Abstract
Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26) whilst siblings (sham-isolated rats, SHAM, n = 27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD.
Highlights
Dyspnoea, panic and urge to flee are the cardinal symptoms of clinical panic [1,2]
Here we examined whether the neonatal social isolation (NSI), an experimental model of childhood separation anxiety (CSA), facilitates panic-like behaviors produced by electrical stimulations of dorsal half of periaqueductal gray matter (PAG) (DPAG) of adult rats
Apart from 1 electrode in the dorsomedial column of PAG (DMPAG) and 3 electrodes in the deeper layers of superior colliculus (DLSC), electrodes were all localized into the DLPAG and LPAG
Summary
Panic and urge to flee are the cardinal symptoms of clinical panic [1,2]. Panic attacks are precipitated by infusions of sodium lactate and inhalations of 5–7% carbon dioxide (CO2) in predisposed patients but not in healthy subjects [3,4,5]. Electrical and chemical stimulations of DPAG produces freezing and flight behaviors along with marked cardiorespiratory responses which are reminiscent of a panic attack [17,18,19, 20,21]. Clinical and epidemiological recent studies reported that neither the CSA [27] nor the early-life adversity [28,29] had any effect on the rate of depression and PD respectively.
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