MBB Class of 2023: Thesis Video Presentations and Abstracts

Sophia Campbell (Human Evolutionary Biology), The evolution of reward circuitry: A comparative study between humans, chimpanzees, rhesus macaques, and capuchin monkeys (advisor, Erin Hecht, Human Evolutionary Biology/FAS) -- Video Presentation
The ventral striatal related reward network is a foundational component in reward processing for sociality and decision-making. Many neurological diseases are linked to this network as well. Subcortical components of this system, like the nucleus accumbens (NA), and cortical components of this system, like projections within the prefrontal cortex (PFC), possess connectivity that is important in encoding reward value. The nonlinear expansion of the cortex, seen in humans and other primates, posits that late-developing cortical regions increase in size faster than early developing regions. Thus, early developing regions (that include subcortical components) occupy a smaller percentage of overall brain volume. In sum, this suggests a potential evolutionary structural change between cortical and subcortical regions of the brain within humans. This study examines the structural connectivity of the ventral striatal related reward network utilizing a comparative approach across humans and nonhuman primates. Specifically, we investigate structural connectivity between the NA and PFC projections: the anterior cingulate cortex, the orbital frontal cortex, and the ventro-medial prefrontal cortex. Human diffusion magnetic resonance imaging data (dMRI) is compared to chimpanzees, rhesus macaques, and capuchin monkey datasets and analyzed using probabilistic tractography. To our knowledge there is no literature examining the ventral striatal related reward network in the context of all four species. Results show that humans have the least robust connectivity between the NA and PFC projections compared to nonhuman primates. Ultimately, these results suggest a potential increase in cortico-cortical connectivity within humans to modulate reward compared to nonhuman primates, and differences in reward processing compared to nonhuman primates.

Allison Chang (Neuroscience), Age-specific functions of microglial C1q in neuronal translational regulation and synaptic plasticity (advisor Beth Stevens, HMS) -- Video Presentation
Within the nervous system, interactions with various elements of the immune system contribute to a wide range of essential brain functions. C1q, an innate immune complement component produced and secreted by microglia in the brain, represents one of these key immune factors, with the protein having been previously implicated in critical processes such as synaptic refinement. Notably, a significant age-mediated aspect has been observed to exist regarding changes in C1q expression, with important consequences for function and behavior in the adult brain that are still not fully understood. This thesis aimed to investigate the functional consequences of age-dependent, microglial-derived C1q in translational regulation and plasticity. After confirming the co-localization of C1q and a subset of ribosomal and RNA-binding proteins at neuronal synapses in the aging brain via proteomic analysis and Proximity Ligation Assay, we identified changes in translational regulation resulting from the age-dependent modulation of C1q expression via the development of a puromycin non-canonical amino acid incorporation assay for the in vivo surveillance of active translation in the brain. Lastly, we observed behavioral changes in relation to age-dependent C1q interactions with RNA and RNA-binding proteins via the use of a fear extinction model. Overall, our work contributed to describing a novel property of the microglial-derived complement protein, C1q, in integrating into neuronal ribonucleoprotein structures and mediating age-specific intraneuronal interactions with translation-implicated RNA-binding proteins. These results support future inquiry into the role of C1q in plasticity, aging, and disease, and continue to motivate the exploration of highly diverse downstream impacts resulting from neuroimmune and glial interactions.

Rachel Chau (Neuroscience), Investigating long noncoding RNAs as novel therapeutic targets in Alzheimer’s Disease (advisors Anna Krichevsky, HMS & Lien Nguyen, HMS) -- Video Presentation
Despite the prevalence and burden of Alzheimer's disease (AD), there is a lack of effective treatments for this neurodegenerative disease. Drug development historically focuses on disease-associated proteins, but RNAs have shown great promise as new therapeutic targets. About 70% of the human genome encodes for non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs play critical roles in modulating gene and protein expression at the epigenetic, transcriptional, and post-transcriptional levels, and ncRNA dysregulation has been associated with neurological disorders. Long ncRNAs (lncRNAs)comprise the largest and most diverse class of ncRNAs. However, their physiological functions in the healthy brain and dysfunctions in AD remain unclear. Utilizing publicly available datasets from the Religious Orders Study, the Memory and Aging Project, and the AD Knowledge Portal, we identified candidate lncRNAs differentially expressed between healthy and AD brains and validated their aberrant levels in stressed human cell lines and additional human AD samples with RT-qPCR. We found that a novel transcript, lnc-HPCA-1:1, was significantly upregulated in stressed human cell lines and AD samples. We further determined that lnc-HPCA-1:1 was transcriptionally upregulated in stress conditions. Future experiments include examining the function of lnc-HPCA-1:1 in AD through knockdown and overexpression and potential role as a miR-501 and let-7a sponge. This research will inform further investigations of lncRNA dysregulation in neurological disease and expand the pool of biomarkers and therapeutic targets in AD, paving the way for new ncRNA technologies to treat neurological disorders.

Evie Coxon (Neuroscience), Examining frontolimbic connectivity and childhood trauma as predictors of non-suicidal self injury in a high-risk cohort of children (Jenna Traynor, HMS) -- VIdeo Presentation
Background: Non-Suicidal Self Injury (NSSI) constitutes a significant global health concern. Childhood trauma has been identified as a risk factor for NSSI and associated with reduced patterns of frontolimbic connectivity. This study examines whether alterations to frontolimbic resting-state functional connectivity (rs-FC) are associated with the development of NSSI in a high-risk cohort. Secondly, it investigates whether childhood trauma has any discernible effects on frontolimbic connectivity in individuals with NSSI. Methods: N = 100 scans were analyzed from a sample of high-risk children in Brazil. The CONN toolbox was used to analyze rs-FC. The Deliberate Self-Harm Inventory (DSHI) and Childhood Maltreatment Assessment were used to measure NSSI and trauma. Between group ROI-to-ROI analysis was performed to characterize patterns of frontolimbic rs-FC. A multivariate F test was conducted to examine effects of childhood trauma and dimensional self-harm (DSHI total score) on brain connectivity. Results: Findings indicated reduced functional connectivity between left and right orbitofrontal cortices in self-harming individuals, compared to healthy controls. Age, site, and gender had no effect on frontolimbic connectivity in self-harm and control groups. Additionally, there were no significant effects of childhood trauma or dimensional self-harm on frontolimbic connectivity in the self-harm group. Conclusions: Findings suggest that reduced connectivity within the orbitofrontal cortex may be associated with the development of NSSI in children at high risk for psychopathology. Low endorsement of childhood trauma and a small sample size may account for a lack of further significant findings in this study.
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Eloise Freitag (Neuroscience), Exploring the neurobiological association between temperament and polygenic risk for psychopathology (advisor Charles Nelson, HMS) -- Video Presentation
Evidence suggests that certain temperament characteristics, such as low effortful control and high negative affectivity, confer risk for later psychopathology. Although genetic risk has been linked to a number of psychiatric conditions, little work has examined the genetic overlap between early temperamental profiles and later mental health outcomes or the variety of neurobiological mechanisms that mediate this relationship. The present study examined associations between polygenic risk scores for anxiety (PRS-Anxiety) and ADHD (PRS-ADHD),frontal asymmetry (FA), and temperament characteristics in a longitudinal sample of children assessed from infancy through age 7 years. Analyses were conducted on two subsamples, a discovery sample (N = 484) and a test sample (N = 122). An age by polygenic risk score interaction effect on negative affectivity and effortful control was observed, such that as children aged, there were stronger positive associations between PRS-Anxiety and negative affectivity and stronger negative associations between PRS-ADHD and effortful control. Results also showed a significant association between FA and temperament such that greater relative left FA was associated with increased effortful control in infancy, and greater relative right FA was associated with increased surgency in infancy and five years old. Overall, the findings suggest shared genetic underpinnings for childhood temperament characteristics and psychopathology.

Katie Gao (Neuroscience) (March degree), Reward network connectivity distinguishes antidepressant mechanisms of action in ECT and TMS: A resting-state fMRI study (advisor Joan Camprodon, HMS) -- Video Presentation
Electroconvulsive Therapy (ECT) and Transcranial Magnetic Stimulation (TMS) are neuromodulation interventions used to treat major depressive disorder (MDD). Anhedonia is a core diagnostic symptom of MDD, described as the inability to experience pleasure. Previous research shows that ECT and TMS are comparably effective in alleviating depressive symptoms, with some differences in remission and tolerance. However, there is little consensus on ECT and TMS’ mechanisms of action, particularly in the domains of anhedonia and reward processing. In this study, we investigated how ECT and TMS influenced anhedonia and reward processing in MDD patients (N=40). Patients with MDD completed pre- and post-treatment assessments, including functional magnetic resonance imaging (fMRI) and clinical measures. Following treatment, ECT and TMS cohorts reported significantly decreased depressive symptoms, reductions in anhedonia, and increased ability to experience reward. Functional connectivity within and between reward, dorsal attention, and ventral attention networks did not change significantly before and after treatment for ECT and TMS cohorts. For the ECT cohort alone, however, linear regression analysis demonstrated significant correlations between baseline functional connectivity and symptoms of anhedonia. Finally, graph theory analyses showed that only ECT modulated connectomics measures of clustering coefficient, eigenvector centrality, and page rank centrality in reward-related regions of interest (ROIs). Altogether, these results preliminarily indicate that ECT and TMS may operate through different mechanisms of action, which warrants future between-group analysis. These findings help to elucidate clinical and mechanistic differences between ECT and TMS that can inform clinical decision-making in MDD treatment.

Ilai Gavish (Neuroscience and Philosophy), Less than reckless: Assessing the role of consciousness in the moral appraisal of risky action (advisor Gabriel Kreiman, HMS) -- Video Presentation
The law typically defines criminal recklessness as having conscious awareness of an unjustifiable risk of harm and choosing to act despite this risk. This thesis investigates the validity of this requirement of conscious awareness using the methods of both neuroscience and philosophy. First, I conducted an electroencephalography (EEG) experiment in which subjects were presented with a binary choice wherein one of the options was sometimes preceded by a stimulus signaling risk of harm to a future participant. This risk-stimulus was presented either consciously or subliminally using a metacontrast masking paradigm. In some analyses, electrical activity at the midline central (Cz) electrode showed a significantly greater post-choice P300 amplitude for risky trials than for trials without a signal of risk, and there was significant interaction with the conscious/unconscious presentation of the stimulus as well as with the strategy employed by the participant. These preliminary results suggest that there is a detectable difference in neural activity between conscious versus unconscious processing of risk. This neuroscientific experiment is supplemented by a broader philosophical discussion of the relationship between consciousness and moral responsibility. I argue that volitionalism, which requires conscious awareness for blameworthiness, prevails over consciousness-optional views on theoretical grounds, and I rebut a set of anti-volitionalist moral intuitions by introducing a distinction between the concepts of responsibility and ownership. In combination, the neuroscience and philosophy research helps to validate both that there is a distinction between conscious and unconscious representation of risk and that this difference is morally meaningful.

Cade Herrera (Neuroscience), Eternal sunshine of the spotless mind: A longitudinal fMRI study on the efficacy of mindfulness training to offset age-related cognitive decline (advisor Sara Lazar, HMS) -- Video Presentation
A healthy memory is essential for maintaining one’s wellbeing. Memory impacts all aspects of day-to-day life, from the execution of essential daily tasks to the formation and maintenance of social relationships. Given the national increased life expectancy, identifying interventions to slow down or re-verse cognitive decline has become of great interest in research and a priority in public health. Mind-fulness meditation practice may be an alternative method for promoting cognitive function and slowing the normal age-related decline of neural structure and function. This thesis assesses the effects of mindfulness meditation using a longitudinal study design with an active control. To test this, we administered a validated memory task while conducting an fMRI brain scan, then searched for behavioral group-by-time interactions in memory scores, as well as differences in activation and connectivity in and between regions of interest. To our knowledge, this is the first study to include a 12-month functional imaging follow-up study on the benefits of mindfulness meditation in aging populations. The meditation group showed increased memory scores after one year. Further, this thesis shows mind-fulness-mediated increases in hippocampal activation and key nodes of the default mode network. The connectivity analysis showed increases between the hippocampus and the default mode network connectivity, interhemispheric hippocampal connectivity, and a prominent increase in a minor memory network in the meditation group. This thesis provides sufficient novel evidence that long-term mindful-ness m/editation provides cognitive benefits and contributes to the maintenance of episodic memory in advanced age.

Shifa Hossain (Neuroscience), Investigating the dynamics of cell death and cell proliferation in dorsal root ganglia of axolotls during peripheral nerve regeneration (advisor Jessica Whited, Stem Cell and Regenerative Biology, HMS/FAS) -- Video Presentation
Peripheral nerve injuries (PNI) arise from various trauma accidents, such as sports, motor vehicle accidents, gunshot wounds, and even during birth. Unlike other specialized organ systems, the peripheral nervous system has some regenerative capacity in humans. However, it is limited depending on factors such as age, degree of PNI, and location of the injury. To explore the repair of PNI, we utilized axolotls, highly regenerative salamanders, as a complement to the regeneration of PNI in mammalian studies. Given its ability to completely regenerate its limb and attain functional recovery, we hypothesized that axolotls have an enhanced nerve repair mechanism compared to mammals. To investigate peripheral nerve regeneration, we specifically targeted the brachial plexus nerves, which innervate the forelimbs and provide sensory and motor function. Transection of the brachial plexus leads to a loss of function. Here, we hypothesize that cell death pathways are active and even support nerve regeneration through their dynamic relation with cell proliferation. To characterize peripheral nerve regeneration, we applied single and repeated transections at the brachial plexus nerves and collected the dorsal root ganglia (DRG) across time points throughout nerve regeneration. Then, we explored our hypothesis by applying immunohistochemistry stains to mark cells undergoing apoptosis and to tag cells undergoing proliferation. Next, these DRG samples were quantified and analyzed, where we observed a significant upregulation in proliferation, but cell death was nonsignificant across all timepoints. This concluded that during peripheral nerve regeneration, DRGs undergo apoptosis but not at significant rates as proliferation.

Autumn Lynne Johnson (Neuroscience), Touch as a key regulator of social need (advisor Catherine Dulac, Molecular and Cellular Biology/FAS) -- Video Presentation
Social interaction is essential to the well-being and survival of both humans and animals. Lack of social activity during periods of isolation effectively enhances the motivational drive for social interactions as revealed by an observable rebound in social contacts once animals are reunited after isolation. This raises the question of how do animals know they are “together” or “alone”? Until now, the sensory contribution to the emergence and fulfilment of social drive has been unclear. Our preliminary data showed that isolated mice with access to visual, auditory, pheromonal, and olfactory cues from other cage mates can still develop a significant social rebound after isolation, suggesting that a different sensory modality such as touch may play a role in informing animals of social encounters and in turn in modulating social drive. In this study, we measured touch seeking behaviors in mice and found that social isolation increases gentle touch seeking following social isolation. Moreover, genetic ablation of touch sensory neurons leads to attenuated social response to isolation, and acute pharmacological inhibition of touch sensation slows down social satiation during reunion. Finally, providing comforting touch during isolation reduces subsequent social rebound. Together these results support that animal-animal somatosensory contact is a critical regulator of internal social drive. Perhaps the importance of touch in social interaction explains why no Zoom call can measure up to the embrace of a loved one.

Maria Kaltchenko (Neuroscience), Maternal exogenous oxytocin administration and the enduring effects of birth manipulations on the fetal brain (advisor Marcy Kingsbury, HMS) -- Video Presentation
The hormone oxytocin (OT), a pleiotropic mammalian neuropeptide that coordinates various aspects of social behavior and reproduction, facilitates the delivery process by stimulating uterine contrac-tions, and it is widely administered in hospitals to induce or augment labor. OT is generally thought of as a neuroprotective hormone, particularly during stressors such as the major physiological stress of birth. Previous research has found that perinatal stressors may contribute to aberrant behaviors such as those observed in autism spectrum disorder (ASD). While endogenous OT is protective for the fe-tal brain, the long-term effects of maternal exogenous OT administration at birth on offspring are poorly understood. Here, we model induction of labor with high-dose OT to investigate the effects of maternal OT administration on the prairie vole brain at adolescence, conducting behavioral assays at postnatal days 24-28 and analyzing brain oxidative stress levels via an aconitase assay at postnatal day 29. We find that female offspring exhibit lower levels of oxidative stress at every maternal treat-ment level as compared to their male counterparts. In females alone, maternal administration of OT reduces oxidative stress levels as compared to the no treatment control, establishing a sexually di-morphic difference in the neuroprotective effects of exogenous OT administration. Behavioral data reveal that the saline injection acts as a stressor and not as a benign control in males with resulting behavioral deficits, which high OT treatment rescues. Increased aggression against an unrelated pup in high-OT females in the alloparental care assay supports the social salience hypothesis of OT.

Nadine Lee (Neuroscience), Modeling temporal lobe epilepsy through prime editing of RAS-MAPK variants (advisor Christopher Walsh, HMS) -- Video Presentation
Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy and is frequently resistant to treatments, leaving many patients with little choice except to undergo surgery. The RAS-MAPK pathway has been reported to be dysregulated in cancer, and it is closely connected to the misregulation of protein expression at synapses in epilepsy. Prior work from Dr. Khoshkhoo and Walsh identified pathogenic somatic variants in the hippocampus surgically resected from patients with drug-resistant TLE, all of which were predicted to activate RAS-MAPK signaling. Notably, many of these somatic variants were in the PTPN11 gene, but the molecular mechanisms of how variants in this gene give rise to epilepsy remain unresolved. To explore PTPN11 variants and their effects within TLE, we attempted to first create a model of PTPN11 mosaicism with admixed mutant and wild type cells through prime-editing (PE). For this thesis, two variants were specifically chosen due to their recurrence in TLE, p.G503R and p.N308D. Given the constraints of the specific genomic loci, 4 guides were each designed for p.N308D and p.G503R. These guides were cloned into the PE constructs available from Anzalone et al. and then tested in the HEK 293T cell line. Amplicon sequencing performed on the DNA derived from edited cells, did not identify the desired edits, suggesting likely guide failure which can be common in PE experiments due to the high precision of the technique. The methodological framework developed as part of this thesis, however, will be implemented in future rounds of experimentation until the desired outcome is achieved.

Seungil (Rick) Lee (Neuroscience) (March degree), Identifying long noncoding RNAs as regulators of genes associated with autism spectrum disorder (advisor Christopher Walsh, HMS) -- Video Presentation
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder affecting approximately 1 in 54 children in the United States. While many studies have identified variants in protein-coding genes that are associated with ASD, noncoding genes have not been studied to the same extent. This paucity of research applies to long noncoding RNAs (lncRNAs), which are noncoding transcripts that are longer than200 nucleotides, despite evidence of their relevance to neurodevelopment. Thus, we conducted an array of knockdown experiments to identify lncRNAs that may regulate ASD-associated genes. We first prioritized 20 lncRNA candidates based on evidence of their differential expression in ASD brains and the function of their nearby ASD-associated protein-coding genes, because lncRNAs have often been found to regulate closely neighboring genes. Subsequently, we knocked down our 20 pairs of lncRNA candidates and their nearby ASD-associated genes using the CRISPR-Cas13d system in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells. We then performed bulk RNA sequencing and differentially expressed gene analysis. Finally, we performed a proliferation assay to understand their functional significance. 3 of 6 lncRNAs whose knockdown efficiencies were greater than50% led to decreased expression of their neighboring ASD-associated genes. Moreover, 9 of 11 lncRNAs whose knockdown efficiencies were greater than 20% led to significant enrichment for differentially expressed ASD-associated genes.Functionally,KMT2E-AS1and ASH1L-AS1knockdownssignificantly decreased proliferation and led to enrichment for differentially expressed genes associated with mitosis. This project establishes an effective analytic framework to study lncRNAs and offers foundational knowledge about promising lncRNAs that may contribute to ASD.

Soo Lee (Neuroscience) (March degree), Investigating the relation between infant functional connectivity and child internalizing behavior (advisor Charles A. Nelson, HMS) -- Video Presentation
Specific functional brain networks have been associated with distinct domains of psychopathology, including depression and anxiety. However, little is known about the developmental origins of these brain-behavior associations. Furthermore, maternal depression has been associated with child psychopathology, but how infant functional connectivity may moderate or mediate this relation has not been studied. The current study examined the link between functional connectivity in infants and 5-year emotional and behavioral outcomes (N =91; M [age] = 8.62 months). Specifically, we measured resting-state functional connectivity in three major functional networks –homologous-interhemispheric connections, frontoparietal network, and default mode network –using functional Near Infrared Spectroscopy. Our results show that functional connectivity in the networks can be detected from as early as infancy. Furthermore, homologous-interhemispheric connections were positively associated with later 5-year internalizing symptoms (B = 6.75, SE = 2.93, p = .023). The default mode network was also associated with stress (B = 0.91, SE = 0.47, p = .05), a subscale of internalizing symptoms, but the frontoparietal network did not exhibit significant associations. Contrary to my hypotheses, infant functional connectivity did not moderate or mediate the relation between maternal depression in infancy and 5-year internalizing symptoms. These findings further our understanding of the development of functional brain networks and help identify potential risk markers for internalizing problems, which may inform early intervention efforts.

Shaked Emily Leibovitz (Neuroscience), Overcoming fear-neuroadaptive changes following mindfulness training enhance fear extinction learning (advisor Sara Lazar, HMS) -- Video Presentation
The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated mindfulness training's capacity to enhance brain mechanisms associated with fear-extinction learning. We investigated blood- oxygenation-level-dependent (BOLD) activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n=42) or exercise-based stress management education program (SME, n=27). The MBSR group was uniquely associated with neuroadaptive changes, including enhanced activation of salience network nodes, and increased hippocampal engagement which was correlated with increased gray matter volume of the presubiculum. In addition, we investigated dynamic functional connectivity changes in the hippocampus and amygdala during stages of extinction learning, which facilitate the rapid response necessary to adapt to changes in threat signals. In the MBSR group, the amygdala increased functional connectivity with the somatosensory cortex during early extinction, implying increased interoceptive attention; and the hippocampus increased functional connectivity with the precuneus during late extinction, supporting reconsolidation and strengthening of the extinction memory during learning. Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli and enhances reappraisal of the extinction memory which can support the development of resiliency to aversive experiences and potentially improve mental health and well-being.

Mikaela Belle Martin (Linguistics), Y’all finna go to the d-hall? –Tense-aspect markers in Black Harvard African American English (advisor Kathryn Davidson, Linguistics, FAS) -- Video Presentation
The Black community at Harvard represents a unique set of undergraduate students that, as a whole, make up a minority at the institution, but are further divided, beyond the scope of the university, into various ethnic groups. With this diversity in identity comes, also diversity in language. African American English (AAE) is spoken within this community by most of its members. One such group is made up of descendants of enslaved Africans on American soil, also known as Generational African Americans (GAA). Most of these students come to Harvard with familial knowledge and experience of AAE, in contrast with their non-GAA peers. Therefore, it can be anticipated that differences would be found within this greater community in the usage of African American English. This study focused on two main features of African American English: stressed BIN and the distinction between finna and gonna. Additionally, responses on changes in participants’ perceived use of AAE and Black identities were gathered. This study found that participants used stressed BIN as predicted by the literature, both as a marker of a distant past action and a mode of correction. Finna was found to occur most frequently in expressions of the immediate future tense and gonna and gon were found most frequently in expressions of the near and indefinite future. Additionally, participants reported a joint decrease in the use of African American English and an increase in code switching, as well as negative changes in their perceptions of their own Black identities since starting at Harvard.

Rio McLellan (Neuroscience), Targeting proteostasis machinery in the brain vasculature to treat neurodegenerative disease (advisor Lee Rubin, Stem Cell and Regenerative Biology, HMS/FAS) -- Video Presentation
Aging is the largest risk factor for late onset neurodegenerative diseases. Using experimental models of heterochronic parabiosis, the surgical joining of young and old mice, seminal studies from our lab demonstrated it is possible to reverse some negative effects of brain aging. To gain insight into the aging reversal process, our lab profiled transcriptional changes occurring throughout the mouse brain during aging and parabiosis. Among the many aging-affected processes, protein homeostasis (proteostasis)was among the most notable. We identified several heat shock proteins (HSPs) which were elevated with age and reduced via parabiosis in brain endothelial cells (BECs) of the blood-brain-barrier. Given chaperone expression generally declines with aging, we were curious as to why these select chaperones exhibited robust upregulation in these critical barrier cells. To investigate this, we overexpressed the most differentially expressed HSP (Hspa1a) in young mouse primary BECs to levels comparable in aged mouse BECs finding that Hspa1aupregulation significantly enriched several functional pathways related to protein degradation. We hypothesized that aged BECs upregulate HSPs as a protective mechanism to limit aging-associated protein aggregate formation. To test this hypothesis, we differentiated human induced pluripotent stem cells genetically engineered to contain a pathogenic Alzheimer’s disease mutation into BEC-like cells and utilized lentiviral constructs to globally inhibit or activate the heat shock response via an engineered HSF1moiety, the master transcription factor regulating downstream HSP expression. As hypothesized, downregulation of HSF1increased protein aggregates and decreased cellular viability rendering HSPs in the vasculature as potential therapeutic targets for neurodegeneration.

Keilina Tita Monteiro Do Canto (Neuroscience), Studying the relationship between neuropeptides regulating stress and anxiety circuitry in the bed nucleus of the stria terminalis: An investigation through the pathology of post-traumatic stress disorder (advisor Sabina Berretta, HMS) -- Video Presentation
Post-traumatic stress disorder (PTSD) is a severe anxiety disorder affecting approximately 10% of persons exposed to traumatic events. Altered responses to threat and stimuli associated with the initial traumatic event can lead to re-experiencing traumatic emotions. Growing evidence indicates that neural circuitry processing fear responses and stress is dysregulated, with expression and functions of several neuro-modulatory peptides having been found to be altered. Among these, the pituitary adenylate cyclase-activating polypeptide (PACAP) plays a key role in plasticity, stress response, and anxiety, and PACAP signaling is thought to regulate neurons expressing corticotropin-releasing hormone (CRH), which plays a fundamental role in coordination of peripheral and central responses to stress. Little is known on the cell-level expression signaling pathways of these proteins, specifically within the bed nucleus of the stria terminalis (BNST) in PTSD. Various neuroimaging studies have shown an increased level of BNST activation in healthy human brains as a result of stressful stimuli, illustrating the importance of the BNST in the consolidation of fear memories. We investigated the relationship between PACAP and CRH pathways using RNAScope, an in-situ hybridization technique that uses probes specific to these proteins. We hypothesized that our data would indicate altered PACAP and CRH positive pathways in the BNST in postmortem brain samples in individuals with PTSD as opposed to healthy human controls. Studying these changes may help us in furthering our understanding of PTSD and psychiatric anxiety disorders.

Sam Murdock (Neuroscience and Philosophy), Theories of theory of mind: Investigating the dimensions and supportive neural architecture of the “mentalizing module” (advisors Randy Buckner, Psychology/FAS & Susanna Siegel, Philosophy/FAS) -- Video Presentation
Many psychologists and neuroscientists have looked for empirical evidence to illuminate the “structure” that underlies cognition, while many philosophers of mind and computer scientists have approached the question using formal logic and theoretical models. In this thesis, methods from all these disciplines were synthesized to provide a comprehensive analysis of a candidate mental module: that which supports cognition for theory of mind. Using data from two tasks that involve cognizing about others’ mental states – the False Belief task and the Other Pain task–we conducted two experiments to investigate the behavioral dimensions and neural correlates of theory-of-mind-related cognition. In experiment one, we examined the domain of the theory of mind tasks with trial-level data from behavioral participants who identified cognitive strategies used during task performance. In experiment two, these strategies were correlated with trial-level functional magnetic resonance imaging (fMRI) data from different participants completing the same theory of mind tasks. This revealed that strategies related to Social Inference and Mind Attribution were most strongly and selectively predictive of activity in Default Network B(DN-B), a network in the association cortex that has been previously associated with theory of mind tasks. Further examination also revealed that some strategies were highly related to task condition and exhibited modified relationships with networks when conditions were analyzed separately. This investigation provides strong evidence for high domain-specificity in DN-B recruitment that is linked to task context, indicating that the network may support a functional module selectively involved in cognition of others’ mental states.

Jennifer Jeanette Near (Neuroscience), Associations between caregiver depression, caregiver-child play interactions, and early childhood social information processing: An fNIRS investigation (advisors Charles Nelson, HMS & Laura Pirazzoli, HMS) -- Video Presentation
Caregivers experiencing symptoms of depression –and similar expressions of emotional distress or low mood –exhibit significantly higher levels of disengaged and negative parenting behaviors than non-depressed caregivers. Quality of caregiving, along with the caregiver-child relationship, all influence a child’s brain and behavioral development; however, many of the underlying mechanisms of how this neurobiological embedding takes place remain elusive. The current study aims to explore the mechanisms determining deficits in the neural underpinnings of children’s social information processing due to compromised caregiver-child relationships. In this study, we used functional near-infrared spectroscopy (fNIRS) to assess neural responses to social and nonsocial stimuli in 2-year-old Bangladeshi children. Additionally, free-play sessions involving the caregiver and child were observed and coded for factors such as caregiver sensitivity, intrusiveness, and detachment. We evaluated the associations among the neural correlates of social information processing over the inferior frontal to posterior temporal cortices, caregiver-child interactions, and markers of caregiver depression assessed using the Childhood Psychosocial Adversity Scale (CPAS) via a proposed mediation model. Consistent with previous work, social discrimination to visual and auditory stimuli was observed over the inferior frontal and posterior temporal cortices. While no mediation was observed, findings suggest that further research centered on elucidating the relationships between caregiver depression and childhood socio-cognitive development in low-and middle-income countries (LMICs) is warranted, in order to begin developing targeted interventions that mitigate the risks of childhood exposure to caregiver depression.

Cole Petersen (Neuroscience), Investigating the protective role of FBXO17 in the integrated stress response of glioblastoma stem cells (advisor Christian E. Badr, HMS) -- Video Presentation
Glioblastoma Multiforme is the most common and deadly malignant tumor of the central nervous system, marked by invasiveness, self-renewal, and proliferation. It is resistant to surgical resection and chemotherapy, conferring a median patient survival time of 12-14 months. A subpopulation of Glioblastoma Stem Cells (GSCs) plays a significant role in both the tumorigenic traits and treatment resistance seen in Glioblastoma through their capacity to reduce and mitigate cellular stress. Through bioinformatics, we identified the poorly characterized F-box protein FBXO17 as a target that is significantly upregulated in Glioblastoma and whose potential as an agent of stress resistance is promising but unexplored. Through cell viability and immunoprecipitation, we determined that FBXO17 protects against activation of the Integrated Stress Response (ISR) in GSCs through Protein Phosphatase 2A (PP2A) dependent mechanisms. Using short-hairpin RNA knockdowns and HA-tagged overexpression plasmids, we altered FBXO17 expression in several GSC lines and treated with ISR activators. Using Western Blot and RT-qPCR, we found that FBXO17 expression alters the progression of the Integrated Stress response, altering global protein synthesis and protecting against otherwise pro-apoptotic effects. Further, we characterized Insulin growth factor-2 binding protein 3 (IGF2BP3) - which is only appreciably expressed in Glioblastoma and other cancers- as a translational regulator of FBXO17. We further demonstrate that FBXO17 can transcriptionally regulate IGF2BP3. We therefore provide evidence that FBXO17 protects against ISR in Glioblastoma by altering global protein synthesis and reducing apoptosis and hypothesize that IGF2BP3 could be a specific therapeutic target in Glioblastoma that sensitizes GSCs to treatment via FBXO17.

Charles Edward Reilly III (Neuroscience), The effects of gap junction-blocking drugs on the survival and behavior of larval zebrafish implanted with glioblastoma (advisor Florian Engert, Cellular and Molecular Biology, FAS) -- Video Presentation
Glioblastoma (GBM) is the most common malignant brain tumor in adults comprising almost half of malignant CNS tumors, and is accompanied by a grim 6.8% 5-year survival rate. GBM have neuron-glioma interactions which are augmented via gap junctional connections. These connections also confer chemotherapeutic resistance to the tumor, and as such, are a prime target for drug intervention. Studying GBM is difficult due to its location within the brain and its high mortality rate, so preclinical models of larval zebrafish have been developed. Larval zebrafish are favorable over in vitro studies of glioblastoma because larval zebrafish transplanted with GBM from a human tissue culture go on to develop disease that is characteristic of glioblastoma in humans, eventually succumbing to the tumor and dying. The effects, particularly behavioral effects, of gap junction blocking drugs have not been extensively studied in larval zebrafish. Using high-speed cameras to capture swimming activity, we have determined the behavioral and development effects of gap junction blocking drugs on healthy fish. We used flow cytometry to determine the apoptotic effects of gap junction blocking drugs in vitro. We began to characterize the effects of various gap junction blocking drugs on the survival and behavior of larval zebrafish with GBM, and we have begun developing a framework for the future study of drug discovery in larval zebrafish with GBM.

Allison Tu (Psychology), Examining intellectual safetyism: Developing a safetyism scale and characterizing its associations in a sample of college students (advisors Richard McNally, Psychology/FAS & Ben Bellet, Psychology/FAS) -- Video Presentation
Intellectual safetyism describes a rising movement across American colleges to shield students from ideas considered potentially emotionally harmful, curtailing free speech and stifling academic discourse. Though widely discussed because of its association with controversial topics, safetyism has not been clearly defined or understood. This study included the development of a scale to measure safetyism, which resulted in a measure with four subscales about the following topics: the belief that words can harm, the desire to avoid negative emotions, the motivation to protect others from emotional harm by limiting free speech, and the feeling of being most comfortable when surrounded by others with similar backgrounds. The scale was administered alongside measures to capture Moral Foundations, moral rigidity, personality, resilience, locus of control, meaning in life, empathy, demographics, prior adversity, and centralization of marginalized identity. The final safetyism scale and its associations indicate that safetyism may be a way to avoid emotional discomfort that is not concerned with the morality or practicality of a decision. Results also indicated that minority groups generally scored higher on safetyism than non-minority groups. The belief that words can harm and the desire to avoid negative emotions were most associated with constructs that lead to poor mental health compared with other subscales. Additionally, safetyism was largely not found to be associated with constructs that lead to better mental health. This research lays a foundation for future safetyism research and informs educational policy.

Jania Josette Tumey (Human Evolutionary Biology), An evolutionary perspective on contraceptive use and its role in global fertility decline (advisor Anke Becker, HBS) -- Video Presentation
Over the past two centuries, industrializing nations have experienced a remark-able convergence toward fertility rates near or below replacement level. Within the United States and other industrialized nations, the correlation between fertility and socioeconomic status has switched from positive to negative over the course of the demographic transition. This study investigates the contraception-driven evolutionary mismatch (CDEM) hypothesis of low fertility, which suggests that modern contraception is responsible for these dramatic changes in fertility patterns. The CDEM hypothesis proposes that by decoupling sex and reproduction, contraceptive use disrupts pathways that historically linked status attainment to reproductive success. Demo-graphic data from the National Longitudinal Survey of Youth 1979 Cohort (NLSY79) was analyzed to test multiple assumptions of the CDEM hypothesis. Income was found to be inversely associated with genetic fitness but positively associated with reproductive opportunity, supporting applicability of evolutionary mismatch theory to fertility decline. Furthermore, there was evidence that contraceptive use influenced some of the inverse relationship between socioeconomic status and fertility. However, the effects of educational attainment on reproductive success were more ambiguous, suggesting that various forms of status impact fertility behaviors differently in industrialized societies.

Peyton Williams (Human Evolutionary Biology), Tend-and-befriend stress response and chronic stress: social risks as effect modifiers of the relationship between social support and psychological well-being during the COVID-19 pandemic (advisors Anne Thorndike, HMS & Daniel Lieberman, Human Evolutionary Biology/FAS) -- Video Presentation
There is limited research on the tend-and-befriend stress response, a theory by evolutionary psychologist Dr. Shelley Taylor that claims women primarily respond to perceived stressors by tending to offspring and befriending others. This thesis aims to expand the tend-and-befriend theory using a more holistic, evolutionary framework that includes key aspects of humans’ inherent social nature. To do this, this thesis focuses on the befriend aspect of tend-and-befriend and uses the term ‘social support’ to broadly encompass this form of pro-social behavior. Specifically, this study investigated how gender, chronic stress, and social status influenced social support’s buffering effect on anxiety and depression outcomes, as well as the amount of stressors experienced during the COVID-19 pandemic, a global stressful event. Participants (age M = 43, SD = 11.4; 77.8% female; 46.2% Hispanic, 30.2% White, 9.5% Black) included 940 Medicaid and commercial accountable care organization patients from 5 community health centers in Boston, MA already enrolled in a longitudinal study evaluating the health impacts of a new Massachusetts social needs policy. Participants completed pre-pandemic (2019) baseline surveys on demographics, depression (Patient Health Questionnaire-8), anxiety (Generalized Anxiety Disorder-7), and social support (Medical Outcomes Social Support survey). One-year follow-up surveys assessed the same measurements taken at baseline, with the addition of questions on COVID-19-specific stressors experienced in the past 12 months. Regression modeling was performed to determine the effects of gender and various proxies for chronic stress and “lower” social status on social support buffering. The results found gender, immigrant status, and financial stress were effect modifiers of the relationship between social support, changes in depression, and COVID-19 stressor score. Compared to males, social support buffering on depression in females was reduced. Moreover, immigrants and participants moderately/severely financially stressed had reduced social support buffering capacities on COVID-19 stressor score and/or depression outcomes. This study suggests social support reduces poor mental health outcomes and the amount of stressors experienced during the COVID-19 pandemic; however, it also contradicts the tend-and-befriend theory by suggesting males have larger social support buffering effects. The results also emphasize how markers of low status (i.e., being an immigrant or financially insecure) relate to chronic stressors, contributing to a diminished social support buffering effect and highlighting a mismatch in human social dynamics. Further research is needed to validate these findings; nevertheless, these results call for the development of interventions focused on maximizing perceived social support and minimizing social risk factors.