Project description:Discussions of the hippocampus often focus on place cells, but many neurons are not place cells in any given environment. Here we describe the collective activity in such mixed populations, treating place and non-place cells on the same footing. We start with optical imaging experiments on CA1 in mice as they run along a virtual linear track and use maximum entropy methods to approximate the distribution of patterns of activity in the population, matching the correlations between pairs of cells but otherwise assuming as little structure as possible. We find that these simple models accurately predict the activity of each neuron from the state of all the other neurons in the network, regardless of how well that neuron codes for position. Our results suggest that understanding the neural activity may require not only knowledge of the external variables modulating it but also of the internal network state.
Project description:Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is biased by inputs from CA1 inhibitory neurons and the visual cortex, but lacks input from the entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target the perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. Our findings also implicate this circuitry in the formation of complex spatial representations and learning of object-place associations.
Project description:Over the past 20 years, there has been tremendous progress in retinal gene therapy. The safety and efficacy results in one early-onset severe blinding disease may lead to the first gene therapy drug approval in the United States. Here, we review how far the field has come over the past two decades and speculate on the directions that the field will take in the future.
Project description:Salient but aversive stimuli inhibit the majority of dopamine (DA) neurons in the ventral tegmental area (VTA) and cause conditioned place aversion (CPA). The cellular mechanism underlying DA neuron inhibition has not been investigated and the causal link to behavior remains elusive. Here, we show that GABA neurons of the VTA inhibit DA neurons through neurotransmission at GABA(A) receptors. We also observe that GABA neurons increase their firing in response to a footshock and provide evidence that driving GABA neurons with optogenetic effectors is sufficient to affect behavior. Taken together, our data demonstrate that synaptic inhibition of DA neurons drives place aversion.
Project description:Advances in optical neuroimaging techniques now allow neural activity to be recorded with cellular resolution in awake and behaving animals. Brain motion in these recordings pose a unique challenge. The location of individual neurons must be tracked in 3D over time to accurately extract single neuron activity traces. Recordings from small invertebrates like C. elegans are especially challenging because they undergo very large brain motion and deformation during animal movement. Here we present an automated computer vision pipeline to reliably track populations of neurons with single neuron resolution in the brain of a freely moving C. elegans undergoing large motion and deformation. 3D volumetric fluorescent images of the animal's brain are straightened, aligned and registered, and the locations of neurons in the images are found via segmentation. Each neuron is then assigned an identity using a new time-independent machine-learning approach we call Neuron Registration Vector Encoding. In this approach, non-rigid point-set registration is used to match each segmented neuron in each volume with a set of reference volumes taken from throughout the recording. The way each neuron matches with the references defines a feature vector which is clustered to assign an identity to each neuron in each volume. Finally, thin-plate spline interpolation is used to correct errors in segmentation and check consistency of assigned identities. The Neuron Registration Vector Encoding approach proposed here is uniquely well suited for tracking neurons in brains undergoing large deformations. When applied to whole-brain calcium imaging recordings in freely moving C. elegans, this analysis pipeline located 156 neurons for the duration of an 8 minute recording and consistently found more neurons more quickly than manual or semi-automated approaches.
Project description:Adult-born neurons (ABNs) in the dentate gyrus bestow unique cellular plasticity to the mammalian brain. We recently found that the activity of ABNs during sleep is necessary for memory consolidation. Here, we describe our method for Ca2+ imaging of ABN activity using a miniaturized fluorescent microscope and sleep recordings. As preparatory surgery and post-recording data processing can be major obstacles, we provide detailed descriptions and problem-solving tips. For complete details on the use and execution of this protocol, please refer to Kumar et al. (2020).
Project description:Lipid nanoparticles (LNPs) have shown remarkable success in delivering genetic materials like COVID-19 LNP vaccines, such as mRNA-1273/SpikeVax by Moderna and BNT162b2/Comirnaty by BioNTech/Pfizer, as well as siRNA for rare inherited diseases, such as Onpattro from Alnylam Pharmaceuticals. These LNPs are advantageous since they minimize side effects, target specific cells, and regulate payload delivery. There has been a surge of interest in these particles due to their success stories; however, we still do not know much about how they work. This perspective will recapitulate the evolution of lipid-based gene delivery, starting with Felgner's pioneering 1987 PNAS paper, which introduced the initial DNA-transfection method utilizing a synthetic cationic lipid. Our journey takes us to the early 2020s, a time when advancements in bionano interactions enabled us to create biomimetic lipoplexes characterized by a remarkable ability to evade capture by immune cells in vivo. Through this overview, we propose leveraging previous achievements to assist us in formulating improved research goals when optimizing LNPs for medical conditions such as infectious diseases, cancer, and heritable disorders.
Project description:Implications In this commentary, we describe the evidence-based approach used to identify the primary cause of EVALI and to curb the 2019 outbreak. We also discuss future research opportunities and public health practice considerations to prevent a resurgence of EVALI.
Project description:The field of Alzheimer disease (AD) prevention has been a culmination of basic science, clinical, and translational research. In the past three years since the new 2011 AD diagnostic guidelines, large-scale collaborative efforts have embarked on new clinical trials with the hope of someday preventing AD. This review will shed light on the historical and scientific contexts in which these trials were based on, as well as discuss potential challenges these trials may face in the coming years. Primary preventive measures, such as lifestyle, multidomain, medication, and supplemental interventions, will be analyzed. Secondary prevention as represented by disease-modifying interventions, such as antiamyloid therapy and pioglitazone, will also be reviewed. Finally, hypotheses on future directions for AD prevention trials will be proposed.