Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo.

A key feature of the CNS is structural plasticity, the ability of neurons to alter their morphology and connectivity in response to sensory experience and other changes in the environment. How this structural plasticity is achieved at the molecular level is not well understood. We provide evidence that changes in sensory experience simultaneously trigger multiple signaling pathways that either promote or restrict growth of the dendritic arbor; structural plasticity is achieved through a balance of these opposing signals. Specifically, we have uncovered a novel, activity-dependent signaling pathway that restricts dendritic arborization. We demonstrate that the GTPase Rem2 is regulated at the transcriptional level by calcium influx through L-VGCCs and inhibits dendritic arborization in cultured rat cortical neurons and in the Xenopus laevis tadpole visual system. Thus, our results demonstrate that changes in neuronal activity initiate competing signaling pathways that positively and negatively regulate the growth of the dendritic arbor. It is the balance of these opposing signals that leads to proper dendritic morphology.

Structural and functional connectivity in premature neonates.

Advances in neuroimaging have increasingly enabled researchers to investigate whether alterations in brain development commonly identified in preterm infants underlie their high risk of long-term neurodevelopmental impairment, including sensory, motor, cognitive, and psychiatric deficits. This review begins by examining the growing body of literature utilizing advanced magnetic resonance imaging (MRI) techniques to probe structural (via diffusion MRI) and functional (via resting state-functional MRI) connectivity development in the preterm brain during the neonatal period, both in the presence and absence of brain injury. It then details the recent work linking neonatal brain connectivity measures to neurodevelopmental and psychiatric outcomes in prematurely-born cohorts. Finally, building upon the recent substantive growth in the utilization of these neuroimaging modalities, it concludes by highlighting areas in which continued optimization of age-specific acquisition and analysis techniques for these data remains necessary, efforts fundamental to advancing the field toward establishing individual-level predictive capabilities in this high-risk population.

Microstructure of the Dorsal Anterior Cingulum Bundle in Very Preterm Neonates Predicts the Preterm Behavioral Phenotype at 5 Years of Age.

BACKGROUND: The cingulum bundle (CB), specifically the dorsal anterior portion of the CB, plays an important role in psychiatric illnesses; however, its role during early development is unclear. This study investigated whether neonatal white matter microstructure in the CB and its subregions is associated with subsequent preterm behavioral phenotype symptoms (internalizing, inattention, and social deficits) in very preterm (VPT) children. METHODS: Diffusion magnetic resonance imaging data were obtained on a 3T scanner in 138 sleeping nonsedated neonates: 55 full-term neonates (gestational age ≥ 36 weeks) and 83 VPT neonates (gestational age < 30 weeks). The CB was tracked using probabilistic tractography and split into anterior and posterior portions. When children were 5 years of age, parents (n = 80) and teachers (n = 63) of VPT children completed questionnaires of preterm behavioral phenotype symptoms. Linear regression models were used to relate measures of neonatal CB microstructure and childhood preterm behavioral phenotype symptoms (n = 56 parent report, n = 45 teacher report). RESULTS: Mean diffusivity in the anterior and posterior CB was increased in VPT neonates compared with full-term neonates. Increased fractional anisotropy and decreased mean diffusivity in the right anterior CB, but not in the posterior CB, were related to increased preterm behavioral phenotype symptoms in VPT children as reported by parents and teachers. CONCLUSIONS: Aberrations in the anterior portion of the right CB may underlie the early development of the preterm behavioral phenotype. This finding provides the foundation for future mechanistic and therapeutic investigations into the role of the anterior cingulum in the development of psychopathology in VPT infants.

Effects of sub-chronic methylphenidate on risk-taking and sociability in zebrafish (Danio rerio).

Attention deficit hyperactive disorder (ADHD) is the most common psychiatric disorder in children affecting around 11% of children 4-17 years of age (CDC 2019). Children with ADHD are widely treated with stimulant medications such as methylphenidate (Ritalin®). However, there has been little research on the developmental effects of methylphenidate on risk-taking and sociability. We investigated in zebrafish the potential developmental neurobehavioral toxicity of methylphenidate on these behavioral functions. We chose zebrafish because they provide a model with extensive genetic tools for future mechanistic studies. We studied whether sub-chronic methylphenidate exposure during juvenile development causes neurobehavioral impairments in zebrafish. Methylphenidate diminished responses to environmental stimuli after both acute and sub-chronic dosing. In adult zebrafish, acute methylphenidate impaired avoidance of an approaching visual stimulus modeling a predator and decreased locomotor response to the social visual stimulus of conspecifics. Adult zebrafish dosed acutely with methylphenidate demonstrated behaviors of less retreat from threatening visual stimuli and less approach to conspecifics compared with controls. In a sub-chronic dosing paradigm during development, methylphenidate caused less robust exploration of a novel tank. In the predator avoidance paradigm, sub-chronic dosing that began at an older age (28 dpf) decreased activity levels more than sub-chronic dosing that began at earlier ages (14 dpf and 21 dpf). In the social shoaling task, sub-chronic methylphenidate attenuated reaction to the social stimulus. Acute and developmental methylphenidate exposure decreased response to environmental cues. Additional research is needed to determine critical mechanisms for these effects and to see how these results may be translatable to neurobehavioral toxicity of prescribing Ritalin® to children and adolescents.