Abstracts 2023

Abstract: The menopause is a critical midlife transition for women. It is a time of dramatic hormonal change as well as of characteristic symptoms, such as hot flashes, night sweats, sleep problems, and mood changes. This talk will present data that challenge the traditional notion that these menopausal symptoms are incidental, benign midlife symptoms, and instead indicate that they are linked to multiple indicators of cardiovascular and neurocognitive health. This presentation will also underscore the importance of considering key experiences earlier in life, such as exposure to trauma, the role of these early life exposures in the menopausal symptom experience, and their links to cardiovascular and brain health at midlife and beyond. The clinical implications of these findings will be discussed.

Beth Stevens

Harvard University

How Microglia and Neuroimmune Interactions Regulates Neuronal Plasticity Across the Lifespan

Abstract: Emerging evidence from genetic association studies shows that dysregulation of the brain’s immune system plays a key role in the onset and progression of age-related neurodegenerative disease. Our research aims to identify and validate disease mechanisms informed by human genetics and identify functional and mechanistic markers of myeloid and glial cells in detrimental states, before cognitive decline, that can be readily detected through imaging and fluid biomarkers. Using single-cell RNA sequencing, spatial transcriptomics and proteomic approaches we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. In addition, we identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.

UMass Faculty speakers

Lynnette Sievert

Dept. of Anthropology

Hot flashes in context: climate, biology, and culture

Abstract: Across populations, hot flashes are experienced during the menopausal transition as sudden, uncomfortable, sensations of heat. Declining levels of estrogen result in a narrowing of the thermoneutral zone – between temperatures that provoke shivering and sweating – and this narrowing contributes to an increased likelihood of hot flashes. Even small changes in core body temperature can induce sweating responses. We just completed a study of brown adipose tissue (BAT) in relation to hot flashes across four winters in western Massachusetts, and it appears that BAT activity significantly increased the odds of bothersome hot flashes (OR 2.65, 95% CI 1.19-5.91) after adjusting for menopausal status and body mass index. To identify universal aspects of symptom experience, we have asked the same questions about hot flashes across multiple countries (e.g., Slovenia, Paraguay, and Mongolia); across ethnic groups within the same country (e.g., Maya vs. non-Maya in Campeche, Mexico); and between Bangladeshi migrants, their new neighbors in London, and women still residing in Bangladesh. We have used ambulatory hot flash monitors in Hawaii and Mexico to show that some cross-population variation in hot flash frequency is due to differences in sensing, noting, and/or reporting symptoms rather than differences in underlying sweat physiology. By studying symptoms associated with menopause across multiple contexts, it has been possible to identify universal experience associated with hormonal changes as well as culture-specific variation. Differences in hot flash experience across populations are associated with norms related to women’s smoking habits, alcohol intake, physical activity, clothing, diet and weight, access to birth control and reproductive history, level of education and socioeconomic status, religious rituals, and sources of stress. The aim of this presentation is to place the physiology of hot flashes in a broader socio-environmental context.

Stephanie Padilla

Dept. of Biology

The hypothalamic response to sustained hormone depletion

Abstract: : Depletion and chronic loss of ovarian hormones is indicative of two physiologic states. Following menopause there is a terminal loss of follicle-derived steroid hormones. After birth, there is an acute and sustained depletion of ovarian hormones that lasts approximately 14 days and is sustained for an extended period in mothers that breast feed. The neuroendocrine response to these two states of hormone depletion, however, is wildly different. Our work investigates the role of the neuroendocrine reproductive axis in coordinated behavioral and physiological responses.

Jennifer Rauch

Dept. of Biochemistry & Molecular Biology

Insights into Mechanistic Drivers of Tauopathy Disease Progression

Abstract: Several neurodegenerative diseases, such as Alzheimer’s disease, are characterized by the spread and aggregation of the protein tau. Recently, we identified a cellular receptor, Low-density lipoprotein Receptor-related Protein 1 (LRP1), that regulates the tau spread pathway (Rauch et al., 2020). Knockdown of LRP1 prevents tau spread in human induced pluripotent stem cell-derived neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be a viable drug target for disease intervention. Unfortunately, a detailed understanding of the tau-LRP1 molecular complex is still lacking. Our lab is focused on deciphering the tau-LRP1 structural interface and discerning how tau aggregate structure can influence LRP1 processing. Further, we have taken a detailed look at how distinct post-translational modifications (PTMs) to tau’s structure can influence tau uptake and spread. We have developed protocols to express and purify tau and LRP1 proteins, and we are mapping the tau-LRP1 interface using covalent-labeling mass spectrometry. We have established cellular platforms to model tau propagation and have shown that this process can be influenced by tau aggregate structure and tau PTMs. We are specifically focused on understanding how modifications like phosphorylation and acetylation can impact the tau-LRP1 interaction and influence tau aggregation in cells. We propose that our work will provide the foundational groundwork for the development and evaluation of potential AD therapeutics.

Rauch, J.N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y.E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B.T., et al. (2020). LRP1 is a master regulator of tau uptake and spread. Nature 580, 381-385.

Joyita Dutta

Dept. of Biomedical Engineering

AI-Enabled Imaging for Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder and a looming public health challenge. Amyloid-β plaques and tau tangles, the two pathophysiological hallmarks of AD, are believed to play key mechanistic roles in AD and are potential therapeutic targets. This talk will discuss novel signal processing and artificial intelligence (AI) approaches that have great promise in AD diagnosis and prognosis. The first part of the talk will focus on AI-based positron emission tomography (PET) image enhancement. The key confounding factors compromising PET image quality are low spatial resolution and high noise. The talk will cover novel deep learning approaches for PET image super-resolution and denoising developed by us and demonstrate their applications to AD neuroimaging datasets. The second part of the talk will focus on the modeling of tau spread in AD. Tau tangles exhibit a stereotypical pattern of spatiotemporal spread which has strong links to AD progression and cognitive decline. Building on preclinical evidence which suggests that tau spread depends on neuronal connectivity rather than physical proximity between different brain regions, we have built a graph neural network model that enables individualized prediction of tau progression along the structural network of the brain. Using longitudinal tau PET data, we will demonstrate that our methods can accurately predict annualized differentials in regional tau.

Madalina Fiterau

College of Information and Computer Sciences

Forecasting Alzheimer’s Disease Two Years Before Onset from Longitudinal Multimodal Data

Abstract: Alzheimer’s disease (AD) is the most common form of dementia, causing progressive cognitive impairment, disorientation, and memory loss. Despite years of clinical trials, there is currently no cure for AD and, by the time of diagnosis, as much as 60% of brain matter is already lost. Thus, forecasting Alzheimer's disease years ahead of onset is critical for attempts at early treatment, the selection of subjects for clinical trials, and to facilitate neurologists’ study of the disease.

Posters Abstracts

1, Properties of rhythms from skin in SCN-ablated mice

Harrington, M, Buhr, E

Smith College

Might our skin provide an example of a peripheral circadian clock with unique properties? In particular, might skin be a directly photo-entrainable peripheral clock tissue? To begin studies addressing this question, we are characterizing the properties of bioluminescent rhythms in K14-Cre; DBP KI/+ male and female mice. We will present results from studies of SCN-ablated mice. Rhythms in bioluminescence are measured continuously over weeks from mice housed in a Lumicycle In Vivo (Actimetrics).

2, Impact of Traumatic Brain Injury on Sensory Neural Function, Behavior, and Neural Structure in C. elegans

White, H., Gorski, V., Holtz, D., Albrecht, D.

Department of Biomedical Engineering, Worcester Polytechnic Institute; Graduate School of Biomedical Sciences, UMass Chan Medical School

Traumatic brain injury (TBI) causes polymodal trauma leading to persistent changes in brain

function, behavior, cellular structure, and is a known risk factor for neurodegenerative disease. Current injury models correlate the presence and duration of injury conditions with animal behavior, but they do not reveal underlying effects on brain function at the cellular and subcellular scale. To identify underlying mechanisms relating acute brain injury with functional outcomes, we developed a scalable TBI model in nematodes to directly observe injury progression at behavioral, neurofunctional and structural levels. Previously, ultrasonic shock waves and vortex-induced blunt force trauma caused paralysis in thrashing animals, with broad population variability. We investigated ultrasonic cavitation as a repeatable and titratable TBI induction method using computer-controlled bath sonication. Video recordings during sonication revealed animals injured in post-array microfluidic devices were uniformly injured. Repeated assessment of neural function of up to 24 hours allowed examination of neurofunctional recovery. Using this platform, we identified sexually dimorphic outcomes in injury response and a channel inhibitor potentially modulating neural activity recovery. Overall, sonication-induced TBI provides repeatable assays for real-time, in vivo assessments of injury outcomes, enabling further study on mechanisms, progression, and potential therapies to minimize damage and enhance recovery.

3, Examining the impact of dog ownership in older adulthood on risk factors for dementia.

Chase CJ; Martini DN; Potter K

Department of Kinesiology; University of Massachusetts Amherst

Physical activity and social interactions resulting from dog ownership and dog walking may benefit older adults’ brain health and reduce dementia risk. However, the relationship between pet ownership and brain-level indicators of dementia risk in older adults, including brain structure and function, remains unknown. PURPOSES: The purposes of this study were to pilot methods for examining behavioral risk factors (physical activity and social interaction) for dementia, as well as to determine differences in cognitive function and brain health (structure and function) in older adult dog owners compared to non-dog owners. METHODS: Older adult participants (n=25; age 75[4] years; 60% female) completed two study visits, consisting of the National Institute of Health (NIH) Toolkit Cognitive Battery and a 45-minute MRI brain scan that included structural brain imaging. The primary cognitive outcome was the fluid composite score from the NIH Toolkit. Participants also wore an activPAL physical activity monitor (24 hrs/d) and logged all dog walking for 7 days. RESULTS: Non-dog-owner and dog-owner mean(SD) step counts were 7106.8(2989.5) steps/day and 8972.2(5650.3) steps/day, respectively. Dog owners took an average of 1865 steps/day more than non-dog-owners. 10/11 dog walkers reported having gotten to know people in their neighborhood as a result of their dog. Of those, 9/10 said they regarded someone they had met through their dog as a friend, and 9/10 received one or more types of social support through someone they had met through their dog. The fluid cognition composite scores for dog owners and non-dog owners were 55.6(8.8) and 58.0(7.1), respectively. There were no group differences in gray matter volume, white matter volume, left or right hippocampal volume, and left or right cortical thickness, when controlling for age, sex, education and total intracranial volume. CONCLUSIONS: This pilot study demonstrated the feasibility of these study methods, and will inform a larger, fully-powered study. If our hypotheses are supported, this research could inform dementia prevention programs and policies that leverage the human-dog bond, such as supporting dog ownership in older adulthood or developing behavioral and environmental programs that support dog walking.

4, Extensive neuropeptide gene expression in central and peripheral neurons of a nudibranch mollusc

Tait, Cheyenne C.; Ramirez, M. Desmond; Katz, Paul S.

Biology, UMass Amherst

Neuropeptides play a role in coordinating complex behaviors across taxa. In gastropod molluscs, many large, individually identifiable peptidergic neurons have been characterized. The process for identifying neurons has been slow and limited by the availability of specific markers. Here, we expanded the known number of peptidergic neurons in a gastropod nervous system by using in situ Hybridization Chain Reaction (HCR) to label gene expression in nudibranch, Berghia stephanieae. In addition to individually identifiable single neurons, we found classes of neurons in head ganglia and in the sub-epithelial neuronal plexus of the sensory appendages (oral tentacles and rhinophores). HCR probes for 10 neuropeptide genes were generated: conopressin, APGWamide, egg-laying hormone (ELH), small cardioactive peptide (SCP), feeding circuit activating peptide (FCAP), neuropeptide F (NPF), buccalin, FMRFamide, pigment dispersing factor (PDF), and CCWamide. Neuronal expression of these genes occurred in all head ganglia consistently enough to generate maps for each peptide. Conopressin neurons were the sparsest, while CCWamide neurons were the most prevalent. We also note specific, large, morphologically identifiable neurons that express three out of these ten neuropeptides. Some specific regions in the brain near nerves and commissures may be peptidergic hotspots, containing layers of small neurons expressing a multitude of neuropeptides. These results are a step towards mapping peptidergic neuronal types throughout the central and peripheral nervous systems, and ultimately determine the behavioral functions of diverse neuropeptides in this mollusc.

5, Silencing Sarm1 pathway improves survival and mitigates pathological TDP-43 and tau accumulation in a murine traumatic brain injury

Elif O. Dogan, MD, James Bouley, BA, Daryl A. Bosco, PhD, Nils Henninger, MD, PhD

Neurology Department, UMass Chan Medical School

Background: Traumatic brain injury (TBI) is one of the leading causes of adult death and disability and, a strong environmental risk factor for many neurodegenerative diseases that are characterized by the pathological accumulation of TAR DNA binding protein 43(TDP-43) and tau. SARM1 (sterile alpha and TIR motif containing) drives a cellular destruction pathway in several categories of neuronal injury including TBI. We and others previously demonstrated that blocking the SARM1 pathway suppresses neuronal injury after TBI. Here we sought to determine whether loss of SARM1 could attenuate TBI associated TDP-43/tau pathology and improve functional outcome in our moderate-to-severe mouse repetitive TBI (rTBI) model.

Methods: Sarm1+/+, Sarm1+/-, and Sarm1-/- mice were subjected to rTBI using a previously established paradigm. We serially assessed neurological deficit severity using the neurological severity score (NSS) from baseline to 1 month after rTBI. In addition, we assess the burden of impact seizures at 1-month survival. Quantitative histological assessment (n=9 per group) for neuronal (NeuN), axonal (MBP), neuroinflammatory (GFAP, IBA-1) markers as well as accumulation of phosphorylated TDP-43 (pTDP-43) and phosphorylated tau (AT8) was performed in non-overlapping cortical regions of interest in cortex (Bregma –1.67 mm) at 1-month after rTBI.

Results: Compared with Sarm1+/+ mice, Sarm1-/- mice had less severe neurological deficits (P=0.009), a lower burden of impact seizures (P<0.05, Chi-Square test), and improved survival (Log rank P=0.004). Moreover, they had significantly attenuated neuronal loss (P=0.009), axonal loss (P=0.018), and microgliosis (P=0.034), whereas there was no significant difference in the cortical GFAP signal between groups (P=0.26). Sarm1-/- mice had significantly fewer pTDP-43 positive cells (P=0.0003) and fewer pTau positive cells (P=0.012) in the cerebral cortex as compared with Sarm1+/+ mice. While the extent of

neuronal and axonal loss was not significantly reduced in Sarm1+/- mice (p>0.05, each), we found that Sarm1 haploinsufficiency significantly attenuated the number of cortical cells containing pTDP-43 (p=0.0002) and pTau (p=0.021)

Conclusions: Genetic ablation of SARM1 attenuated neurological deficit severity and neuropathology after moderate-to-severe rTBI. Our study first to show that Sarm1-/- may also attenuate injury-associated seizures, improve survival, as well as suppress pathological pTDP-43 and pTau accumulation. These observations suggest that targeting SARM1 may be a promising strategy to improve outcome after moderate-to-severe TBI. Further study is required to understand the role of Sarm1 in TBI-associated neurodegenerative diseases that are characterized by TDP-43 and Tau pathology.

6, Characterizing the LRP1 sheddome, a driver of neuroinflammation

Nulman, J.; Montes, J.M.M.; Rauch, J.

Biochemistry & Molecular Biology, UMass

Alzheimer’s Disease (AD) is the most common form of dementia. It accounts for 44 million cases worldwide, a number expected to triple by 2050 (Li et al., 2022). The formation and spread of aggregates of the protein Tau known as neurofibrillary tangles (NFTs) have been linked to pathology in AD and other neurodegenerative diseases, termed tauopathies. Recent evidence suggests that Tau pathology results in chronic neuroinflammation that further amplifies cytotoxic Tau pathology in a positive feedback mechanism (Pascoal et al., 2021). The low-density lipoprotein receptor-related protein 1 (LRP1) plays a central role in Tau uptake and spread (Rauch et al., 2020). LRP1 has more than one hundred known ligands, some of which have been shown to cause the proteolytic shedding of its ectodomain. This process, termed ‘LRP1 shedding’, results in a potently pro-inflammatory soluble moiety, soluble LRP1, or sLRP1 (Brifault et al., 2017). However, the role of LRP1-shedding in AD-associated neuroinflammation and the shedding-inducing capabilities of many LRP1 ligands, including Tau, remain unknown. Thus, the LRP1 sheddome represents a significant gap in knowledge as the Tau-LRP1 interaction may be an enticing therapeutic target to reign in neuroinflammation in AD and other tauopathies. Here, I present a novel luminescence-based approach to characterize the shedding-inducing capabilities of LRP1’s many ligands. This assay can be further optimized for higher-throughput modalities or to characterize the ectodomain shedding events of other AD-associated receptors such as TREM2.

7, Neuronal mapping in the head ganglia of a gastropod mollusc using single cell transcriptomics

Ramirez, MD; Bui, TN; Katz, PS

Biology, UMass Amherst

Neuroscience research on gastropod molluscs has provided important insights into neural circuit function, focused primarily on large identifiable neurons in the central ring ganglia (CRG). However, these efforts ignored many smaller cells not amenable to sharp electrode recording and relied on low-throughput techniques to look at neuronal gene expression. Here we use 10x Genomics single-cell sequencing to create transcriptomes for about 2000 cells across the entire brain of the nudibranch, Berghia stephanieae, including the CRG and the peripheral rhinophore ganglia (RhG). Cell types were distinguished based on similarity clustering and differential gene expression. Most RhG neurons form two distinct clusters, marked either by nitric oxide (NO) synthase, or the NO receptor, soluble guanylate cyclase. Other neuron types include likely mechanosensory afferents, expressing Brn3, and somatic efferents, expressing Lhx1 and ChAT. Putative differentiating neurons express neural differentiation genes like Sox6, Scratch1, and neurogenin. We also found marker genes for putative glia in molluscs, which are still mostly unknown. We mapped gene sets for neurons in the brain by multiplexing fluorescence in-situ hybridization chain reaction. Neurotransmitter and neuropeptide classes were identified, uncovering general rules of neurotransmitter phenotypes. Some genes had widespread expression, including CCWamide. Others, including the transcription factor Six6, define particular zones of neurons or specific ganglia. Large numbers of unannotated genes were expressed in specific neuron types, showing that lineage-specific genes should not be disregarded when characterizing cell types. The results provide insight into the organization and identity of gastropod neurons and provide the basis for future large-scale neural research on Berghia.

8, A connectomics approach to an enigmatic ganglion in a gastropod mollusc

Sant H, Drescher B, Meirovitch Y, Schalek R, Wu Y, Lichtman J, Katz P

Biology Dept, UMass Amherst

The central nervous system (CNS) of nudibranchs and other gastropod molluscs are well known for their large identifiable neurons. In addition, there are peripheral ganglia that contain much smaller neurons of unknown identity and function. Here, we took a connectomics approach to determine the structural organization of neurons in the rhinophore ganglion (RhG), which sits at the base of the rhinophore, the chemosensory appendage, in the nudibranch, Berghia stephanieae. Based on its position, the RhG should be analogous to the antennal lobe of insects or the olfactory bulb of vertebrates. However, the neuronal architecture and connectivity of the RhG is unknown. To address this, we serially sectioned an entire RhG at 33 nm thickness and completed imaging each of the 2175 sections at 4x4 nm lateral resolution. We determined that the RhG contains around 9000 neuronal somata, which is almost twice as many neurons as the rest of the brain. The somata ranged from 5 to 15 µm in diameter. The RhG had a variety of regions including distinctive clusters of somata, neuropil, and axon tracts. The axon tracts were separated by glial cells, which were often associated with exosomes. Some axons traversed the ganglion without synapsing. Neurons had unique ultrastructural features including large membranous particles, different staining densities, vesicles of varying sizes, and vesicle-free neurites. We found some neuronal somata that projected an axon into the nerve connective to the cerebral ganglion. This connective contained about 30,000 axons, some as small as 90 nm in diameter. We are applying machine learning algorithms to automatically segment all the cells and neuronal processes intrinsic to and coursing through the RhG to provide a first draft of the connectome. A complete connectome of this ganglion will provide insights into the structural organization of this enigmatic ganglion, which is likely to be involved in higher order olfactory processing in this mollusc.

9, Visual object categorization in the jumping spider brain

Winsor AM; Remage-Healey L; Hoy RR, Jakob EM

Biology (Organismic and Evolutionary Biology)

Many animals use visual information to rapidly classify objects into appropriate categories such as prey, predators, or conspecifics. Important questions include whether animals use particular features or combinations of features to identify objects, and where in the brain these features are extracted. We explore these questions in the modular yet highly integrated visual system of jumping spiders (Araneae: Salticidae). Salticids have eight eyes with complementary functions. The secondary eyes serve as motion detectors with wide fields of view, while the forward-facing principal eyes are capable of high spatial resolution and color vision. The principal-eye retinas have narrow visual fields, but are situated at the back of moveable tubes that enable scanning motions to examine objects. In Phidippus audax, we simultaneously monitored gaze direction using our custom-built eyetracker while also collecting the first reported in vivo dual extracellular recordings of both lower and higher-order protocerebral neuropils. We presented spiders with a randomized stimulus set of abstract and ethologically relevant holistic objects, including views of prey, conspecifics, heterospecific salticids, predators, and unpalatable prey. We also presented images with stepwise reductions of complexity that distill objects into their elemental components to parse whether spiders respond to local visual features or global object structure. Our results across nine subjects show that multi-unit activity within both the lower-order principal-eye lamina and higher-order arcuate body brain regions are strongly driven by images of palatable prey and suppressed by images of unpalatable prey, compared to the baseline firing rate. We have begun sorting single units and detected a ~68% neuronal activation when the spider viewed palatable prey, and a ~72% neuronal suppression when the spider viewed unpalatable prey. Furthermore, our data suggest that relatively simple features are extracted for recognition. Ongoing analyses examine responses within stimulus categories and to their simpler image components, and correlations between retinal exploration of images (using DeepLabCut) with neural activity. To further inform this work, we are conducting behavioral trials to test whether we can predict spider behavioral responses to stimuli from their neural responses. In summary, our work reveals neural correlates of prey categorization in a highly visual and behaviorally complex predator.

10, Rescue Effect of Acyclovir in HSV-1 Infection-associated Alzheimer’s Disease Markers

Samantha Chigas 1-4†, Pepper Dawes1-4†, Liam Murray1-4†, Adrian Orszulak 1-4†, Meagan Olson1-4, Khanh Tran1-4, Nathaniel Barton1-4, Rigel Chan1-3, Elaine Lim1-4

Massachusetts Chan Medical School

† These authors contributed equally

Our objective is the examination of the relationship between Herpes Simplex Virus 1 (HSV-1) and Alzheimer’s disease (AD) through the quantification of expression & protein isoform perturbations, as well as the investigation of potential drug therapies. Multiple herpesviruses have been linked to increased likelihood of AD, suggesting microbial involvement in the disease’s development. HSV-1 has high prevalence (>65% of Americans are seropositive) & has been shown to cause AD-like changes in in vitro models. We employed ELISA assays & transcriptomic technologies to further investigate this relationship in the context of cerebral organoids (cOrgs). We developed infection protocols employing HSV-1, HSV-1 with the antiviral acyclovir (ACV), ultraviolet inactivated HSV-1, and/or Influenza A (IAV). Supernatant samples were collected from an infection protocol specialized to increase protein concentration. ELISA assays for amyloid beta (Aβ) isoforms 38, 40, & 42 were run on these samples. Bulk RNA sequencing was performed to examine the impact of infection & treatment. ELISA assays found a decreased ratio of Aβ42 versus Aβ40 concentration in HSV-1-infected samples, indicative of AD. Notably, not only was such a decrease not observed in IAV-infected samples, but HSV-1-infected samples treated with ACV also exhibited no significant decrease. Principal component analyses of HSV-1-infected cells from cOrgs reveal transcriptomic variation that is not shared in HSV-1-infected hiPSCs. This is further corroborated by differential expression analysis results demonstrating AD specific GWAS-associated gene perturbation in cOrgs but not in hiPSCs or SH-SY5Y differentiated neurons, pointing to a potential cell type specific effect in AD-associated DEG response. Similar AD specific enrichment was not found in our DE analyses of IAV infected cOrgs versus control cOrgs. ACV-treated HSV-1-infected cOrgs show transcriptomic rescue of AD-associated genes compared to control samples. However, replication data did not show the same rescue effect except in ACV treated infected samples compared to samples treated with UV-inactivated HSV-1, which we hypothesize, due to much higher HSV-1 viral transcript counts in replication data, may point to ACV treatment dependent response. Our results contribute to the growing body of work evincing the relationship between HSV-1 & AD, specifically by interrogating the genomic effect across diverse cell types.

11, Confirming Unbiased Antigen Screening of MS Patient CSF Using Cerebral Organoid Models

Barton N*, Olson M*, Tran K*, Chigas S, Dawes P, Murray L, Orszulak A, Ionete C, Hemond C, Lim E, Chan R

Department of Neurology, UMass Chan Medical School

Multiple sclerosis (MS) is a prevalent and chronic autoimmune disease characterized by the accumulation of demyelinating lesions that occur in the white matter and the grey matter of the brain and spinal cord. Recent studies have established a strong association between MS and Epstein-Barr virus (EBV), suggesting that EBV infection may trigger the production of cross-reactive antibodies, resulting in a neuroinflammatory response. We performed an unbiased antigen screen of 210 cerebrospinal fluid (CSF) samples to verify published results related to EBNA1 and to discover novel viral and autoimmune epitopes. Consistent with current literature, we showed that EBNA1400–429 is significantly associated with MS (FDR = 0.031) and determined an additional MS-associated epitope at EBNA1147-165 (FDR = 0.008). In addition to confirming EBNA1 autoantigenicity, our screen identified 8 additional viral proteins and 13 human proteins associated with MS. To replicate our findings with a human cerebral organoid model derived from a control individual, we first confirmed the presence of oligodendrocytes in the cerebral organoids using flow cytometry with the biomarkers O1, O4, and OLIG1 with respective positivity of 80%, 76%, and 23%. We seek to confirm the results of the antigen screening by using ELISA essays to examine the interaction of EBNA1-specific antibodies, as well as the other MS-associated viral and human proteins identified from the screen, and quantify their concentration within CSF samples from MS patients and controls. We predict that the CSF samples from MS patients will show more antibody positivity than non-MS CSF samples in our ELISA assays. Additionally, we aim to understand the effect of MS-associated antibodies on neural cell types by applying CSF samples from MS patients or controls to cerebral organoids and observing changes in cell type populations with flow cytometry. We expect oligodendrocyte cell markers to decrease in our brain organoids in response to MS patient CSF being applied, due to antibodies targeting the myelin sheath. Our study aims to uncover novel viral and autoimmune epitopes related to MS and shed light on the mechanisms underlying MS pathogenesis, including the role of EBV. These findings may facilitate the development of targeted immune therapies and enable early identification of MS at-risk individuals.

12, Westborough High School Mental Health Predictive Analyses

Lo, Wesley; Nephew, Benjamin C; Rodriguez, Angela C; Korkin, Dimitry

Worcester Polytechnic Institute

With the rise in mental health challenges over the years, especially in student populations, the need to develop targeted diagnostic and treatment tools has increased. Given the substantial research to highlight the tremendous variation in mental health symptomology, efforts to develop intervention strategies may benefit from insights into the individual. In this study, we investigate the predictive capabilities of random forest classifiers (RFC) in prediction of mental health risk scores in mental health data from the Westborough High School. Our results show variation in mental health outcomes across different student populations and underscore the need for personalized interventions over a one-size-fits-all approach.

13, Maternal circadian desynchronization disrupts sleep and prefrontal cortex function in adult offspring

Roberts B; Cupertino N; Sorensen W; Karatsoreos N

Department of Psychological and Brain Sciences, University of Massachusetts – Amherst

Sleep and circadian (daily) rhythms impact nearly all aspects of physiology. As such, perturbations in sleep and deviations from natural light/dark cycles influence epigenetic, cellular, and behavioral processes. These disruptions lead to metabolic disorders, neuropsychiatric illness, increased stress, and cognitive dysfunction. The prefrontal cortex (PFC) regulates stress, fear responses, cognition, and learning and memory. Our lab has previously shown that environmental circadian desynchronization (ECD) alters PFC associated behaviors, and both the anatomical structure and neurophysiological function of PFC neurons. The PFC undergoes significant development in utero and early life, and environmental disturbances during this period can have significant long-term ramifications. Notably, sleep disruption of mothers and offspring during this time is all too common. However, few studies have focused on the long-term outcomes of maternal circadian disruption. Using a mouse model of ECD developed in our lab, we determined how maternal ECD (mECD) modulates sleep in adult offspring by measuring sleep/wake using a novel non-invasive piezoelectric sleep recording system. Given our recent reports on how ECD impacts mPFC structure/function, we also determined how mECD impacts PFC neural function in adult offspring with ex vivo patch-clamp electrophysiology, exploring how mECD impacts resting membrane properties, and action potential dynamics. Together, these experiments form the foundation for future studies to understand the lifelong neurobehavioral impact of mECD.

14, Neuroimmune responses to an intranasal virus-like stimulus are primed by time of day

Pearson G; Falcy B; Wang J; Santos N; Gottwals S; Denaroso G; Akli S; Karatsoreos I

Neuroscience and Behavior, UMass Amherst

BACKGROUND. The neuroimmune mechanisms underlying resilience to neurotropic infections are not well understood. We have shown that time of day of exposure to a neurotropic virus impacts survival, suggesting that time of day can be used to elucidate mechanisms of resilience to neurotropic viruses. Here, we investigate how time of day impacts neuroimmune responses of the olfactory bulb, the site of neurotropic virus entry into the brain. Our preliminary work demonstrated that 30% of the olfactory bulb’s neuroinflammation-related transcriptional profile is rhythmically expressed, including transcripts enriched in anti-viral and microglia function pathways. Given these transcriptional oscillations, we hypothesized that time of day would prime the olfactory bulb to mount differential anti-viral and microglial responses to an intranasal poly(I:C) challenge.
METHODS. First, we intranasally challenged male mice at resting phase onset (ZT0) or active phase onset (ZT12) with poly(I:C) and collected tissues at 3-, 12-, and 24-hours post-inoculation (n = 4 mice/inoculation ZT/collection time, N = 24). Olfactory bulb transcriptional responses were measured using NanoString technology. Second, we intranasally challenged male mice with vehicle or poly(I:C) at ZT0 or ZT12 (n = 4 mice/inoculation ZT/treatment, N = 16). We then isolated olfactory bulb microglia at 24 hours post-inoculation and used imaging flow cytometry to analyze microglia.

RESULTS. First, we demonstrated that time of day alters the trajectory of the olfactory bulb’s transcriptional response to intranasal poly(I:C). Specifically, we observed upregulated anti-viral pathways by olfactory bulbs of ZT12 challenged mice at both 12- and 24-hours post-inoculation. Conversely, the olfactory bulbs of ZT0 challenged mice did not have significant upregulation of anti-viral pathways until 24 hours post-inoculation. These data suggest that the olfactory bulb’s response to intranasal poly(I:C) at ZT12 occurs faster than the response to intranasal poly(I:C) at ZT0. Second, we observed a greater change in CD11b surface expression by OB microglia following intranasal poly(I:C) at ZT12 compared to ZT0.

CONCLUSION. We conclude that time of day primes the olfactory bulb to differentially mount neuroimmune responses to intranasal inflammatory stimuli, providing a potential gating mechanism underlying resilience to neurotropic virus exposure.

15, The Impact of Lysine Acetylation on the Tau-LRP1 Complex and Tau Propagation

Caiqin Wang, Jennifer Rauch

MCB, UMass Amherst

The spread and aggregation of the protein tau has been linked to a variety of neurodegenerative diseases including Alzheimer’s disease (AD). A growing body of evidence suggests that aggregated tau spreads throughout the brain via cell-to-cell transmission, termed “seeding”, in a prion-like manner (Iba et al., 2013, Clavaguera et al.,2009, Guo et al., 2016). High resolution quantitative mass spectrometry has provided new correlative data on tau PTMs in disease progression (Wesseling et al., 2020). We have preliminarily shown that lysine modifications can influence tau endocytosis, but it is still unclear if this phenotype is dependent on LRP1. LRP1 binding proteins have previously been reported to use lysine motifs to interface with LRP1. We have mutated several lysine residues (K to A) on tau’s MTBR and have found that there are indeed potential “hotspots” that are important for tau endocytosis. Intriguingly, one of these sites (Mut5: K311, K317) is highly modified in AD brains[3]. In this study, we will examine how lysine acetylation influence the interaction between tau and LRP1, and the ability for tau to aggregate in vitro and in cells.

16, Impact of traumatic brain injury on glial and neural function in the hippocampus

Dougan CE, Roberts BL, Karatsoreos IN, Peyton SR

Chemical Engineering Umass

Traumatic brain injury (TBI) is linked to increased risk for a variety of neurodegenerative diseases including dementia, Alzheimer’s disease, and chronic traumatic encephalopathy (CTE). Precise models for understanding how TBI impacts brain function and repair are lacking. Using needle-induced cavitation (NIC), a needle is inserted into the hippocampal region of a mouse brain slice, fluid is pressurized until a bubble injury occurs, and pressure is monitored in real-time to relate NIC forces with the extent of injury. We demonstrate that NIC consistently results in tissue damage and astrocyte activation without complete tissue destruction. Astrocyte activation leads to the secretion of glial fibrillary acidic protein (GFAP) and extracellular matrix (ECM) proteins, such as tenascin-C (TNC), thrombospondin (TSP), and connective tissue growth factor (CTGF), which promote inflammatory responses and neural repair. Immediately post-injury, GFAP is prominently expressed near the injured region, and continues to be expressed two days post-injury. There is a higher expression of ECM proteins two days post-injury. We observe that synaptic function decreases significantly after injury, but recovers within minutes to or above baseline activity. NIC provides a valuable method to study real time neuronal response to small scale injuries that can elucidate the acute sub-concussive pathways involved in mild traumatic brain injury.

17, Precise spatiotemporal identification of amygdala neurons active during sensorimotor gating

Wanyun Huang; Karine Fenelon

Biology, UMass Amherst

Prepulse inhibition (PPI) of the acoustic startle reflex refers to the inhibition of a startle response when a weak stimulus (“prepulse”) is presented prior to an alarming stimulus (“pulse”). PPI is a standard operational measure of sensorimotor gating. As a hallmark of schizophrenia, PPI impairments are also found in other neuropsychiatric disorders and are associated with cognitive overload and attention deficits (Braff et al., 2001). Therapeutic advances are limited by the gap in our knowledge of the PPI underlying neuronal circuitry. In fact, the currently used dopaminergic-based antipsychotics have shown inconsistent effects on PPI in affected individuals (Frau et al., 2014).

Previous stimulation and electrophysiological studies showed that giant glutamatergic neurons located in the brainstem Caudal Pontine reticular nucleus (PnC) mediate the startle response (Lengenhöhl and Friauf, 1992). The PnC neuronal population includes both giant glutamatergic neurons and glycinergic neurons (Koch and Friauf, 1995; Rampon et al., 1996; Zeilhofer et al., 2005) which receive various glutamatergic inputs. We recently showed that the central nucleus of the amygdala (CeA) contributes to PPI by sending glutamatergic inputs to PnC glycinergic neurons (Cano et al., 2021). But the CeA neurons active during PPI remain unknown.

To answer this question, we used Cal-light, a calcium-dependent and blue light-sensitive method that enables the identification and manipulation of active neurons during a given behavior (Lee et al., 2017). By delivering Cal-light viral components to the CeA of wildtype mice (n = 3), we were able to identify a specific subset of CeA neurons (accounting for 13.1% of total neurons in the CeA) active during PPI, because upon calcium entry and in the presence of blue light, these neurons became green fluorescent. Since Cal-light targeted CeA neurons also expressed the inhibitory optogenetic tool Halorhodopsin sensitive to yellow light, photo-inhibiting these neurons with yellow light yielded a 25.1-52.8% reduction in PPI level measured at various interstimulus intervals between the prepulse and the pulse. Overall, our results confirm that CeA-PnC synapses contribute to PPI and Cal-light allows us to identify the CeA neurons involved, with high spatiotemporal resolution. Our findings provide critical insights toward identifying potential therapeutic targets for diseases associated with PPI deficits.

18, Development of a Platform for Non-Invasive Electrical Stimulation in C. elegans

Kamara, V; White, H; Badley, D; Alrecht, D

Biomedical Engineering, Worcester Polytechnic Institute

We developed a platform for electrical stimulation of C. elegans to characterize how deep brain stimulation alters the excitability of neurons. The dynamic variation of stimulation parameters caused transient increases and decreases in neural excitability that were both rapid and repeatable. Further alteration of system parameters, including frequency and polarity of stimulation, allow for optimization of techniques employed by various stimulator devices on the market and investigation of their physiological consequences.

19, Experimental and Computational Analysis of Interstitial Flow After Spinal Cord Injury

Kwon H; Cornelison R

Chemical Engineering, Engineering University

Purpose

Approximately 17,000 people sustain a spinal cord injury (SCI) in the U.S. each year, and over a quarter million Americans currently live with paralysis due to SCI. Injury severity and functional deficits due to SCI correlate with the extent of fluid accumulation (i.e., edema) occurring immediately after injury. Previous studies showed fluid pressure around the injured spinal cord (supraspinal) remains elevated for at least three days and contributes to a phase of tissue damage known as secondary injury. While neural cells will more directly interface with fluid within the spinal cord (interstitial), it is currently unknown how SCI affects interstitial fluid pressure and if interstitial forces also contribute to secondary injury. We use a combination of in silico and in vivo models to address these questions. Understanding the contributions of fluid forces and flows after SCI may enable strategies to limit tissue damage and functional deficits after SCI.

Methods

We developed an in silico model to simulate interstitial flow after SCI using COMSOL Multiphysics and the porous medium module. We obtained the flow parameters of white matter from literature and set the initial and boundary conditions based on literature or experimentally determined values. The simulation of white matter and grey matter was conducted separately because the flow calculated in the grey matter would mask the flow in white matter due the difference in diffusion rate. For in vivo validation, Sprague-Dawley rats (8-10 weeks) were anesthetized and subjected to a cervical C4 hemi-contusion using an Infinite Horizons spinal cord impactor. Intraspinal pressure was measured at 1 hour, 3 days, and 7 days after injury using a catheter-based pressure sensor from ADinstrument. To label flow pathways in vivo, Evans Blue dye was injected in the tail vein 24 hours prior to tissue harvest at 3 days and 7 days post injury (dpi). In a separate cohort, we used the technique of convection enhanced delivery (CED) to exogenously enhanced interstitial flow after SCI. The spinal cord was re-exposed 7 days after injury, and a blunt-end 27-gauge catheter was used to deliver 5 µL of sterile saline at 1 µL/min, or three times the physiological rate of interstitial flow. The tissue was harvested three days later, cryosectioned at 20 microns, and stained with Luxol Fast Blue for stereological lesion volume quantification.

Results and Discussion

We find interstitial pressure increases from negative three mmHg to positive eight mmHg at 1 hour post injury, further increases by 3 days post injury, and plateaus near one mmHg after 7 days. This is similar to how the supraspinal pressure increases to 8 mmHg for the first hour post injury. The supraspinal pressure peaks at 12 mmHg for 3 dpi, then plateaus close to zero by 7 dpi. We used reported and measured pressure values to develop a 3D in silico model to interrogate pressure effects on interstitial fluid velocity after hemi-contusion SCI. For an idealized spherical injury, COMSOL simulations predict heightened flow out of the cavity and towards the center of the uninjured white matter, with higher flow velocities at 3 dpi versus at 7 dpi. To validate the model, we used Evans Blue dye to label in vivo fluid flow pathways after SCI. We show that, while the lesion size might be smaller at 3 days post injury, there is more dye transport out of the injury cavity and into adjacent uninjured tissue compared to the 7 days post injury timepoint. These results align with the pressure measurements and the model simulation results. Finally, we find adding flow increases lesion size after SCI, determined by increased volume of demyelination by Luxol Fast Blue staining.

Conclusion

Our results show traumatic injury causes an immediate and drastic increase in interstitial pressure in the spinal cord, which only resolves by 7 days after injury. COMSOL simulations suggest this increase in interstitial pressure drives elevated interstitial flow velocity into the tissue around the original lesion, which was confirmed by Evans Blue dye extravasation in vivo. Using convection enhanced delivery, we show that a significant increase in interstitial flow increases secondary spinal cord injury and the resulting lesion size. In the future, we can build on this knowledge to explore the mechanisms of how increased flow causes cellular death and potentially identify therapeutic targets for neuroprotection.

20, Identification of neural proliferative zones in juveniles of the gastropod mollusc, Berghia stephanieae

Kang M, Sant H, Katz P

Biology, UMass Amherst

Neural proliferative zones are the places where new neurons are added to the brain and nervous system. In humans, there is little neurogenesis (generation of neurons) after birth and what there is, occurs in discrete brain regions. However, the gastropod mollusc Berghia stephanieae shows extensive neurogenesis throughout its life. To better understand where neural proliferative zones are located in Berghia, we performed immunohistochemistry on juvenile Berghia of varying ages to identify neural progenitor cells. The animals were fixed, treated, and imaged using fluorescence confocal microscopy and analyzed using FIJI software. As an organism ages, neurogenesis is thought to decrease, we therefore expected there to be more proliferation during the earlier stages of juvenile development and for neural proliferation to diminish as the organism develops into an adult. We found that as juvenile Berghia develop, neurogenesis in the brain decreases suggesting there may be other mechanisms at work responsible for the addition of new neurons into the Berghia nervous system Ultimately this project can help further elucidate how nervous systems may have evolved and further the understanding of how neurogenesis occurs. Understanding neurogenesis in juvenile Berghia could lay the foundation for future research on neural stem cells and progenitors and how they could be activated in the mammalian brain.

21, Effects of Race on Chronic Pain in a Randomized Clinical Trial of Integrative Medical Group Visits

Polcari, J.J.; Incollingo Rodriguez, A.C. PhD; Nephew B.C. PhD; Melican, V.; King J. PhD; Gardiner, P. MD MPH.

Department of Biology & Biotechnology, Worcester Polytechnic Institute

Chronic pain is one of the most common reasons adults seek medical care in the US, with estimates of prevalence ranging from 11% to 40% and relatively higher rates in diverse populations. Mindfulness meditation has been associated with significant improvements in pain, depression, physical and mental health, sleep, and overall quality of life. Group medical visits are increasingly common and are effective at treating myriad illnesses including chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence based integrative medicine, and medical group visits and can be used as adjuncts to medications, particularly in diverse underserved populations with limited access to non-pharmacological therapies. The objective of the present study was to assess the effects of race on the primary pain outcomes and evaluate potential relationships between race and additional patient

characteristics in data from a randomized clinical trial of IMGV in socially diverse, marginalized patients suffering from chronic pain and depression. It was hypothesized that there would be racial differences in the effects of IMGV on pain outcomes. Our analyses identified significant

racial differences in the response to IMGV. Black subjects had increased pain severity throughout the duration of the 21-week study but were less likely to respond to the pain intervention compared to White subjects. These results may be related to differential comorbidity rates, catastrophizing, and digital health literacy among these participant groups. To improve patient outcomes in similar studies, interactions between pain outcomes and these factors require further investigation to affect levels and trajectory of pain severity and enhance the response to complementary interventions.

22, Cue reactivity in vivo: Links between GPS-based real world cue exposure, neural cue reactivity, and daily eating behaviors among teenagers

Lopez R; Moughan E; Wagner D; Browning C; Bai P; Boettner B; and Way B.

Department of Social Science and Policy Studies, Psychology and Neuroscience Programs, WPI

Previous neuroimaging research has identified robust neural correlates of reward, regulation, and valuation in the eating and drug domains, with regions such as ventral striatum and orbitofrontal cortex reliably activating to appetitive cues to promote eating and drug-seeking behaviors, while other regions such as dorsolateral prefrontal cortex (DLPFC) serving more regulatory functions to help curb consummatory behaviors. However, relatively little is known about people's incidental exposure to appetitive cues in their immediate physical surroundings (e.g., neighborhoods) and how such exposure might shape neural cue reactivity and subsequent self-regulatory behaviors. This would be especially useful to examine in adolescents, a group whose self-regulatory processes are still in flux, partly due to immature PFC development. In the present study, we conducted preregistered analyses in a large sample of teenagers residing in the Columbus, Ohio area (N=272, 148 Female; Mean age=15.43, SD=2.09) who participated in a longitudinal study that employed GPS tracking, an fMRI scanning session that included a cue reactivity task, and ecological momentary assessment to capture daily self-regulatory behaviors.

Preliminary findings demonstrated that acute exposure to appetitive cues in daily life is associated with altered neural cue reactivity. Specifically, there was an overall positive relationship between participants' idiosyncratic food exposure (within 500m of daily walking paths) and whole-brain pattern expression reflecting cognitive control. Next, greater expression of this pattern was associated with more resistance to daily food desires. Notably, these relationships were driven by adolescent females (vs. males), indicating that this group may experience real world appetitive cues as signals to regulate, which is consistent with previous theorizing on counteractive self-control. Moreover, these effects were observed with a whole-brain pattern expression measure (vs. activity in individual ROIs), suggesting that self-regulatory processes as they occur in daily life may be instantiated across disparate systems in the brain. Future studies can replicate and extend the present work by taking a similar, integrative approach combining GPS measures, brain imaging, and EMA to further elucidate neural mechanisms by which real world exposure to appetitive cues can hamper—or help— one's attempts to regulate eating behaviors.

23, Does Additional Training on an Explicit Motor Sequence Task Improve Sleep-Dependent Memory Consolidation For Older Adults?

Delvey, C.; Cortina, L.; Spencer, R.M.C.

Psychological and Brain Sciences, UMass Amherst

While sleep has been shown to improve memory performance, not all memory domains have demonstrated this effect, particularly in older adults. Prior studies have shown that hippocampal engagement is necessary for sleep to show improved memory consolidation when compared to wake. Procedural memory, where improvements must be demonstrated rather than recited, is believed to engage other areas, namely the cerebellum, frontal lobes, and striatum, and thus has inconsistently demonstrated sleep-related gains. However, prior literature has shown that awareness of a pattern or sequence enables skill-learning benefits of sleep by engaging the hippocampus. Moreover, strong learners may also engage the hippocampus, increasing the possibility of sleep-related procedural memory gains. In an ongoing study, we use an explicit serial reaction time task, during which participants are made aware that there is an underlying sequence of button presses, and we recommend that they try to learn what it is. We will compare the change in performance before and after an interval spent awake to that of an interval spent asleep. Finally, we will compare performance in older adults who receive additional task training to those who receive a standard amount of training. We predict that the additional practice will provide an opportunity for greater hippocampal engagement during encoding, thereby improving the chances that older adults will demonstrate sleep-related memory gains which are not found after standard training.

24, The Chilean brush tailed mouse (Octodon degus): a diurnal precocial rodent as a new model to study visual receptive field properties of superior colliculus neurons.

MÁRQUEZ N.I., FERNÁNDEZ-ABURTO P., DEICHLER A.R., PERALES I., LETELIER J.C., MARÍN J.C, MPODOZIS J., PALLAS S.L.

Department of Biology, UMASS

The midbrain superior colliculus (SC) is responsible for a variety of visually driven behaviors such as gaze shifts, orientation toward objects of interest, and defensive responses to looming objects. Neurons from the superficial layers of the SC are tuned to specific configurations of visual stimuli. Developmental studies in rodents have shown that the organization of SC receptive fields (RFs) is well established in newborns, and that visual experience is critical to maintain RF properties. However, rodent species studied so far (hamsters, rats, and mice) are nocturnal, altricial, and possess a very simple visual system. As an initial step to establish a viable alternative, we have characterized the RF properties of SC neurons in the Chilean degu, a diurnal, precocial rodent species with a better-elaborated visual system. We characterized isolated neuronal responses from the degu SC using four types of visual stimuli: (1) a moving white square on a dark background, (2) sinusoidal gratings with varying spatial frequencies, (3) a black expanding circle (looming), and (4) a stationary black circle. RF sizes of single units were consistently smaller in the most superficial layers (25-80 deg2 above 500 μm) and increased in size in deeper layers (30-290 deg2 below 500 μm). Most neurons displayed spatial frequency tuning ranging from 0.08 to 0.24 cycles/degree. Finally, we found looming-responsive units, all of which increased their firing rate as the looming object increased in size. When tested with a stationary stimulus, looming units showed ON, OFF, or ON-OFF responses. Our study is an important step in understanding the role of visual experience in a rodent species that differs in visual habits and phylogenetic position from more commonly studied species.

25, Genomics Resource Laboratory, UMass Amherst: Capabilities and Resources

Ranjan, Ravi

Institute for Applied Life Sciences

The Genomics Core Facility at UMass Amherst provides a suite of services to address high-throughput next-generation sequencing (NGS), including solutions for sample processing such as nucleic-acid isolation, nucleic-acid quantitative and qualitative analysis, NGS library preparation, quantitative-PCR analysis, etc. The facility has recently acquired 10x Genomics Chromium Controller system, enabling single cell genomics research projects.

The Genomics Facility is a fee-for-service lab and provides a sample processing and library preparation such as whole genome sequencing, shotgun metagenomics, metatranscriptomics, 16S/18S rRNA targeted amplicon sequencing, RNA-Seq, Single Cell Genomics, etc., to address genomics project needs. The facility accepts samples and performs requested analysis. We offer training to users to conduct experimentation for use on a fee for service basis to both internal and external researchers, academic or industry.

The Genomics Core Facility is equipped with - Illumina NextSeq500 and MiSeq NGS systems, 10x Genomics Chromium Controller System, Nexcelom Cellometer K2 Cell Counter, Diagenode Bioruptor Pico, Agilent 2100 Bioanalyzer, SageScience BluePippin, BioRad CFX96 Touch Real-Time PCR system, Qubit Fluorometer, Gel Electrophoresis, FastPrep 24-G Homogenizer, Savant Speed-Vac, and other ancillary lab equipment.

Contact: ranjan@umass.edu | Phone: 413-577-4501

Website: https://www.umass.edu/ials/genomics

26, Forecasting Alzheimer’s Disease Two Years Before Onset from Longitudinal Multimodal Data

Sidong Zhang, Madalina Fiterau

Computer Science UMass Amherst

Alzheimer’s disease (AD) is the most common form of dementia, causing progressive cognitive impairment, disorientation, and memory loss. Despite years of clinical trials, there is currently no cure for AD and, by the time of diagnosis, as much as 60% of brain matter is already lost. Thus, forecasting Alzheimer's disease years ahead of onset is critical for attempts at early treatment, the selection of subjects for clinical trials, and to facilitate neurologists’ study of the disease.

Past research on machine learning for Alzheimer’s disease prediction was limited to using cognitive test scores and highly engineered volumetric features, while failing to leverage the potential information found in brain MRIs. Attempts to train 3D and 2D CNNs on the MRIs have been unsuccessful thus far, due to the insufficient amount of data samples available for the massive amount of parameters that need to be learned. Moreover, forecasting AD using standard statistical models, simple MLPs and sequential models is typically limited to 6-12 months windows, model stability and performance dropping significantly for longer time windows.

To introduce more complex longitudinal data and detect future disease stages, we propose a sequential deep learning approach that is expressive enough to handle multimodal longitudinal data, with an added unsupervised mutual information CNN encoder to process the 3D MRI scans, while still maintaining stable forecasting performance over forecasting windows of two years or more. We integrate certain domain knowledge via selective features of the disease-relative areas’ volumetric data, cognitive test scores and demographic information. The model is designed to get latent features from the multimodal data during the training process that are informative to the forecasting task. To achieve this, we propose a hybrid model of RNN and CNN. On the RNN side, we study a RNN-like structure introducing latent anticipated features to enhance the forecasting performance. On the CNN side, we train a mutual information based unsupervised encoder and extract latent features from the 3D MRIs as supportive side information. The model we are developing will be capable of performing forecasting tasks 2-year ahead of time, while the instability issue brought by long-term forecasting is addressed by our new mechanism of training different parts of the model separately in different stages. The future goal of the project lies in forecasting the disease on a longer time gap without loss of accuracy and robustness.

27, DHED hormonal therapy : effects on cognition, sleep, and thermoregulation in marmosets

Amato J; Paternoster A; Saia C; Jeong D; Kania N; Cournoyer H; Lacreuse A

Psychological and Brain Sciences, UMass Amherst

Aromatase inhibitors (AIs), which prevent the conversion of testosterone to estradiol, are prescribed to patients with estrogen-responsive breast cancers to prevent cancer recurrence. However, AIs are associated with side effects such as insomnia, hot flashes, and cognitive deficits that critically impair quality of life. The present study uses an animal model to examine whether brain-selective estrogen therapy can safely alleviate AI-induced CNS symptoms. DHED is a prodrug that converts to 17β-estradiol in the brain without affecting peripheral tissues. Gonadectomized common marmosets (Callithrix jacchus) were treated with the AI letrozole (0.4 mg/kg/d, PO), letrozole and DHED (100 µg/kg/d, PO), or oil vehicle for 4 months. Sleep/wake patterns, thermoregulation, and cognitive performance were examined at baseline and following 6 months of treatment. Preliminary results indicate that DHED may improve selective aspects of recognition memory and sleep quality. This study will advance the field of behavioral neuroendocrinology by (1) improving our understanding of the central effects of estrogens on the brain and behavior and (2) testing potential therapeutics for symptoms associated with estrogen deficiency in a translational non-human primate model. Supported by NIH grant R01CA246929

28, Automating Image Analysis for High-Throughput Screening of Neuromodulators in Living Organisms

Avery, F.; Lagoy, R.; Albrecht, D.

Biomedical Engineering, Worcester Polytechnic Institute

Chemical modulators of neural excitability represent potential therapeutics for neuropsychological disorders. We developed a functional screening method of neural activity in whole, living organisms to identify and quantitate these modulators. The high through-put method allows for quick generation of large imaging data sets, yet manual data analysis is time consuming, not scalable, and can be error prone. This work focuses on automating data analysis to increase efficiency, decrease errors, and obtain drug classification results within hours instead of days or weeks. The increase in speed and accuracy should accelerate the drug discovery process and identify new modulators with therapeutic or research potential.

29, A critical review of Neuro-Architecture approaches for occupant-centric building design

Valido K; Ma N

Neuroscience, University of Pennsylvania

Occupants’ well-being, cognitive performance, and emotional states are crucial as they are the primary building service recipients in buildings. Incorporating principles from neuroscience into building design can lead to a better understanding of how the brain and body interact with the built environment, ultimately developing occupant-centric spaces. Humans are active and dynamic, yet many buildings often feel static and unchanging despite the variety of daily activities conducted in them. Neuroscience gives architecture a unique insight into how people: act, feel, think, sense, and perceive in spaces.

30, Computer science for brain interfaces

Vadim Strizhov, Navid Ziaei, and Ali Yousefi

Worcester Polytechnic Institute

The Brain-computer interfaces develop compensating systems to help people with motor control problems to recover mobility. The computational models make movement predictions. They analyze brain signals along with the stimuli and user response. The processor to run models is implanted in the cranium. This technology drives exoskeletons to regain movement for patients with impaired mobility.

31, Phenotyping a Subpopulation of Cells in the Amygdala Affected by Alcohol Exposure

Flores-Bonilla A, Akli S, Senthikumar R, De Oliveira B, Rajvanshi A, Amira N, Richardson HN

Psychological and Brain Sciences, UMass Amherst

A subpopulation of central nucleus of the amygdala (CeA) GABAergic long-range projection neurons co-express the stress peptide corticotropin-releasing factor (CRF) and calcium calmodulin kinase 2 alpha (CaMKIIɑ). These cells project to the ventral tegmental area (VTA) and CRF plays an anti-stress role, as ablating the Crf gene in this population leads to increased behavioral responses to stress. Reduced CRF peptide has been observed following binge drinking in adolescence or chronic alcohol exposure in adulthood. Chronic alcohol exposure has also been shown to potentiate AMPA receptor activity through CaMKIIɑ activation on these cells, which promotes alcohol self-administration in rats. If these alcohol-induced peptidergic changes are specific to this GABA/CaMKIIɑ/CRF population of CeA cells, it may explain the transition to a negative affective state after adolescent binge drinking or by an increased stress response and exacerbation of problematic drinking. Alternatively, there could be structural changes that interfere with the anti-stress signaling in this neuronal pathway. GABAergic axons have unique myelin characteristics, with greater myelin thickness on these axons compared to excitatory axons in white matter structures such as the corpus callosum. In the CeA, downregulation of gene expression associated with myelin and myelinating cells (oligodendroglia) occurs after chronic alcohol. The objective of this project was to begin exploring these two potential mechanisms by examining peptide content changes and evidence of myelin deficits in a single study. We used a transgenic mouse reporter line (NG2CreERt:Tau-mGFP or OLi-mGFP) to track changes in myelin ensheathment of CeA axons following adolescent binge drinking. During the first two weeks a modified version of the drinking in the dark paradigm was used to expose adolescent male and female OLi-mGFP mice to voluntary alcohol binge drinking (n=9) or water-drinking controls (n=11). After 2 months of abstinence, mice were intracardially perfused, and brains were extracted and sectioned. We are currently processing brain tissue for immunofluorescent labeling experiments. Confocal microscopy will be used to quantify how alcohol impacts the proportion of GAD67+/CaMKIIɑ+ cells that express CRF in the CeA and to test for myelin ensheathment of the axons from these cells to test predictions of these alternative hypotheses.

32, Transgenic tagging and tracking of oligodendroglia for spatial and temporal mapping de novo myelination patterns in the mouse brain.

De Anda Gamboa C, Flores-Bonilla A, Akli S, Richardson H

Neuroscience, UMass Amherst

Myelin sheaths increase the speed of transmission of electrical signals along axons, enhancing neural communication between cells in the brain. The cellular events of myelination include the proliferation and differentiation of oligodendrogial progenitor cells (OPCs) into oligodendrocytes (OLs), which mature and extend their processes and wrap axons, forming concentric lipid-rich myelin sheaths. Myelination may be contributing to neural functioning that changes across the lifespan. Cognitive abilities show substantial improvement with adolescent maturation while cognitive abilities decline later with aging, yet there is limited understanding of how cellular dynamics of myelinating cells differ at these different ages. The goal of this project was to explore age-related differences in the cellular dynamics of de novo myelin formation in developing and aging animals. We used a conditional transgenic mouse line NG2-CreERTM:Tau-mGFP that with tamoxifen being administered to preadolescent (postnatal day 21) versus older (1 year old) male and female mice. Tamoxifen induction of Cre-recombination allows for green fluorescent protein (GFP) to be expressed in the membranes of myelinating OLs and associated myelin segments along axons. Brains were collected at different timepoints after tamoxifen that were matched across age groups. Differentiation of OPC into OLs has been shown to be faster in white matter axonal pathways compared to grey matter structures. We therefore are using multilabel immunohistochemical procedures to visualize GFP and ASPA co-labeling to identify and track and map pre-existing (GFP-) and newly formed myelin (GFP+) in white and grey matter regions in younger and older animals. Using confocal microscopy, we are currently imaging the brain sections of these animals to visualize and quantify the newly formed myelin at the different timepoints. From imaged tissue, we see a strong positive signal of GFP that is co-localized with a marker of myelinating OLs in brain areas such as the piriform cortex and anterior commissure, which indicates that myelin is forming on axonal connections from the olfactory bulb to the forebrain. This research can enhance our understanding the role of myelin in central nervous system circuitry function throughout adolescent maturation and with aging.

33, Chemogenetic activation of the medial preoptic area ameliorates deficits in maternal motivation in the wistar-kyoto rat model of depression

Anderson A, Hester M, Pereira M

Psychological and Brain Sciences/Neuroscience and Behavior, UMass Amherst

Drug use in new mothers is a serious clinical problem that affects postpartum women’s health and the health of their children severely. Accumulating evidence strongly suggests that cocaine use during the postpartum period is significantly impacted by the competing motivation to care for the child. However, this relapse-resistant phase is not achieved in new mothers experiencing postpartum depression, suggesting that depression-related deficits in maternal motivation underlie the higher rates of drug relapse rates. Given the demonstrated importance of the medial preoptic area (mPOA) in maternal motivation, the present study investigated the functional sufficiency of the mPOA in preventing relapse of cocaine seeking in new mothers. To accomplish this goal, we used the well-validated Wistar-Kyoto (WKY) rat model of depression, which prior studies in our lab demonstrated exhibits reduced maternal motivation, and employed a novel adaptation of the extinction-reinstatement conditioned place preference (CPP) model of relapse. We used Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) to investigate the effect of chemogenetically activating the mPOA in preventing relapse to cocaine seeking in new WKY mothers. Virgin WKY and control Sprague-Dawley (SD) females were trained to acquire a cocaine CPP, which afterwards was extinguished during pregnancy, and subsequently retested during early postpartum, when the new mothers were concurrently faced with a highly salient new stimulus in their environment, their offspring, by re-exposure to cocaine (sub-threshold challenge dose). Consistent with the clinical literature, WKY mothers exhibited high reinstatement rate, with the majority (80+%) preferring the cocaine- over the pup-associated option during cocaine-primed reinstatement testing, highly contrasting the distribution of preferences of control SD mothers. Results thus far suggest that chemogenetic activation of the mPOA biased the decision making of WKY mothers toward pup-associated cues. In addition, mPOA activation ameliorated the caregiving deficits of WKY mothers. Together, results suggest that altered activity of mPOA circuits underlies depression-related deficits in maternal motivation. Considering the impact of maternal cocaine use on both mother and child health, it is of major clinical significance to understand how maternal motivation reduces relapse to drug seeking.

34, PneuHOPE Hand exoskeleton for studying brain activity during hand movement using fMRI

Meier T, Nycz J, Fischer G

Robotics Engineering, Worcester Polytechnic Institute

Upper motor neuron injuries such as traumatic brain injury and stroke can cause hemiparesis and hand impairment. We have previously designed a hand orthosis with powered finger extension, the HOPE Hand, to assist individuals with spasticity and hypertonicity with opening and closing their hand. This exoskeleton is meant to be worn as an assistive device to help individuals perform activities of daily living. In addition to being worn for assistance, hand exoskeletons can also be rehabilitative. Repeated hand movements in physical therapy are shown to maintain flexibility and potentially facilitate regaining functionality. To further understand motor impairment and rehabilitation, we are interested in studying how the brain is activating during use of a hand exoskeleton. We have reimagined the original HOPE Hand to now be MRI conditional for safe use during functional MRI scans. The PneuHOPE Hand is a wearable MRI conditional research platform to enable the studying of brain activation during functional hand movements and operation of the exoskeleton to learn about neurorehabilitation. The PenuHOPE Hand uses pneumatic double acting cylinders to push and pull flexible strips along the dorsal surface of the hand to extend and flex the user’s fingers, maintaining the same mechanical behavior of the original HOPE Hand. We can track the position of the fingers which allows us to slowly increase the force we are applying to extend the fingers against the subject’s increased resting muscle tone. This control method acts as an “assist-as-needed” paradigm to tailor the provided hand exoskeleton hand movement to each subject’s muscular resistance level for each opening and closing of the hand. We are presenting the PneuHOPE Hand as a research platform for doing any number of fMRI studies relating to hand exoskeleton design, user control methods, and therapeutic routines.

35, Selective recruitment of offspring-responsive medial preoptic area networks modulates caregiving behavior attuned to the needs of offspring

Copelas K, Celestin N, Pereira, M
Neuroscience and Behavior, UMass Amherst

The medial preotic area (mPOA) is acriticalintegration site where hormonal signals and offspring-related sensory information converge to facilitatematernalcaregiving behavior. The mPOA mediates flexiblecaregiving behaviors through projections to areas including the infralimbic cortex (IL) and the ventral tegmental area (VTA). The objective of this study was to map out the distribution of offspring-responsive IL-and VTA-projecting mPOA neurons and evaluate how recruitmentof these regions changes during interactions with pups of varying needs. To this aim, Iused fluorescent retrograde axonal tracersandcFos immunohistochemistryto visualize the subregional origins of cFos-expressing IL-and VTA-projectingneurons in the maternal mPOA during mother-litter social interactions. Results thusfar showthat the proportion of mPOAneurons recruited that projectto these two regions isgreater under demanding pup conditions comparedto non-demanding conditions, and that certain mPOA subregions (MnPO, MPA, VMPO) may be more sensitive to offspring need signals than others. By mappingthe large-scale functional circuitry of mPOA neurons that are specifically responsive to offspringsignals, we can gain greater insight into how mothers tune behavior to offspring needs.

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