Neural codes underlying memory and flexible navigation in health and Alzheimer’s disease Restricted; Files Only
Prince, Stephanie (Spring 2023)
Published
Abstract
In our day-to-day lives, we seamlessly integrate our past experiences, present circumstances, and future plans in our thoughts. Our brains constantly switch between memories and incoming information in order to decide between potential options and make plans. But how do we flexibly adapt those plans when pursuing our goals? And what underlies the degradation of these processes in neurodegenerative diseases such as Alzheimer’s?
In the first part of this dissertation, we asked how neural representations of future goals influence our ability to flexibly adapt plans with new information. We designed a novel decision-making task in which we precisely controlled the introduction of new, pivotal information using virtual reality, and recorded neural activity from hippocampus and prefrontal cortex as animals had to adapt their behavior in response to new information. We found that prospective codes are rapidly modulated by new information from dynamic stimuli, specifically when the new information indicates animals must update their previous choices to obtain a reward. We also found that failure to switch from old to new choice representations in prefrontal cortex occurred when animals were unable to adapt to new information. These results show how prospective codes for future locations or choices play a role in the ability to rapidly adapt behavior in response to new information.
In the second part of this dissertation, we asked how neural representations important for memory were disrupted during navigation in Alzheimer’s disease. We recorded neural activity from the 5XFAD mouse model of Alzheimer’s disease during spatial navigation and found deficits in interneuron connection strength onto pyramidal cells in hippocampus. These deficits occurred in awake, behaving mice and were most pronounced during sharp-wave ripple oscillations that are important for memory and require inhibition. In addition to these synaptic deficits in vivo, we also found the mouse model of Alzheimer’s disease had fewer and shorter sharp-wave ripple oscillations and impaired reactivation of neuronal firing during sharp-wave ripples. These results show that inhibitory synaptic dysfunction occurs during spatial navigation in 5XFAD mice and suggest a potential mechanism underlying deficits in network activity that is critical for memory and cognitive function.
The results of this work demonstrate how prospective codes in hippocampus and prefrontal cortex adapt for flexible behavior in our dynamic world and show how neural codes for memory in the hippocampus might be disrupted by Alzheimer’s pathology via synaptic dysfunction.
Table of Contents
CHAPTER 1 - INTRODUCTION..................................................................................................... 1
1.1 Integrating past, present, and future experiences in navigation and decision making. 2
1.1.1 The role of hippocampus in memory and navigation......................................................... 2
1.1.2 The role of prefrontal cortex in decision making and navigation....................................... 4
1.2 Hippocampal-prefrontal interactions and neural codes for memory and decision making 5
1.2.1 Theoretical frameworks for hippocampal-prefrontal interactions...................................... 5
1.2.2 Anatomical features and connections between hippocampus and prefrontal cortex........ 6
1.2.3 Neural codes during theta in the hippocampus............................................................... 10
1.2.4 Neural codes during sharp-wave ripples in the hippocampus......................................... 12
1.2.5 Hippocampal-prefrontal interactions during theta and sharp-wave ripples..................... 14
1.3 Network-level approaches to understanding Alzheimer’s disease................................ 16
1.3.1 Cognitive deficits to memory and planning processes in Alzheimer’s disease............... 16
1.3.2 Network dysfunction in Alzheimer’s disease................................................................... 17
1.4 Dissertation objectives......................................................................................................... 20
1.4.1 How do hippocampal and prefrontal cortex prospective codes contribute to flexible decision making when new information is presented?................................................................................................................................................... 20
1.4.2 Are hippocampal neural codes of memory and in vivo synaptic activity altered in a mouse model of Alzheimer’s disease? 21
CHAPTER 2 – NEW INFORMATION TRIGGERS PROSPECTIVE CODES FOR FLEXIBLE ADAPTATION OF ONGOING CHOICES 23
2.1 Abstract.................................................................................................................................. 24
2.2 Introduction........................................................................................................................... 25
2.3 Results................................................................................................................................... 28
2.3.1 Animals rapidly update their choices in response to new information in a spatial memory task 28
2.3.2 Enhanced non-local codes of both goal locations in hippocampus in response to new pivotal information 31
2.3.3 Rapid switch from old to new choice estimates in prefrontal cortex when new information is presented 38
2.3.4 Goal codes predict ability to accurately update decisions in response to new information 42
2.3.5 Increased goal representations are correlated with choice commitment........................ 47
2.4. Discussion............................................................................................................................ 51
2.5. Methods................................................................................................................................. 54
2.5.1 Animals............................................................................................................................. 54
2.5.2 Surgical procedures......................................................................................................... 55
2.5.3 Behavioral task and training............................................................................................. 55
2.5.4 Electrophysiology recordings........................................................................................... 57
2.5.5 Local field potential and single unit preprocessing.......................................................... 58
2.5.6 Behavioral analysis.......................................................................................................... 59
2.5.7 Choice modelling.............................................................................................................. 60
2.5.8 Decoding analyses........................................................................................................... 60
2.5.9 Theta cycles and phase................................................................................................... 62
2.5.10 Prediction of behavioral choice...................................................................................... 63
2.5.11 Statistical analyses......................................................................................................... 64
2.6 Supplementary Figures and Tables.................................................................................... 65
CHAPTER 3 - ALZHEIMER'S PATHOLOGY CAUSES IMPAIRED INHIBITORY CONNECTIONS AND REACTIVATION OF SPATIAL CODES DURING SPATIAL NAVIGATION............................................................................................... 88
3.1 Abstract.................................................................................................................................. 90
3.2 Introduction........................................................................................................................... 91
3.2.1. Synaptic dysfunction in Alzheimer’s disease.................................................................. 91
3.2.2. Deficits in neural activity across multiple models of Alzheimer’s disease...................... 91
3.3. Results.................................................................................................................................. 94
3.3.1. 5XFAD mice and wild-type littermates lick for reward in a virtual reality spatial task.... 94
3.3.2. Interneuron-to-pyramidal monosynaptic connections are weaker in 5XFAD mice........ 96
3.3.3. 5XFAD mice have shorter and fewer sharp-wave ripples compared to WT mice....... 103
3.3.4. Place cells of 5XFAD mice have decreased reactivation during sharp-wave ripples.. 105
3.4. Discussion.......................................................................................................................... 109
3.4.1. Linking synaptic dysfunction and interneuron deficit hypotheses in Alzheimer’s disease 109
3.4.2. Synaptic changes and sharp-wave ripple deficits could underlie memory impairment 111
3.5. Methods............................................................................................................................... 114
3.5.1. Animals.......................................................................................................................... 114
3.5.2. Surgical procedures...................................................................................................... 114
3.5.3. Behavioral training and analysis................................................................................... 115
3.5.4. Electrophysiology recordings........................................................................................ 116
3.5.5. Local Field Potential Analyses...................................................................................... 117
3.5.6. Classification of cell types............................................................................................. 118
3.5.7. Identification of monosynaptic connections.................................................................. 120
3.5.8. Quantification of connection strength........................................................................... 121
3.5.9. Place cell identification.................................................................................................. 123
3.5.10. Reactivation during sharp-wave ripples...................................................................... 124
3.5.11. Quantification and statistical analysis......................................................................... 126
3.6. Supplementary Figures and Tables................................................................................. 128
CHAPTER 4 - DISCUSSION...................................................................................................... 146
4.1 Results summary................................................................................................................ 147
4.2 Caveats and limitations...................................................................................................... 149
4.2.1 Ethological validity of virtual reality experiments........................................................... 149
4.2.2 Clinical relevance of mouse models of Alzheimer’s disease......................................... 150
4.3 Future directions................................................................................................................. 150
4.3.1 Causally manipulating prospective codes to impact behavior....................................... 150
4.3.2 Integrating environmental changes and neural activity................................................. 152
4.3.3 Rescuing neural activity deficits and memory in Alzheimer’s disease.......................... 153
4.3.4 Leveraging unique virtual reality tasks to test cognitive function.................................. 153
4.4 Conclusions......................................................................................................................... 155
CHAPTER 5 – APPENDIX: A SPATIAL NAVIGATION PARADIGM TO TEST FLEXIBLE DECISION MAKING IN MICE USING VIRTUAL REALITY..................................................................................................................................... 156
5.1 Introduction......................................................................................................................... 156
5.2 Behavioral task development and validation.................................................................. 157
5.2.1 A virtual reality paradigm to test flexible decision making in response to new information 157
5.2.2 Virtual reality environments across stages of behavior training.................................... 159
5.2.3 Behavioral training procedure........................................................................................ 162
5.2.4 Behavioral interventions for successful task acquisition and performance................... 165
5.3 Software and analysis features......................................................................................... 168
5.3.1 Automation approaches to task software use and behavioral training.......................... 168
5.3.2 Synchronization to other acquisition systems................................................................ 169
5.4 Discussion........................................................................................................................... 170
REFERENCES............................................................................................................................ 172
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