The Role of State-Dependent Thalamocortical Communication in Visual System Plasticity

Sleep is a phylogenetically conserved state of unconsciousness that plays a critical role in cognitive processing and underlying synaptic plasticity. However, the mechanism through which sleep contributes to brain function remains a mystery. During non-Rapid Eye Movement (non-REM) sleep, coordinated firing of neurons in the thalamocortical circuit of the brain generate oscillations characteristic of this sleep stage. These oscillations have been correlated with increases in memory retention and learning in a number of animal models. My dissertation examines the role of this state-specific thalamocortical activity in mediating sleep-dependent synaptic plasticity within the mouse visual circuit – orientation specific response potentiation (OSRP). Orientation-Specific Response Potentiation (OSRP) is a form of plasticity that takes place in adult mice after exposure to an oriented grating stimulus. OSRP occurs at thalamocortical synapses between the visual thalamus (LGN) and primary visual cortex (V1) and expresses as increased V1 firing to the presented stimulus. Our lab has demonstrated that OSRP is sleep-dependent. Furthermore, OSRP is positively correlated with the time spent in either rapid eye movement (REM) or non-REM (NREM) sleep. To further characterize the cortical nuances of OSRP, I examined the changes in neural activity following OSRP induction. V1 firing rates increase specifically across both NREM and REM sleep states, but not across wakefulness. Additionally, sleep differentially affects firing rates of V1 neurons, re-distributing firing rates such that sparsely-firing neurons increase their firing over sleep, while faster-firing neurons decrease their firing. Sparsely-firing neurons also fire more independently of the rest of the population, are more visually-responsive, and undergo the largest plastic changes in OSRP. Together, these data indicate re-distribution of firing may serve a functional role in sleep-dependent visual plasticity. Since OSRP occurs through thalamocortical relay it is also critical to elucidate how stimulus information is communicated to V1 during post-stimulus sleep. Using dual site LGN/V1 recordings, I found that, in contrast to V1 neurons, LGN neurons show immediate, stimulus-specific changes. Furthermore, LGN firing coherence with V1 field potentials increases at during NREM sleep, at both delta (0.5-4 Hz) and spindle (7-14 Hz) frequencies. The largest coherence increases occur in LGN neurons are the highly stimulus responsive, indicating these neurons may provide stimulus specific information to V1 during NREM sleep. However, this evidence is correlational. To characterize the necessity of NREM-specific oscillations in OSRP, a technician and I used optogenetics to state-specifically inhibit the circuitry that coordinates these oscillations. NREM-specific inhibition decreases the power and synchrony of NREM oscillations, subsequently preventing the consolidation of OSRP. Inhibition during REM and wake did not affect the oscillations or plasticity. Thus, I concluded that NREM oscillations promote the transfer of visually-specific information from LGN to V1. Together, this work sheds light on sleep’s role in brain plasticity in both an experience-specific and multi-regional manner. This thesis challenges major hypotheses in the field which argue that sleep uniformly downscales synaptic activity. V1 shows sleep-mediated, bidirectional alterations in firing – increasing the activity in experience-responsive neurons while decreasing the firing of others. Furthermore, it highlights a role for the thalamus as an active participant in cortical plasticity, rather than a simple relay for waking sensory information. Elucidating these changes opens the door for future work to explore these mechanisms in a manner that does justice to both the structure-specific and memory-specific changes that occur during sleep.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/150027/1/djaclyn_1.pd

Sleep Promotes, and Sleep Loss Inhibits, Selective Changes in Firing Rate, Response Properties and Functional Connectivity of Primary Visual Cortex Neurons

Recent studies suggest that sleep differentially alters the activity of cortical neurons based on firing rates during preceding wake—increasing the firing rates of sparsely firing neurons and decreasing those of faster firing neurons. Because sparsely firing cortical neurons may play a specialized role in sensory processing, sleep could facilitate sensory function via selective actions on sparsely firing neurons. To test this hypothesis, we analyzed longitudinal electrophysiological recordings of primary visual cortex (V1) neurons across a novel visual experience which induces V1 plasticity (or a control experience which does not), and a period of subsequent ad lib sleep or partial sleep deprivation. We find that across a day of ad lib sleep, spontaneous and visually-evoked firing rates are selectively augmented in sparsely firing V1 neurons. These sparsely firing neurons are more highly visually responsive, and show greater orientation selectivity than their high firing rate neighbors. They also tend to be “soloists” instead of “choristers”—showing relatively weak coupling of firing to V1 population activity. These population-specific changes in firing rate are blocked by sleep disruption either early or late in the day, and appear to be brought about by increases in neuronal firing rates across bouts of rapid eye movement (REM) sleep. Following a patterned visual experience that induces orientation-selective response potentiation (OSRP) in V1, sparsely firing and weakly population-coupled neurons show the highest level of sleep-dependent response plasticity. Across a day of ad lib sleep, population coupling strength increases selectively for sparsely firing neurons—this effect is also disrupted by sleep deprivation. Together, these data suggest that sleep may optimize sensory function by augmenting the functional connectivity and firing rate of highly responsive and stimulus-selective cortical neurons, while simultaneously reducing noise in the network by decreasing the activity of less selective, faster-firing neurons

Form and Function of Sleep Spindles across the Lifespan

Since the advent of EEG recordings, sleep spindles have been identified as hallmarks of non-REM sleep. Despite a broad general understanding of mechanisms of spindle generation gleaned from animal studies, the mechanisms underlying certain features of spindles in the human brain, such as “global” versus “local” spindles, are largely unknown. Neither the topography nor the morphology of sleep spindles remains constant throughout the lifespan. It is likely that changes in spindle phenomenology during development and aging are the result of dramatic changes in brain structure and function. Across various developmental windows, spindle activity is correlated with general cognitive aptitude, learning, and memory; however, these correlations vary in strength, and even direction, depending on age and metrics used. Understanding these differences across the lifespan should further clarify how these oscillations are generated and their function under a variety of circumstances. We discuss these issues, and their translational implications for human cognitive function. Because sleep spindles are similarly affected in disorders of neurodevelopment (such as schizophrenia) and during aging (such as neurodegenerative conditions), both types of disorders may benefit from therapies based on a better understanding of spindle function

Moonlighting in residency: a dermatology perspective

Background: Moonlighting refers to the practice of medicine outside one’s training institution in exchange for financial compensation. High medical debt-to-income ratios drive residents to seek additional compensation during residency.Objective: To gather information to establish the current practices of moonlighting and to better understand the thoughts and experiences of dermatology residency program directors regarding moonlighting.Methods: All allopathic and osteopathic dermatology residency program directors in the United States and Puerto Rico received a blinded survey between February 1, 2017 and April 1, 2017 through an email link.Results: Response rate was 47.0%. Of the programs that responded, 63.16% allowed moonlighting. In three regions, 100% of programs allowed moonlighting. The geographic area with the lowest percentage of programs permitting moonlighting was New England with 25%.Limitations: This survey only reflects the field of dermatology and beliefs/policies of program directors.Conclusion: This survey highlighted that training programs allowing moonlighting tend to have a more positive outlook on the practice than programs who do not. Results revealed trends that suggest that states in regions with less access to dermatologic care were more inclined to allow moonlighting

Neurofibromin 1 regulates early developmental sleep in Drosophila

Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including Drosophila, suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene Neurofibromin 1 (Nf1) in sleep during numerous developmental periods. Mutations in Neurofibromin 1 (Nf1) are associated with sleep and circadian disorders in humans and adult flies. We find in flies that Nf1 acts to regulate sleep across the lifespan, beginning during larval stages. Nf1 is required in neurons for this function, as is signaling via the Alk pathway. These findings identify Nf1 as one of a small number of genes positioned to regulate sleep across developmental periods

Multi-kilowatt fibre laser with azimuthal mode output beam for advanced material processing

A multi-kilowatt high-power fibre laser with adjustable azimuthal mode output beam profile is presented for the first time. The beam properties, and applications in laser cutting and welding of various metals are presented