Afadin Sorts Different Retinal Neuron Types into Accurate Cellular Layers.

Neurons use cell-adhesion molecules (CAMs) to interact with other neurons and the extracellular environment: the combination of CAMs specifies migration patterns, neuronal morphologies, and synaptic connections across diverse neuron types. Yet little is known regarding the intracellular signaling cascade mediating the CAM recognitions at the cell surface across different neuron types. In this study, we investigated the neural developmental role of Afadin, a cytosolic adapter protein that connects multiple CAM families to intracellular F-actin.

High-Complexity Barcoded Rabies Virus for Scalable Circuit Mapping Using Single-Cell and Single-Nucleus Sequencing.

Single cell genomics has revolutionized our understanding of neuronal cell types. However, scalable technologies for probing single-cell connectivity are lacking, and we are just beginning to understand how molecularly defined cell types are organized into functional circuits. Here, we describe a protocol to generate high-complexity barcoded rabies virus (RV) for scalable circuit mapping from tens of thousands of individual starter cells in parallel.

Modified human mesenchymal stromal/stem cells restore cortical excitability after focal ischemic stroke in rats.

Allogeneic modified bone marrow-derived human mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue, and peripheral blood at a chronic stage after ischemic stroke in a rat model.

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.

Background: The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders.

Understanding the neural code of stress to control anhedonia.

Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder. The neural underpinnings of anhedonia and how this emotional state drives behaviour remain unclear. Here we investigated the neural code of anhedonia by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient.

Implementation and validation of single-cell genomics experiments in neuroscience.

Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors.

Benzodiazepine rescue medication administration for seizure clusters: Real-world retrospective outcomes.

Objective: Benzodiazepine rescue medications are established as therapy for acute termination of seizure clusters. A post-hoc analysis of a clinical trial of seizure cluster treatment with diazepam nasal spray found a potential longer-term impact over a year of treatment. In this retrospective analysis, we tested the hypothesis that benzodiazepine-treated seizure clusters are associated with prolonged time to the next seizure cluster compared with untreated seizure clusters in a patient-reported real-world database.

Inhibition of Indirect Pathway Activity Causes Abnormal Decision-Making In a Mouse Model of Impulse Control Disorder in Parkinson's Disease.

Healthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson's disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping.

Functional organization and natural scene responses across mouse visual cortical areas revealed with encoding manifolds.

A challenge in sensory neuroscience is understanding how populations of neurons operate in concert to represent diverse stimuli. To meet this challenge, we have created "encoding manifolds" that reveal the overall responses of brain areas to diverse stimuli with the resolution of individual neurons and their response dynamics. Here we use encoding manifold to compare the population-level encoding of primary visual cortex (VISp) with five higher visual areas (VISam, VISal, VISpm, VISlm, and VISrl).

Representations of stimulus meaning in the hippocampus.

The ability to discriminate and categorize the meaning of environmental stimuli and respond accordingly is essential for survival. The ventral hippocampus (vHPC) controls emotional and motivated behaviors in response to environmental cues and is hypothesized to do so in part by deciphering the positive or negative quality of these cues. Yet, what features of the environment are represented in the activity patterns of vCA1 neurons, and whether the positive or negative meaning of a stimulus is present at this stage, remains unclear.

Striatal lateral inhibition regulates action selection in a mouse model of levodopa-induced dyskinesia.

Striatal medium spiny neurons (MSNs) integrate multiple external inputs to shape motor output. In addition, MSNs form local inhibitory synaptic connections with one another. The function of striatal lateral inhibition is unknown, but one possibility is in selecting an intended action while suppressing alternatives.

Tau P301S Transgenic Mice Develop Gait and Eye Movement Impairments That Mimic Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available.

Dysregulation of the fluid homeostasis system by aging.

Chronic dehydration is a leading cause of morbidity for the elderly, but how aging alters the fluid homeostasis system is not well understood. Here, we used a combination of physiologic, behavioral and circuit analyses to characterize how fluid balance is affected by aging in mice. We found that old mice have a primary defect in sensing and producing the anti-diuretic hormone vasopressin, which results in chronic dehydration.

Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements.

CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes.

Receptive-field nonlinearities in primary auditory cortex: a comparative perspective.

Cortical processing of auditory information can be affected by interspecies differences as well as brain states. Here we compare multifeature spectro-temporal receptive fields (STRFs) and associated input/output functions or nonlinearities (NLs) of neurons in primary auditory cortex (AC) of four mammalian species. Single-unit recordings were performed in awake animals (female squirrel monkeys, female, and male mice) and anesthetized animals (female squirrel monkeys, rats, and cats).

Opposing GPCR signaling programs protein intake setpoint in Drosophila.

Animals defend a target level for their fundamental needs, including food, water, and sleep. Deviation from the target range, or "setpoint," triggers motivated behaviors to eliminate that difference. Whether and how the setpoint itself is encoded remains enigmatic for all motivated behaviors.

Andersen-Tawil syndrome.

Andersen-Tawil syndrome (ATS) is one of the periodic paralyses, a set of skeletal muscle disorders that cause transient weakness of the arms and legs lasting minutes to many hours. Distinguishing features of ATS include facial and limb dysmorphisms, cardiac arrhythmia, difficulties with executive function, and association with dominant mutations in the potassium channel, KCNJ2. In this review, we discuss the key features of ATS, diagnostic testing, pathophysiology and treatment of ATS, and compare them with other periodic paralyses.

Oligodendrocytes and myelin limit neuronal plasticity in visual cortex.

Developmental myelination is a protracted process in the mammalian brain. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity.

Negative feedback control of hypothalamic feeding circuits by the taste of food.

The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety.

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding.

Adaptive regulation of feeding depends on linkage of internal states and food outcomes with contextual cues. Human brain imaging has identified dysregulation of a hippocampal-lateral hypothalamic area (LHA) network in binge eating, but mechanistic instantiation of underlying cell-types and circuitry is lacking. Here, we identify an evolutionary conserved and discrete Prodynorphin ()-expressing subpopulation of Somatostatin ()-expressing inhibitory neurons in the dorsolateral septum (DLS) that receives primarily dorsal, but not ventral, hippocampal inputs.

Identifying dysfunctional cell types and circuits in animal models for psychiatric disorders with calcium imaging.

A central goal of neuroscience is to understand how the brain transforms external stimuli and internal bodily signals into patterns of activity that underlie cognition, emotional states, and behavior. Understanding how these patterns of activity may be disrupted in mental illness is crucial for developing novel therapeutics. It is well appreciated that psychiatric disorders are complex, circuit-based disorders that arise from dysfunctional activity patterns generated in discrete cell types and their connections.

State-dependent effects of responsive neurostimulation depend on seizure localization.

Brain-responsive neurostimulation is firmly ensconced among treatment options for drug-resistant focal epilepsy, but over a quarter of patients treated with the RNS System do not experience meaningful seizure reduction. Initial titration of RNS therapy is typically similar for all patients, raising the possibility that treatment response might be enhanced by consideration of patient-specific variables. Indeed, small, single-center studies have yielded preliminary evidence that RNS System effectiveness depends on the brain state during which stimulation is applied.