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• Anjali Bose
• Candy Li
• Catherine O'Connor
• Maya Peiris
• Doudou Tshiyena
• Serena Xu

Anjali Bose

Advisor: Cora Mukerji

Functioning Processes Moderated by Functional Anisotropy in White Matter tract in the Limbic Circuitry

Previous research has demonstrated that prolonged early deprivation has strong effects on neurodevelopment and function. Recent studies have suggested that prolonged exposure to institutionalization in childhood can have lasting effects on the development of white matter, especially in tracts connecting frontal and limbic structures (Kumar, 2014; Bick et al., 2015; Sheridan et al., 2022). Furthermore, frontolimbic white matter tracts have been implicated in the development of internalizing and externalizing behaviors in non-institutionalized adolescents and children who have experienced early institutionalization (Kumar, 2013; Bick et al., 2015; Sheridan et al., 2022), suggesting that these regions are especially important in regards to studying risk for psychopathology (Andre, 2020). The effects of limbic structure on psychopathology can be seen through white matter activity, measured through fractional anisotropy (FA), which indirectly measures white matter structural integrity (Govindan, 2010). The Bucharest Early Intervention program (BEIP) is a randomized control trial that investigates brain and behavioral differences that are influenced by institutionalization and foster care in Romania (Bick et al., 2015; Sheridan et al., 2022). In the BEIP sample, the integrity of the cingulum and the fornix, two structures in the limbic system, have been linked with the development of internalizing and externalizing factors at age 9 (Bick et al, 2015). Sheridan and colleagues found that children exposed to institutionalization had reduced white matter integrity compared to children in never institutionalized groups at 9 years old (Sheridan et al., 2022). Therefore, for my SSR project, I will investigate how structural integrity in white matter tracts connecting frontal and limbic brain areas, specifically the cingulum and the fornix, and associations with the development of internalizing and externalizing factors at age 16 in the BEIP study sample. I will use Diffusion Tensor Imaging (DTI) data, which provides measures of water molecule diffusivity and FA. I hypothesize that there will be a significant association between integrity of white matter tracts in the limbic system, specifically the cingulum and the fornix, and the development of internalizing and externalizing factors of psychopathology. Furthermore, I hypothesize that this relationship will be moderated by group, such that participants reared in the care as usual group (CAUG) with have reduced FA levels in the limbic system white matter tracts associated with the regions of interest compared to the foster care group (FCG) and never institutionalized group (NIG).

Works Cited

Andre, Q.R., Geeraert, B.L. & Lebel, C. Brain structure and internalizing and externalizing behavior in typically developing children and adolescents. Brain Struct Funct 225, 1369–1378 (2020).

Bick J, Zhu T, Stamoulis C, Fox NA, Zeanah C, Nelson CA. Effect of Early Institutionalization and Foster Care on Long-term White Matter Development: A Randomized Clinical Trial . JAMA Pediatr. 2015;169(3):211–219. doi:10.1001/jamapediatrics.2014.3212

Govindan, R. M., et al. “Altered Water Diffusivity in Cortical Association Tracts in Children with Early Deprivation Identified with Tract-Based Spatial Statistics (TBSS).” Cerebral Cortex, vol. 20, no. 3, 2009, pp. 561–569, .

Sheridan, Margaret A., et al. “Early Deprivation Alters Structural Brain Development from Middle Childhood to Adolescence.” Science Advances, vol. 8, no. 40, 2022, .

Kumar, Ajay, et al. “Microstructural Abnormalities in Language and Limbic Pathways in Orphanage-Reared Children.” Journal of Child Neurology, vol. 29, no. 3, 2013, pp. 318–325, .

Candy Li

Advisor: Laura Grafe

Contribution of Gonadal Hormones in Orexin Expression and Activation in Female Rats

            Women are twice as likely as men to suffer from stress-related mental disorders such as Major Depressive Disorder (MDD) and Post-traumatic Stress Disorder (PSTD), but the biological mechanism behind the sex differences remains unclear. Orexins are neuropeptides that are important in arousal and the stress response. Specifically, orexins and stress have a reciprocal relationship: orexins promote the stress response and orexins are activated by exposure to stress. Previous research from our lab has shown that female rats have a higher baseline expression, activation, and release of orexins compared to male rats, which contribute to impaired habituation to repeated restraint stress and subsequent cognitive deficits in female rats. However, the mechanism underlying sex differences in orexin expression, activation, and release is unknown. One likely candidate that may explain upregulation of orexins in females is the gonadal hormone estrogen. Importantly, preliminary data demonstrates that estrogen receptors are expressed in orexin neurons and there is a positive correlation between estrogen levels in the blood and orexin activation in the brain in female rats. This project will further explore how gonadal hormones such as estrogen and progesterone affect the expression, activation, and release of orexin. Ultimately, we hope to better understand sex differences in the stress response and inform individualized treatment of stress-related psychiatric disorders.

Catherine O'Connor

Advisor: Cora Mukerji

Relationships between the uncinate fasciculus, executive function and psychopathology in previously-institutionalized youth   

Institutionalization can have negative consequences for development in a variety of domains, including the use of language, cognition, social interactions, executive function, and mental health. Additionally, early life deprivation has shown to impact the structural integrity of white matter tracts in the brain that connect the frontal lobe to the temporal lobe, including the left uncinate fasciculus. Poorer structural connectivity can be measured by reduced fractional anisotropy (Govindan et al., 2010). Reduced fractional anisotropy in the uncinate fasciculus has in turn been associated with internalizing symptoms, such as depression, in adolescence (LeWinn et al., 2014). Further, the poor structural integrity of the uncinate fasciculus due to traumatic brain injury in children ages 6-15 predicted executive function abilities a year after injury (Johnson et al., 2011). In the current study, we will examine the relationship between the structural integrity of the uncinate fasciculus and executive function abilities and symptoms of psychopathology at age 16 using data from the Bucharest Early Intervention Project (BEIP). The BEIP randomly assigned young children in institutional care in Romania to receive a high-quality foster care intervention or to remain in the institution. Exploring relationships among behavioral, emotional, cognitive and neurological outcomes related to the early environments of the participants has the potential to (a) highlight how variation in white matter structure is related to individual differences in self-regulation and emotion regulation and (b) examine the potential remedial effects of early caregiving interventions. To examine the relationships between the structural integrity of the uncinate, executive function, emotional regulation and internalizing symptoms, we will use previously-collected data obtained through Diffusion Tensor Imaging (DTI), a technique that measures the movement of water along a neuron’s axon. We expect that greater fractional anisotropy will be associated with enhanced behavioral, cognitive and emotional regulation and fewer internalizing symptoms. We further expect these relationships to be moderated by early caregiving experiences. In addition to revealing the influence of the uncinate fasciculus on emotional and behavioral outcomes in adolescence, this research may demonstrate the importance of early interventions to address the detrimental impacts of poor caregiving environments on development.

Maya Peiris

Advisor: Laura Grafe

The Effect of the Menstrual Cycle on Stress, Coping, and Sleep in Women

Stress-related disorders such as Post-Traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD) are twice as common in women compared with men. Importantly, the increased incidence of these disorders in women arises with puberty and lessens with the onset of menopause, suggesting that cyclic fluctuation of sex hormones (such as estrogen and progesterone) during the menstrual cycle may contribute to stress disorders. Another important factor that may affect vulnerability to stress is the type of coping strategy used to deal with the stressor. For example, maladaptive coping mechanisms such as avoidance can lead to sleep impairments, which is a key symptom of stress disorders. To better understand how the menstrual cycle and coping strategies affect stress and sleep in women, our lab collected subjective and objective data from 49 college aged participants across their menstrual cycle.  Specifically, we used questionnaires and Fitbits to track their menstrual cycle and measure stress, coping, and sleep over the span of 5 weeks. Analyzing the collected data, we hope to answer the following questions: How/do coping strategies change over the menstrual cycle and what impact does this have on stress and sleep? How is sleep affected by stress and how does this change over the menstrual cycle? How/is heart rate variability correlated with stress and sleep during the menstrual cycle? In broadening our understanding of how stress, sleep, coping strategies, and the menstrual cycle intersect, we can provide insight into improving treatment of stress-related disorders in women.

Doudou Tshiyena

Advisor: Cora Mukerji

Links between inhibitory control and frontostriatal and frontolimbic circuits in previously-institutionalized children

Executive functioning refers to the set of cognitive processes that allow someone to self-regulate based on their ability to apply working memory, flexible thinking and self control to their daily tasks. Inhibitory control is included in this set of processes, as it is the skill of effectively regulating automatic responses and selecting a response that is appropriate for a given situation (Diamond, 2013). Learning how to exercise inhibitory control is necessary for self-regulation but can be disrupted and moderated by unconventional caregiving experiences through adverse childhood experiences (Ji and Wang, 2018). Previous research has suggested important neural circuitry, such as frontostriatal and frontolimbic circuits, involved in inhibitory control are compromised in children with histories of institutionalization (Bick et al. 2015; Sheridan et al., 2022). Researching the link between brain structure and executive functioning processes is necessary to understanding how children in adverse environmental contexts develop self-regulation abilities.  The Bucharest Early Intervention Project (BEIP) is a longitudinal randomized control trial meant to research the effects of early caregiving (high quality foster care versus remaining in case as usual) on the development of previously-institutionalized children, provides a unique opportunity to understand complex relationships between white matter development, inhibitory control, and early caregiving adversity. Using BEIP data, I will be examining relationships between white matter development and  inhibitory control in adolescence and whether these are moderated by caregiving experiences. Through diffusion tensor imaging data from the BEIP study, we will analyze the integrity of the white matter tracts and their associations with inhibitory control in later adolescence (age 16). I predict that there will be a link in the abnormalities of white matter and individual differences in children’s inhibitory control and that the strength of this relationship will be moderated by early caregiving environments. It is necessary to study the impact of institutionalization on development as it could mitigate the negative effects deprivation may have on the cognition, behavioral and mental health of children impacted.

Serena Xu

Advisor: Laura Grafe

Sex Differences in the Effect of Orexin Inhibition in the Orbitofrontal Cortex on Cognitive Flexibility Under Stress in the Rodent Model

Panic disorder, Major Depressive Disorder (MDD), and Post-Traumatic Stress Disorder (PTSD) are stress-related disorders that are twice as common in women. Importantly, a decline in cognitive flexibility is a key phenotype in these disorders, with women showing worse impairments. However, the neurobiological mechanisms behind this sex difference remains unknown. Previous studies in the lab have shown that high levels of the neuropeptides orexins impair cognitive flexibility and stress in female rats, and impaired cognition is remedied after orexin inhibition. However, the mechanism by which orexin acts on the brain to cause cognitive inflexibility is unknown. Previous research has revealed that the orbitofrontal cortex (OFC) is employed during cognitive-flexibility-related tasks such as the attentional set-shifting task and the reverse-learning tasks, and that the task performance would deteriorate if subjects had OFC impairment. A major manifestation of such cognitive flexibility decline is perseveration, where the individuals would fail to learn rules for a new task in the paradigm. Our research aims to fill in the gap of knowledge by examining whether orexins act on the OFC to impair cognitive flexibility in female rats after stress. Importantly, studies show that the orexin type-1 receptor (OX1R) is present in several subregions of the prefrontal cortex (which includes the OFC). Thus, we will administer an OX1R antagonist targeting the OFC to inhibit orexin action in both male and female rats prior to restraint stress and test their subsequent cognitive flexibility in an attentional set-shifting task. We hypothesize that inhibition of OX1R in the OFC will improve overall cognitive flexibility in female rats after stress. As rats have a high genomic resemblance with humans, our results will be translatable to inform society about the reliability of the current FDA-approved orexin antagonist medications in affecting cognitive flexibility.