Milou Straathof

Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism- related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1 ^-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1 ^-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS. ONE SENTENCE SUMMARY: An age-dependent brain connectivity phenotype in a rat model of FXS is not rescued by lovastatin and aligns with human RSC hypoconnectivity

The female brain undergoes substantial reorganization during major hormonal transitions, yet whether puberty, pregnancy, and menopause engage shared or distinct neuroplastic mechanisms remains unknown. We conducted the first study comparing longitudinal structural brain changes across all three transitions using identical analytical methods (n=1292), with stable control groups to isolate transition-specific effects. Both pubertal girls transitioning through menarche and women transitioning to motherhood showed cortical gray matter reductions across the majority of examined regions, with cross-cohort comparisons confirming broad mostly convergence but also regional divergence across the cortex. The menopausal transition showed a fundamental divergence from both puberty and pregnancy, as women transitioning through menopause showed no accelerated volumetric loss, while stable pre- and postmenopausal control groups did. These findings demonstrate that puberty and pregnancy share a broadly convergent signature of cortical remodeling, while menopause represents a qualitatively distinct neuroplastic state defined by the absence rather than acceleration of volumetric change.

While we have previously shown that a first pregnancy changes women’s brain structure and resting-state brain activity, it is currently unknown how a woman’s brain is transformed when she undergoes another pregnancy. Therefore, we performed a prospective pre-conception cohort study involving 110 women, including women who became pregnant of their second (PRG2) or first child (PRG1) and nulliparous women. Multimodal MRI data were acquired and differential changes between PRG2 and PRG1 were observed in grey matter volume, white matter tracts and functional neural network organization. Together, these results show similar but less pronounced structural and functional changes in the default mode and frontoparietal network in PRG2, suggesting a primary adaptation of these networks in first-time mothers that is further fine-tuned across a second pregnancy. Furthermore, stronger alterations were found in PRG2 in the dorsal attention and somatomotor network including the corticospinal tract, pointing to an enhanced plasticity within these externally-oriented networks. Neurostructural changes in both groups related to mother-infant attachment and peripartum depression. These findings show that a second pregnancy uniquely changes a woman’s brain, entailing both convergent and distinct neural transformations.

Pregnancy is associated with prominent structural changes in brain areas involved in Theory of Mind (ToM), pointing to the possibility of modifications in ToM‐related behavior and brain responses in parents. We performed a systematic review screening for studies that examined ToM in pregnant and/or early postpartum parents. The evaluation of the included 12 studies allowed us to construct an overview of ToM changes during pregnancy and postpartum as well as other associated factors, such as oxytocin, mental health, and parental behavior. Four studies examined ToM changes by comparing pregnant/early postpartum parents with nulliparous parents or prepregnancy measures. They reported no differences between groups measured with a self‐report questionnaire but found group differences using an experimental approach. The results from the summarized studies further suggest a mediatory role of oxytocin between ToM and certain parental behavior. In addition, while no link between postpartum depression and ToM was observed, findings do point to an association between depressive and remote maternal behavior and anxious attachment style and ToM abilities in pregnant participants. Research findings regarding the interaction of ToM with both parity and maternal attachment to the fetus are ambivalent. Overall, research on this topic is scarce, limiting our ability to draw firm conclusions and stressing the need for further research on this topic. This review presents an overview of research findings on ToM and associated factors in pregnancy and the postpartum period and discusses directions for future research.

Rationale: Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment. Objective: Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity. Methods: Juvenile Sprague–Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8). Results: Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections. Conclusions: The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI.

An improved understanding of the structure-function relationship in the brain is necessary to know to what degree structural connectivity underpins abnormal functional connectivity seen in disorders. We integrated high-field resting-state fMRI-based functional connectivity with high-resolution macro-scale diffusion-based and meso-scale neuronal tracer-based structural connectivity, to obtain an accurate depiction of the structure-function relationship in the rat brain. Our main goal was to identify to what extent structural and functional connectivity strengths are correlated, macro- and meso-scopically, across the cortex. Correlation analyses revealed a positive correspondence between functional and macro-scale diffusion-based structural connectivity, but no significant correlation between functional connectivity and meso-scale neuronal tracer-based structural connectivity. Zooming in on individual connections, we found strong functional connectivity in two well-known resting-state networks: the sensorimotor and default mode network. Strong functional connectivity within these networks coincided with strong short-range intrahemispheric structural connectivity, but with weak heterotopic interhemispheric and long-range intrahemispheric structural connectivity. Our study indicates the importance of combining measures of connectivity at distinct hierarchical levels to accurately determine connectivity across networks in the healthy and diseased brain. Although characteristics of the applied techniques may affect where structural and functional networks (dis)agree, distinct structure-function relationships across the brain could also have a biological basis.