Evidence That the Periaqueductal Gray Matter Mediates the Facilitation of Panic-Like Reactions in Neonatally-Isolated Adult Rats

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.

Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression

“…However, experimental studies of PLB and depression comorbidity are scarce. Several reports suggest antagonistic, rather than agonistic relationship between PLB induced by DPAG activation and depressive-like behaviors [13]. The possible explanation for the differences between the cited and our study is the interference of additional phenomena on the PD-depression comorbidity such as the maternal separation during neonatal age of the animals.…”

“…Neurons in the dorsal region of DR (DRD) project into the forebrain and facilitate anxiety-related behaviors, including PA; while the neurons in the dorsal raphe ventrolateral (DRVL)/ventrolateral periaqueductal gray (VLPAG) are involved in the inhibition of panic-reactions [11, 12]. Furthermore, the role of the dorsal periaqueductal gray (DPAG) in the expression of unconditioned defensive reactions and panic is well established [8, 13]. This process implicates ascending connections from DPAG to the prosencephalic centers, such as the amygdala, through the medial forebrain bundle, which allows the animal to assess the aversive situation and helps in the recognition of the frightening stimuli [8, 13].…”

“…Furthermore, the role of the dorsal periaqueductal gray (DPAG) in the expression of unconditioned defensive reactions and panic is well established [8, 13]. This process implicates ascending connections from DPAG to the prosencephalic centers, such as the amygdala, through the medial forebrain bundle, which allows the animal to assess the aversive situation and helps in the recognition of the frightening stimuli [8, 13]. In research setting, exogenous activation of the DPAG has been proposed as a rodent model of PD.…”

In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion

“…These findings were corroborated by c-fos immunohistochemistry data showing the activation of both the nucleus of the solitary tract (NTS) and the DPAG in rats that developed escape reactions to 8% hypoxia (Casanova et al, 2013). Overall, these data endorse extensive research suggesting the DPAG mediation of panic (Deakin and Graeff, 1991;Schenberg et al, 2001Schenberg et al, , 2014Mobbs et al, 2007;Quintino-Dos-Santos et al, 2014).…”

Respiratory manifestations of panic disorder in animals and humans: A unique opportunity to understand how supramedullary structures regulate breathing

“…Mammals (including humans) are not exempt from this basic principle as research on numerous species show that perinatal stress is a significant risk factor for a variety of psychological and physiological diseases ranging from ischemic heart disease, hypertension, asthma, states of panic and anxiety, depression, and sleep disorders (Barker and Osmond, 1986;Dugovic et al, 1999;Herman and Cullinan, 1997;Rietveld et al, 1999). In recent years, work from several laboratories have established that exposure to a nonsystemic stress during the neonatal period disrupts development of the neural circuits that regulate breathing in rats and mice.…”