatase calcineurin (CaN, protein phosphatase 2B) in learning and memory remain unclear, although recent work indicates that CaN may play a differential role in training and reversal training. To gain more insight into the involvement of CaN in these two types of learning, hippocampal CaN activity, protein levels, and expression patterns were studied in mice subjected to a reference memory version of the Y-maze task. We show that (1) training but not habituation induces a decrease in cytosolic CaN activity, (2) the recovery of cytosolic CaN activity is reversal training specific and does not reflect normal restoration of basal levels unrelated to subsequent learning, (3) cytosolic protein levels for the catalytic subunit of CaN (CaNA) are decreased at the early phase of training, but not at the early phase of reversal training, (4) CaNA immunoreactivity in the dorsal hippocampus is enhanced in the CA1 and CA3 area (but not in the dentate gyrus [DG] or subiculum [SUB]) only during reversal training. These findings indicate that memory formation is accompanied by reduced CaN activity, whereas adapting to changes in a familiar environment is accompanied by restored CaN activity. Moreover, reversal training selectively affects hippocampal CA3 and CA1 regions, suggesting a specific function of these hippocampal subregions in reversal learning.
Restoration of phosphorylated eukaryotic translation initiation factor 4E binding protein 2 (4EBP2) in the hippocampus rescues memory impairments due to sleep deprivation
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The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease
Full text linkParkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α-synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca2+ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α-synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD-related genes Parkin, PINK1 and DJ-1. We establish that these mutant varieties can set in motion the same degenerative process involving α-synuclein, cytosolic catecholamines and Ca2+ . Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ-1 model organisms often lack a convincing PD-like phenotype.</p
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