Research on the circuits mediating the acquisition of conditioned fear responses constitutes our best hope of understanding human anxiety disorders. The model typically used to study this process is classical fear conditioning where a neutral sensory stimulus (CS) acquires the ability to elicit fear responses after pairing to a noxious stimulus. However, perhaps more important from a clinical perspective is to understand how fear responses subside. Experimentally, this extinction process is modeled with repetitive presentations of the CS alone, resulting in the decline of conditioned fear to control levels. This approach is similar to that used to treat human phobias where subjects are presented with the feared object in the absence of danger. Extinction is known to result from a new learning, which takes place in the amygdala, and competes with the original fear memory to prevent the expression of conditioned fear. However, the mechanisms underlying this new extinction learning remain unclear. This proposal tests the hypothesis that the intercalated (ITC) neurons of the amygdala mediate extinction. The acquisition of conditioned fear is known to involve a potentiation of CS inputs to the basolateral amygdala (BLA). In turn, BLA cells excite more neurons in the central amygdala (CE), which, via their projections to the brainstem and hypothalamus, evoke fear responses. We focus on ITC neurons because they can control the impact of BLA inputs on CE neurons and hence the expression of conditioned fear. Indeed, ITC cells are GABAergic, they receive glutamatergic inputs from BLA, and they generate feed-forward inhibition in CE. Moreover, BLA inputs to ITC neurons can undergo NMDA-dependent LTP. Last, ITC neurons receive a heavy projection from the infralimbic cortex, a cortical area thought to play a critical role in extinction. This leads us to hypothesize that extinction results from an NMDA-dependent potentiation of BLA synapses conveying CS information to ITC neurons, leading to a decreased responsiveness of CE cells to BL inputs about the CS. To test the hypothesis, we will first examine whether extinction is associated with a potentiation of BLA inputs to ITC cells by comparing the amplitude of BLA-evoked responses in ITC neurons recorded with the patch method in slices obtained from rats that underwent fear conditioning only vs. rats that underwent fear conditioning and extinction. Next, we will perform extracellular recordings of ITC cells during fear conditioning, extinction training, and extinction recall, and ask do ITC neurons become more responsive to the CS as a result of extinction training, as predicted by our model. Finally, to test whether ITC cells mediate the influence of the infralimbic cortex on extinction, we will study the responses of extracellularly recorded ITC neurons to infralimbic stimuli and test whether the nature, latency, and duration of evoked responses are compatible with the idea that ITC neurons generate the inhibition of CE neurons by IL stimuli.

Public Health Relevance

Although anxiety disorders affect close to 13% of the population, most available pharmacological treatments have a limited efficacy and entail important side effects. It is thus imperative that we improve our understanding of the mechanisms underlying anxiety disorders to design better treatment strategies. If supported, the hypothesis tested here would open new strategies for the treatment of anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083710-05
Application #
8402410
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (04))
Program Officer
Vicentic, Aleksandra
Project Start
2009-03-19
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$367,092
Indirect Cost
$129,492
Name
Rutgers University
Department
None
Type
Organized Research Units
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Haufler, Darrell; Pare, Denis (2014) High-frequency oscillations are prominent in the extended amygdala. J Neurophysiol 112:110-9
Duvarci, Sevil; Pare, Denis (2014) Amygdala microcircuits controlling learned fear. Neuron 82:966-80
Kim, Dongbeom; Pare, Denis; Nair, Satish S (2013) Mechanisms contributing to the induction and storage of Pavlovian fear memories in the lateral amygdala. Learn Mem 20:421-30
Paz, Rony; Pare, Denis (2013) Physiological basis for emotional modulation of memory circuits by the amygdala. Curr Opin Neurobiol 23:381-6
Kim, Dongbeom; Pare, Denis; Nair, Satish S (2013) Assignment of model amygdala neurons to the fear memory trace depends on competitive synaptic interactions. J Neurosci 33:14354-8
Duvarci, Sevil; Popa, Daniela; Pare, Denis (2011) Central amygdala activity during fear conditioning. J Neurosci 31:289-94
Popescu, Andrei T; Pare, Denis (2011) Synaptic interactions underlying synchronized inhibition in the basal amygdala: evidence for existence of two types of projection cells. J Neurophysiol 105:687-96
Amano, Taiju; Duvarci, Sevil; Popa, Daniela et al. (2011) The fear circuit revisited: contributions of the basal amygdala nuclei to conditioned fear. J Neurosci 31:15481-9
Amir, Alon; Amano, Taiju; Pare, Denis (2011) Physiological identification and infralimbic responsiveness of rat intercalated amygdala neurons. J Neurophysiol 105:3054-66
Li, Guoshi; Amano, Taiju; Pare, Denis et al. (2011) Impact of infralimbic inputs on intercalated amygdala neurons: a biophysical modeling study. Learn Mem 18:226-40

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