Impacts of sleep loss versus waking experience on brain plasticity:Parallel or orthogonal?

Recent 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

Electrocorticographic recording of cerebral cortex areas manipulated using an adeno-associated virus targeting cofilin in mice

The 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

Spatial and temporal gene function studies in rodents:Towards gene-based therapies for autism spectrum disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy

Multisensory cortical processing and dysfunction across the neuropsychiatric spectrum

Sensory processing is affected in multiple neuropsychiatric disorders like schizophrenia and autism spectrum disorders. Genetic and environmental factors guide the formation and fine-tuning of brain circuitry necessary to receive, organize, and respond to sensory input in order to behave in a meaningful and consistent manner. During certain developmental stages the brain is sensitive to intrinsic and external factors. For example, disturbed expression levels of certain risk genes during critical neurodevelopmental periods may lead to exaggerated brain plasticity processes within the sensory circuits, and sensory stimulation immediately after birth contributes to fine-tuning of these circuits. Here, the neurodevelopmental trajectory of sensory circuit development will be described and related to some example risk gene mutations that are found in neuropsychiatric disorders. Subsequently, the flow of sensory information through these circuits and the relationship to synaptic plasticity will be described. Research focusing on the combined analyses of neural circuit development and functioning are necessary to expand our understanding of sensory processing and behavioral deficits that are relevant across the neuropsychiatric spectrum

Genetic manipulation of cyclic nucleotide signaling during hippocampal neuroplasticity and memory formation

Decades 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