Faculty Bibliography

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability was correlated with UP/DOWN states in mouse default mode network, with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN→UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain, yet failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a coreceptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 was coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppressed NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibited NGF/TrkA signaling, whereas NRP1 overexpression enhanced signaling. NGF bound NRP1 with high affinity and interacted with and chaperoned TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggested that the C-terminal R/KXXR/K NGF motif interacts with the extracellular "b" NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G α interacting protein C-terminus 1 (GIPC1), which scaffolds NRP1 and TrkA to myosin VI, colocalized in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogated NGF-evoked excitation of nociceptors and pain-like behavior. Thus, NRP1 is a nociceptor-enriched coreceptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via the GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited nonopioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.

INTRODUCTION/UNASSIGNED:Older adults undergoing surgery are at risk of postoperative neurocognitive disorders, prompting the need for preoperative cognitive screening in this population. Traditionally, cognitive screening has been conducted in-person using brief assessment tools such as the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE). More comprehensive test batteries, such as the Uniform Data Set (UDS) Neuropsychological Battery, and its remote testing version, the Uniform Data Set version 3 tele-adapted test battery (UDS v3.0 T-cog), have been developed to assess cognitive decline in normal aging and disease conditions, but have not been applied in the perioperative setting. METHODS/UNASSIGNED:We assessed the feasibility of using this remote UDS v3.0 T-cog battery for preoperative cognitive assessment in 81 older adults 65+ scheduled for lower extremity joint replacement surgery. RESULTS/UNASSIGNED:Our results indicate that the UDS v3.0 T-cog achieves 99% completion rates and demonstrates high patient satisfaction. Further, we found 28% of subjects were cognitively impaired in this patient cohort. DISCUSSION/UNASSIGNED:These findings suggest that the UDS v3.0 T-cog is a feasible tool for assessing cognitive function in the older adult perioperative population. To our knowledge, this is the first study to apply this comprehensive remote test battery in the preoperative setting.

The posterior "tail" region of the striatum receives dense innervation from sensory brain regions and is important for behaviors that require sensorimotor integration. The output neurons of the striatum, D1 and D2 striatal projection neurons (SPNs), which make up the direct and indirect pathways, are thought to play distinct functional roles, although it remains unclear if these neurons show cell-type-specific differences in their response to sensory stimuli. Here, we examine the strength of synaptic inputs onto D1 and D2 SPNs following the stimulation of upstream auditory pathways. We report that auditory-evoked depolarizations onto D1 SPN responses are stronger and faster. This is due to differences in feedforward inhibition, with fast-spiking interneurons forming stronger synapses onto D2 SPNs. Our results support a model in which differences in feedforward inhibition enable the preferential recruitment of D1 SPNs by auditory stimuli, positioning the direct pathway to initiate sound-driven actions.

OBJECTIVES/UNASSIGNED:This study aims to synthesize current knowledge and outcomes related to pediatric auditory brainstem implantation (ABI) in children with severe inner ear malformations (IEMs). It highlights the clinical management practices, challenges, and potential future directions for consensus development in this field. METHODS/UNASSIGNED:A systematic review of findings presented at the Third International Pediatric ABI Symposium organized by the Hacettepe Cochlear Implant team between 3 and 5 September 2020 was conducted, incorporating data from 41 departments across 19 countries. Relevant clinical outcomes, imaging techniques, surgical approaches, and rehabilitation strategies were analyzed to identify key trends and variability in practices. RESULTS/UNASSIGNED:The review indicates that children receiving ABIs exhibit diverse auditory outcomes influenced by individual anatomical variations and developmental factors. Early implantation, particularly before the age of three, positively correlates with better auditory and language development. Multicenter experiences underscore the necessity of tailored decision-making, which considers both surgical candidacy and comprehensive rehabilitation resources. DISCUSSION:/UNASSIGNED:The variability in outcomes emphasizes the need for improved consensus and guidelines regarding eligibility, surgical techniques, and multidisciplinary rehabilitation approaches. Notable complications and the necessity for thorough imaging assessments were also identified as critical components affecting clinical decisions. CONCLUSION/UNASSIGNED:A formal consensus statement is warranted to standardize best practices in ABI management. This will not only enhance patient outcomes but also guide future research efforts to address the remaining challenges in the treatment of children with severe IEMs. Enhanced collaboration among team members will be pivotal in achieving these objectives.

INTRODUCTION/UNASSIGNED:Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. RESULTS/UNASSIGNED:NK cells in the bone barrow and spleen. DISCUSSION/UNASSIGNED:subunit Kir6.1 has a key role in NK-cell development.

Alzheimer's disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss. In an AD-related mouse model expressing APOE4, XY sex chromosomes heightened interferon (IFN) response and tau-induced demyelination. The X-linked gene, Toll-like receptor 7 (Tlr7), regulated sex-specific IFN response to myelin. Deletion of Tlr7 dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that Tlr7 plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.