| Authors: |
*R. M. SEARS1,
J. E. LEDOUX1,2;
1Ctr. for Neural Sci., New York Univ., New York, NY; 2Nathan
S, Kline Inst. for Psychiatric Res., Orangeburg, NY |
| Abstract: |
Anxiety disorders involve
alterations of fear, due in part to persistent changes in defense circuits
in the brain. The current work seeks to demonstrate an unexplored interaction
between the hypothalamic orexin system and brain regions that are critical
for aversive memory, as explored through studies of Pavlovian defense (fear)
conditioning. We hypothesize a circuit involving orexin synthesizing neurons
in the perifornical lateral hypothalamus, the locus coeruleus (LC), and
the lateral nucleus of the amygdala. Central (ICV) administration of the
orexin type 1 receptor (OrxR1) antagonist SB 334867, but not the orexin
type 2 receptor (OrxR2) antagonist TCS OX2 29, prior to training impairs
defense conditioning. To understand the neural circuits through which orexins
might alter defense conditioning, we first explored the effects of bilateral
administration of the orexin receptor type 1 antagonist SB 334867 in LC,
which is a major source of norepinephrine (NE) in the brain and has neurons
that are excited by orexins via OrxR1. Direct LC administration of SB 334867
impaired the acquisition, but not consolidation of defense conditioning.
Given that NE in lateral amygdala (LA) also contributes to the acquisition
but not consolidation of defense conditioning, we examined the effects of
disconnecting orexin signaling in LC from NE signaling in LA. To do this,
SB 334867 was unilaterally injected into the LC and the beta-adrenergic
receptor antagonist, propranolol, was injected in LA. Consistent with an
indirect, orexin-mediated modulation of amygdala function, contralateral
but not ipsilateral infusions disrupted conditioning. Dysregulation of the
orexin system may contribute to susceptibility to fear and anxiety disorders
and provide both a diagnostic measure and treatment target for these disorders.
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