Brain imaging and machine learning reveal uncoupled functional network for contextual threat memory in long sepsis.

Positron emission tomography (PET) utilizes radiotracers like [F]fluorodeoxyglucose (FDG) to measure brain activity in health and disease. Performing behavioral tasks between the FDG injection and the PET scan allows the FDG signal to reflect task-related brain networks. Building on this principle, we introduce an approach called behavioral task-associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat.

Brain imaging and machine learning reveal uncoupled functional network for contextual threat memory in long sepsis.

Positron emission tomography (PET) is a highly sensitive tool for studying physiology and metabolism through positron-emitting radionuclides that label molecular targets in the body with unparalleled specificity, without disturbing their biological function. Here, we introduce a small-animal technique called behavioral task-associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat. Associative threat conditioning occurs between the scans.

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling.

Aims: This study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses.

Dominance hierarchy regulates social behavior during spatial movement.

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food.

Neurobehavioral Impairments Predict Specific Cerebral Damage in Rat Model of Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe form of stroke that can cause unpredictable and diffuse cerebral damage, which is difficult to detect until it becomes irreversible. Therefore, there is a need for a reliable method to identify dysfunctional regions and initiate treatment before permanent damage occurs. Neurobehavioral assessments have been suggested as a possible tool to detect and approximately localize dysfunctional cerebral regions.

In utero exposure to maternal anti-aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring.

The fetal brain is constantly exposed to maternal IgG before the formation of an effective blood-brain barrier (BBB). Here, we studied the consequences of fetal brain exposure to an antibody to the astrocytic protein aquaporin-4 (AQP4-IgG) in mice. AQP4-IgG was cloned from a patient with neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease that can affect women of childbearing age.

Framework for automated sorting of neural spikes from Neuralynx-acquired tetrode recordings in freely-moving mice.

Background: Extracellular recording represents a crucial electrophysiological technique in neuroscience for studying the activity of single neurons and neuronal populations. The electrodes capture voltage traces that, with the help of analytical tools, reveal action potentials ('spikes') as well as local field potentials. The process of spike sorting is used for the extraction of action potentials generated by individual neurons.

Contributions of Sex Chromosomes and Gonadal Hormones to the Male Bias in a Maternal Antibody-Induced Model of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that is four times more commonly diagnosed in males than females. While susceptibility genes located in the sex chromosomes have been identified in ASD, it is unclear whether they are sufficient to explain the male bias or whether gonadal hormones also play a key role. We evaluated the sex chromosomal and hormonal influences on the male bias in a murine model of ASD, in which mice are exposed to a maternal antibody reactive to contactin-associated protein-like 2 (Caspr2), which was originally cloned from a mother of a child with ASD (termed C6 mice henceforth).

Reversible dysregulation of renal circadian rhythm in lupus nephritis.

Background: We have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis.

Methods: Molecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period.

In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to behavioral abnormalities resembling autism spectrum disorder in male mice.

The concept that exposure in utero to maternal anti-brain antibodies contributes to the development of autism spectrum disorders (ASD) has been entertained for over a decade. We determined that antibodies targeting Caspr2 are present at high frequency in mothers with brain-reactive serology and a child with ASD, and further demonstrated that exposure in utero to a monoclonal anti-Caspr2 antibody, derived from a mother of an ASD child, led to an-ASD like phenotype in male offspring. Now we propose a new model to study the effects of in utero exposure to anti-Caspr2 antibody.

Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer's disease.

Background: Macrophage Migration Inhibitory Factor (MIF) is a potent proinflammatory cytokine that promotes the production of other immune mediators. MIF is produced by most cell types in the brain including microglia, astrocytes and neurons. Enhanced expression of MIF might contribute to the persistent activation of glial, chronic neuroinflammation and neurodegeneration.

Assessment of glutamatergic synaptic transmission and plasticity in brain slices: relevance to bioelectronic approaches.

Background: Glutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity. Abnormalities in glutamatergic neurons are linked to several brain disorders and their modulation represents a potential opportunity for emerging bioelectronic medicine (BEM) approaches. Here, we have used a set of electrophysiological assays to identify the effect of the pyrimidine nucleoside uridine on glutamatergic systems in ex vivo brain slices.

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory.

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B.

Large-Scale Validation of the Paddling Pool Task in the Clockmaze for Studying Hippocampus-Based Spatial Cognition in Mice.

Rationally designed behavioral tests are important tools to assess the function of specific brain regions. The hippocampus is a crucial neural substrate for spatial cognition, and many studies have linked hippocampal dysfunction with defects on spatial learning and memory in neurological conditions ranging from Alzheimer's disease to autoimmune syndromes, such as neuropsychiatric lupus. While our understanding of hippocampal function, from the molecular to the system levels, has increased dramatically over the last decades, this effort has not yet translated into efficacious therapies for cognitive impairment.

Extracellular cold inducible RNA-binding protein mediates binge alcohol-induced brain hypoactivity and impaired cognition in mice.

Background: Alcohol abuse affects the brain regions responsible for memory, coordination and emotional processing. Binge alcohol drinking has shown reductions in brain activity, but the molecular targets have not been completely elucidated. We hypothesized that brain cells respond to excessive alcohol by releasing a novel inflammatory mediator, called cold inducible RNA-binding protein (CIRP), which is critical for the decreased brain metabolic activity and impaired cognition.

Standardization of methods to record Vagus nerve activity in mice.

Background: The vagus nerve plays an important role in the regulation of organ function, including reflex pathways that regulate immunity and inflammation. Recent studies using genetically modified mice have improved our understanding of molecular mechanisms in the neural control of immunity. However, mapping neural signals transmitted in the vagus nerve in mice has been limited by technical challenges.

Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory.

Long-term sepsis survivors sustain cryptic brain injury that leads to cognitive impairment, emotional imbalance, and increased disability burden. Suitable animal models of sepsis, such as cecal ligation and puncture (CLP), have permitted the analysis of abnormal brain circuits that underlie post-septic behavioral phenotypes. For instance, we have previously shown that CLP-exposed mice exhibit impaired spatial memory together with depleted dendritic arbors and decreased spines in the apical dendrites of pyramidal neurons in the CA1 region of the hippocampus.

CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice.

CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1(-/-)) mice and investigate CALHM1 role in neuronal and cognitive functions.

Cytokine-specific Neurograms in the Sensory Vagus Nerve.

The axons of the sensory, or afferent, vagus nerve transmit action potentials to the central nervous system in response to changes in the body's metabolic and physiological status. Recent advances in identifying neural circuits that regulate immune responses to infection, inflammation and injury have revealed that vagus nerve signals regulate the release of cytokines and other factors produced by macrophages. Here we record compound action potentials in the cervical vagus nerve of adult mice and reveal the specific activity that occurs following administration of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 1β (IL-1β).

Integrative neuroscience approach to neuropsychiatric lupus.

We present a succinct review of our approach to study the interactions between the DNA-reactive antibodies that cross-react with the GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor, denoted DNRABs, and their brain targets in subjects with neuropsychiatric systemic lupus erythematosus (NPSLE). We have analyzed the DNRAB-based brain symptomatology in mouse models of NPSLE by using an integrative neuroscience approach, which includes behavioral assessment coupled with electrophysiological studies of neural networks and synaptic connections in target brain regions, such as the CA1 region of the hippocampus. Our results suggest a framework for understanding the interactions between immune factors and neural networks.

Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-D-Aspartate Receptor.

Patients with systemic lupus erythematosus (SLE) experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size.

Overexpression of extracellular superoxide dismutase protects against brain injury induced by chronic hypoxia.

Extracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.