Thursday, December 26, 2024
12/26/2024
SUMMARY In day-to-day life, we often flexibly select actions based on what we anticipate the outcomes will be. Stress can lead to failures in flexible goal seeking in rodents and humans alike, causing organisms to defer to familiar, routinized behaviors that can contribute to compulsions, over-eating, or other health concerns. To obtain desired outcomes, we often must encode new information about these outcomes (how to get them, what their value is, etc.), and then retrieve those memories later to execute action strategies. The ventrolateral orbitofrontal cortex (VLO) is necessary for rodents to encode and retrieve new memories regarding optimal action strategies. Moreover, basolateral amygdala-to-VLO inputs are necessary for memory encoding, and ventral hippocampal-to-VLO projections are necessary for memories to be durable and long-lasting. Further, VLO neurons that are active during memory encoding are necessary for memory retrieval, suggesting that specific VLO neurons form stable memory traces for new action strategies. This proposal will focus on this neuron population, operationally referred to as “memory trace” neurons. The structural plasticity of deep-layer VLO neurons, which receive subcortical inputs, appears necessary for new action memory formation. Further, specific protein activities controlling the structural plasticity of postsynaptic compartments are also necessary. It is sensible to imagine that specific inputs to, and protein activities within, memory trace neurons are essential for new action memory formation. Our aims are: Aim 1: Determine how VLO neurons form cohesive memory traces. We will use a tool termed “trapping” to gain genetic access to specific memory trace cells in the VLO. We will first stimulate them following training conditions that typically induce inflexible, habit-based responding. We hypothesize that their stimulation will override habit-like behavior, owing to action memory retrieval. We will then combine TRAP and multiplexed chemogenetic strategies to identify subcortical inputs necessary for memory traces to form. Aim 2: Identify the anatomical and developmental determinants of learning-related dendritic spine plasticity in the VLO. We will next combine TRAP and chemogenetic strategies to test the hypothesis that amygdalar or hippocampal neuron activity is necessary for learning-related dendritic spine plasticity on VLO neurons that form action memory traces. Next, we hypothesize that chronic developmental social isolation, which obstructs action flexibility, also obstructs learning-related spine plasticity, while delayed isolation will not. Aim 3: Determine whether action flexibility involves specific protein activities. Finally, we will use inducible, site-selective viral-mediated gene transfer to selectively reduce Rho-kinase (ROCK2) in memory trace VLO neurons. We anticipate that suppressing ROCK2 will enrich the capacity for action flexibility and override habit-like behavior. Finally, we will test the hypothesis that ROCK2 activity is dynamically tuned with new learning, its suppression triggered by concurrent excitatory plasticity in the amygdala or hippocampus.
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