Structural changes in the maternal brain following birth

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Maternal Love by Lisa Marsman [14]

The maternal brain undergoes various structural changes after birth to ensure the female brain is suitably primed and developed into a maternal brain. These adaptive changes ensure the mother is suitably prepared to raise her offspring [1]. Neural changes occur to illicit a stronger face recognition response from the mother when viewing her child [1]. Neural rewiring also induces a strong maternal attachment to the offspring mediated through the brain’s reward pathways and related structures, specifically the substantia nigra [2]. Following the post-partum period, as offspring age, the maternal brain remains adaptive and dynamic rewiring itself to the diminishing needs of the offspring. As mothering is a social behavior, a mother’s ability to raise her offspring can be impaired following physical trauma to the prefrontal cortex or following psychological trauma inducing long-lasting changes in prefrontal cortex [3]. These cortical and subcortical structures help shape the maternal brain, and thus behavior, to ensure the mother is well prepared to raise her offspring.

1 Medial Preoptic Area

Among the first experiments studying structural changes in the maternal brain utilized rat models to examine the structural changes that took place in lactating mammals. One of the first regions of interest was the medial preoptic area (MPOA). Due to the high density of estradiol, progesterone, prolactin, vasopressin, opioid, and oxytocin receptors located within the MPOA, changes in the levels of these hormones during and following pregnancy guide the changes experienced by mothers [4]. The role of the MPOA was first appreciated when estradiol benzoate was injected in the brains of 16-day pregnant, hysterectomized, ovariectomized female rats [2]. Two locations were targeting for injection, the MPOA and the ventromedial hypothalamus. Rats with MPOA injections experienced an earlier onset of maternal behavior towards foster pups than rats with ventromedial hypothalamic injections or virgin rats [2].

Furthermore, when virgin rats are presented with pups, the onset of maternal behavior is correlated with the expression of higher levels of Fos proteins (cFos and Fos B) by MPOA neurons [5]. As Fos proteins act as mediators of cell proliferation, it is theorized that this increase in Fos protein levels is linked to a subsequent phenotypical change in the neurotransmitter density in the MPOA.

Maternal Behaviour
Dam exhibiting typical maternal behaviour including
pup retrieval and licking as well as nest building [15]

1.1 Lesioning the medial preoptic area

The role of the MPOA in facilitating maternal behavior was further examined through lesioning experiments, with the lesioning of the MPOA retarding the onset of maternal behavior in virgin rats and disrupting maternal behavior in maternal rats (when performed in the post-partum period) [4] [2].

1.2 Connection with dopaminergic systems

The MPOA also interacts with dopaminergic (DA) systems to regulate maternal behavior in rats [4]. The hypothalamic DA's input into the MPOA serves to prime the MPOA that in turn exerts appetitive maternal behavior by acting on the mesolimbic DA system (via input into the Nucleus Accumbens) [4].

2 Amygdala

Due to the importance of the amygdala in emotional reactions and decision making, it has also been the focus of research regarding maternal behavior elicitation. Neurons in the amygdalae of rat mothers exhibited increased levels of c-Fos protein [5]. Furthermore, dams that interacted more with pups during the early post-partum period had higher expression of c Fos protein in the amygdala than mothers who interacted with pups less [5]. Furthermore, the grey matter of the amygdala of human mothers was shown to increase shortly after birth of the child. The grey matter of the mothers was measured at 2-4 weeks after birth and then again 3-4 months after birth with significant changes in the grey matter volume being observed [5]. Studies utilizing functional magnetic resonance imagining (fMRI) confirm the importance of the amygdala in maternal behavior. Mothers viewing pictures of their own children had significantly higher activation of the amygdala than when viewing pictures of other children [6]. This increased sensitivity to facial cues to a mother’s own offspring demonstrates the emotional attachment of the mother to her offspring.

Neurogenesis in the maternal brain
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The maternal brain with regions shown in red subject to statistically
significant neurogenesis between the early postpartum period
(2-4 weeks after birth) and the late postpartum period (3-4 months after birth) [5]

Interestingly, amygdala activation, specifically in the medial amygdala, in virgin rats inhibits maternal behavior [5]. However during the post-partum period, the rewiring of this pathway is thought to be necessary for mothers to consolidate maternal motivation to respond to infant cues [5]. This isolation in these first few months can be detrimental due to interrupted bonding and interruption of amygdala rewiring. Thus the amygdala can be seen to switch roles, at first inhibiting maternal behavior and later serving to reinforce emotional motivation for pup cues.

Rat mothers engaged in social nesting (i.e. mothers allowed to build nests in groups) were found to have more oxytocin receptors in their amygdala and exhibited maternal behavior earlier than the control group, which built a nest without social interactions [7]. Thus structural changes in mothers are not only due to hormonal changes, but possible social changes as well.

3 Substantia Nigra and reward pathway activation:

Studies examining mother rats’ preference for her pup over cocaine have revealed interesting results. In the early post-partum period (4-7 days post-partum), dams have a preference for their pups when given the option of entering one of two chambers, one with access to the pup and one with access to cocaine [8]. More interestingly, this preference is not permanent. Later in the post-partum period (12-15 days), the dam begins to favor the cocaine-containing chamber over the pup-containing chamber [8]. This phenomenon brings to light the interesting notion that maternal behavior is not static, but rather dynamic. Some structural changes brought on by pregnancy can be subsided and reversed with time [8]. The plasticity in behavior is due to changes in pup-bias attributed to different structures. In the early post-partum period, the MPOA, through dopaminergic inputs, and the prefrontal cortex (along with the anterior cingulate subregions and the ventral tegmental area) form a pup-biased motivational circuitry. Later in the post-partum period, the role of the dopaminergic inputs into the MPOA in mediating maternal behavior is diminished with the prefrontal cortex overseeing maternal behaviour [5] [8].

Furthermore, grey matter increases in human mother substantia nigra in the post-partum period also support the evidence that the substantia nigra is responsible for maternal behavior. Human mothers exhibited a significant increase in their grey matter volume in the substantial nigra 3-4 months after birth (compared to 2-4 weeks after birth) [5]. More evidence comes in the form of fMRI studies. Human mothers exposed to videos of both their children and other women’s children in stressful and cheerful contexts (for the child). The study showed significant activation of the substantia nigra when a mother viewed the video of her child’s face, compared to another child’s face, in both the stressful and cheerful contexts [1]. Furthermore, there was a significant difference in the activation between the stressful context and cheerful context when a mother say her own child, as mothers responded more intensely (i.e. more activation of the aforementioned regions) to their children exposed to stressful context than in cheerful context [1].

Comparison of hippocampal expression of oxytocin receptor
mRNA and oxytocin receptor protein in WT and CB1R KO mice
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There was a statistically significant difference between not
only oxytocin receptor mRNA, but also the protein itself across the
WT and CB1R KO dams. * P<0.05, **P<0.001 [9]

4 Hippocampus:

A recent study examining the effects of endocannabinoid receptor deficiency on maternal behavior revealed interesting results. Endocannabinoid receptor-1 (CB1R) knockout (KO) mice were compared to wild-type (WT) mice [9]. Female KO mice were then mated and gave birth to KO mice. KO dams were slower to retrieve their pups (decreased maternal behavior) and exhibited lower hippocampal oxytocin receptor mRNA expression as well as lower BDNF receptor expression [9]. Thus, the disruption of endocannabinoid receptor signaling alters the expression of oxytocin and BDNF receptors and leads to subsequent degeneration of maternal behaviour.

4.1 NMDA-dependent synapses

While there is widespread belief that estrogen levels mediate learning and memory, there is no conclusive evidence providing a causative link [10]. However, increased estradiol levels in rat brains are associated with structural changes specifically increased dendritic spine synapses on CA1 pyramidal cells [10]. Furthermore, these synapses are thought to be primarily NDMA-dependent. However, no link has been found connecting these NMDA-dependent spine synapses to behavioral changes, particular hippocampal-dependent spatial memory [10].

5 Prefrontal Cortex

As the prefrontal cortex (PFC) is the seat if higher-order brain functions, including moderating social behavior, it plays a major role in maintaining maternal behavior [11]. Studies utilizing fMRI have shown that the PFC is activated significantly more when a mother views the face of her own child compared to when she views the face of an unrelated child [1]. Furthermore, the grey mater volume of the PFC increases in mothers shortly after birth, with significant changes observed when comparing the grey matter volume of the PFC at 2-4 weeks after birth and 3-4 months after birth [5]. In rat dams, maternal behavior is correlated with c Fos levels in the PFC, further implicating the PFC for its role in mediating maternal behavior [5].

Prefrontal cortex lesioning in rhesus monkey brains
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The prefrontal cortex of rhesus monkeys was removed to observe the deficits created.
Among the deficits was maternal behaviour, implicating the prefrontal cortex with a mediating
role in maternal behaviour [12].

5.1 Lesioning the prefrontal cortex

The strongest evidence for the role of the PFC in mediating maternal behavior comes from lesion studies. Rhesus monkeys who had bilateral ablations of the PFC exhibited severely decreased levels of infant retrieval and decreases in infant cuddling [12]. Similar lesioning experiments confirm the findings in rat models, with similar reductions found in pup retrieval and pup licking [13].

6 Effects of isolation on maternal behavior-related structural changes

Anecdotal observation has pointed to a correlation between abusive or distant maternal behavior negatively affecting daughters who would in turn become abusive or cold towards their daughters [3]. However, concrete proof for this observation was demonstrated in a cross-adoption study examining the effects of maternal isolation on child maternal behavior, performed in rhesus monkeys [12]. The study examined the effects of isolating infant rhesus monkeys from mothers, intervals at a time, or leaving rhesus monkey infants to interact with a mother in a natural state. The infants were not the mothers’ own, but rather cross-adopted to rule out genetic determinants causing the debilitation of maternal behavior [12]. Rhesus monkeys who were subject to isolation periods were shown to have diminished maternal behavior when they produced offspring of their own, compared to the non-isolation group [12]. The exact structural changes implicated in the changes responsible for this disruption of maternal behavior are not known, however further research into the systems affecting post-partum depression have been and are being conducted[3]. Dysfunction of the dopaminergic systems connecting to and from the MPOA as well as in the amygdala priming process are two possible explanations for the observed deficits in maternal behavior [3] [4].

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