Abstract
The onset of appropriate maternal behaviour is essential for the survival and development of offspring in mammals. It has previously been identified that lactogenic hormones (e.g. prolactin, placental lactogens) play an important role in regulating maternal behaviour, through their action on prolactin receptors (Prlr) in the medial preoptic area (MPOA) of the hypothalamus (Brown et al., 2017). However, the mechanism by which lactogenic action in this region induces the display of maternal behaviour is unclear. It has been demonstrated that engagement of reward circuitry through activation of MPOA neuronal projections to the ventral tegmental area (VTA) is necessary for maternal behaviour (Fang et al., 2018). Based on these findings, the aim of this PhD thesis was to investigate the hypothesis that lactogenic hormones activate reward pathways in the brain to promote the rewarding effect of offspring and drive motivation to interact with offspring.
As an important basis for addressing this hypothesis, changes in pup-related preference and motivation were characterised in female mice across reproductive states, using three behavioural paradigms. In a conditioned place preference test, virgin and pregnant female mice developed a preference for a pup-associated context, suggesting that pups are rewarding to these groups. In a novel T-maze test and in a home cage barrier climbing test, motivation to retrieve pups was low in virgin and pregnant females, compared to high levels in lactating mice, indicating that maternal motivation arises around the time of parturition. This increased maternal motivation appears to be transient, with levels declining over time in reproductively experienced females after weaning of pups.
The subsequent aim was to identify a potential mechanism through which lactogenic hormones could act on reward circuitry. Importantly, Prlr expression is absent in key regions within this circuitry, so lactogenic hormones would need to act indirectly through neuronal projections. Two complimentary retrograde tracing methods were used to identify prolactin-responsive neuronal input to the VTA. Cell bodies of prolactin-sensitive projections to the VTA were detected in the MPOA, bed nucleus of the stria terminalis (BNST), and the sublenticular extended amygdala (SLEA), revealing regions in which lactogenic action might modulate activity in the reward circuitry.
After providing the essential behavioural characterisation and identifying a potential mechanism of action, the role of lactogenic hormones in pup-related reward and motivation behaviours was assessed. Firstly, prolactin-responsive MPOA neurons were chemogenetically inhibited to investigate whether activity of these neurons is necessary for the expression of motivated maternal behaviours. Preliminary results suggest that acute inhibition of Prlr-expressing MPOA neurons does not disrupt maternal motivation in a home cage test, a T-maze test or barrier climbing test.
Subsequently, experiments were conducted to test whether lactogenic action through the Prlr is required for pup-related reward and motivation behaviour. Prolactin itself was found to act as a rewarding stimulus, with virgin females developing a conditioned place preference for a prolactin-paired context. A separate experiment showed that repeated exposure to pups induced rises in circulating prolactin levels in virgin female mice. Together, these findings suggest that lactogenic hormones may contribute to the rewarding effect of pups. However, deletion of lactogenic action from forebrain neurons or GABA neurons did not affect pup-related preference during lactation, indicating that lactogenic action on these populations is not necessary for the rewarding effect of pups. Next, mouse lines with a deletion of Prlr from specific populations of neurons were tested in the T-maze and barrier test to assess the involvement of lactogenic action in maternal motivation behaviour. Specifically, lactating females with a Prlr deletion from GABAergic neurons showed significant impairments in maternal motivation in the T-maze test, revealing that maternal motivation is at least partly regulated through lactogenic action on GABA neurons.
This PhD study has provided clear evidence for the involvement of lactogenic hormones in offspring-related reward and motivation behaviours. While it remains unknown whether maternal motivation underpins the essential effect of lactogenic action in the MPOA, these studies have highlighted that lactogenic hormones likely contribute to making interactions with offspring rewarding to females, and that the action of lactogenic hormones in the brain plays an important role in promoting maternal motivation.