Imaging experience dependent plasticity in the mouse barrel cortex

IMAGING EXPERIENCE-DEPENDENT PLASTICITY IN THE MOUSE BARREL CORTEX LO SHUN QIANG (A0023928A) BACHELOR OF SCIENCE (HONS), NATIONAL UNIVERSITY OF SINGAPORE A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHYSIOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2014 Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. _________________ Lo Shun Qiang 25th September 2014 Acknowledgements This journey would not have been possible without the kindness and help of many people. For that, I am deeply grateful and thankful for all of you who have shaped my life and imparted valuable insights and support. Firstly, I will like to thank George, my supervisor. You have been a great mentor to me, and I will always be grateful for your patience, guidance and care. I appreciate your help during all these years, and will always continue to my best to improve and to work towards the truth as a scientist. I will also like to thank Prof Soong for your kind help and guidance as well. You took me in when I wanted to pursue neuroscience, and I am grateful. Thank you to Prof Laszlo Orban for taking me in as an intern during my undergraduate years and gifting me with lots of encouragement and an enthusiasm to pursue research and work at the lab. Thank you to Dr Judy and Dawn from SICS, for introducing me to the somatosensory cortex and for spending many afternoons teaching me about immunohistochemistry and stereotaxic surgery. You have always been kind and generous, and your support has been invaluable during my candidature. Thank you too, to other members from the Neuroepigenetics lab, Patrick, Vania, Fiza and Tendy, who are great friends and have been a great help over the years. I will also like to thank the many wonderful people I met in the GA lab – especially Peggy and Harin for your support and friendship, James, Greg and Jinsook for your advice and listening ears over the years, Sachiko for being a great friend and neighbor, and Praneeth, for having the patience to teach me the basics of Matlab programming and signal processing. Thank you to the other members of the laboratory as well, for being great friends and wonderful colleagues; Karen, Jennifer, Masahiro, Martin, Sheeja, Su-In, Lei, Yanxia, Cherry, Isamu, Susu and Zach. I will also like to thank the Physiology department, NUS, the facilities people at Biopolis, the friends I made at MBL, Woods Hole and many other people who have provided assistance and helped me along the way. Your help was much appreciated. Thank you to my beloved Jasmine, for your love, support and quiet strength. With you by my side, I could work hard and happily without worry. Thank you to my dear parents and sister, and rest of my family too, for your care, constant support and unconditional love. You are all my role models. Lastly, I will like to thank you, the reader, for taking the time to go on this journey with me. I hope you will enjoy reading and find some insights in my thesis. Table of Contents Declaration Acknowledgements List of publications Abstract List of figures List of abbreviations 11 Chapter Introduction 13 1.1 The relationship between whiskers and the somatosensory barrel cortex 15 1.2 Multiple critical periods in the barrel cortex 18 1.3 Experience-dependent plasticity in inhibitory circuits 24 1.4 Voltage-sensitive dye imaging of circuit activity 29 1.5 Probing cortical circuits with optogenetic photostimulation 33 1.6 Summary and statement of purpose 36 Chapter Materials and methods 40 2.1 Animals used 40 2.2 Sensory deprivation protocol 41 2.3 Slice preparation 41 2.4 Histological characterization 42 2.5 Voltage-sensitive dye imaging 44 2.6 High-speed Optogenetic mapping of inhibitory circuits 46 Chapter Results 49 3.1 Imaging changes in circuit function caused by sensory deprivation 49 3.2 Differential effects of deprivation on excitatory and inhibitory circuits 59 3.3 Effects of deprivation on inhibitory feedback/feedforward circuit 65 3.4 Deprivation reduces inhibition by parvalbumin interneurons 75 Chapter Discussion 92 4.1 A critical period for parvalbumin interneurons in the somatosensory cortex 94 4.2 Differential effects of whisker deprivation on excitatory and inhibitory circuits 99 4.3 The emergence of the layer 2/3 critical period 101 4.4 Future projections 108 Conclusion 112 References 113 List of publications Neurosciences (related to the thesis) Brent Asrican, George J. Augustine, Ken Berglund, Susu Chen, Nick Chow, Karl Deisseroth, Guoping Feng, Bernd Gloss, Riichiro Hira, Carolin Hoffmann, Haruo Kasai, Malvika Katarya, Jinsook Kim, John Kudolo, Li Ming Lee, Shun Qiang Lo, James Mancuso, Masanori Matsuzaki, Ryuichi Nakajima, Li Qiu, Gregory Tan, Yanxia Tang, Jonathan T. Ting, Sachiko Tsuda, Lei Wen, Xuying Zhang and Shengli Zhao (2013). Next-generation transgenic mice for optogenetic analysis of neural circuits Front. Neural Circuits 7:160. George J. Augustine, Susu Chen, Harin Gill, Malvika Katarya, Jinsook Kim, John Kudolo, Li Ming Lee, Hyunjeong Lee, Shun Qiang Lo, Ryuichi Nakajima, Min-Yoon Park, Gregory Tan, Yanxia Tang, Peggy Teo, Sachiko Tsuda, Lei Wen, and Su-In Yoon (2013). High-speed optogenetic circuit mapping. Proc. SPIE, 8586, Optogenetics: Optical Methods for Cellular Control, 858603, edited by Samarendra K. Mohanty, Nitish V. Thakor. George J. Augustine, Ken Berglund, Harin Gill, Carolin Hoffmann, Malvika Katarya, Jinsook Kim, John Kudolo, Li M. Lee, Molly Lee, Daniel Lo, Ryuichi Nakajima, Min Yoon Park, Gregory Tan, Yanxia Tang. Peggy Teo, Sachiko Tsuda, Lei Wen, Su-In Yoon (2012). Optogenetic mapping of brain circuitry. Proc. SPIE, 8548, Nanosystems in Engineering and Medicine, 85483Y Neurosciences (unrelated to the thesis) Chew KC, Ang ET, Tai YK, Tsang F, Lo SQ, Ong E, Ong WY, Shen HM, Lim KL, Dawson VL, Dawson TM, Soong TW (2011). Enhanced autophagy from chronic toxicity of iron and mutant A53T α-synuclein: implications for neuronal cell death in Parkinson disease. J Biol Chem. 286:33380-33389. Ang ET, Tai YK, Lo SQ, Seet R, Soong TW (2010). Neurodegenerative diseases: exercising toward neurogenesis and neuroregeneration. Front. Aging Neurosci. 2:25 Genomics (unrelated to the thesis) Kolics B, Ács Z, Chobanov DP, Orci KM, Qiang LS, Kovács B, Kondorosy E, Decsi K, Taller J, Specziár A, Orbán L, Müller T. (2012). Re-visiting phylogenetic and taxonomic relationships in the genus Saga (Insecta: Orthoptera). PLoS One 7:e42229 Posters presented (related to the thesis): Lo S.Q., Koh D., Sng J., Augustine G. (2013) Imaging experiencedependent plasticity in the mouse barrel cortex. The Society for Neuroscience 43rd Annual Meeting 2013, 9–13 November, San Diego, USA. Abstract During development, whisker loss affects the development and function of somatosensory cortex circuits. However, the cellular and molecular mechanisms underlying such experience-sensitive circuit changes are poorly understood. I used voltage-sensitive dye imaging and optogenetic circuit mapping in brain slices to characterize experience-sensitive circuit changes occurring in layers and 2/3 of somatosensory cortex of whisker-deprived P30 mice. Deprivation weakened synaptic inhibition because inhibitory postsynaptic potentials evoked in layer 2/3 by electrical stimulation of layer were reduced in deprived slices compared to controls. Excitation also spread more into neighboring barrels in deprived slices, indicating reduced columnar specificity of excitatory circuits. To directly examine interneuron contributions, interneurons I photostimulated expressing the parvalbumin-expressing light-sensitive cation (PV) channel, Channelrhodopsin-2. Sensory deprivation decreased the range and amplitude of inhibitory postsynaptic current input onto layer 2/3 pyramidal neurons. This effect on PV interneurons is age-sensitive, with the critical period time window closing around postnatal day 10. My mapping of light-evoked IPSCs provides a quantitative and direct measurement of the strength and spatial organization of this inhibitory circuit and the response of this circuit to experience-dependent plasticity. My characterisation of the PV interneuron critical period can thus be used as a benchmark for identifying possible regulators of critical period plasticity in this circuit. List of figures Figure 1.1: Critical periods in the somatosensory cortex Figure 1.2: Simplified circuit diagram of parvalbumin circuits in the barrel column Figure 2.1: Barrels in slices Figure 3.1: Voltage sensitive dye imaging of the barrel cortex slice Figure 3.2: Postsynaptic layer 2/3 responses following layer stimulation Figure 3.3: Spatial range and time course of VSD responses along column C Figure 3.4: Characterization of population responses along entire layers and in column C Figure 3.5: Chronic sensory deprivation alters excitatory responses following layer stimulation Figure 3.6: Chronic sensory excitation Figure 3.7: Chronic deprivation altered excitatory responses along layer but not layer 2/3 Figure 3.8: Chronic sensory deprivation did not significantly affect postsynaptic EPSPs Figure 3.9: Chronic sensory deprivation results in depressed IPSP responses deprivation alters the spread of Figure 3.10: Expression of ChR2 in Thy1 line-18 mice Figure 3.11: All-optical mapping setup and photostimulation of layer pyramidal neurons Figure 3.12: Photostimulation of Layer pyramidal neurons lead to intercolumnal spread of postsynaptic activity Figure 3.13: Chronic whisker deprivation did not significantly affect layer pyramidal neuron-driven excitatory responses in all layers Figure 3.14: Chronic whisker did not affect layer feedback inhibition. 2013), will allow imaging of inhibition in many postsynaptic neurons. Thus, it will be possible to photostimulate specific types of ChR2expressing interneurons and test how different paradigms of whisker deprivation affect inhibition onto layer 2/3 pyramidal neurons. Furthermore, the use of optogenetic actuators like ChR2 or halorhodopsin (Mancuso et al., 2011) will let me stimulate or block synaptic transmission between PV or SOM interneurons and layer 2/3 pyramidal neurons during established critical periods, and the degree of expected critical period circuits changes can be measured. Thus, experiments testing both the sufficiency and necessity of these inhibitory circuits for the emergence of the layer 2/3 critical periods can be made. By coupling ChR2 photostimulation in presynaptic interneurons with the measurement of inhibition in many pyramidal neurons, it is thus possible to high-throughput testing of circuit changes with different whisker deprivation paradigms. Gaining insights into how these circuit mechanisms might affect critical period plasticity will aid our general understanding of the development of cortical circuits. 111 Conclusion “Critical periods” are time windows of heightened neuronal plasticity, when cortical circuits are particularly susceptible to regulation in response to environmental stimuli (Jeanmonod et al., 1981). My study has shown that sensory deprivation from birth causes long-lasting changes in an inhibitory circuit in the somatosensory cortex. Cortical inhibition is decreased with chronic deprivation and this change is mediated by PV interneurons, which are sensitive to sensory experience and express a critical period that closes around postnatal day 10. This form of activity-dependent plasticity might regulate layer 2/3 pyramidal neuron circuits as well. Indeed, my work suggests that interaction between PV interneuron circuits and excitatory circuits could give rise to the receptive field critical period. 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Elgueta, 2012) These properties make PV interneurons prime targets for exhibiting experience- dependent plasticity during development There is evidence that PV interneurons are involved in experience- dependent plasticity in both the somatosensory and visual cortices (Jiao et al., 2006; Southwell et al., 2010) Evidence that PV interneurons in the barrel cortex exhibit experience- dependent plasticity comes... period, there has been no analysis of the time course of experience- dependent plasticity in local circuits involving PV interneurons and it will be insightful to determine whether PV interneurons exhibit a critical period 26 27 Another possible candidate for inhibitory circuit plasticity is the somatostatin-expressing (SOM) interneuron SOM interneurons are another major group of interneurons found in all... are influenced by sensory experience, when such experience- dependent plasticity occur, and whether these circuits possess a critical period of sensitivity to sensory stimuli Within cortical inhibitory circuits, one possible candidate for experience- dependent plasticity is the parvalbumin-expressing (PV) interneuron About 36% of Gad67-expressing interneurons in the somatosensory cortex express the calcium-binding... relatively little is known about inhibitory circuit plasticity in the somatosensory cortex, so the nature of the experiencedependent plasticity that might be occurring in these circuits is unclear In my thesis, I have examined the effects of deprivation of sensory input from postnatal (P) days P0 – P30 on circuits in the somatosensory cortex, with particular emphasis on inhibitory circuits I found that... at the cortex, while maintaining the normal topographic organization of the functional map (Simons et al., 1984) Representation of spared whiskers expands into the deprived regions, such that stimulation of the spared whisker can then activate neurons in the column associated with the lost whisker (Simons et al., 1984) These changes in the activity of the barrel cortex are mainly due to sensory experience. .. circuits during development of the barrel cortex brings up the question of whether still other circuits are also sensitive to experience Defining which neurons underlie experiencedependent plasticity and testing whether they have critical periods of sensitivity separate from those described above will provide useful insights into how layer-specific critical periods may arise from the development of individual... calcium-binding protein PV (Lee et al., 2010), making PV interneurons the largest group of cortical interneurons Chandelier cells and about 50% of basket cells (mainly fast-spiking) in the somatosensory cortex express PV (Han, 1994) These PV interneurons are important for regulating local excitatory circuits in the barrel column (as illustrated in simplified circuit diagram below, Figure 1.2), making them... and the basis for testing how critical period plasticity can be manipulated in the future The ability to manipulate and reinitiate critical period plasticity in adulthood will allow 23 treatment of disabilities arising from a lack of sensory experience during development 1.3 Experience- dependent plasticity in inhibitory circuits Although studies of these critical periods in layers 2/3 and 4 have mainly... circuits come into play during the critical period 24 hours of enriched whisker experience can lead to an increase in synapse density, specifically in the formation of long-lasting inhibitory input onto dendritic spine necks (Knott et al., 2002) This indicates that inhibitory circuits can be affected by sensory input However, there is also a gap in our understanding of which somatosensory inhibitory circuits... postsynaptic inhibitory potentials (IPSPs) in layer 2/3 The decrease in inhibition was mediated by parvalbumin (PV) interneurons, which have a critical period of sensitivity to sensory experience for the first two postnatal weeks of development In the next few sections, I will summarize what is known about experience- dependent plasticity and critical periods in the somatosensory cortex, and in inhibitory . Introduction 13 1.1 The relationship between whiskers and the somatosensory barrel cortex 15 1.2 Multiple critical periods in the barrel cortex 18 1.3 Experience- dependent plasticity in inhibitory. somatosensory cortex, so the nature of the experience- dependent plasticity that might be occurring in these circuits is unclear. In my thesis, I have examined the effects of deprivation of sensory input. (2013) Imaging experience- dependent plasticity in the mouse barrel cortex. The Society for Neuroscience 43 rd Annual Meeting 2013, 9–13 November, San Diego, USA. 8 Abstract During development,