Cellular and Oscillatory Substrates of Extinction Learning
Davis, Patrick.
2019
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Abstract: In contrast to the hard-wired components characteristic of electronic circuits and some invertebrate nervous systems, mammalian brains contain modifiable elements within circuits that are capable of both robustness and remarkable adaptability. This balance is exemplified by the capacity of mammals to both learn and update previously formed associations, and to select from opposing behavi... read moreoral strategies based on a diversity of previous experience. A classic example of this is the paradigm of contextual fear conditioning and extinction learning, whereby an animal first forms a fearful association with a conditioned context, but subsequently learns that the context is safe. Because these two learning processes have distinct and opposing behavioral consequences, this paradigm grants experimental access to the features of the brain which enable both the formation of an associative memory and the subsequent modification of that memory with continued experience, as well as to the circuits which govern ultimate behavioral output. To date, the mechanisms underlying the modification of associative fear memories through extinction learning have yet to be completely understood. Using a novel combination of chemo- and optogenetics, activity-based neuronal-ensemble labeling, circuit tracing, and in vivo¬ electrophysiology, we have identified cellular and oscillatory substrates of fear extinction learning that depend critically on parvalbumin (PV)- expressing interneurons in the basolateral amygdala (BLA). Specifically, we found that extinction learning confers PV- interneurons in the BLA with a dedicated role in the suppression of a previously encoded fear memory via selective suppression of BLA fear-encoding neurons. BLA PV-interneurons are positioned to gate reciprocal communication between BLA and medial prefrontal cortex (mPFC), and their activity controls the activation of spatially localized and functionally opposing ensembles within mPFC. We establish that BLA PV-interneurons are critical to the generation of two opposing oscillatory states across the mPFC-BLA circuit. Extinction learning modifies the relationship between these two states to allow for "competition" between them. Artificial induction of these oscillatory states by direct manipulation of PV-interneurons is sufficient to elicit bidirectional, learning-dependent control over mPFC-BLA circuit coordination and fear behavior. Finally, we provide evidence potentially linking these circuit oscillatory properties with ensemble data through the phenomenon of resonance. These findings identify cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV-interneurons. The role of the BLA PV-network in mediating interactions between previously learned functional network states and memory-encoding ensembles is likely to be broadly applicable to interneuron microcircuit function in both physiological and pathological states.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Neuroscience.
Advisor: Jamie Maguire.
Committee: Thomas Biederer, and Yongjie Yang.
Keyword: Neurosciences.read less - ID:
- wh247533g
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