recruitment

TACTIC: Tuberculosis Active Case Tracking via Interpersonal Connections

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) remains the leading infectious cause of death worldwide. Interruption of transmission is the most effective strategy to reduce incident infections, yet current approaches often fail to reach individuals for timely testing and treatment. This study addresses that gap by leveraging social networks to identify individuals at highest risk of transmitting TB, specifically, people who use drugs (PWUD). We will evaluate respondent-driven sampling (RDS), a peer7 based community recruitment strategy, to identify TB cases among PWUD and the household contacts (HHCs) of those with TB disease (RDS-TB) in Kampala, Uganda. Conducting this work in a high-prevalence setting such as Kampala where our team has established expertise allows us to overcome recruitment challenges common in settings in the United States while generating findings that are directly translatable. This is particularly relevant given that higher TB prevalence and larger outbreaks in the United States have been associated with the use of methamphetamine, heroin, and crack/cocaine, drugs that we will study. In Aim 1, we will compare the effectiveness and reach of RDS-TB with a traditional clinic-based index case HHC approach for TB case finding. We will screen 2,000 PWUD and their HHCs, estimate the number needed to screen to identify one case of TB disease, and compare the demographic and network characteristics of RDS-TB recruits with clinic-based HHCs. Whole genome sequencing will be used to characterize transmission dynamics. In Aim 2, we will compare the yield of individual and combined TB diagnostic strategies for community-based active case finding. Participants will undergo chest radiography with computer-aided detection, tongue swab testing for TB nucleic acid amplification tests (NAAT), and sputum testing for NAAT and mycobacterial culture. We will identify the minimal combination of tests needed to meet World Health Organization target product profile thresholds for screening. In Aim 3, we will define the conditions under which RDS-based screening can effectively interrupt TB transmission. We will develop an agent-based model informed by social network data from individuals with and without TB, incorporating drug use patterns and demographic characteristics. This project will generate a practical, scalable roadmap for social network–based TB active case finding in high28 risk communities. The approach will be readily adaptable to settings in the United States and will inform strategies to interrupt transmission and advance progress toward TB elimination, in alignment with the NIH Strategic Plan for TB Research.

Increasing Lung Cancer Screening Uptake Among High-Risk Emergency Department Patients

PROJECT SUMMARY/ABSTRACT Lung cancer is the leading cause of cancer death in the US. Although lung cancer screening (LCS), using low- dose CT scan, decreases lung cancer mortality through early disease identification, fewer than 1 in 6 eligible individuals get screened, with significant differences based on demographic and socio-economic factors. LCS is a process, not just a test. The critical first steps in this process are (1) identification of high-risk individuals who are eligible for LCS, and (2) recruitment of these individuals into an LCS program. The Emergency Department (ED) setting is optimal for an intervention to promote LCS by accomplishing these steps. Individuals at high risk for lung cancer are over-represented in the ED population, including: individuals that smoke, non-White individuals, patients with lower education levels, and the under-insured. In fact, over 2.3 million high-risk people pass through EDs every year who are eligible for LCS but have never been screened. The investigators’ long-term goal is to develop a low-cost, scalable intervention that increases LCS uptake among ED patients and is deployable in any ED with a regionally referrable LCS program. The objective of the proposed randomized clinical trial is to test the efficacies of text messaging and a facilitated referral strategy to promote uptake of LCS in order to achieve this goal. Step 1 of the approach is to identify participants that are eligible for LCS. Step 2 is to randomize eligible participants, using a 2x2 design, among four study arms: (1) basic referral for LCS (i.e. verbal referral with written materials; comprising an enhanced control arm), (2) basic referral plus a subsequent series of text messages, grounded in behavioral change theory, aimed at generating intention and motivation to get screened, (3) facilitated referral for LCS (i.e. submission of a requisition to LCS program by staff), and (4) facilitated referral plus text messages. The investigators’ pilot work demonstrated the feasibility and efficacy of the proposed approach. A total of 1036 individuals eligible for LCS will be recruited from a high-volume urban ED and a low-volume rural ED, randomized among study arms, and followed-up at 120 days to assess interval LCS uptake. The Specific Aims of the proposed project are, (1) Compare LCS program uptake among study arms that receive text messages to study arms that do not, (2) Compare LCS program uptake among study arms with basic referral to study arms with facilitated referral, (3) Investigate the interaction between receipt of text messages (yes/no) and referral type (basic/facilitated), and (4) Evaluate participant feedback on (a) differential barriers to LCS across sub-groups and (b) acceptability and appropriateness of ED-based promotion of LCS. The study team is at the forefront of developing ED-based interventions to promote cancer screening. This project leverages the universal access setting of the ED to identify individuals at greatest risk for lung cancer and get them screened. A scalable ED-based intervention that increases LCS uptake would save lives.

Perturbation of mammary immunoglobulins during maternal antibiotic administration

Project Summary Prescribed in up to 40% of pregnancies, antibiotics represent the most commonly used class of medication during pregnancy. Although this practice is often necessary for maternal health, accumulating evidence suggests that antibiotic exposure may have unintended consequences for the mother-infant dyad. Epidemiologic studies associate maternal antibiotic exposure, especially in the absence of infection, with increased risk of neonatal complications including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), yet the mechanisms driving these associations remain poorly understood. Secretory IgA (sIgA) in milk is an essential component of neonatal mucosal immunity, shaping early gut microbial colonization and providing protection against enteric pathogens. The mechanisms by which maternal physiology regulates the abundance and microbial specificity of these antibodies in milk remain poorly understood. In animal models, the maternal gut–mammary axis governs the generation of milk IgA: IgA-committed lymphocytes from the maternal intestine migrate to the mammary gland during advancing pregnancy via CCL- 28/CCR10 signaling. Our preliminary data suggest that maternal antibiotic exposure disrupts this process leading to a decrease in milk IgA. However, the timing and extent of antibody dysbiosis are undefined; the downstream effects on neonatal intestinal health are unknown; and the underlying mechanisms—whether due to altered microbial stimulation, impaired recruitment of IgA⁺ cells to the mammary gland, or both—remain to be elucidated. Our central hypothesis is that maternal antibiotic exposure reduces pathogen-reactive IgA in milk by impairing gut-to-mammary immune cell trafficking thereby compromising neonatal mucosal immunity and increasing infection susceptibility. We will address this hypothesis through three integrated aims: (1) Determine the magnitude and duration of antibiotic-mediated mammary antibody dysbiosis in women who deliver preterm and at term; (2) Identify microbial targets of mammary antibodies diminished by maternal antibiotic exposure and (3 Determine the role of maternal antibiotics in the disruption of mammary resident IgA+ plasma cells in animal models. This integrative human and animal study will uncover critical mechanisms by which maternal antibiotic use alters the maternal-infant immune axis. The results will provide mechanistic insight into the risks associated with perinatal antibiotic exposure and inform clinical strategies to mitigate risk to neonatal health.

TAR RNA binding to INI1/SMARCB1 and its role in HIV-1 transcription and latency reactivation

Abstract The goal of this application is to study the role of interplay between the components of chromatin remodeling SWI/SNF (BAF complex) and HIV-1 transcription machinery, focusing on the interaction of a BAF component, INI1 (Integrase Interactor 1) with TAR RNA. HIV-1 reservoirs are a mixture of latent cells harboring proviruses silenced at transcriptional level. Cure strategies need a deeper understanding of HIV-1 transcriptional regulation. HIV-1 transcription, initiated by RNA Pol II, pauses producing short TAR transcripts. pTEFb recruitment to TAR by Tat overcomes this transcriptional pause, facilitating elongation. Beyond Tat, the action of chromatin remodeling complexes (CRCs) is required to facilitate elongation. The BAF complexes CBAF and PBAF play distinct roles. While CBAF represses proviral transcription by maintaining nucleosomes in an unfavorable state, PBAF remodels nucleosomes to facilitate elongation. INI1 is a component of both CBAF and PBAF, and its role in transcription is not fully understood. INI1 was identified as a binding partner for HIV-1 integrase (IN) and exerts multifacted roles in virus assembly, production and morphogenesis. INI1 has multiple functional domains. IN binding Rpt1 domain structurally mimics TAR RNA & is necessary for late events. We have made a novel observation that another domain of INI1, the N-terminal Winged Helix DNA binding domain (WHD) specifically binds to TAR RNA and that this interaction is necessary for mediating HIV-1 transcriptional elongation. These exciting results suggest that different functional domains of INI1(Rpt1 and WHD) involved in “TAR RNA mimicry” or “TAR RNA binding” regulate distinct stages of replication. We hypothesize that INI1 WHD domain-TAR interaction is necessary for recruitment of PBAF to HIV-1 LTR for transcriptional elongation and latency reactivation. Disrupting this interaction results in transcriptional repression. We will investigate the role of this novel INI1:TAR RNA interaction in HIV-1 transcription and latency reactivation. This is a multi-PI application involving Drs. Kalpana (HIV-1 virologist), Heng (NMR biophysicist) and Zou (computational biologist/protein-RNA structure). In Aim 1, we will characterize INI1-WHD:TAR interaction in vitro and in vivo via molecular/genetic analyses (Kalpana/Heng). We will employ alanine scanning mutagenesis based on WHD NMR structure to test WHD:TAR interaction. We will use biophysical & biochemical approaches to probe TAR structural elements required for this interaction. In Aim 2, we will employ computational modeling and NMR to determine the structure of INI1- WHD:TAR RNA complex (Zou/Heng). In Aim 3, we will determine the role of INI1:TAR interactions in HIV-1 transcription, latency reactivation and mechanism of action (Kalpana). We will analyze the effect of TAR- Interaction-Defective (TID) INI1 mutants on transcription of LTR-reporters and full-length HIV in INI1-/- cells. Latent cells in which TID-INI1 mutants are knocked in (KI) will be used to assess effect on reactivation via RNA-FISH and qRT-PCR assays. Our studies will establish INI1:TAR interaction as a drug target. Inhibiting this interaction could block latency reactivation promoting deep latency and advancing cure strategies.

ATPase Chromatin Remodeling Complexes as Modulators of HIV-1 Latency and Therapeutic Targets

Abstract Significance: HIV persists in long-lived CD4⁺ T cell reservoirs despite suppressive ART, as integrated proviruses remain poised for reactivation. Chromatin remodeling is a central barrier to durable silencing, yet most studies have focused on SWI/SNF family members. The roles of non- SWI/SNF remodelers remain poorly defined, limiting our ability to rationally design host-directed “block-and-lock” cure strategies. Our unbiased shRNA screen of all 16 human remodeler ATPases identified EP400, CHD1, and CHD9 as repressors and INO80A, SMARCA5, and CHD2 as activators, establishing chromatin remodeling as a key determinant of HIV latency. Innovation: Our prior studies revealed that the p400 complex regulates HIV transcription through dual mechanisms: directly, by engaging Tat via the DMAP1 subunit to block Tat-TAR RNA interactions and restrict p-TEFb recruitment; and indirectly, by altering host transcriptional programs that control T cell activation states. Building on this mechanistic precedent and methodological platform, we now focus on INO80A, SMARCA5, CHD1, and CHD2, remodelers from distinct ATPase families that govern Tat-independent checkpoints at initiation, pause release, and elongation. Methodologically, we will apply TurboID-ChAP-MS (locus-specific proteomics), BEM-seq (single-nucleosome mapping), and degron-mediated acute depletion with ATPase-dead rescue to interrogate remodeler function with unprecedented resolution. Approach: Aim 1 will define the ATPase requirement and transcriptional checkpoints regulated by INO80A, SMARCA5, CHD1, and CHD2 using degron/CRISPR perturbations, ChIP-seq, nascent RNA profiling, and nucleosome mapping. Aim 2 will characterize remodeler-specific complexes and Tat dependence at the HIV promoter via TurboID proximity labeling integrated with chromatin affinity purification-mass spectrometry. Aim 3 will test combinatorial perturbations in Jurkat and primary CD4⁺ T cell latency models, including ART-suppressed donor cells, to identify synergistic “block-and-lock” strategies that enforce durable proviral silencing. Impact: By defining remodeler-specific mechanisms at discrete transcriptional checkpoints and leveraging their enzymatic, druggable activities, this work will establish chromatin remodeling as a therapeutic axis for durable HIV suppression and functional cure.

Chromatin-Based Mechanisms Linking Transcriptional Dysregulation to Genome Instability in Neurodevelopmental Disorders.

PROJECT SUMMARY/ABSTRACT Neurons depend on a finely tuned interplay between chromatin regulation and genome maintenance, yet they are acutely vulnerable to DNA damage generated during activity-dependent transcription of long, synaptic genes. Disruption of this balance is increasingly recognized as a driver of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), intellectual disability, and epilepsy. High-confidence genetic studies converge on regulators of histone H3 lysine 4 (H3K4) methylation, such as the writers ASHIL and Klv1T2C and the eraser KDNISB, as recurrently mutated loci in NTIDs. The overarching goal of this study is to investigate how dysregulated H3K4 methylation compromises genome integrity in human neurons, thereby contributing to the pathogenesis of NDDs. The central, hypothesis is that coordinated II3K4 methylation safeguards neuronal genomes by maintaining an open chromatin architecture that permits the efficient detection and repair of transcription-coupled DNA lesions. The rationale/Or this study is to define the epigenetic control of DNA repair, which will illuminate a shared pathogenic hub across multiple ~I)D-linked genes. During the mentoredK99 phase, I will define how ASHIL, KMT2C, and KDM5B regulate chromatin structure and DNA repair at baseline and during transcriptional stress. Aim-1: I will use isogenic iPSC-derived cortical neurons with patient-relevant mutations or CRrSPRi knockdowns of these regulators, applying an integrated multi-omic pipeline: CUT&Tag and Micro-C to map H3K4 methylation and 3D chromatin topology. Aim-2: I will use Paired-Damage-seq, and CUT&RUN to chart oxidative lesions, repair synthesis, and recruitment of key repair factors; and RNA-seq to relate damage hotspots to altered gene expression. Aims l and 2 will be performed under the guidance of Dr. Lizarraga and Dr. Morrow, experts in the field of neurodevelopmental biology. My advisory team brings unique and complementary skills, enhancing my knowledge in 3D chromatin structure, transcription-coupled repair, gene editing, and multi-omics analysis. I will utilize these skills in the R00 phase (Aim 3), expanding the framework to include additional H3K4 regulators (e.g., LSD1, KMT2A) and broader neural lineages, thereby developing a comprehensive model. This study is innovative in its integration of single-cell D.NA damage mapping with chromatin topology and transcriptional profiling, enabling a direct and mechanistic connection between disrupted H3K4 methylation and genome instability. By uncovering how H3.K4 methylation prevents transcription-coupled genome instability in the developing brain, this research will address a critical gap in our understanding of NDD mechanisms. This award will enable me to launch an independent research program dedicated to determining mechanisms of chromatin-based processes that maintain genome stability in the developing human brain.

Functional Plasticity in the Language Network – evidence from Neuroimaging and Neurostimulation

Efficient cognition requires flexible interactions between distributed neural networks in the human brain. These networks adapt to challenges by flexibly recruiting different regions and connections. In this talk, I will discuss how we study functional network plasticity and reorganization with combined neurostimulation and neuroimaging across the adult life span. I will argue that short-term plasticity enables flexible adaptation to challenges, via functional reorganization. My key hypothesis is that disruption of higher-level cognitive functions such as language can be compensated for by the recruitment of domain-general networks in our brain. Examples from healthy young brains illustrate how neurostimulation can be used to temporarily interfere with efficient processing, probing short-term network plasticity at the systems level. Examples from people with dyslexia help to better understand network disorders in the language domain and outline the potential of facilitatory neurostimulation for treatment. I will also discuss examples from aging brains where plasticity helps to compensate for loss of function. Finally, examples from lesioned brains after stroke provide insight into the brain’s potential for long-term reorganization and recovery of function. Collectively, these results challenge the view of a modular organization of the human brain and argue for a flexible redistribution of function via systems plasticity.

Circuit Mechanisms of Remote Memory

Memories of emotionally-salient events are long-lasting, guiding behavior from minutes to years after learning. The prelimbic cortex (PL) is required for fear memory retrieval across time and is densely interconnected with many subcortical and cortical areas involved in recent and remote memory recall, including the temporal association area (TeA). While the behavioral expression of a memory may remain constant over time, the neural activity mediating memory-guided behavior is dynamic. In PL, different neurons underlie recent and remote memory retrieval and remote memory-encoding neurons have preferential functional connectivity with cortical association areas, including TeA. TeA plays a preferential role in remote compared to recent memory retrieval, yet how TeA circuits drive remote memory retrieval remains poorly understood. Here we used a combination of activity-dependent neuronal tagging, viral circuit mapping and miniscope imaging to investigate the role of the PL-TeA circuit in fear memory retrieval across time in mice. We show that PL memory ensembles recruit PL-TeA neurons across time, and that PL-TeA neurons have enhanced encoding of salient cues and behaviors at remote timepoints. This recruitment depends upon ongoing synaptic activity in the learning-activated PL ensemble. Our results reveal a novel circuit encoding remote memory and provide insight into the principles of memory circuit reorganization across time.

Divergent Recruitment of Developmentally-Defined Neuronal Ensembles Supports Memory Dynamics

Sex hormone regulation of neural gene expression

Gonadal steroid hormones are the principal drivers of sex-variable biology in vertebrates. In the brain, estrogen (17β-estradiol) establishes neural sex differences in many species and modulates mood, behavior, and energy balance in adulthood. To understand the diverse effects of estradiol on the brain, we profiled the genomic binding of estrogen receptor alpha (ERα), providing the first picture of the neural actions of any gonadal hormone receptor. To relate ERα target genes to brain sex differences we assessed gene expression and chromatin accessibility in the posterior bed nucleus of the stria terminalis (BNSTp), a sexually dimorphic node in limbic circuitry that underlies sex-differential social behaviors such as aggression and parenting. In adult animals we observe that levels of ERα are predictive of the extent of sex-variable gene expression, and that these sex differences are a dynamic readout of acute hormonal state. In neonates we find that transient ERα recruitment at birth leads to persistent chromatin opening and male-biased gene expression, demonstrating a true epigenetic mechanism for brain sexual differentiation. Collectively, our findings demonstrate that sex differences in gene expression in the brain are a readout of state-dependent hormone receptor actions, rather than other factors such as sex chromosomes. We anticipate that the ERα targets we have found will contribute to established sex differences in the incidence and etiology of neurological and psychiatric disorders.

Cortical seizure mechanisms: insights from calcium, glutamate and GABA imaging

Focal neocortical epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood, but is likely to relate to the intermittent collapse of feed-forward GABAergic inhibition. Inhibition could fail through multiple mechanisms, including (i) an attenuation or even reversal of the driving force for chloride in postsynaptic neurons because of intense activation of GABAA receptors, (ii) an elevation of potassium secondary to chloride influx leading to depolarization of neurons, or (iii) insufficient GABA release from interneurons. I shall describe the results of experiments using fluorescence imaging of calcium, glutamate or GABA in awake rodent models of neocortical epileptiform activity. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagatedcentrifugally. GABA transients lasted longer than glutamate transients and were maximal ~1.5 mm from the focus. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing runaway recruitment of excitatory neurons as a fundamental mechanism underlying the escape of seizures from local inhibitory restraint.

NMC4 Short Talk: Two-Photon Imaging of Norepinephrine in the Prefrontal Cortex Shows that Norepinephrine Structures Cell Firing Through Local Release

Norepinephrine (NE) is a neuromodulator that is released from projections of the locus coeruleus via extra-synaptic vesicle exocytosis. Tonic fluctuations in NE are involved in brain states, such as sleep, arousal, and attention. Previously, NE in the PFC was thought to be a homogenous field created by bulk release, but it remains unknown whether phasic (fast, short-term) fluctuations in NE can produce a spatially heterogeneous field, which could then structure cell firing at a fine spatial scale. To understand how spatiotemporal dynamics of norepinephrine (NE) release in the prefrontal cortex affect neuronal firing, we performed a novel in-vivo two-photon imaging experiment in layer ⅔ of the prefrontal cortex using a green fluorescent NE sensor and a red fluorescent Ca2+ sensor, which allowed us to simultaneously observe fine-scale neuronal and NE dynamics in the form of spatially localized fluorescence time series. Using generalized linear modeling, we found that the local NE field differs from the global NE field in transient periods of decorrelation, which are influenced by proximal NE release events. We used optical flow and pattern analysis to show that release and reuptake events can occur at the same location but at different times, and differential recruitment of release and reuptake sites over time is a potential mechanism for creating a heterogeneous NE field. Our generalized linear models predicting cellular dynamics show that the heterogeneous local NE field, and not the global field, drives cell firing dynamics. These results point to the importance of local, small-scale, phasic NE fluctuations for structuring cell firing. Prior research suggests that these phasic NE fluctuations in the PFC may play a role in attentional shifts, orienting to sensory stimuli in the environment, and in the selective gain of priority representations during stress (Mather, Clewett et al. 2016) (Aston-Jones and Bloom 1981).

Do you hear what I see: Auditory motion processing in blind individuals

Perception of object motion is fundamentally multisensory, yet little is known about similarities and differences in the computations that give rise to our experience across senses. Insight can be provided by examining auditory motion processing in early blind individuals. In those who become blind early in life, the ‘visual’ motion area hMT+ responds to auditory motion. Meanwhile, the planum temporale, associated with auditory motion in sighted individuals, shows reduced selectivity for auditory motion, suggesting competition between cortical areas for functional role. According to the metamodal hypothesis of cross-modal plasticity developed by Pascual-Leone, the recruitment of hMT+ is driven by it being a metamodal structure containing “operators that execute a given function or computation regardless of sensory input modality”. Thus, the metamodal hypothesis predicts that the computations underlying auditory motion processing in early blind individuals should be analogous to visual motion processing in sighted individuals - relying on non-separable spatiotemporal filters. Inconsistent with the metamodal hypothesis, evidence suggests that the computational algorithms underlying auditory motion processing in early blind individuals fail to undergo a qualitative shift as a result of cross-modal plasticity. Auditory motion filters, in both blind and sighted subjects, are separable in space and time, suggesting that the recruitment of hMT+ to extract motion information from auditory input includes a significant modification of its normal computational operations.

Interpreting the Mechanisms and Meaning of Sensorimotor Beta Rhythms with the Human Neocortical Neurosolver (HNN) Neural Modeling Software

Electro- and magneto-encephalography (EEG/MEG) are the leading methods to non-invasively record human neural dynamics with millisecond temporal resolution. However, it can be extremely difficult to infer the underlying cellular and circuit level origins of these macro-scale signals without simultaneous invasive recordings. This limits the translation of E/MEG into novel principles of information processing, or into new treatment modalities for neural pathologies. To address this need, we developed the Human Neocortical Neurosolver (HNN: https://hnn.brown/edu ), a new user-friendly neural modeling tool designed to help researchers and clinicians interpret human imaging data. A unique feature of HNN’s model is that it accounts for the biophysics generating the primary electric currents underlying such data, so simulation results are directly comparable to source localized data. HNN is being constructed with workflows of use to study some of the most commonly measured E/MEG signals including event related potentials, and low frequency brain rhythms. In this talk, I will give an overview of this new tool and describe an application to study the origin and meaning of 15-29Hz beta frequency oscillations, known to be important for sensory and motor function. Our data showed that in primary somatosensory cortex these oscillations emerge as transient high power ‘events’. Functionally relevant differences in averaged power reflected a difference in the number of high-power beta events per trial (“rate”), as opposed to changes in event amplitude or duration. These findings were consistent across detection and attention tasks in human MEG, and in local field potentials from mice performing a detection task. HNN modeling led to a new theory on the circuit origin of such beta events and suggested beta causally impacts perception through layer specific recruitment of cortical inhibition, with support from invasive recordings in animal models and high-resolution MEG in humans. In total, HNN provides an unpresented biophysically principled tool to link mechanism to meaning of human E/MEG signals.

Making memories in mice

Understanding how the brain uses information is a fundamental goal of neuroscience. Several human disorders (ranging from autism spectrum disorder to PTSD to Alzheimer’s disease) may stem from disrupted information processing. Therefore, this basic knowledge is not only critical for understanding normal brain function, but also vital for the development of new treatment strategies for these disorders. Memory may be defined as the retention over time of internal representations gained through experience, and the capacity to reconstruct these representations at later times. Long-lasting physical brain changes (‘engrams’) are thought to encode these internal representations. The concept of a physical memory trace likely originated in ancient Greece, although it wasn’t until 1904 that Richard Semon first coined the term ‘engram’. Despite its long history, finding a specific engram has been challenging, likely because an engram is encoded at multiple levels (epigenetic, synaptic, cell assembly). My lab is interested in understanding how specific neurons are recruited or allocated to an engram, and how neuronal membership in an engram may change over time or with new experience. Here I will describe both older and new unpublished data in our efforts to understand memories in mice.

Meta-analytic evidence of differential prefrontal and early sensory cortex activity during non-social sensory perception in autism

To date, neuroimaging research has had a limited focus on non-social features of autism. As a result, neurobiological explanations for atypical sensory perception in autism are lacking. To address this, we quantitively condensed findings from the non-social autism fMRI literature in line with the current best practices for neuroimaging meta-analyses. Using activation likelihood estimation (ALE), we conducted a series of robust meta-analyses across 83 experiments from 52 fMRI studies investigating differences between autistic (n = 891) and typical (n = 967) participants. We found that typical controls, compared to autistic people, show greater activity in the prefrontal cortex (BA9, BA10) during perception tasks. More refined analyses revealed that, when compared to typical controls, autistic people show greater recruitment of the extrastriate V2 cortex (BA18) during visual processing. Taken together, these findings contribute to our understanding of current theories of autistic perception, and highlight some of the challenges of cognitive neuroscience research in autism.

Blindspot: Hidden Biases of Good People

Mahzarin Banaji and her colleague coined the term “implicit bias” in the mid-1990s to refer to behavior that occurs without conscious awareness. Today, Professor Banaji is Cabot Professor of Social Ethics in the Department of Psychology at Harvard University, a member of the American Academy of Arts and Sciences, the National Academy of Sciences and has received numerous awards for her scientific contributions. The purpose of the seminar, Blindspot: Hidden Biases of Good People, is to reveal the surprising and even perplexing ways in which we make errors in assessing and evaluating others when we recruit and hire, onboard and promote, lead teams, undertake succession planning, and work on behalf of our clients or the public we serve. It is Professor Banaji’s belief that people intend well and that the inconsistency we see, between values and behavior, comes from a lack of awareness. But because implicit bias is pervasive, we must rely on scientific evidence to “outsmart” our minds. If we do so, we will be more likely to reach the life goals we have chosen for ourselves and to serve better the organizations for which we work.

Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning

How is it that some memories fade in a day while others last forever? The formation of long-lasting (remote) memories depends on the coordinated activity between the hippocampus and frontal cortices, but the timeline of these interactions is debated. Astrocytes, star-shaped glial cells, sense and modify neuronal activity, but their role in remote memory is scarcely explored. We manipulated the activity of hippocampal astrocytes during memory acquisition and discovered it impaired remote, but not recent, memory retrieval. We also revealed a massive recruitment of cortical-projecting hippocampal neurons during memory acquisition, a process that is specifically inhibited by astrocytic manipulation. Finally, we directly inhibited this projection during memory acquisition to prove its necessity for the formation of remote memory. Our findings reveal that the foundation of remote memory can be established during acquisition with projection-specific effect of astrocytes.

The recruitment of spatial cells in large-scale space & an AI approach to neural discovery

Prof Caswell Barry, Professorial Research Fellow, Cell & Developmental Biology, Division of Biosciences, University College London. He and his team are trying to understand how the brain works - how it creates that experience of being human, and more specifically, how the brain creates, stores, and updates memories for places and events. They are trying to answer this is by studying areas of the brain linked to memory, the hippocampus and associated sections of cortex – by recording the activity of neurons in these areas we can visualise and hopefully understand the processes the trigger memory formation and retrieval.

Cognitive deficits in mouse model of Fragile X Syndrome reflect specific memory ensemble recruitment failure along the ventral hippocampus-prelimbic cortex axis

Control of post-synaptic density protein recruitment by optogenetic manipulation of the spine cytoskeleton

HBK-15 preferentially activates ß-arrestin recruitment and GIRK channels after binding to the 5-HT1A receptor and reverses long-term memory impairments in mice

Learning trajectory predicts the level of recruitment of a primary sensory cortex in a negative reinforcement behavioral paradigm

Parkinson’s disease LRRK2-G2019S disrupts HDAC6-mediated recruitment of misfolded protein aggregates into aggresomes

Prediction and prevention of compulsive behaviors by closed-loop optogenetic recruitment of striatal interneurons

Spatio-temporal recruitment of adult neural stem cells during pregnancy for transient neurogenesis

Divergent recruitment of birthdated hippocampal neuronal ensembles supports memory dynamics

FENS Forum 2024

GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles

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HBK-10, a multimodal compound, selectively blocks 5-HT1A receptor-mediated β-arrestin recruitment and mitigates memory deficits in mice

FENS Forum 2024

Intact systems consolidation in pre-symptomatic AD mice relies on recruitment of compensatory subcortical and cortical regions

FENS Forum 2024

Investigating the recruitment of parvalbumin and somatostatin interneurons into engrams for associative recognition memory

FENS Forum 2024

Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes

FENS Forum 2024

Optimizing muscle recruitment by exploring different parameters of intraneural electrical stimulation

FENS Forum 2024

Potential role for microRNA regulation in the tuning of engram recruitment during fear memory consolidation

FENS Forum 2024

Prediction and prevention of compulsive behaviors by closed-loop optogenetic recruitment of striatal interneurons

FENS Forum 2024

Recruitment of prefrontal cortical neurons by both cognitive and motor tasks

FENS Forum 2024