Abstracts

Whether to grab a cookie or skillfully play piano, life requires movement. However, movements must first be learned. While it is now understood that learning encompasses distributed circuits, it is unclear how these adapt for skill attainment. We have been exploring two mechanisms which could mediate this process: (1) whether cell types are differentially recruited as learning progresses, and/or (2) whether cell states facilitate the necessary changes for motor learning.

To examine these ideas, we have focused on the primary motor cortex (M1) in mice. We developed a screen to label and molecularly profile active neuronal populations during motor learning and identified several cell types with significant enrichment at different learning stages. We then characterized the specific contribution of one late learning enriched type, the FoxP2+ corticothalamic neurons. An examination of the activity of this population demonstrated that, unlike other M1 neurons that positively correlate with movement, this population is suppressed during movement execution. Furthermore, preventing suppression of these neurons strongly perturbed movement execution, demonstrating the importance of this activity profile within the motor circuit.

Our current work is now focused on learning-induced cell states. By taking a more comprehensive examination of all the transcriptional changes identified in my initial screen, we are classifying differentially expressed genes into cellular pathways in a cell type specific manner. This approach will inform how transcriptional programs could provide a molecular mechanism for the cellular changes underlying motor learning.

Inna Nechipurenko

Biology & Biotechnology, Worcester Polytechnic Institute

Functional classification of GNAI1 disorder variants in C. elegans uncovers conserved and cell-specific mechanisms of dysfunction

Neurodevelopmental disorders (NDDs) comprise a range of conditions that commonly include intellectual and learning disabilities, autism, attentiondeficit/hyperactivity disorder (ADHD), and impairment of sensory modalities. Variants in the human GNAI1 gene, which encodes Gαi1 subunit of the heterotrimeric G(αβγ) proteins were recently identified as a cause of a novel NDD characterized by developmental delay, hypotonia, seizures and/or autistic features; however, the functional consequences of these variants or mechanisms of their dysfunction remain unknown.

We found that knockdown of GNAI1 in human cells interferes with the assembly of primary cilia – specialized signaling compartments that play critical roles in neuronal development. Similarly, C. elegans Gαi/o-like ODR-3, which exhibits 48% sequence identity and 66% similarity to Gαi1, localizes to cilia and shapes cilia morphology in a subset of ciliated neurons. Here, we leveraged the well-defined genetics of odr-3 together with the robust cellular phenotypes of odr-3(lf) mutants to functionally classify five patient GNAI1 variants that map to conserved, identical residues in the C. elegans ODR-3. We find that all examined variants diVerentially impair ODR-3 localization to primary cilia. Interestingly, we observe neuron type-specific diVerences in the impact of these mutations on cilia morphology and cilia-mediated neuronal function. Experiments in human cells further showed that the impact of the examined NDD GNAI1 variants on ciliary traVicking of their protein products is also evolutionarily conserved. Overall, this study provides a new insight into the conserved and cell-specific cellular mechanisms that are disrupted by the GNAI1 patient mutations and establishes a genetic pipeline for rapid functional classification of NDD-associated variants.

Kelly Wallace

Biology & Program in Neuroscience, Amherst College

Neural and Behavioral Mechanisms of Territoriality in Betta Fish

How does artificial selection for aggression shape the neural mechanisms of social behavior? The fighting fish Betta splendens has been bred for increased territoriality behavior for centuries, making it a highly tractable and relevant model for studying questions at the intersection of cognitive ecology and social neuroscience. Yet, few studies have comprehensively assessed Betta behavior across both social and nonsocial contexts, and even fewer have explored the underlying neural mechanisms mediating territoriality in this species.

My lab is currently (1) assessing the impacts of repeated competitions in Betta (2) correlating the outcomes of competitions to other dimensions of behavior like stress responses, and (3) assessing the activation of nonapeptide-producing neurons during these competitions. Taken together, this work aims to establish a novel model system for the study of territoriality and for social neuroendocrinology more broadly.

Short talks

1, Sex differences in drinking patterns and microstructure during voluntary adolescent-onset ethanol intake and subsequent brain-wide cFos activity during forced ethanol abstinence

Edwards, C.M., Hallal, S., Simerly, R.B., Winder, D.G.

UMass Chan Medical School

Adolescent alcohol use increases the risk of developing alcohol use disorder (AUD), with negative affect during abstinence heightening relapse risk. This study aimed to analyze ethanol drinking patterns and microstructure and brain-wide neural changes during abstinence in male and female mice with adolescent-onset ethanol consumption. Adolescent C57BL/6J mice (~PND30) were placed into the Lick Instance Quantifier (LIQ) system with two bottles containing ethanol and water or both water as controls. Mice underwent the Chronic Drinking Forced Abstinence paradigm with continuous access to the bottles and precise measures of drinking behavior, including lick count, duration, bout number, and bout size, were monitored throughout. While there were no major sex differences in total licks at the ethanol bottle, females exhibited higher bout numbers compared to males. Additionally, the timing of drinking relative to dark onset differed, with females drinking more before dark onset and males drinking more immediately after dark onset. Ethanol was then removed, and brains were collected at 24hrs and 2wks of forced abstinence. Brain tissue was cleared, immunostained for cFos, and imaged using light sheet microscopy. Brain-wide cFos densities were analyzed for regionally specific changes and related to drinking behaviors. Hierarchical clustering and network analysis showed decreased network modularity during acute withdrawal, with a return to higher modularity during protracted abstinence. The combined LIQ and whole brain cFos data within the same animals offers insight into neural mechanisms underlying the development of negative affective behaviors during abstinence and their relationship to drinking behavior in adolescence.

2, Multi-cell type and multi-species co-culture system reveals differences in metabolic functions of the primate brain

Rickelton, Katherine; Sandiri, Rithvik; Dalier, Aliyah; Roy, Jessica; Babbitt, Courtney

Biology, UMass Amherst

Primates are distinguished by their large brains relative to body size, which evolved alongside advanced cognitive abilities like language, social cognition, and decision-making. This link between brain size and cognition is thought to be facilitated by metabolic activity, as larger brains are more energetically costly. Humans have evolved an especially metabolically demanding brain, utilizing over 20% total glucose metabolism while chimpanzees use less than 10%. Allometric scaling on its own does not explain this increase, suggesting that the evolution of higher cognitive processes may be driving the brain’s high energy requirement. Brain metabolism is critical for neurological function by providing cellular energy necessary for neuron firing. Much of metabolism in the brain is carried out by astrocytes: a type of glial cell that have long been viewed as passive support cells for neurons. More recent research has highlighted the unique roles of astrocytes in many critical neurological processes; however, it is less understood how astrocytes differ among species and their broader roles in brain evolution.

To better understand the mechanisms of primate brain evolution, specifically from a metabolic perspective, we utilized iPSC technology and co-cultured iPS-derived astrocytes and neurons of humans and chimpanzees together to assess species and cell-type specific effects on metabolic activity. We conducted single-cell RNA-sequencing in order to look at gene expression differences, as well as Seahorse XF Mitochondrial Stress tests to analyze live-cell metabolic differences. We observed that human neural cells in monoculture maintain increased basal metabolic rates, increased ATP production, and increased glycolytic rates compared to chimpanzee neural cells. Co-culture further revealed that human astrocytes and neurons together consume significantly greater amounts of oxygen compared to chimpanzee astrocytes and neurons, translating to species differences in basal metabolism and ATP production. Multi-species co-culture systems also highlight that neurons are driving basal differences in ATP production and respiration, while human astrocytes provide additional key energy sources via the astrocyte-neuron lactate shuttle (ANLS). We conclude that both neurons and astrocytes have evolved differently across primates, and that this evolution of neural cell types is key to the differences in metabolic demands of human and chimpanzee brains.

3, Mbnl1, an RNA splicing factor, associates with Arc in an activity-dependent manner

Zinter M, Xiao C, M'Angale P, Zhao-Shea R, Freels T, Tapper A.R., Thomson T

Neurobiology, UMass Chan Medical School

The Drosophila activity-regulated cytoskeleton-associated protein (dArc1) can facilitate viral-like synaptic transfer of its own mRNA through dArc1 oligomerization and capsid formation. This transfer has been demonstrated to promote synaptic maturation at the Drosophila neuromuscular junction and shows conservation to the mammalian neural synapse through dArc1’s mammalian ortholog (Arc). It was long asked whether dArc1/Arc is capable of transferring transcripts other than its own. Recently, we established that dArc1 can interact with numerous transcripts in Drosophila including the transcript of the RNA splicing factor muscleblind (Mbl). Here, we demonstrate this interaction is further conserved to Arc and the mammalian Mbl ortholog Muscleblind Like Splicing Regulator 1 (Mbnl1). In the mouse neuro2a (N2A) cell line, immunoprecipitation of Arc protein enriches for both the Arc and Mbnl1 transcript. Upon differentiation of these N2A cells, Arc’s ability to bind its own transcript and Mbnl1 are both abolished while potassium stimulation of these cells restores Arc’s interactions with both transcripts. These data are indicative of Arc’s association with Mbnl1 mRNA being an activity-dependent process. This interaction is further conserved to the mammalian central nervous system, where Mbnl1 shows increased colocalization with Arc protein in the dentate gyrus of foot shocked mice. Furthermore, we demonstrate that both Arc and Mbnl1 RNA can be detected in extracellular vesicles (EVs) derived from N2A cells and that potassium stimulation of differentiated N2A alters the ratio of Arc to Mbnl1 in EVs. We then established that Mbnl1, unlike the Arc transcript, is not directly encapsulated by Arc protein, elucidating a novel method for transsynaptic transfer of RNA either via interactions with the capsid surface of Arc or lower oligomerization states of the Arc protein. Lastly, Arc capsid associated Mbnl1 RNA is likely linear, not circular, as it is not protected from RNAse R digestion. Taken together, our data suggest that Arc protein interacts with Mbnl1 RNA in an activity-dependent manner and this interaction may facilitate transsynaptic transfer of Mbnl1 RNA through the EVs.

4, Characterization of Tau HMW-F from human brain tissue and investigation of their propagation

Bhasne K; Shultz A; Eyles SJ; Gierasch LM; Rauch JN

BMB, UMass Amherst

The misfolding and accumulation of Tau protein, leading to the formation of intracellular aggregates, represents a pathological hallmark of neurodegenerative conditions like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Pick's Disease (PiD), and many other Tauopathies. Recent cryo-EM structures of Tau aggregates (strains) from human brain tissue have provided exciting evidence to support structural diversity between Tau strains that are dependent on disease identity. A cellular receptor known as LRP1 (Low-density lipoprotein Receptor-related Protein 1) was identified as a regulator of the Tau spread pathway (Rauch et al. Nature 2020). However, we do not know if the LRP1 pathway is critical across different disease-relevant Tau strains (i.e., Tau aggregates extracted from unique human Tauopathy tissue). To address this question, we obtained brain tissue samples from patients diagnosed with AD, CBD, PSP, and PiD and isolated high molecular weight fractions (HMW-F) containing Tau protein. We have characterized HMW-F from patients using a range of biophysical tools, including size exclusion chromatography, dot blot, AFM, Mass Spectrometry (MS), binding assays, and fluorescence imaging. We have shown that HMW-F has high seeding potential using a FRET biosensor cell assay. MS data indicates heterogeneity in HMW-F, and we have constructed an interactome map of all strains. To test whether HMW-F interacts with LRP1 for spread, we performed a binding competition assay using a split NanoLuc system. Among all four strains, AD HMW-F displayed competition with monomeric Tau for LRP1 binding. To test for LRP1 interaction in cellular conditions, we used H4 neuroglioma cells and observed that AD HMW-F was internalized and LRP1-knockdown reduced HMW-F uptake. Our study sheds light on the molecular mechanisms driving Tau uptake and elucidates a crucial step in developing and evaluating the Tau-LRP1 complex as a therapeutic target for Tauopathies.

5, Beyond TRANSPORT2: Testing Safety and Tolerability of Even Higher tDCS Doses Applied Concurrently with mCIMT

Abraham Madjidov, Abigail Hay, Anant Shinde, Gottfried Schlaug

Neurology, UMass Chan Medical School

Background: Rehabilitation therapies like constraint-induced movement therapy (CIMT) have shown improvements in motor impairment beyond standard methods. Combining brain stimulation (tDCS) with these therapies may further enhance stroke recovery. A meta-analysis revealed a dose-response relationship between current density (current density/pad size) and motor improvement on the Fugl-Meyer Upper-Extremity (FM-UE) scale. Moreover, studies in healthy subjects indicate that higher doses (e.g., 3–4mA) of tDCS yield superior effects on motor skills, motor evoked potentials (MEPs), and imaging measures of brain activity, while remaining safe and tolerable. This highlights stimulation dose as a critical factor in enhancing therapy.

Objective: In a 3+3 dose-escalation study, we aim to evaluate the safety and tolerability of even higher tDCS doses than those currently used with mCIMT over 10 daily sessions in patients experiencing their first clinically relevant stroke.

Methods: Patients with mild to moderate persistent motor impairment (FM-UE ≤54) and residual finger and wrist movements, 1 to 6 months post-stroke, are enrolled. Following the TRANSPORT2 multicenter trial model, we assess safety (adverse events) and tolerability (VAS scores). This 3+3 design escalates doses in 0.5mA steps, starting at 4.5mA, using a bihemispheric montage (anodal over the lesional region, cathodal over the contralesional motor region) with a 2-mm-thick, 4-cm diameter rubber electrode and a 2-mm layer of Ten20 conductive paste placed over C3 and C4 of the 10–20 EEG system. Safety is monitored through adverse event collection, skin inspections, and VAS scores. Dose escalation stopping rules include: 1) Occurrence of any serious adverse events related to the dose application (e.g., visible skin burn/raised skin edema under the electrode; seizure; neurologic worsening by 4 or more points on the NIHSS); 2) Any change in magnetic resonance imaging measures, such as the regional apparent diffusion coefficients (ADC) by >10% underneath the electrodes; 3) If 2 of 3 subjects indicate the applied dose to be intolerable (>8 on a VAS scale), either in the first set of 3 subjects or when 3 additional subjects are entered at a particular dose.

Results: To date, 6 subjects (4 Females, 2 Males; mean age 65 years) have received tDCS at 4.5mA and 5mA. No major adverse events or intolerable VAS scores have occurred. One subject experienced transient mild headache during 2/10 sessions at 5.0mA. Pre- and post-MRI comparisons revealed no new lesions, and all subjects improved beyond the minimal clinically important difference (MCID) of 4.5 points.

Conclusions: Preliminary results of this ongoing study suggest that even higher doses of tDCS than those currently used in multicenter trials are safe, well tolerated, and might lead to a reduction in motor impairment to a similar or greater degree than that observed in studies using up to 4mA.

6, The nudibranch mollusc Berghia stephanieae as an emerging study system for neuroscience.

Perez-Moreno JL, Katz PS

Biology, UMass Amherst

Understanding the neural underpinnings of behavior and sensory processing in non-traditional model organisms can yield novel insights into the evolution, structure, and function of nervous systems across species. Berghia stephanieae, a nudibranch mollusc, is a small, tractable organism, with short generation times, that is easy to breed and maintain in laboratory conditions. Like other sea slugs, B. stephanieae possesses large and accessible neurons amenable to manipulation, visualization, and electrophysiological recordings, presenting key advantages for neurobiological research. We are currently building a neuronal connectome of Berghia's brain from serial EM images. Here, we describe our efforts to develop a robust genetic toolkit to address questions regarding neurogenesis, sensory processing, and behavior in this emerging study system. A challenge has been identifying delivery methods to efficiently introduce the genetic constructs that we have designed. However, the promise of delivery via lipid nanoparticles (LNPs) offers a potential solution thanks to their versatility and biocompatibility across taxonomic scales. The use of LNPs with transport peptide-tagging to facilitate both delivery to neural tissues in adults (e.g., transferrin/penetratin) and nuclear integration in oocytes (e.g., vitellogenin) offers an opportunity to capitalize on homologous peptides/receptors found in the sea slug’s transcriptome. This approach facilitates construct delivery/gene-editing, supporting the application of advanced techniques, such as the use of biosensors for real-time monitoring of neuronal activity (i.e., GCaMP) and optogenetic manipulation (e.g., channelrhodopsin). By harnessing these innovations, B. stephanieae stands to become a valuable model for comparative neurobiology, offering insights into neural circuit function to inform studies across molluscan lineages, including cephalopods, and other complex invertebrates. Furthermore, this toolkit provides a foundation for the use of B. stephanieae and similar non-traditional models in neurobiology, opening new avenues for exploring neural mechanisms and advancing tools across emerging study systems.

7, Dose Dependent Impact of Maternal IL-4 on Offspring Neurodevelopment and Behavior In EPM and JRSI

Veronica J. Rhoten, Xhayla N. Strickland, Jenna N. Russo, & Jared J. Schwartzer

Neuroscience and Behavior, Mount Holyoke College

Elevated interleukin-4 (IL-4), often associated with allergic inflammation, during pregnancy is associated with an increased risk of having a child diagnosed with neurodevelopmental disorders later in life. To test for a causal link, female mice were injected with one of three doses of IL-4 throughout pregnancy and then their offspring were tested social deficits in a juvenile social interaction task (JRSI) and anxiety-like behaviors in an elevated plus maze task (EPM). In JRSI female offspring showed a dose-dependent decrease in social interaction when born from dams who were exposed to elevated IL-4 throughout pregnancy. While males did not show the same dose-dependent decrease, offspring of the highest dose of IL-4 showed the most severe social deficits comparable to female offspring. The data suggests a causal role for maternal IL-4 in shaping offspring brain and behavior development.

8, Pre-Clinical Safety and Efficacy of AAV9 gene therapy for Mucolipidosis type IV (ML4)

Tyler Mola, Olivia Morales, Simon Wentworth, William Callahan, McKenna Watson, Ananya Uppalapati, Ana Rita Batista, Miguel Sena-Esteves

Genetic & Cellular Medicine - Neurology, UMass Chan Medical School

Mucolipidosis type IV (ML4) is an autosomal recessive lysosomal storage disease caused by mutations in the MCOLN1 gene, encoding for the transient receptor potential channel, mucolipin 1 (TRP-ML1). Evidence has shown that TRP-ML1 acts as a non-selective cation channel whose channel activity is pH- and Ca2+- dependent and that it regulates lipid trafficking by regulating late endosomal/lysosomal fission and fusion events. However, the exact function of TRP-ML1 and how the mutated versions interfere with lysosomal function is still unknown. It has been shown that AAV-mediated CNS gene transfer of human MCOLN1 results in rescue of motor deficits and delayed time to paralysis with correction of brain pathology in ML4 mice (Mcoln1-/-). We are conducting a blinded long-term dose escalation efficacy study in Mcoln1-/- mice treated neonatally (P0-P1) by bilateral intracerebral ventricular (ICV) injection of 1E10, 3E10 or 1E11 vg of scAAV9-JeT-hMCOLN1 vector or PBS. Behavioral performance is assessed at 2 and 6 months of age in the Open Field and rotarod tests to assess efficacy and durability of effect. Interim data analysis of survival showed that almost all animals have perished in group B with a median survival of 200 days. The identity of group B was unblinded prior to conclusion of the study and corresponds to mice treated with PBS. For the other groups, there appears to be a dose effect with two groups (A and C) with several animals that have reached the humane endpoint (median survival in group C is 251 days), and one group (Group D) where all mice remain alive at 303 days of age. Performance in the rotarod test was comparable across groups at 2 months of age, but it declined significantly in PBS-treated animals by 6 months of age. Performance was significantly better in AAV-treated mice compared to PBS-treated mice at 6-months of age and remained unchanged between 2 and 6 months of age for groups A and D. Importantly, there have been no adverse events in age-matched carrier and wild type littermates that also receive AAV vector at birth. Molecular and histological analyses of tissues are ongoing.

Conclusions: Our survival and behavioral data show that neonatal ICV treatment with scAAV9-JeT- hMCOLN1 vector has a substantial therapeutic effect, rescuing motor deficits and increasing survival of ML4 mice. We are currently analyzing tissues for MCOLN1 expression and impact of treatment on storage material and myelination, which is defective in ML4 mice. We are also developing a MCOLN1 knockout HEK293T cell line to assess vector potency across AAV vector batches. The interim results show a durable benefit of neonatal treatment with scAAV9-JeT-MCOLN1 vector and support transition of this AAV gene therapy to a phase I/II clinical trial in ML4 patients.

Posters Abstracts

1, The Influence of Core Body Temperature on Sleep Architecture During Menstrual Phases in Young Women

Gandikote Niveditha; Rodheim Katrina, Spencer Rebecca

Psychology and Brain Sciences, UMass Amherst

Core body temperature (CBT) plays a crucial role in sleep regulation, yet its fluctuations across menstrual phases and potential effects on sleep remain understudied. This study examines CBT variations and their relationship with sleep architecture across menstrual phases. Young women(mean age = 19.78 ± 1.86 years) underwent two nights of polysomnography during their follicular and luteal phases. CBT was continuously recorded via a telemetric pill, smoothed over 7.5-minute intervals, and averaged during sleep. Analyzed CBT variables included In-Bed Temperature(average CBT from sleep onset to wake time), Raw Minimum Temperature, Pre-sleep Temperature(3 hours before sleep onset), and the Temperature Drop Period (time from sleep onset to raw minimum CBT). Paired-samples t-tests compared these variables between phases. Results showed significant differences in In-Bed Temperature (t(8)=4.09, p=0.0035) and Raw Minimum Temperature (t(8)=4.05, p=0.0037), both higher in the luteal phase. Pre-sleep Temperature showed no significant difference (t(8)=1.53, p=0.164). The Temperature Drop Period was significantly longer in the luteal phase (t(8)=3.20, p=0.0126), suggesting a delayed CBT decline, which may contribute to prolonged sleep onset latency and disrupted sleep. Since a steeper and faster temperature drop is linked to better sleep quality, these findings suggest that menstrual phase-related CBT changes may contribute to sleep disturbances. Further analysis will examine how these variations impact sleep architecture.

2, Identification of glial cell types in the mollusc Berghia stephanieae using gene expression and volume electron microscopy

Harshada H. Sant1, Alexzander M. Cook1, Zahraa Salloum1, Srimaan Sridharan1, Ginaldo Verdieu1, Yuelong Wu2, Richard Schalek2, Jeff W. Lichtman2, Paul S. Katz1

1. Department of Biology, University of Massachusetts Amherst

2. Department of Molecular and Cellular Biology, Harvard University

Biology, UMass Amherst

Glial cells play an important role in nervous system development and function. However, little is known about glial cell types in molluscs. We identified marker genes for glial subtypes using single-cell transcriptomics (scRNA-seq) and visualized their expression using in-situ hybridization chain reaction (HCR) in the gastropod mollusc Berghia stephanieae. Apolipophorin, a known marker for Drosophila astrocytes, and recently identified as a glial cell marker in Octopus vulgaris, was also differentially expressed in scRNA-seq by glia in Berghia. Apolipophorin HCR labeling revealed abundant glia, including some giant glia in Berghia’s nervous system, suggesting its use as a pan-glial marker. Glial cell types were also identified in a volume electron microscopy dataset of the rhinophore ganglion based on ultrastructural features. Glial cells have distinct ultrastructural features and diverse morphologies. There are large glia that encase numerous neuronal soma. Some glial cells partitioned axon bundles or synaptic areas of neuropil. Others bordered the sheath and vasculature. Membrane-to-membrane junctions between glia suggest a potential glial signaling network. Glial cells identified in Berghia appear analogous to wrapping glia, astrocytes, cortex glia, and ensheathing glia described in other animals. The 3D structures of various glial cells were reconstructed. Modern molecular and imaging techniques have provided unprecedented access to studying glia in molluscan nervous systems. Future research on molluscan glia will offer insights into the function and evolution of glia across animals. 

3, Effects of Maternal IL-4 Signaling on Offspring Stress Response

Abdel Maksoud F, Lee G

Neuroscience and Behavior, Mount Holyoke College

Increased signaling of the immune cytokine interleukin-4 (IL-4) during pregnancy is associated with behavioral differences in offspring, some of which may impact the offspring’s ability to cope with a stressor. To test the effects of maternal IL-4 on offspring stress responsiveness, pregnant female mice were treated with IL-4 throughout pregnancy and their offspring were tested in the forced swim task. Preliminary data suggest that elevated maternal IL-4 levels throughout pregnancy do not modulate offspring stress coping responses.

4, Partnering and Patterns: Auditory and Social Behavior Processing in the Lateral Ventromedial Nucleus of the Hypothalamus

Ruth Berganross, Felipe A. Cini, Jeremy A. Spool, and Luke Remage-Healey

Neuroscience and Behavior, UMass Amherst

Zebra finches live in large colonies and communicate with one another using a rich vocal repertoire. Both song and calls contain signatures that allow birds to individually identify one another. To what extent do social brain regions parse sensory cues from distinct individuals, including monogamous pair mates? In vertebrates, the Ventromedial Nucleus of the Hypothalamus (VMH) is involved in feeding and reproductive behaviors. Newly published work shows the lateral VMH encodes external auditory stimuli in birds. Therefore, we asked to what extent VMHl responds differentially to vocalizations from individuals that vary in their social significance: their socially monogamous partner; familiar males and females; male and female strangers. We first quantified a bird’s preference to each of these social categories using an isolation reunion paradigm. Each focal bird went through 5 trials of a 15-minute interaction with their partner, a male and female familiar bird, and a male and female stranger bird. We then conducted single unit in vivo electrophysiology in VMHl using auditory playback of songs and calls from the same individuals (i.e., partner, familiars, strangers). Preliminary results show high levels of social interaction in zebra finches regardless of social significance. Females appear to pause activity when presented with their pairbonded male. General movement was higher in trials with a bird’s partner compared to both the familiar and stranger trials. Ongoing analyses are exploring the activity of single neurons in VMHl to ascertain neural correlates of these socially-specific behaviors.

5, Do listeners access abstract morphological representations while processing speech? A representational similarity analysis of event-related potentials

Chang, Chiung-Yu; Jesse, Alexandra; Sanders, Lisa D.

Psychological & Brain Sciences, UMass Amherst

The English plural suffix is pronounced as /z/, /s/, or /ɪz/ depending on the phonological context. Classical linguistic analyses posit an abstract representation of the suffix, while episodic theories do not. Neither of these approaches specify the timing of abstraction during speech processing. This study explored the representational geometries predicted by these theories. We recorded event-related potentials (ERPs) elicited by four types of sounds: /z/ as the canonical plural suffix (e.g., hill-/z/), /s/ as an illegal substitute for the plural suffix (e.g., hill-/s/), /z/ as the coda of a noun (e.g., maze), and /s/ as the coda of a noun (e.g., moose). Additionally, we manipulated the suffix predictability by adding a number (e.g., two hill-/z/) or a definite article (e.g., the hill and the hill-/z/). The acoustic-phonetic model supposes no abstract representation of the suffix, predicting that ERPs for /z/ will always differ from those for /s/. In contrast, abstractionist models predict that ERPs for /z/ and /s/ will be more similar when they serve the same syntactic function. Representational dissimilarity matrices (RDMs) based on these predictions were compared to RDMs derived from the observed ERP data in early and late time windows (i.e., 100-200 and 400-500 ms after /s/ or /z/ onset). Results from 25 participants suggest that the acoustic-phonetic model best predicts the observed data, supporting episodic theories. However, an abstractionist model performs equally well for the late time window when the plural suffix is predictable, suggesting an interplay between predictability and allomorph representations during speech processing.

6, Genomics Core Facility, UMass Amherst: Resources and Technologies

Ranjan, Ravi

IALS, UMass Amherst

The Genomics Facility at UMass Amherst provides a suite of services for molecular biology, genomics and high-throughput next-generation sequencing (NGS) projects.

The Genomics Facility is a fee-for-service lab and provides sample processing such as nucleic-acid isolation, nucleic-acid quantitative and qualitative analysis, quantitative-PCR analysis, etc. NGS library preparation services such as whole genome sequencing, shotgun metagenomics, metatranscriptomics, targeted 16S rRNA amplicon sequencing, RNA-Seq, 10x Genomics Single Cell RNAseq, etc.

The Genomics Facility is equipped with - Illumina 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. We also facilitate high throughput NGS projects using production scale sequencers, and are proficient in molecular cloning projects.

Contact:

Ravi Ranjan, PhD, MB(ASCP)CM

Genomics Resource Laboratory, Institute for Applied Life Sciences (IALS)

Morrill1 Room N330, University of Massachusetts Amherst

Email: ranjan@umass.edu Phone (o): 413-545-3848

Genomics Facility Webpage: www.umass.edu/ials/core-facilities/genomics-resource-laboratory

7, Race and weight loss outcomes: Exploring the mediating role of the home food environment

Watts, M; Crochiere, R

Psychology Department, Williams College

Objective: Previous studies have consistently demonstrated less weight loss among Black adults enrolled in behavioral weight loss (BWL) interventions compared to white adults. Certain BWL programs target the obesogenic home food environment (as measured via the Home Food Inventory; HFI) to facilitate weight loss. This raises the possibility that BWL is less effective in reducing the HFI in Black versus white participants, which would help explain disparities in weight loss outcomes by race. The goal of the present study is to explore the potential mediating factor of the home food environment between race and weight loss outcomes during a BWL intervention.

Methods: N = 283 adults enrolled in a year-long BWL intervention through Drexel University. Participants completed the Home Food Inventory (HFI) at baseline (T1), mid-treatment (6-months; T2), and end-of-treatment (T3). Percent weight change from baseline was calculated at each time point. Linear regression models explored three pathways: a) the effect of race on changes in the HFI from T1 to T2; b) the effect of changes in the HFI from T1 to T2 on percent weight change from T1 to T3; and c) the effect of race on percent weight change from T1 to T3.

Results: Findings demonstrated that white participants (M= -5.05, SD= 6.40) experience a greater reduction in HFI scores compared to Black participants (M= -3.01, SD= 6.38) from T1 to T2 (pathway a: b= -2.04, SE= 0.94, p= 0.03). Changes in HFI from T1 to T2 were not significantly associated with percent weight change from T1 to T3 (pathway b: b= 0.08, SE= 0.08 p= 0.31). Black participants (M= -6.39, SD= 6.62) experienced less percent weight change compared to white participants (M= -11.33, SD= 7.52) from T1 to T3 (pathway c: b= -4.93, SE= 0.96, p= <0.001).

Conclusion: Our findings support previous findings that white participants experience a greater reduction in weight compared to Black participants during BWL interventions. We found statistical significance in that race predicts changes in HFI in the context of BWL programs. While that did not significantly predict weight change, it still may mean that white participants have healthier home food environments than Black participants, suggesting that BWL programs should consider modifications to address that gap.

8, Exploring Glial Subtype-Specific Epigenetic Alterations in a Drosophila Model of Glial Tauopathy

Zamora Varela, A., Colodner K.

Neuroscience and Behavior, Mount Holyoke College

The microtubule-associated protein tau is found in all human brains where it contributes to normal cellular structure and function. However, the aggregation of tau is a characteristic feature of a variety of neurodegenerative diseases called tauopathies, such as Alzheimer’s disease. Tau “tangles”, or hyperphosphorylated and aggregated tau, are found in both neuronal and glial cells, and have been shown to correlate with degeneration. One of the ways in which tau is thought to promote degeneration is through the disruption of the epigenetic regulation of neuronal DNA structure. It is unclear whether tau similarly disrupts epigenetic regulation when found in glial cells. We hypothesize that tau will disrupt DNA dynamics in glial cells, potentially highlighting a similarity with the neuronal Drosophila tauopathy model. This project examines the relationship between the neurodegenerative effects of tau in glial cells, its capacity for epigenetic alteration, and possibilities of DNA recovery through histone modification.

9, Glial Regulation of Neurotransmitter Release: the H+ hypothesis

Kreitzer, MA, Tchernookova, BK, & Malchow, RP

Psychology, College of the Holy Cross

Much evidence suggests that glial cells can modulate the strength of synaptic connections between nerve cells, and alterations in glial cell intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) underlying glial cell-mediated alterations between neurons remains contentiously debated. Our experiments suggest that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from retinal Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending from Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+ electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well positioned to be key mediators of synaptic modulation. We suggest that release of H+ from glial cells may play a key and essential role modulating neurotransmission. Here we present data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell - mediated H+ efflux. We further hypothesize that extracellular H+ released by glia might play a role in in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.

10, Ecological Niche Holds Greater Evolutionary Weight than Phylogeny in the Experience-Dependent Development of Mammalian Visual Cortex

Sudana K., Aburto P., Suarez Casanova V.M., Griswold S., van Hooser S.D., Pallas S.L.

Biology, UMass Amherst

The maturation of mammalian sensory cortical networks has generally been ascribed to experience-dependent plasticity: the shaping of neural circuits

through sensory inputs during critical periods. In the visual system, dark rearing (DR) disrupts the normal development of neuronal representations of visual space, known as receptive fields (RF), in the primary visual cortex (V1). However, our work suggests that nocturnal or crepuscular mammals develop mature RF properties without visual experience. Hamsters, a crepuscular species, exhibit refined V1 RFs by adolescence even if kept in the dark, but their RFs enlarge in adulthood, implicating a dependence on light for RF development but not for mature RF maintenance (Balmer & Pallas, 2015). This project characterizes V1 RF development in two more species: crepuscular ferrets and nocturnal mice. We hypothesized that ecological niche, rather than phylogenetic relations, determines the need for light exposure in development of RF properties. Nocturnal mice are thus predicted to be independent of light throughout life, but crepuscular ferrets, like hamsters, would build but not maintain their RFs if light-deprived, despite being more genetically distant. Our preliminary data support the hypothesis; ferret RF development and dependence on visual experience is similar to that of hamsters, whereas our data from nocturnal mice suggest that both refinement and maintenance of RFs can occur without visual experience. Our preliminary data support the hypothesis and thus reveal that visual cortical development research on mice is less applicable to humans than research

on crepuscular (and perhaps diurnal) mammals. Investigating these differences will help future researchers utilize more appropriate animal models for studying human visual development and disorders.

11, Microglia modulation alleviates depression-related maternal behavior deficits in the new mother rats

Krasakova M., Cullen A., Pereira M.

Psychological & Brain Sciences, UMass Amherst

Transition into motherhood is associated with rapid neurobiological adjustments in the maternal brain, including immune adaptations. Recent studies suggest that microglia – the brain’s immune cells involved in CNS development, homeostasis, and disease - plays a critical role in this transition and facilitates the expression of maternal behavior. Postpartum depression is a serious public health problem worldwide characterized by significant disturbances in parenting, with tragic implications for both mother and child. Recent evidence implicates microglial dysregulation as a contributing factor in the pathophysiology of depression. Our goal was to examine whether microglia dysregulation of the maternal circuit contributes to depression-related parenting disturbances in new mothers. To this aim, we examined the effects of minocycline, a microglial modulator, in ameliorating the maternal behavior deficits of the utilized Wistar-Kyoto (WKY) mother rats, a well-established animal model of depression. Our prior work shows that WKY mothers exhibit maternal behavior deficits compared to control that are associated with dysfunctional activity in the medial preoptic area (mPOA), a critical region for maternal behavior. Furthermore, WKY mothers show differences in microglia morphology within the mPOA, characterized by larger territory areas and longer, more branched processes compared to controls, which negatively correlate with their maternal behavior.

WKY and control new mothers were evaluated for their maternal behaviors following daily systemic treatment with minocycline (1 or 10 mg/kg) or vehicle from gestation day 10 to postpartum day 7. Microglial activation was evaluated through double-label immunofluorescent analysis of Iba1 and c-Fos. Our results revealed that 1.0 mg/kg minocycline treatment shifted microglia phenotype and ameliorated deficits in maternal behavior in WKY rats. In contrast, treatment with 10 mg/kg minocycline exacerbated the behavioral deficits of WKY mothers and their microglia tended to exhibit a hyper-ramified profile. These findings show that microglia manipulation alleviates depression-related deficits in maternal behavior and suggest a mechanistic link between postpartum microglial adaptations in the mPOA and healthy maternal behaviors.

12, Stress-Responsive Learning Domains in Affective and Non-affective Behavioral Contexts: A Characterization of Sensitivity and Resilience

Zhao A, Ng Q, Penna SR, Cazares VA

Neuroscience, Williams College

While 89.7% of US adults experience at least one traumatic event in their life, only 1 in 11 will be diagnosed with post-traumatic stress disorder (PTSD) in their lifetime. In the laboratory, stress-enhanced fear learning (SEFL) has emerged as a good model for PTSD and trauma-induced maladaptive affective behavior, as a single stressful episode can produce long-lasting effects. For example, PTSD patients exhibit sustained dysfunctions in cognition, attention, and information processing after exposure to a traumatic experience. Similarly, rodents that undergo the SEFL protocol exhibit exaggerated conditioned fear responses to mild aversively motivated unconditioned stimuli (US). This behavior attributed to fear sensitization is hypothesized to be non-associative and may contribute to deficits in other behavioral domains. The purpose of this study is to identify behavioral phenotypes that are unrelated yet sensitive to the trauma-like episode. In particular, we focused on fear learning, appetitive motivation, unlearned defensive behaviors, and spatial working memory in mice. Our preliminary data recapitulates previous effects on fear learning, demonstrating that footshock stress results in fear sensitization (stress vs. non-stressed, p<0.001) and in reduced exploration in an open field (p=0.0044); though, we did not observe any differences in measures of learned helplessness (p=0.16) or reward-seeking behavior (p=0.10). Overall, our results replicated the previously established effects and identified new sensitive and non-sensitive sequelae of this model for trauma-like stress.

13, Investigating the use of neuroimaging biomarkers to predict baseline motor impairment and improvement after therapy in stroke patients

Hay, A.; Madjidov, A.; Shinde, A.; Schlaug, G.

Neurology, UMass Chan Medical School

Background: Post-stroke motor impairment can have lasting effects on patients’ quality of life. The degree to which their motor function will improve may be influenced by variables such as age, gender, intensity of therapy, initial motor impairment, lesion volume, and degree of injury to the corticospinal tract (CST). Neuroimaging biomarkers may provide an affordable and accessible method to quantify CST injury, predict motor impairment, and predict improvement from rehabilitation therapy. Previous research has found that weighted CST lesion load (wCST-LL), measured in the acute phase, is correlated with 3-month motor outcomes. In this study, we expand on this work by investigating supplementary markers that assess two specific aspects of motor system injury that were not previously accounted for: cortical injury and Wallerian degeneration. We will evaluate if a) wCST-LL, wCortical-LL, and/or wWD-LL correlate with initial motor impairment; b) if any combination of these markers correlate with motor improvement following therapeutic intervention; and c) if the presence or absence of Wallerian degeneration, defined as visible linear hypointense signal within the CST distal to the lesion, correlates with motor outcomes.

Methods: T1 MRI sequences were obtained for 28 participants enrolled in TRANSPORT2 and Beyond TRANSPORT2 at Baystate Medical Center. Lesion maps of the index stroke and Wallerian degeneration signal (when present) were hand drawn on segmented, spatially normalized images. Index lesion maps were overlayed with the probabilistic canonical CST and a spatial representation of the pre- and post-central gyri generated from healthy volunteer brains. Calculations determined the wCST-LL and weighted cortical lesion load (wCortical-LL) from these overlays. Wallerian degeneration maps were overlayed with the canonical CST to calculate the weighted Wallerian degeneration lesion load (wWD-LL). Clinical baseline impairment and improvement in motor function were assessed using the Fugl-Meyer Upper-Extremity (FM-UE) scale.

Results: Preliminary results indicate that a measure of total system's injury (cortical lesion, white matter lesions) better correlates with baseline impairment level. Participants without Wallerian degeneration display greater improvement in FM-UE scores from baseline to 3 months (10.96 vs 7.22), and among participants with Wallerian degeneration those with less FM-UE improvement tend to have higher wWD-LL values.

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