Acute Sleep Loss Upregulates the Synaptic Scaffolding Protein, Homer1a, in Non-canonical Sleep/Wake Brain Regions, Claustrum, Piriform and Cingulate Cortices

Abstract

Homer proteins are a component of the post-synaptic density of neurons that are necessary for the maintenance and consolidation of behavioral state. The dominant negative protein homer1a is rapidly increased by neuronal activity and sleep loss. Homer1a knockout mice with globally absent homer1a have reduced ability to sustain wakefulness during the active period. It is not known whether homer1a is required globally or in very specific brain regions or neurons for its role in maintaining wake. In this study, we examined the expression of homer1a, an immediate early gene involved in intracellular signaling cascades, in mice subjected to extended wakefulness. We found that mice displayed increased expression of homer1a in the claustrum, a brain region thought to be involved in consciousness, as well as the cingulate and piriform cortices compared to non-sleep deprived mice. In situ hybridization (ISH) studies also indicate that homer1a is not induced in the known wake promoting regions with sleep deprivation, but is instead upregulated primarily in the claustrum and piriform cortex. Examination of homer1a expression levels with recovery sleep after sleep deprivation indicate that baseline homer1a expression levels were restored. Further, we have identified that homer1a is upregulated in excitatory neurons of the claustrum suggesting that homer1a promotes wakefulness through activating excitatory neurons. This work identifies regions previously unknown to be involved in sleep regulation that respond to acute sleep deprivation or enhanced waking.

Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping

“…Alterations in brain clock gene expression with SD has been widely reported (Franken et al, 2007;Mongrain et al, 2011;Wisor et al, 2002;Wisor et al, 2008). Along with transcripts such as Homer1a (Maret et al, 2008;Zhu et al, 2020), SD-driven increases in transcripts such as Per2 are hypothesized to play a role in homeostatic aspects of sleep regulation (Franken et al, 2007;Mang and Franken, 2015). Our data suggest that similar to plasticity-regulating transcripts (including Homer1a), SD-mediated changes in clock gene transcripts on ribosomes are cell type-and brain region-specific (Figures 8 and 9).…”

Sleep Loss Drives Brain Region-Specific and Cell Type-Specific Alterations in Ribosome-Associated Transcripts Involved in Synaptic Plasticity and Cellular Timekeeping

“…Alterations in brain clock gene expression with SD has been widely reported ( Wisor et al, 2002 , 2008 ; Franken et al, 2007 ; Mongrain et al, 2011 ; Bolsius et al, 2021 ). Along with transcripts such as Homer1a ( Maret et al, 2007 ; Zhu et al, 2020 ), SD-driven increases in clock transcripts such as Per2 are hypothesized to (1) act as an immediate-early gene response (similar to increases in Arc and Cfos ; Balsalobre et al, 1998 ; Kuhlman et al, 2003 ; Lee et al, 2010 ) and (2) play a role in homeostatic aspects of sleep regulation ( Franken et al, 2007 ; Mang and Franken, 2015 ). Our data suggest that similar to plasticity-regulating transcripts (including Homer1a ), SD-mediated changes in clock gene transcripts on ribosomes are cell type specific and brain region specific ( Fig.…”

The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology

“…Functional and anatomical disorders in claustrum are therefore associated with progressive dementia in Parkinson’s disease [ 75 ]. Atrophic lesions in the claustrum may be a manifestation of pathophysiological changes in patients with Parkinson’s disease [ 76 , 77 ]. In Parkinson’s disease, the levels of dopamine and norepinephrine are significantly reduced within the claustrum [ 77 ].…”

“…Atrophic lesions in the claustrum may be a manifestation of pathophysiological changes in patients with Parkinson’s disease [ 76 , 77 ]. In Parkinson’s disease, the levels of dopamine and norepinephrine are significantly reduced within the claustrum [ 77 ]. Dopamine and norepinephrine deficiency in the claustrum may affect the mechanisms of information processing.…”