Neural Circuits of Contextual Fear and Extinction: Contributions of the Basal Amygdala and Bed Nucleus of the Stria Terminalis.
Sasaki Russell, Jennifer.
Feelings of fear and anxiety are evolutionarily conserved traits which have been
selected to be protective against dangerous situations, but their effects can be
debilitating when uncontrolled. Examples of uncontrolled fear responses include
post-traumatic stress disorder (PTSD) and a variety of fear and anxiety disorders that
afflict approximately 18% of the adult US population. Ma... read moreny of these disorders are
characterized by having an impairment in the learning or extinction of fear, thus
inhibiting the gradual decrease of the fear response that normally occurs over time.
Understanding the functional synaptic connections between brain regions that participate
in the fear and extinction circuits will offer insight into the neural mechanisms of
fear and provide a basis for therapies of a dysfunctional circuit. The basal amygdala
(BA) has been established as the primary control center in the brain that underlies
contextual fear learning and memory. The bed nucleus of the stria terminalis (BNST), a
limbic structure in the forebrain, has been implicated to preferentially support
contextual fear, although its precise functional connectivity with the amygdala in
contextual fear remains poorly understood. Here, we used a c-fos based reporter mouse
(TetTag mouse) to investigate the activity of the BNST in contextual fear learning and
memory. We found that the oval BNST subdivision (ovBNST) was activated during contextual
fear conditioning while the anterodorsal BNST subdivision (adBNST) was not, underscoring
the divergent functionality of these two dBNST subdivisions. To further characterize
amygdalar input to the ovBNST, we used anterograde and retrograde tracers to identify a
direct projection from the BA to the ovBNST. We then combined retrograde tracer
injections with the TetTag mouse to investigate the activity of a BA-BNST pathway during
the acquisition and retrieval of contextual fear. In support of a direct functional
interaction between the BA and the BNST during the learning of fear, we identified
BNST-projecting neurons in the posterior subdivision of the BA that were activated
during contextual fear conditioning without reactivation during retrieval. We also
identified a separate, non-BNST-projecting population of neurons in the anterior
subdivision of the BA that were preferentially reactivated during fear retrieval. Our
results suggest that a direct BA-ovBNST pathway might support the acquisition and/or
consolidation of contextual fear, while BA neurons that do not project to the BNST
support the storage of the contextual fear memory and are incorporated into the memory
engram. We additionally used the TetTag system to investigate the extinction-induced
synaptic changes that occur around neurons in the BA after contextual fear extinction.
We found that extinction training leads to a decrease in fear response concomitant with
a decreased reactivation of fear neurons in the mouse amygdala. This decrease in
reactivated neurons was not seen in the hippocampus or medial prefrontal cortex,
suggesting that the silenced BA neurons were a selective site of extinction-induced
suppression. We found that extinction led to an increase in inhibitory perisomatic PV
selectively around these silenced fear neurons in the BA, as well as an increase in CB1R
localized to CCK perisomatic synapses around active fear neurons. These modulatory
synaptic changes matched the silent or active state of the postsynaptic cell, inferring
a target-specific mechanism through which the extinction circuit can directly interact
with and suppress the fear circuit in the BA. Together, our findings add to the
understanding of the complex fear circuit and the synaptic mechanisms underlying fear
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Neuroscience.
Advisor: Leon Reijmers.
Committee: Peter Juo, Jamie Maguire, and Maribel Rios.
Keyword: Neurosciences.read less