Biology subjects

Frank, M. G.

Publications and source records attributed to Frank, M. G..

8 recordsLinked to original sources

bioRxiv2026

Cell-specific effects of acute sleep deprivation on transcriptomic signatures of non-neuronal cells in the mouse hippocampus and prefrontal cortex

Sleep is essential for maintaining cognitive, emotional, metabolic, and immune functions. Although research on sleep homeostasis is traditionally neuron-centric, increasing evidence indicates non-neuronal cells also play critical roles. In this study, we performed transcriptomic analyses of non-neuronal nuclei from the hippocampus and prefrontal cortex of mice subjected to acute sleep deprivation (SD). We found that acute SD induces robust, cell-type- and region-specific transcriptional reprogramming in astrocytes and oligodendrocytes. The most pronounced changes occurred in astrocytes, including downregulation of cholesterol biosynthesis genes in both brain regions, accompanied by region-specific and opposing regulation of genes involved in mitochondrial function and neurodegeneration-related pathways. Notably, genes associated with primary cilia were selectively induced in cortical astrocytes. In oligodendrocytes, acute SD led to downregulation of genes encoding cell-adhesion molecules. Together, these findings provide molecular evidence that non-neuronal cells actively contribute to sleep regulation and suggest novel potential mechanisms that broaden our understanding of sleep homeostasis.

neuroscience↗

bioRxiv2023

A Global Transcriptional Atlas of the Effect of Sleep Deprivation in the Mouse Frontal Cortex

Sleep deprivation (SD) has negative effects on brain function. Sleep problems are prevalent in neurodevelopmental, neurodegenerative and psychiatric disorders. Thus, understanding the molecular consequences of SD is of fundamental importance in neuroscience. In this study, we present the first simultaneous bulk and single-nuclear (sn)RNA sequencing characterization of the effects of SD in the mouse frontal cortex. We show that SD predominantly affects glutamatergic neurons, specifically in layers 4 and 5, and produces isoform switching of thousands of transcripts. At both the global and cell-type specific level, SD has a large repressive effect on transcription, down-regulating thousands of genes and transcripts; underscoring the importance of accounting for the effects of sleep loss in transcriptome studies of brain function. As a resource we provide extensive characterizations of cell types, genes, transcripts and pathways affected by SD; as well as tutorials for data analysis.

neuroscience↗

bioRxiv2023

Prior experience with behavioral control over stress facilitates social dominance

Dominance status has extensive effects on physical and mental health, and an individuals relative position can be shaped by experiential factors. A variety of considerations suggest that the experience of behavioral control over stressors should produce winning in dominance tests and that winning should blunt the impact of later stressors, as does prior control. To investigate the interplay between competitive success and stressor control, we first examined the impact of stressor controllability on subsequent performance in a warm spot competition test modified for rats. Prior experience of controllable, but not physically identical uncontrollable, stress increased later effortful behavior and occupation of the warm spot. Controllable stress subjects consistently ranked higher than did uncontrollable stress subjects. Pharmacological inactivation of the prelimbic (PL) cortex during behavioral control prevented later facilitation of dominance. Next, we explored whether repeated winning experiences produced later resistance against the typical sequelae of uncontrollable stress. To establish dominance status, triads of rats were given five sessions of warm spot competition. Reversible inactivation of the PL or NMDA receptor blockade in the dorsomedial striatum led to a long-term reduction in social rank. Stable dominance blunted the later stress-induced increase in dorsal raphe nucleus serotonergic activity, as well as prevented stress-induced social avoidance. In contrast, endocrine and neuroimmune responses to uncontrollable stress were unaffected, indicating a selective impact of prior dominance. Together, these data demonstrate that instrumental control over stress promotes later dominance, but also reveal that winning experiences buffer against the neural and behavioral outcomes of future adversity.

neuroscience↗

bioRxiv2023

Ontogenesis of the molecular response to sleep loss

Sleep deprivation (SD) results in profound cellular and molecular changes in the adult mammalian brain. Some of these changes may result in, or aggravate, brain disease. However, little is known about how SD impacts gene expression in developing animals. We examined the transcriptional response in the prefrontal cortex (PFC) to SD across postnatal development in male mice. We used RNA sequencing to identify functional gene categories that were specifically impacted by SD. We find that SD has dramatically different effects on PFC genes depending on developmental age. Gene expression differences after SD fall into 3 categories: present at all ages (conserved), present when mature sleep homeostasis is first emerging, and those unique to certain ages in adults. Developmentally conserved gene expression was limited to a few functional categories, including Wnt-signaling which suggests that this pathway is a core mechanism regulated by sleep. In younger ages, genes primarily related to growth and development are affected while changes in genes related to metabolism are specific to the effect of SD in adults.

neuroscience↗

bioRxiv2023

Activation of basal forebrain astrocytes induces wakefulness without compensatory changes in sleep drive

Mammalian sleep is regulated by a homeostatic process that increases sleep drive and intensity as a function of prior wake time. Sleep homeostasis has traditionally been thought to be a product of neurons, but recent findings demonstrate that this process is also modulated by glial astrocytes. The precise role of astrocytes in the accumulation and discharge of sleep drive is unknown. We investigated this question by selectively activating basal forebrain (BF) astrocytes using designer receptors exclusively activated by designer drugs (DREADDs). Activation of the Gq-protein-coupled pathway in BF astrocytes produced long and continuous periods of wakefulness that paradoxically did not cause the expected homeostatic response to sleep loss (e.g., increases in sleep time or intensity). Further investigations showed that this was not due to indirect effects of the ligand that activated DREADDs. These findings suggest that the need for sleep is not driven by wakefulness per se, but specific neuronal-glial circuits that are differentially activated in wakefulness.

neuroscience↗

bioRxiv2022

REM sleep promotes bidirectional plasticity in developing visual cortex in vivo

Sleep is required for the full expression of plasticity during the visual critical period (CP). However, the precise role of rapid-eye-movement (REM) sleep in this process is undetermined. Previous studies in rodents indicate that REM sleep weakens cortical circuits following MD, but this has been explored in only one class of cortical neuron (layer 5 apical dendrites). We investigated the role of REM sleep in ocular dominance plasticity (ODP) in layer 2/3 neurons using 2-photon calcium imaging in awake CP mice. In contrast to findings in layer 5 neurons, we find that REM sleep promotes changes consistent with synaptic strengthening and weakening. This supports recent suggestions that the effects of sleep on plasticity are highly dependent upon the type of circuit and preceding waking experience.

neuroscience↗

bioRxiv2019

A role for astroglial calcium in mammalian sleep

Mammalian sleep is characterized by dramatic changes in neuronal activity, and waking neuronal activity is thought to increase sleep need. Changes in other brain cells (glia) across the natural sleep-wake cycle and their role in sleep regulation are comparatively unexplored. We show that sleep is also accompanied by large changes in astroglial activity as measured by intracellular calcium concentrations in unanesthetized mice. These changes in calcium vary across different vigilance states and are most pronounced in distal astroglial processes. We find that reducing intracellular calcium in astrocytes impaired the homeostatic response to sleep deprivation. Thus, astroglial calcium changes dynamically across vigilance states and is a component of the sleep homeostat.\n\nOne Sentence SummaryAstroglial calcium concentrations vary with sleep and wake, change after sleep deprivation, and mediate sleep need.

neuroscience↗

bioRxiv2018

Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

Autism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Dec2, Hlf, Tef, and Reverb. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall our study shows that Shank3 is an important modulator of sleep and clock gene expression.

neuroscience↗