GABAA receptor signaling in caudal periaqueductal gray regulates maternal aggression and maternal care in mice

Abstract

Maternal aggression (maternal defense) is exhibited by lactating females towards intruders and contributes to the protection of offspring. Enhancement of GABA A receptor signaling by benzodiazepines elevates maternal aggression, and we previously found indirect evidence (via cFos immunhistochemistry) that caudal periaqueductal gray (cPAG) and lateral septum (LS) could be sites where benzodiazepines increase aggression. We recently found that GABA A receptor signaling in LS modulates maternal aggression, and in this study, we tested the hypothesis that GABA A receptor signaling in cPAG also regulates this behavior. Site-directed injections to cPAG were made in lactating mice using the GABA A receptor antagonist, bicuculline (3-9 ng) or the GABA A receptor positive modulator, chlordiazepoxide (CDP), a benzodiazepine (2.5-20 µg). Maternal aggression, other maternal behaviors, and anxiety-like measures (using the light-dark box) were then examined. GABA A receptor positive modulator did not increase aggression, which could have resulted from a ceiling effect. However, 8 ng and 9 ng of bicuculline in cPAG significantly decreased maternal aggression without altering other maternal behaviors or light-dark box performance, suggesting some GABA A receptor signaling in cPAG is required for full maternal aggression expression. Additionally, 7 ng of bicuculline significantly increased licking/ grooming of pups, and decreased the number of transitions between the light and dark compartments of the light-dark box without affecting aggression. Given these results indicating that antagonizing GABA A -receptor in cPAG dose-dependently promotes offspring grooming behavior while impairing aggression, it is possible that the cPAG represents a key site for decision making (aggression versus other behaviors) in the lactating female.

Glutamic acid decarboxylase 65 and 67 expression in the lateral septum is up-regulated in association with the postpartum period in mice

“…LSc also projects to AH, nucleus of the diagonal band, BNST, amygdala, ventral tegmental area, and supramammillary nucleus. Our finding of selective up-regulation of GAD in LSr subdivision of maternal brain supports the idea that altered GABA signaling in LSr plays an important role in changes in behavioral profiles during the postpartum period as LSr has high connectivity with regions previously implicated in maternal defense and emotional state, including periaqueductal gray, amydgala, BNST, and PVN (Consiglio et al, 2005; Consiglio and Lucion, 1996; Lee and Gammie, 2010; Lonstein and Gammie, 2002; Lonstein and Stern, 1997; Sheehan et al, 2004). The LSr contains neurons that express mRNA for neurotensin and enkephalin, while the LSc contains neurons that express mRNA for somatosta-tin, mineralocorticoid receptor and androgen receptor (Risold and Swanson, 1996, 1997a,b).…”

“…GABA is also linked to offspring protection as the activation of GABA A receptor with various benzodiazepines (GABA A receptor agonists) elevated protective behavior (Lee and Gammie, 2007; Mos and Olivier, 1989; Yoshimura and Ogawa, 1991). Further, antagonism of GABA A receptor with bicuculline prominently disrupted maternal aggression while leaving other components of maternal behavior relatively intact in lactating females (Hansen and Ferreira, 1986; Lee and Gammie, 2009, 2010). GABA is synthesized from its immediate precursor glutamate by the rate-limiting enzyme glutamic acid decarboxylase (GAD).…”

Amygdala–midbrain connectivity indicates a role for the mammalian parental care system in human altruism

“…GABA may also modulate offspring care behaviours through inhibitory signalling in the ventrolateral PAG, which is the location of highly organized afferent amygdala GABAergic input [24]. For example, in rodents, GABA A receptor antagonism in ventrolateral PAG promotes licking and grooming of pups while decreasing anxiety and aggression [62].…”

Traumatic Stress Induces Prolonged Aggression Increase through Synaptic Potentiation in the Medial Amygdala Circuits

“…Mice were tested for aggression before (baseline test) and after foot shock. Because a further increase in aggression may not be induced in mice with high aggression because of a ceiling effect ( O'Donnell et al, 1981 ; Lee and Gammie, 2009 , 2010 ), only mice exhibiting a total attack time of <3% in the baseline test, which was considered as low aggression in previous studies ( Hong et al, 2014 ), were used for further analysis. Eleven mice (5.29% of total) were excluded based on this criterion.…”