Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay

Abstract

BackgroundIn man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment.MethodologyHaving spent the first 24 hours after birth with their biological mother, outbred NMRI mice were cross-fostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments.ResultsCross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2-enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the trait's stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett χ = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals.ConclusionsA mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some non-inferential physiological measurements can enhance animal models of human neurodevelopmental anxiety disorders.

Increased affective ultrasonic communication during fear learning in adult male rats exposed to maternal immune activation

“…increased heart rate and blood pressure. Furthermore, respiratory behavior is affected in rodents exposed to stressful experiences during early life, particularly under aversive conditions, along with an elevation of systemic inflammation markers (D'Amato et al, 2011;Genest et al, 2007). Increased repetition rates of 22-kHz USVs may therefore be linked to perceived threat in the sender and be of potential importance for the perception of the urgency of a response in the receiver.…”

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

“…From a clinical perspective, the protocols used aim to mimic conditions such as maternal depression, unstable parental environment, and special medical care at birth all of which interfere with normal mother-infant interactions. The effects on respiratory control typically persist well into adulthood and depending on the procedure used, the impact may be sex-specific (D'Amato et al, 2011;Kinkead et al, 2013). The neonatal stress protocols differ slightly amongst studies but they essentially aim to interfere with normal motherpup interactions sometime during the first 2 weeks of life as this period is critical for neurological development in rodents.…”

Separation anxiety disorder across the lifespan: DSM-5 lifts age restriction on diagnosis

“…The formulation was supported by family aggregation and twin studies, the latter suggesting a common heredity pattern underling PD-Ag and separation anxiety disorder (Weissman et al, 1984;Battaglia et al, 2009;D'Amato et al, 2011;Roberson-Nay et al, 2012). In addition, adults with PD-Ag and children with separation anxiety disorder have been shown to exhibit a common and distinctive psychophysiological response to laboratory induced CO 2 inhalation (Battaglia et al, 2009;D'Amato et al, 2011;Roberson-Nay et al, 2010;Atli et al, 2012). This tradition, supported by some empirical evidence, has entrenched the notion that children with separation anxiety disorder who experience persisting or recurrent symptoms in adulthood are most likely to manifest PD-Ag.…”

“…The prevailing model was that panic disorder-agoraphobia (PDAg) linked to early separation anxiety formed a distinctive ''endogenous'' type of anxiety (Klein, 1964;Sheehan et al, 1980). The formulation was supported by family aggregation and twin studies, the latter suggesting a common heredity pattern underling PD-Ag and separation anxiety disorder (Weissman et al, 1984;Battaglia et al, 2009;D'Amato et al, 2011;Roberson-Nay et al, 2012). In addition, adults with PD-Ag and children with separation anxiety disorder have been shown to exhibit a common and distinctive psychophysiological response to laboratory induced CO 2 inhalation (Battaglia et al, 2009;D'Amato et al, 2011;Roberson-Nay et al, 2010;Atli et al, 2012).…”