Anxiety, aggression, reward sensitivity, and forebrain dopamine receptor expression in a laboratory rat model of early-life disadvantage.

Despite early-life disadvantage (ELD) in humans being a highly heterogenous construct, it consistently predicts negative neurobehavioral outcomes. The numerous environmental contributors and neural mechanisms underlying ELD remain unclear, though. We used a laboratory rat model to evaluate the effects of limited resources and/or heavy metal exposure on mothers and their adult male and female offspring. Dams and litters were chronically exposed to restricted (1-cm deep) or ample (4-cm deep) home cage bedding postpartum, with or without lead acetate (0.1%) in their drinking water from insemination through 1-week postweaning. Restricted-bedding mothers showed more pup-directed behaviors and behavioral fragmentation, while lead-exposed mothers showed more nestbuilding. Restricted bedding-raised male offspring showed higher anxiety and aggression. Either restricted bedding or lead exposure impaired goal-directed performance in a reinforcer devaluation task in females, whereas restricted bedding alone disrupted it in males. Lead exposure, but not limited bedding, also reduced sucrose reward sensitivity in a progressive ratio task in females. D1 and D2 receptor mRNA in the medial prefrontal cortex and nucleus accumbens (NAc) were each affected by the early-life treatments and differently between the sexes. Most notably, adult males (but not females) exposed to both early-life treatments had greatly increased D1 receptor mRNA in the NAc core. These results illuminate neural mechanisms through which ELD threatens neurobehavioral development and highlight forebrain dopamine as a factor.

Partner-seeking and limbic dopamine system are enhanced following social loss in male prairie voles (Microtus ochrogaster).

Death of a loved one is recognized as one of life's greatest stresses, and 10%-20% of bereaved individuals will experience a complicated or prolonged grieving period that is characterized by intense yearning for the deceased. The monogamous prairie vole (Microtus ochrogaster) is a rodent species that forms pair bonds between breeding partners and has been used to study the neurobiology of social behaviors and isolation. Male prairie voles do not display distress after isolation from a familiar, same-sex conspecific; however, separation from a bonded female partner increases emotional, stress-related, and proximity-seeking behaviors. Here, we tested the investigatory response of male voles to partner odor during a period of social loss. We found that males who lost their partner spent significantly more time investigating partner odor but not non-partner social odor or food odor. Bachelor males and males in intact pairings did not respond uniquely to any odor. Furthermore, we examined dopamine (DA) receptor mRNA expression in the anterior insula cortex (aIC), nucleus accumbens (NAc), and anterior cingulate (ACC), regions with higher activation in grieving humans. While we found some effects of relationship type on DRD1 and DRD2 expression in some of these regions, loss of a high-quality opposite-sex relationship had a significant effect on DA receptor expression, with pair-bonded/loss males having higher expression in the aIC and ACC compared with pair-bonded/intact and nonbonded/loss males. Together, these data suggest that both relationship type and relationship quality affect reunion-seeking behavior and motivational neurocircuits following social loss of a bonded partner.

Neurobiology of Loneliness, Isolation, and Loss: Integrating Human and Animal Perspectives.

In social species such as humans, non-human primates, and even many rodent species, social interaction and the maintenance of social bonds are necessary for mental and physical health and wellbeing. In humans, perceived isolation, or loneliness, is not only characterized by physical isolation from peers or loved ones, but also involves negative perceptions about social interactions and connectedness that reinforce the feelings of isolation and anxiety. As a complex behavioral state, it is no surprise that loneliness and isolation are associated with dysfunction within the ventral striatum and the limbic system - brain regions that regulate motivation and stress responsiveness, respectively. Accompanying these neural changes are physiological symptoms such as increased plasma and urinary cortisol levels and an increase in stress responsivity. Although studies using animal models are not perfectly analogous to the uniquely human state of loneliness, studies on the effects of social isolation in animals have observed similar physiological symptoms such as increased corticosterone, the rodent analog to human cortisol, and also display altered motivation, increased stress responsiveness, and dysregulation of the mesocortical dopamine and limbic systems. This review will discuss behavioral and neuropsychological components of loneliness in humans, social isolation in rodent models, and the neurochemical regulators of these behavioral phenotypes with a neuroanatomical focus on the corticostriatal and limbic systems. We will also discuss social loss as a unique form of social isolation, and the consequences of bond disruption on stress-related behavior and neurophysiology.

Postpartum State, but Not Maternal Caregiving or Level of Anxiety, Increases Medial Prefrontal Cortex GAD65 and vGAT in Female Rats.

Upregulation of the inhibitory neurotransmitter, GABA, is involved in many of the behavioral differences between postpartum and nulliparous female rodents. This is evidenced by studies showing that pharmacological blockade of GABAergic activity impairs maternal caregiving and postpartum affective behaviors. However, the influence of motherhood on the capacity for GABA synthesis or release in the medial prefrontal cortex (mPFC; brain region involved in many social and affective behaviors) is not well-understood. Western blotting was used to compare postpartum and nulliparous rats in protein levels of the 65-kD isoform of glutamic acid decarboxylase (GAD65; synthesizes most GABA released from terminals) and vesicular GABA transporter (vGAT; accumulates GABA into synaptic vesicles for release) in the mPFC. We found that postpartum mothers had higher GAD65 and vGAT compared to virgins, but such differences were not found between maternally sensitized and non-sensitized virgins, indicating that reproduction rather than just the display of maternal caregiving is required. To test whether GAD65 and vGAT levels in the mPFC were more specifically related to anxiety-related behavior within postpartum mothers, we selected 8 low-anxiety and 8 high-anxiety dams based on their time spent in the open arms of an elevated plus maze on postpartum day 7. There were no significant differences between the anxiety groups in either GAD65 or vGAT levels. These data further indicate that frontal cortical GABA is affected by female reproduction and more likely contributes to differences in the display of socioemotional behaviors across, but not within, female reproductive state.

Decreased mesolimbic dopaminergic signaling underlies the waning of maternal caregiving across the postpartum period in rats.

RATIONALE: Mesolimbic dopamine (DA) signaling is essential for the high maternal caregiving characteristic of the early postpartum period, but little is known about dopamine's role in the expression of maternal caregiving thereafter. OBJECTIVES: We tested the hypothesis that decreased mesolimbic dopaminergic signaling is particularly responsible for the natural decline in maternal caregiving that occurs as the postpartum period progresses. METHODS: Sprague-Dawley (SD) mother rats received intraperitoneal injections of either vehicle, the DA D1 receptor agonist SKF38393, the DA D2 receptor agonist quinpirole, or both agonists twice daily from postpartum days 9 to 15. In a separate experiment involving Long-Evans (LE) rats, we examined whether DA D1 and D2 receptor mRNAs in the nucleus accumbens (NA) shell and ventral tegmental area (VTA), along with DA turnover in the VTA, decline across the postpartum period in parallel with the decreasing maternal behavior. RESULTS: All drug treatments significantly maintained higher frequencies of active maternal behaviors (nesting, pup licking, retrieval) compared to vehicle. Furthermore, the majority of mothers treated with SKF38393 either alone or combined with quinpirole maintained full expression of maternal behavior during behavioral testing. D2 receptor mRNA levels were found to be lower in the late postpartum NA shell and VTA compared to early postpartum, but D1 receptor mRNA levels in the NA shell were higher in the late postpartum period. Furthermore, both late postpartum and recently parturient LE mothers had higher VTA DA turnover compared to nulliparae, suggesting changes in mesolimbic signal-to-noise ratio both at the end and beginning of motherhood. CONCLUSIONS: Collectively, our results suggest that alterations in mesolimbic DA is part of the neural substrate responsible for dynamic maternal caregiving across the entire postpartum period.

Serotonin-specific lesions of the dorsal raphe disrupt maternal aggression and caregiving in postpartum rats.

The behavioral modifications associated with early motherhood, which include high aggression, caring for the young, and low anxiety, are all affected by acute pharmacological manipulation of serotonin signaling. However, the effects on all these behaviors of permanently disrupting serotonin signaling from one of its primary sources, the dorsal raphe nucleus (DR), have not been examined in detail. To address this, serotonin-specific lesions centered on the dorsomedial DR (DRdm; DR subregion strongly implicated in emotional behaviors) were induced at mid-pregnancy (day 15) or early postpartum (day 2) in rats using a saporin-conjugated neurotoxin targeting the serotonin transporter (Anti-SERT-SAP). Prepartum or postpartum Anti-SERT-SAP reduced DRdm serotonin immunoreactivity by ∼40-65%, and postpartum Anti-SERT-SAP also reduced it in the ventromedial and lateral wings of the DR, as well as in the median raphe. Serotonin-immunoreactive fibers were significantly reduced in the anterior hypothalamus, but not medial preoptic area, of lesioned dams. Pre- or postpartum lesions both greatly reduced maternal aggression, but while prepartum lesions did not affect later undisturbed maternal caregiving, the larger postpartum lesions prevented the postpartum decline in kyphotic nursing and reduced pup licking. Serotonin lesions did not affect pup retrieval, but the prepartum lesions temporarily increased maternal hovering over and licking the pups observed immediately after the disruptive retrieval tests. Dams' anxiety-like behaviors and litter weight gains were unaffected by the lesions. These findings suggest that DRdm serotonin projecting to the AH is particularly critical for maternal aggression, but that more widespread disruption of midbrain raphe serotonin is necessary to greatly impair maternal caregiving. Postpartum anxiety may rely more on other neurochemical systems or different midbrain serotonergic cell populations.