Jason Gerstner, PhD

• University of Pennsylvania, Center for Sleep and Circadian Neurobiology, Post-Doctoral Fellowship
• University of Wisconsin-Madison, PhD in Neuroscience Training Program
• University of Wisconsin-Madison, Bachelor of Science in Zoology and Communication Arts

The molecular mechanisms that govern and integrate sleep, circadian rhythms, and memory formation.

Our research interests focus on how the molecular mechanisms involved in the generation of circadian rhythms and sleep interact with learning and memory. While the precise function of sleep remains elusive, one possible function may be to serve synaptic plasticity and memory formation. A key feature of long-term memory formation is that it requires de novo gene expression and protein synthesis, which changes synaptic strength. How are these newly initiated signaling cascades and pathways able to sustain memory over time? What are the mechanisms responsible for the maintenance of specific synaptic connections? Many of the molecular pathways involved in memory storage and synaptic plasticity are shared with those involved in the regulation of sleep and circadian rhythms, supporting the hypothesis that sleep and circadian rhythms facilitate memory formation. Therefore, other yet to be discovered molecular signaling pathways may also be shared between these behaviors. Our approach to answer these hypotheses is to combine both hypothesis-driven and discovery-based methods in evolutionarily distant model species. Our studies have used gene expression profiling in mice to identify novel transcripts that are involved in modulating sleep, circadian rhythms, and memory formation. In order to determine evolutionary conservation of these newly identified pathways, studies also utilize the fruit fly, Drosophila melanogaster, and the power of fly genetics and behavior to determine the functional relevance of specific genes on sleep, circadian rhythms, and memory.

NOVEL MECHANISMS INTEGRATING SLEEP, CLOCKS AND MEMORY

These studies have led to the discovery of novel transcripts, such as the brain-type fatty-acid binding protein (Fabp7). We first identified Fabp7 to be one of few unique transcripts with synchronized cycling in three brain regions of mouse hypothalamus necessary for circadian rhythms, sleep, and wakefulness. To determine functional significance, we then turned to the Drosophila model to generate transgenic overexpression Fabp7, or the fly homologue, dFabp, and showed that Fabp-induced sleep produces enhancement of long term memory. Given these observations, we returned back to the mouse model to better characterize the expression pattern and identify mechanisms that regulate Fabp7 expression. We found that the subcellular localization of Fabp7 and relative levels of Fabp7 mRNA oscillate in the perisynaptic astrocytic process compartment over the light-dark cycle in mice. These time-of-day dependent changes in Fabp7 mRNA trafficking are coupled with alterations in polyadenylation state, suggesting that Fabp7 mRNA is actively transported to the perisynaptic astrocytic process where it is locally translated. We then showed that cytoplasmic polyadenylation elements exist in the Fapb7 mRNA 3′ untranslated region to regulate cytoplasmic Fabp7 mRNA translational processing. We believe these pathways regulate neural-glial interactions to influence synaptic plasticity, and are coordinated with sleep and circadian rhythm behavior. Ongoing studies are to elucidate the function of Fabp7 and related mRNAs in the regulation of behavioral state-dependent morphological changes in the fine perisynaptic astrocytic processes. A major challenge to these studies is to determine the way in which astrocytes influence synaptic function leading to changes in behavioral output. To accomplish this, we employ a variety of techniques, including transgenic fluorescent tagging of synaptic proteins combined with in vivo 2-photon microscopy, electrophysiology, and calcium imaging.

APPLICATION TO HUMAN HEALTH AND DISEASE

Fabp7 has been implicated in neurological disorders such as schizophrenia, as well as neurodegenerative disease, including Alzheimer’s disease. A second avenue of study involves the way in which these recently discovered genes and pathways are involved in CNS diseases. The goal of this second set of studies is to determine whether these newly identified pathways are also novel targets for the treatment of psychiatric and neurodegenerative disease.

In the Media

• Astrocytes: Sleeping under the stars takes new meaning
  The Spokesman-Review, Nov. 7, 2018
• Sleep Gene
  BBC Radio, April 6, 2017 (begins at 8:08 mark)
• Tiny fruit flies offer a few clues to sleep-related Alzheimer’s mysteries
  The Spokesman-Review, March 13, 2017
• WSU sleep researchers discover why some people may toss and turn more than others
  The Spokesman-Review, April 14, 2017
• WSU Researchers Find ‘Sleep Gene’ Common To 3 Species Including Humans
  Northwest News Network, April 5, 2017
• Scientists believe the secret of a good night’s sleep is all in our genes
  The Guardian, April 9, 2017

• Gerstner, JR, Flores, CC, Lefton, M, Rogers, B, Davis, CJ. FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function
Frontiers in Systems Neuroscience 17, 1212213. doi.org/10.3389/fnsys.2023.1212213
• Needham, H, Torpey, G, Flores, CC, Davis, CJ, Vanderheyden, WM, Gerstner, JR. A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis. Front Neurosci. 2022; 16: 798994. doi.org/10.3389/fnins.2022.798994
• Vanderheyden, WM, Lefton, M, Flores, CC, Owada, Y, Gerstner, JR. Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice. Neuroglia 3 (2), 73-83 doi.org/10.3390/neuroglia3020005
• Shola-Dare, O, Bailess, S, Flores, CC, Vanderheyden, WM, Gerstner, JR. Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease.
International Journal of Molecular Sciences 22 (23), 12740. doi.org/10.3390/ijms222312740
• Vanderheyden WM, Fang B, Flores CC, Jager J, Gerstner JR. The transcriptional repressor Rev-erbα regulates circadian expression of the astrocyte Fabp7 mRNA.
Curr Res Neurobiol. 2021;2:100009. Epub 2021 Mar 23. doi: 10.1016/j.crneur.2021.100009
• Davis CJ, Gerstner JR, Vanderheyden WM. Single prolonged stress blocks sleep homeostasis and pre-trauma sleep deprivation does not exacerbate the severity of trauma-induced fear-associated memory impairments. PLoS One. 2021 Jan 6;16(1):e0243743. doi: 10.1371/journal.pone.0243743
• Re CJ, Batterman AI, Gerstner JR, Buono RJ, Ferraro TN. The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy. Front Neurol. 2020 Jun 23;11:520. doi: 10.3389/fneur.2020.00520
• Gerstner JR, Paschos GK. Circadian expression of Fabp7 mRNA is disrupted in Bmal1 KO mice. Mol Brain. 2020 Feb 24;13(1):26. doi: 10.1186/s13041-020-00568-7
• Vanderheyden WM, Van Dongen HPA, Frank MG, Gerstner JR. Sleep pressure regulates mushroom body neural-glial interactions in Drosophila. Matters Select, 2019 Mar 22 doi: 10.19185/matters.201903000008
• Vanderheyden WM, Goodman AG, Taylor RH, Frank MG, Van Dongen HPA, Gerstner JR. Astrocyte expression of the Drosophila TNF-alpha homologue, Eiger, regulates sleep in flies.
PLoS Genet. 2018 Oct 31;14(10):e1007724. doi.org/10.1371/journal.pgen.1007724
• Vanderheyden WM, Lim MM, Musiek ES, Gerstner JR. Alzheimer’s Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models. J Neurosci. 2018 Mar 21;38(12):2901-2910. doi.org/10.1523/JNEUROSCI.1135-17.2017
• Gerstner JR, Koberstein JN, Watson AJ, Zapero N, Risso D, Speed TP, Frank MG, Peixoto L. Removal of unwanted variation reveals novel patterns of gene expression linked to sleep homeostasis in murine cortex. BMC Genomics. 2016 Oct 25;17(Suppl 8):727 doi.org/10.1186/s12864-016-3065-8
• Gerstner JR, Perron IJ, Riedy SM, Yoshikawa T, Kadotani H, Owada Y, Van Dongen HPA, Galante RJ, Dickinson K, Yin JCP, Pack AI, Frank MG. Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7. Science Advances. 2017 Apr 5;3(4):e1602663. DOI: 10.1126/sciadv.1602663
• Gerstner JR, Lenz O, Vanderheyden WM, Chan MT, Pfeiffenberger C, Pack AI. Amyloid-β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila. J Neurosci Res. 2016 Jun 19. doi: 10.1002/jnr.23778
• Gerstner, JR, Smith, G, Lenz, O, Perron IJ, Buono RJ, Ferraro, TN. BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice. Front Syst Neurosci. 2014 Jun 26; 8:121. doi.org/10.3389/fnsys.2014.00121
• Lim, MM, Gerstner, JR, Holtzman, DM. The sleep–wake cycle and Alzheimer’s disease: what do we know? Neurodegenerative disease management 4 (5), 351-362 doi.org/10.2217/nmt.14.33
• Vanderheyden, WM, Gerstner, JR, Tanenhaus, A, Yin, JCP, Shaw, PJ. ERK Phosphorylation Regulates Sleep and Plasticity in Drosophila. PLoS One 2013 Nov 14;8(11):e81554. doi.org/10.1371/journal.pone.0081554
• Grandner, MA, Jackson, N, Gerstner, JR, Knutson, KL. Sleep symptoms associated with intake of specific dietary nutrients. J Sleep Res. 2013 Sep 2 onlinelibrary.wiley.com/doi/full/10.1111/jsr.12084
• Tubon, TC, Zhang, J, Friedman, E, Jin, H, Gonzalez, ED, Zhou, H, Drier, D, Gerstner, JR, Paulson, E, Fropf, R, and Yin, JCP. dCREB2-mediated Enhancement of Memory Formation. J Neurosci. 2013 Apr 24;33(17):7475-87  doi.org/10.1523/JNEUROSCI.4387-12.2013
• Gerstner, JR. On the evolution of memory: A time for clocks. Front Mol Neurosci. 2012;5:23. doi.org/10.3389/fnmol.2012.00023
• Gerstner, JR, Vanderheyden,WM, LaVaute, TM, Westmark, CJ, Rouhana, L, Pack, AI, Wickens, M, Landry, CF. Time-of-day regulates subcellular trafficking, tripartite synaptic localization and polyadenylation of the astrocytic Fabp7 mRNA. J Neurosci. 2012 Jan 25;32(4):1383-94. doi.org/10.1523/JNEUROSCI.3228-11.2012
• Gerstner, JR, Vanderheyden, WM, Shaw, PJ, Landry, CF, and Yin, JCP. Cytoplasmic to nuclear localization of fatty-acid binding protein correlates with specific forms of long-term memory inDrosophila. Commun & Integr Biol 2011. doi.org/10.4161/cib.16927
• Gerstner, JR, Vander Heyden, WM, Shaw, PJ, Landry, CF, and Yin, JCP. Fatty-acid binding proteins modulate sleep and enhance long-term memory consolidation in Drosophila. PLoS One. 2011 Jan 27;6(1) doi.org/10.1371/journal.pone.0015890
• Gerstner, JR, Yin JC. Circadian rhythms and memory formation. Nat Rev Neurosci. 2010 Aug;11(8):577-88 nature.com/articles/nrn2881
• Gerstner, JR, Lyons LC, Wright KP Jr, Loh DH, Rawashdeh O, Eckel-Mahan KL, Roman GW. Cycling behavior and memory formation. J Neurosci. 2009 Oct 14;29(41):12824-30 doi.org/10.1523/JNEUROSCI.3353-09.2009
• Gerstner, JR, Bremer QZ, Vander Heyden WM, Lavaute TM, Yin JC, Landry CF. Brain Fatty Acid binding protein (fabp7) is diurnally regulated in astrocytes and hippocampal granule cell precursors in adult rodent brain. PLoS One. 2008 Feb 20;3(2):e1631. doi.org/10.1371/journal.pone.0001631

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