Altered Dopamine Signaling in Naturally Occurring Maternal Neglect

Child neglect is the most common form of child maltreatment, yet the biological basis of maternal neglect is poorly understood and a rodent model is lacking.The current study characterizes a population of mice (MaD1) which naturally exhibit maternal neglect (little or no care of offspring) at an average rate of 17% per generation. We identified a set of risk factors that can predict future neglect of offspring, including decreased self-grooming and elevated activity. At the time of neglect, neglectful mothers swam significantly more in a forced swim test relative to nurturing mothers. Cross-fostered offspring raised by neglectful mothers in turn exhibit increased expression of risk factors for maternal neglect and decreased maternal care as adults, suggestive of possible epigenetic contributions to neglect. Unexpectedly, offspring from neglectful mothers elicited maternal neglect from cross-fostered nurturing mothers, suggesting that factors regulating neglect are not solely within the mother. To identify a neurological pathway underlying maternal neglect, we examined brain activity in neglectful and nurturing mice. c-Fos expression was significantly elevated in neglectful relative to nurturing mothers in the CNS, particularly within dopamine associated areas, such as the zona incerta (ZI), ventral tegmental area (VTA), and nucleus accumbens. Phosphorylated tyrosine hydroxylase (a marker for dopamine production) was significantly elevated in ZI and higher in VTA (although not significantly) in neglectful mice. Tyrosine hydroxylase levels were unaltered, suggesting a dysregulation of dopamine activity rather than cell number. Phosphorylation of DARPP-32, a marker for dopamine D1-like receptor activation, was elevated within nucleus accumbens and caudate-putamen in neglectful versus nurturing dams.These findings suggest that atypical dopamine activity within the maternal brain, especially within regions involved in reward, is involved in naturally occurring neglect and that MaD1 mice are a useful model for understanding the basis of naturally occurring neglect

Maternal touch moderates sex differences in juvenile social play behavior.

Additional somatosensory contact of preterm human infants improves a variety of developmental assessment scores, but less is known about its lasting consequences. In rodents, maternal contact may influence the programming of juvenile social play behavior. Therefore, we used a paradigm where we can control the levels of somatosensory contact associated with maternal care. We find that additional somatosensory contact of offspring can have lasting consequences on juvenile social play behavior in a sex-dependent manner. Specifically, additional somatosensory stimuli reduced male social play behavior, but did not change female play behavior. We then examined if this additional infant contact altered some neurobiological substrates associated with play within the juvenile amygdala. Control males had lower levels of 5HT2a receptor mRNA levels contrasted to females; however, similar to its sex-dependent effect on juvenile social play, males that received additional somatosensory contact had higher serotonin 5HT2a receptor mRNA levels than control males. No difference was found in females. As serotonin signaling typically opposes juvenile play behavior, these data suggest that maternal touch can program lasting differences in juvenile social play and 5HT2a receptors mRNA levels within the juvenile amygdala

Simulated maternal grooming selectively alters 5HT2a mRNA levels.

<p>A) 5HT1a mRNA levels were not altered by SMG or sex (p>0.05). B) There is a sex difference in control-handled animals, where control females have significantly higher levels of 5HT2a than control males (p<0.01). Males that were given SMG until P10 had significantly higher levels of 5HT2a than control-handled males (p<0.05).</p

Simulated maternal grooming alters male social play behavior.

<p>Between P26 to P29, control-handled males played significantly more than control-handled females (*, p<0.05). Males that were given SMG until P10 engaged in significantly less rough-and-tumble play than control-handled males (*, p<0.01). No difference was found between females who received either control-handling or SMG (p>0.05).</p

Mean (±SE) number of c-Fos positive cells in additional brain regions in neglectful and nurturing mice.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001974#pone-0001974-g006" target="_blank">Fig. 6</a> for c-Fos in dopamine releasing and responding regions.</p><p>Abbreviations: LSV = lateral septum ventral; CG = cingulate cortex; MeA = medial amygdala; CeA = central amygdala; LH = lateral hypothalamus; Pir = piriform cortex; PVN = paraventricular nucleus; cPAG = caudal periaqueductal gray; cPAG1 = more caudal aspect of cPAG; MPOM = medial preoptic nucleus; MPA = medial preoptic area; AHA = anterior hypothalamic area; SCN = suprachiasmatic nucleus. #- data non-normal, analyzed with ANOVA on Ranks.</p

Pups born to previously neglectful mice elicit decreases in maternal care.

<p>When raised by either previously nurturing MaD1 mice or Outbred-S mice, pups that were born to previously neglectful MaD1 mothers received significantly higher levels of maternal neglect relative to pups born to previously nurturing MaD1 mice (A). Similarly, the proportion of pups weaned was significantly lower for pups born to previously neglectful MaD1 mothers when raised by either previously nurturing MaD1 mothers or Outbred-S mothers (B). Previously neglectful (relative to nurturing) MaD1 mice weaned a lower proportion of pups when the pups were from nurturing mothers, but the differences did not reach significance (p = 0.071). Bars represent means±SE. *  = p<0.05; **  = p<0.01.</p

Altered pDARPP-32 expression with maternal neglect.

<p>Previously neglectful dams (N = 5) have significantly darker optical density of pDARPP-32 expression in Ac and CP when compared to previously nurturing dams (N = 6). Ac = nucleus accumbens, LS = lateral septum, CP = caudate-putamen, BST = bed nucleus of stria terminalis, dorsal, CeA = central amygdala. Bars represent means±SE. *  = p<0.05.</p