University of Groningen Sleep as a synaptic architect Raven, Frank

Sleep as a synaptic architect

Raven, Frank

DOI:

10.33612/diss.131687500

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Publication date: 2020

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Raven, F. (2020). Sleep as a synaptic architect: How sleep loss influences memory and synaptic plasticity. University of Groningen. https://doi.org/10.33612/diss.131687500

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General introduction

Human beings and most other animals have the fundamental ability to form and retrieve memories. This ability enables the organism to adapt to an ev-er-changing environment, which is essential for survival [1, 2]. In humans, these memories to a large degree define who we are. Fading and eventually losing memories can be detrimental and may have an enormous impact on one’s life and the people around it.

One brain region critical for memory processes is the hippocampus, locat-ed in the mlocat-edial temporal lobe of the human brain and beneath the cortex in the mouse brain (Figure 1). The idea that the hippocampus was import-ant for memory was first developed on the basis of the case study of H.M., who had parts of his temporal lobe (including the hippocampus) surgical-ly removed from both sides of the brain, to prevent epileptic seizures [3]. Apparently, H.M. was no longer able to form new memories [3]. By virtue of research in different organisms, it became generally accepted that the hippocampus is one of the most important brain structures for memory, and the hippocampus has been in the center of memory research ever since [4-9]. In addition, as rodents (e.g., mice, rats) are capable of performing complex behavioral tasks to study memory, and the anatomy of their hip-pocampus is quite similar to the hiphip-pocampus in humans, rodents are of-ten the leading model organism in the field of learning and memory [10].

Memory processing

The process of forming a stable, retrievable memory can be divided into three main stages. The first stage involves the acquisition of new sensory informa-tion, for example by taking in a new environment and looking at the objects in it [11]. The next step is to store and consolidate the information in the brain, a complex process that involves regions such as the hippocampus and parts of the neo cortex [11]. Lastly, stored memories can be recalled, a process often referred to as memory retrieval [11, 12]. On a temporal scale, memory can be subdivided into three types: working memory, short-term memory and long-term memory. Working memory lasts from seconds to minutes, whereas short-term memory lasts from several minutes to a few hours [13, 14]. Long-term memories, on the other hand can last from days to many years [13]. In order for memories to be created, sensory input is translated into neuronal activity that transfers signals from the sensory organs to higher brain areas, such as the entorhinal cortex and the hippocampus. The information is then projected to the perforant pathway onto the granule cells of the dentate gy-rus (DG), and then through different hippocampal subregions [15-17] (Figure 2). Axons from the granule cells, also known as the mossy fibers, connect to pyramidal cells of the cornu ammonis (CA) 3 area. Then, CA3 pyramidal cell axons, i.e., Schaffer collaterals, project to pyramidal cells in the CA1 area. The information from CA1 terminates in the subiculum and then goes on to the deeper layers of the entorhinal cortex [15-17]. It is important to note that there is also a direct connection between the cortical layers and CA3 and CA1 neurons. Because the DG filters information that enters the hip-pocampus [18], it has been suggested that this subregion plays a key role in learning, memory and spatial coding [19]. Thus, the hippocampus con-sists of multiple regions and is crucial for learning and memory (Figure 2).

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2).

▲Figure 2:. Simplified overview of the mouse hippocampus and the trisynaptic circuit. Information from higher

brain areas flows via the perforant pathway into the hippocampus, for example onto granule cells of the dentate gyrus (DG). Then, signals are converted via the mossy fibers to pyramidal cells of the CA3 region. Lastly, the CA3 transmits signals via the Schaffer collaterals to the CA1 region of the hippocampus. The CA1 completes the circuit by firing back to deeper layers of the entorhinal cortex.

Memory at the synaptic level

So, what happens during memory formation within the hippocampus at the level of individual brain cells? The human brain consists of billions of neurons and every single one of them can connect to thousands of other neurons [20], indicating that there are trillions of neuronal connections or synapses. These synapses form the location where neuronal communication occurs, which is essential for fundamental processes such as the ability to create and store memories in the brain. For example, when new memories are being created, signal transduction between neurons of the DG and CA3 increases, leading to enhanced synaptic efficacy [21]. This phenomenon of increased efficiency of synaptic transmission is a widely known as long-term potentiation (LTP), and is considered to be the biological basis of memory [7]. Therefore, study-ing how memory works at the synaptic level has attracted widespread inter-est in the field of neuroscience these past few decades.

Early light microscopy studies identified tiny protrusions on postsynap-tic neuronal fibers [22]. These protrusions, also known as dendripostsynap-tic spines, are the points where neurons connect and synapses are shaped [22, 23]. Dendritic spines are specialized membranous compartments that contain various organelles and neurotransmitter receptors necessary for synaptic transmission (e.g., AMPA and NMDA glutamate receptors)[23, 24]. The size and shape of the spines are to a large extend determined by internal actin

protein filaments (Figure 3). The spines were first recognized by Santiago Ramón y Cajal at the end of the 19th century using a Golgi staining, and have attracted much attention in the field of neuroscience ever since [22]. Different morphological subtypes of spines have been described such as mushroom, filopodia and thin spines, and it is hypothesized that the mor-phology not only influences synaptic efficacy, but also regulates receptor content, and how well they can adjust their shape as a response to envi-ronmental stimuli. For example, during learning and memory the morphol-ogy of a spine changes dynamically including enlargement of the spine head, as well as the widening of the spine neck [25]. Conversely, aberrant spine morphology has been observed in multiple neurodegenerative diseas-es such as Alzheimer’s, Parkinson and Huntington disease [26]. Altogeth-er, dendritic spines are the locus of neuronal communication and therefore highly important for learning and memory and underlying synaptic plasticity.

▲Figure 3:. Schematic overview of a synapse. Increased efficiency of synaptic transmission between two

neu-rons is a widely considered as the biological basis of memory. Lower part: Postsynaptic dendritic spines (cyan), consist of F-actin and contain various organelles and neurotransmitter receptors necessary for synaptic trans-mission (e.g., glutamate receptors). During sleep, (active) cofilin levels are relatively low, thereby promoting spine growth and memory consolidation (left). Conversely, sleep loss disrupts molecular processes that regulate the activity of cofilin, which results in F-actin destabilization (right). This leads to a loss of spines, and eventually produces learning and memory deficits.

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Several proteins have been discovered that impact actin turnover and there-by potentially alter spine shape and size. This in turns influences synaptic strength, neuronal signal transduction, and ultimately learning and memo-ry processes. For example, cofilin is an actin binding protein known for its ability to induce F-actin disassembly via filament severing or depolymer-ization and ubiquitously expressed in all neurons [27-29]. The phosphor-ylation of the cofilin molecule at serine 3 by a set of kinases (e.g., LIMK and TES kinases) makes it inactive and incapable of disassembling actin filaments, allowing for spine growth [27, 28, 30]. Conversely, cofilin is acti-vated by a group of phosphatases (e.g., slingshot and chronopin) and or-chestrates spine shrinkage that can eventually lead to spine loss [31, 32] (Figure 3). Notably, active cofilin is also necessary for generating the actin dynamics needed for the transport of certain proteins within the spine, and therefore also might benefit memory. Indeed, directly after the induction of LTP, (active) cofilin levels increase shortly for approximately 30mins [33].

Sleep deprivation and hippocampal memory

Sleep and sleep loss have a profound effect on alertness, mood and cog-nitive performance, including memory [34-37]. The world we are currently living in has slowly changed to a 24/7 society. Economically as well as so-cially there is a lot of pressure to be available beyond the normal work hours [38]. As a result, the percentage of the population not getting enough sleep is growing, negatively influencing quality of life, mood and health [39]. The impact sleep loss has on our brain includes a loss of attention and impaired learning and memory [40]. For example, sleep deprivation explicitly impacts hippocampus-dependent learning and memory [1, 34, 37, 41-44].

Different types of hippocampal learning and memory are affected by sleep deprivation [35, 40, 43, 45-48]. For example, one night of SD impaired recall in a verbal learning task and decreased activity in the temporal lobe in young healthy volunteers [49]. Other studies also found that one night of SD prior to learning impairs memory encoding in parallel with deficits in hippocampal activity [50, 51]. Furthermore, the storage of information in a hippocampus- dependent navigation task is also hampered when subjects are sleep de-prived after learning [52]. These findings are supported by animal studies. For instance, one has also shown that a brief period of 5-6 hours of sleep deprivation (SD) disrupts the consolidation of object-place recognition

mem-ory, which depends on the hippocampus [46]. It was also found in Wistar rats that SD for 5-6 hours directly following training disrupts the consolidation of hippocampus-dependent contextual fear memory [53], but not that of hippo-campus-independent cued fear memory [45]. Hagewoud et al. found that a period of 10-12 hours of SD during the normal resting phase impairs spatial working memory in C57BL/6J mice, using a novel arm recognition task [54]. It has also been found in humans that sleep deprivation following task ac-quisition in a hippocampus-dependent declarative memory task, impaired memory consolidation in this task [55]. Together, these findings show that SD has a negative effect on the consolidation and acquisition of different types of memory, especially these types of memory that require the hippocampus. Despite the fact that the underlying molecular mechanisms of both sleep and the formation of memories still have to be unraveled, evidence is emerging from the field that suggests a facilitating role for sleep in neuronal plasticity, while sleep deprivation on the other hand has detrimental effects on hippo-campal synaptic plasticity as will be discussed in the next paragraph [35].

Sleep deprivation and hippocampal synaptic plasticity

Recent findings indicate that even relatively mild sleep loss can have a ma-jor impact on neuronal connectivity in the brain. A study in mice showed that five hours of SD already results in a great reduction in the number of spines on neurons in the hippocampus [46, 56]. Several studies showed that SD decreases synapse density and amount of dendritic spines in several brain regions, including the hippocampus [46, 57-60]. Until now, it is still unknown if a short period of SD also affects the hippocampal dentate gyrus at the den-dritic spine level. In addition, it has been shown in C57BL/6J mice that a brief period of 5-6hrs of SD impairs long-lasting forms of LTP in the hippocampus [46, 48]. Hence, sleep loss also affects the formation of memory on a cellular level by perturbing structural and synaptic plasticity.

Furthermore, cofilin has been causally linked to the negative consequenc-es of SD on structural and synaptic plasticity. It has been reported that SD reduces cofilin phosphorylation and thereby increases the activity of cofilin [46, 61]. As mentioned before, the prolonged activity of cofilin may eventual-ly result in the shrinkage and loss of spines through its depoeventual-lymerizing and severing activity [27-29, 46]. Notably, expressing a dominant negative form of cofilin (CofilinS3D_{) in the hippocampus of mice prevents the impairment of}

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object-location memory caused by SD [46]. Another aspect of the role co-filin plays in spine plasticity, is the regulation of AMPA receptor trafficking during synaptic potentiation [62]. The transient activation of cofilin generates the actin dynamics important for AMPA receptor trafficking and the follow-ing inactivation might allow for spine growth [35, 62]. The glutamate AMPA receptors have been found to have a stabilizing effect on spine morphology [63, 64]. Hence, the ability of spines to change their morphology or grow new spines is regulated by cofilin, a protein whose prolonged activity, which can be caused by sleep deprivation, leads to a shrinkage and loss of spines. However, it is unknown whether an increase in cofilin activity, thereby pro-moting synaptic plasticity, can also have benefits on the behavioral level, for example short-term memory. In summary, sleep loss disrupts the molecular pathways that regulate the activity of cofilin, which results in a loss of spines and eventually leads to problems in learning and memory (Figure 3).

Thesis outline

The main aim of the present project was to investigate how hippocampus-de-pendent memory processes are affected by sleep deprivation and time-of-day. In addition, we examined the potential molecular mechanisms underly-ing these effects. In Chapter 2 we present an overview of the effects of sleep and sleep loss on structural plasticity in the hippocampus. In addition, we de-scribe how changes in dendritic spines alter cognition, with a special empha-sis on hippocampus-dependent learning and memory. Chapter 3 describes the effect of a brief period of SD on spine density in the dentate gyrus of the hippocampus. In this chapter we also investigate how SD affects different spine subtypes and in different proximity to the cell body. In Chapter 4, we examine if the negative consequences of sleep loss in hippocampus-depen-dent memory are mediated by increased levels of glucocorticoid stress hor-mones released during SD. Whereas chronic high levels of cofilin can mimic the negative effects of SD on long-term hippocampus-dependent memory processing, Chapter 5 investigates the effects of cofilin overactivation on short-term hippocampus-dependent memory. In Chapter 6, we aimed to elucidate the temporal dynamics of memory consolidation by investigating when hippocampus-dependent memory consolidation requires de novo pro-tein synthesis. Lastly, a summary of the main findings and general discussion is presented in Chapter 7.

References

1. Rasch B, Born J. About sleep's role in memory. Physiol Rev. 2013;93(2):681-766.

2. Bruel-Jungerman E, Davis S, Laroche S. Brain plasticity mechanisms and memory: a party of four. Neuroscientist. 2007;13(5):492-505.

3. Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957;20:11-21.

4. Zeineh MM, Engel SA, Thompson PM, Bookheimer SY. Dynamics of the Hippocampus During Encoding and Retrieval of Face-Name Pairs. Science. 2003;299(5606):577-80. 5. Nadel L, Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal

complex. Curr Opin Neurobiol. 1997;7(2):217-27.

6. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31-9.

7. Bliss TVP, Lømo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. The Journal of Physiology. 1973;232(2):331-56.

8. Morris RGM, Garrud P, Rawlins JNP, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297(5868):681-3.

9. Squire LR. Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychological review. 1992;99(2):195-231.

10. Ellenbroek B, Youn J. Rodent models in neuroscience research: is it a rat race? Dis Model Mech. 2016;9(10):1079-87.

11. Abel T, Lattal KM. Molecular mechanisms of memory acquisition, consolidation and re-trieval. Curr Opin Neurobiol. 2001;11(2):180-7.

12. Tonegawa S, Pignatelli M, Roy DS, Ryan TJ. Memory engram storage and retrieval. Curr Opin Neurobiol. 2015;35:101-9.

13. Cowan N. What are the differences between long-term, short-term, and working memory? Prog Brain Res. 2008;169:323-38.

14. Curtis CE, D'Esposito M. Persistent activity in the prefrontal cortex during working memo-ry. Trends Cogn Sci. 2003;7(9):415-23.

1

1

Neuro-biol. 1993;3(2):225-9.

16. Andersen P, Bliss TV, Skrede KK. Lamellar organization of hippocampal pathways. Exp Brain Res. 1971;13(2):222-38.

17. Nguyen PV, Kandel ER. A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. J Neurosci. 1996;16(10):3189-98.

18. Havekes R, Abel T. Genetic dissection of neural circuits and behavior in Mus musculus. Adv Genet. 2009;65:1-38.

19. Aimone JB, Deng W, Gage FH. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron. 2011;70(4):589-96. 20. Herculano-Houzel S. The human brain in numbers: a linearly scaled-up primate brain.

Front Hum Neurosci. 2009;3.

21. McNaughton BL, Morris RGM. Hippocampal synaptic enhancement and information stor-age within a distributed memory system. Trends Neurosci. 1987;10(10):408-15.

22. Cajal SRY. The Croonian Lecture: La Fine Structure des Centres Nerveux. Proceedings of the Royal Society of London. 1894;55(331-335):444-68.

23. Hering H, Sheng M. Dendritic spines: structure, dynamics and regulation. Nat Rev Neuro-sci. 2001;2(12):880-8.

24. Maiti P, Manna J, Ilavazhagan G, Rossignol J, Dunbar GL. Molecular regulation of den-dritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases. Neurosci Biobehav Rev. 2015;59:208-37.

25. Kennedy MB. Synaptic Signaling in Learning and Memory. Cold Spring Harb Perspect Biol. 2013;8(2):a016824-a.

26. van Spronsen M, Hoogenraad CC. Synapse pathology in psychiatric and neurologic dis-ease. Curr Neurol Neurosci Rep. 2010;10(3):207-14.

27. Van Troys M, Huyck L, Leyman S, Dhaese S, Vandekerkhove J, Ampe C. Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol. 2008;87(8-9):649-67.

28. Bernstein BW, Bamburg JR. ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 2010;20(4):187-95.

29. Bamburg JR. Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu Rev Cell Dev Biol. 1999;15:185-230.

30. Bamburg JR, Wiggan OP. ADF/cofilin and actin dynamics in disease. Trends Cell Biol. 2002;12(12):598-605.

31. Bosch M, Castro J, Saneyoshi T, Matsuno H, Sur M, Hayashi Y. Structural and molecu-lar remodeling of dendritic spine substructures during long-term potentiation. Neuron. 2014;82(2):444-59.

32. Grosmark AD, Mizuseki K, Pastalkova E, Diba K, Buzsaki G. REM sleep reorganizes hip-pocampal excitability. Neuron. 2012;75(6):1001-7.

33. Chen LY, Rex CS, Casale MS, Gall CM, Lynch G. Changes in Synaptic Morphology Ac-company Actin Signaling during LTP. The Journal of Neuroscience. 2007;27(20):5363-72. 34. Saygin M, Ozguner MF, Onder O, Doguc DK, Ilhan I, Peker Y. The impact of sleep

deprivation on hippocampal-mediated learning and memory in rats. Bratisl Lek Listy. 2017;118(7):408-16.

35. Raven F, Van der Zee EA, Meerlo P, Havekes R. The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function. Sleep Med Rev. 2017.

36. Abel T, Havekes R, Saletin JM, Walker MP. Sleep, plasticity and memory from molecules to whole-brain networks. Curr Biol. 2013;23(17):R774-88.

37. Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11(2):114-26.

38. Rajaratnam SM, Arendt J. Health in a 24-h society. Lancet. 2001;358(9286):999-1005. 39. Khan MS, Aouad R. The Effects of Insomnia and Sleep Loss on Cardiovascular Disease.

Sleep Med Clin. 2017;12(2):167-77.

40. Krause AJ, Simon EB, Mander BA, Greer SM, Saletin JM, Goldstein-Piekarski AN, et al. The sleep-deprived human brain. Nat Rev Neurosci. 2017;18(7):404-18.

41. Born J, Wilhelm I. System consolidation of memory during sleep. Psychol Res. 2012;76(2):192-203.

42. Havekes R, Meerlo P, Abel T. Animal studies on the role of sleep in memory: from behav-ioral performance to molecular mechanisms. Curr Top Behav Neurosci. 2015;25:183-206.

1

1

vul-nerability: changes in neuronal plasticity, neurogenesis and cognitive function. Neurosci-ence. 2015;309:173-90.

44. Prince T-M, Abel T. The impact of sleep loss on hippocampal function. Learn Mem. 2013;20(10):558-69.

45. Graves LA, Heller EA, Pack AI, Abel T. Sleep deprivation selectively impairs memory con-solidation for contextual fear conditioning. Learn Mem. 2003;10(3):168-76.

46. Havekes R, Park AJ, Tudor JC, Luczak VG, Hansen RT, Ferri SL, et al. Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1. Elife. 2016;5:e13424.

47. Palchykova S, Winsky-Sommerer R, Meerlo P, Durr R, Tobler I. Sleep deprivation impairs object recognition in mice. Neurobiol Learn Mem. 2006;85(3):263-71.

48. Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, et al. Sleep depri-vation impairs cAMP signalling in the hippocampus. Nature. 2009;461(7267):1122-5. 49. Drummond SP, Brown GG, Gillin JC, Stricker JL, Wong EC, Buxton RB. Altered brain

re-sponse to verbal learning following sleep deprivation. Nature. 2000;403(6770):655-7. 50. Yoo SS, Hu PT, Gujar N, Jolesz FA, Walker MP. A deficit in the ability to form new human

memories without sleep. Nat Neurosci. 2007;10(3):385-92.

51. Saletin JM, Goldstein-Piekarski AN, Greer SM, Stark S, Stark CE, Walker MP. Human Hippocampal Structure: A Novel Biomarker Predicting Mnemonic Vulnerability to, and Recovery from, Sleep Deprivation. J Neurosci. 2016;36(8):2355-63.

52. Orban P, Rauchs G, Balteau E, Degueldre C, Luxen A, Maquet P, et al. Sleep after spa-tial learning promotes covert reorganization of brain activity. Proc Natl Acad Sci U S A. 2006;103(18):7124-9.

53. Hagewoud R, Whitcomb SN, Heeringa AN, Havekes R, Koolhaas JM, Meerlo P. A time for learning and a time for sleep: the effect of sleep deprivation on contextual fear condition-ing at different times of the day. Sleep. 2010;33(10):1315-22.

54. Hagewoud R, Havekes R, Novati A, Keijser JN, Van der Zee EA, Meerlo P. Sleep depriva-tion impairs spatial working memory and reduces hippocampal AMPA receptor phosphor-ylation. J Sleep Res. 2010;19(2):280-8.

55. Gais S, Lucas B, Born J. Sleep after learning aids memory recall. Learn Mem. 2006;13(3):259-62.

56. Raven F, Meerlo P, Van der Zee EA, Abel T, Havekes R. A brief period of sleep depriva-tion causes spine loss in the dentate gyrus of mice. Neurobiol Learn Mem. 2018. 57. Frank MG, Cantera R. Sleep, clocks, and synaptic plasticity. Trends Neurosci.

2014;37(9):491-501.

58. Li W, Ma L, Yang G, Gan WB. REM sleep selectively prunes and maintains new synapses in development and learning. Nat Neurosci. 2017;20(3):427-37.

59. Puentes-Mestril C, Aton SJ. Linking Network Activity to Synaptic Plasticity during Sleep: Hypotheses and Recent Data. Front Neural Circuits. 2017;11:61.

60. Yang G, Lai CS, Cichon J, Ma L, Li W, Gan WB. Sleep promotes branch-specific formation of dendritic spines after learning. Science. 2014;344(6188):1173-8.

61. Wong L-W, Tann JY, Ibanez CF, Sajikumar S. The p75 Neurotrophin Receptor Is an Es-sential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation. The Journal of Neuroscience. 2019;39(28):5452-65.

62. Gu J, Lee CW, Fan Y, Komlos D, Tang X, Sun C, et al. ADF/cofilin-mediated actin dy-namics regulate AMPA receptor trafficking during synaptic plasticity. Nat Neurosci. 2010;13(10):1208-15.

63. Lamprecht R, LeDoux J. Structural plasticity and memory. Nat Rev Neurosci. 2004;5(1):45-54.

64. Fischer M, Kaech S, Wagner U, Brinkhaus H, Matus A. Glutamate receptors regulate ac-tin-based plasticity in dendritic spines. Nat Neurosci. 2000;3(9):887-94.