Cellular and Oscillatory Substrates of Extinction Learning
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 b... read moreehavioral 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
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