@article{Experiences::10102,
      recid = {10102},
      author = {Ratigan, Heather Cassidy},
      title = {Memories of Aversive Experiences: Insights from the  Thalamic Nucleus Reuniens to Hippocampal CA1 Pathway and  CA1 Neuronal Dynamics},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2023-12},
      pages = {243},
      abstract = {Being able to flexibly remember aversive events is a  critical neural function for mammals. However, aversive  memories can have a negative impact on animal well-being if  they are not restricted to the appropriate context, or not  updated with new information over time. The hippocampus is  a key brain region for both forming and updating aversive  memories –specifically, the dorsal section of hippocampal  area CA1 is crucial for integrating spatial and non-spatial  information into coherent contextual memories. My doctoral  work focuses on understanding the hippocampal circuits  underlying the formation, recall, and extinction of  aversive memories. In Chapter 2, I reveal the contextual  fear-suppressive role of the projection from the thalamic  subregion nucleus reuniens (NR) to dorsal CA1. I  implemented a novel head-restrained virtual reality  contextual fear conditioning paradigm (VR-CFC) where I  administered mild tail shocks in one context (shocked) but  not the other (neutral). I showed that inactivation of the  NR-CA1 pathway following VR-CFC increases fearful freezing,  induces fear generalization to a neutral context, and  delays extinction of fearful responses. Using in vivo  sub-cellular calcium imaging, I found that NR-axons become  selectively tuned to fearful freezing only after VR-CFC.  
In Chapter 3, I demonstrate how the NR-CA1 pathway impacts  population dynamics in excitatory pyramidal neuron somata  in dorsal CA1 throughout VR-CFC. I reveal that with the  NR-CA1 pathway intact, CA1 somata are preferentially active  in the shocked context after shocks, globally remap their  place fields to more flexible post-fear extinction maps,  tune to both shocks and to freezing epochs, and increase  both the frequency and scale of simultaneous neural  activations. In contrast, I show that inhibiting the NR-CA1  pathway prevents preferential activity in the shocked  context post-shocks by over-activating somata, interferes  with global remapping by retaining more stable  post-extinction maps, increases freeze-tuning, and disrupts  simultaneous neural activations. Lastly, in Chapter 4, I  investigated the differential activity of the basal and  apical dendritic arbors through novelty and reward  manipulation. I reveal functional segregation between  predominantly spatial representations in the basal  dendrites and predominantly non-spatial reward and  novelty-modulated representations in the apical dendrites,  paving the way for future investigations of dendritic  mechanisms underlying somatic activity changes in VR-CFC.  
Overall, this dissertation provides both methodological  and experimental leaps forward in our understanding of how  the hippocampus flexibly encodes aversive experiences by  highlighting the critical role of projections from thalamic  nucleus reuniens to hippocampal dorsal CA1. I pioneered a  novel contextual fear conditioning paradigm in virtual  reality that reliably elicits context-dependent freezing  behaviors similar to non-head-fixed behavior. I imaged two  distal subcellular components for the first time – NR axons  and dorsal CA1 distal apical tuft dendrites – and developed  a new technique for identifying population-level  synchronized activity in dorsal CA1 somata. Our findings  paint a picture of hippocampal dorsal CA1 as a critical  region for memory that both encodes a variety of salient  features to aversive contextual memories and flexibly  updates fear memories to extinguish fear responses through  modulating inputs from thalamic nucleus reuniens.
},
      url = {http://knowledge.uchicago.edu/record/10102},
      doi = {https://doi.org/10.6082/uchicago.10102},
}