Adult-neurogenesis allows for representational stability and flexibility in early olfactory system.

In the early olfactory system, adult-neurogenesis, a process of neuronal replacement results in the continuous reorganization of synaptic connections and network architecture throughout the animal's life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors and therefore allow for stable sensory perceptions amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level.

Differential disruptions in population coding along the dorsal-ventral axis of CA1 in the APP/PS1 mouse model of Aβ pathology.

Alzheimer's Disease (AD) is characterized by a range of behavioral alterations, including memory loss and psychiatric symptoms. While there is evidence that molecular pathologies, such as amyloid beta (Aβ), contribute to AD, it remains unclear how this histopathology gives rise to such disparate behavioral deficits. One hypothesis is that Aβ exerts differential effects on neuronal circuits across brain regions, depending on the neurophysiology and connectivity of different areas.

Algebraic approach to spike-time neural codes in the hippocampus.

Although temporal coding through spike-time patterns has long been of interest in neuroscience, the specific structures that could be useful for spike-time codes remain highly unclear. Here, we introduce an analytical approach, using techniques from discrete mathematics, to study spike-time codes. As an initial example, we focus on the phenomenon of "phase precession" in the rodent hippocampus.

Network size affects the complexity of activity in human iPSC-derived neuronal populations.

Multi-electrode recording of neural activity in cultures offer opportunities for understanding how the structure of a network gives rise to function. Although it is hypothesized that network size is critical for determining the dynamics of activity, this relationship in human neural cultures remains largely unexplored. By applying new methods for analyzing neural activity to human iPSC derived cultures at either low-densities or high-densities, we uncovered the significant impacts that neuron number has on the individual neurophysiological properties of cells (such as firing rates), the collective behavior of the networks these cultures formed (as measured by entropy), and the relationship between the two.

High-resolution structural and functional retinal imaging in the awake behaving mouse.

The laboratory mouse has provided tremendous insight to the underpinnings of mammalian central nervous system physiology. In recent years, it has become possible to image single neurons, glia and vascular cells in vivo by using head-fixed preparations combined with cranial windows to study local networks of activity in the living brain. Such approaches have also succeeded without the use of general anesthesia providing insights to the natural behaviors of the central nervous system.

Emerging Multiorgan Klebsiella pneumoniae Invasive Syndrome Leading to Septic Shock: A Case Report and Review of the Literature.

is a community-acquired pathogen that typically causes pneumonia and urinary tract infections. Rarely, it can affect other organ systems such as the gastrointestinal tract, as well as the meninges, ears, eyes, and spine. We present the case of a 62-year-old male admitted with septic shock secondary to necrotizing pneumonia and multiple hepatic liver abscesses, which to the best of our knowledge, is the first reported case of multiorgan invasive infection, including the presence of a newly recognized syndrome referred as Invasive Liver Abscess Syndrome (ILAS).

Top-down feedback enables flexible coding strategies in the olfactory cortex.

In chemical sensation, multiple models have been proposed to explain how odors are represented in the olfactory cortex. One hypothesis is that the combinatorial identity of active neurons within sniff-related time windows is critical, whereas another model proposes that it is the temporal structure of neural activity that is essential for encoding odor information. We find that top-down feedback to the main olfactory bulb dictates the information transmitted to the piriform cortex and switches between these coding strategies.

From synapses to circuits and back: Bridging levels of understanding in animal models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by behavioural changes that include memory loss and cognitive decline and is associated with the appearance of amyloid-β plaques and neurofibrillary tangles throughout the brain. Although aspects of the disease percolate across multiple levels of neuronal organization, from the cellular to the behavioural, it is increasingly clear that circuits are a critical junction between the cellular pathology and the behavioural phenotypes that bookend these levels of analyses. In this review, we discuss critical aspects of neural circuit research, beginning with synapses and progressing to network activity and how they influence our understanding of disease processed in AD.

Divergence in Population Coding for Space between Dorsal and Ventral CA1.

Molecular, anatomic, and behavioral studies show that the hippocampus is structurally and functionally heterogeneous, with dorsal hippocampus implicated in mnemonic processes and spatial navigation and ventral hippocampus involved in affective processes. By performing electrophysiological recordings of large neuronal populations in dorsal and ventral CA1 in head-fixed mice navigating a virtual environment, we found that this diversity resulted in different strategies for population coding of space. Populations of neurons in dorsal CA1 showed more complex patterns of activity, which resulted in a higher dimensionality of neural representations that translated to more information being encoded, as compared ensembles in vCA1.

Changes in pairwise correlations during running reshape global network state in the main olfactory bulb.

Neural codes for sensory inputs have been hypothesized to reside in a broader space defined by ongoing patterns of spontaneous activity. To understand the structure of this spontaneous activity in the olfactory system, we performed high-density recordings of neural populations in the main olfactory bulb of awake mice. We observed changes in pairwise correlations of spontaneous activity between mitral and tufted (M/T) cells when animals were running, which resulted in an increase in the entropy of the population.

Top-Down Control of Inhibitory Granule Cells in the Main Olfactory Bulb Reshapes Neural Dynamics Giving Rise to a Diversity of Computations.

Growing evidence shows that top-down projections from excitatory neurons in piriform cortex selectively synapse onto local inhibitory granule cells in the main olfactory bulb, effectively gating their own inputs by controlling inhibition. An open question in olfaction is the role this feedback plays in shaping the dynamics of local circuits, and the resultant computational benefits it provides. Using rate models of neuronal firing in a network consisting of excitatory mitral and tufted cells, inhibitory granule cells and top-down piriform cortical neurons, we found that changes in the weight of feedback to inhibitory neurons generated diverse network dynamics and complex transitions between these dynamics.

Altered dorsal CA1 neuronal population coding in the APP/PS1 mouse model of Alzheimer's disease.

While the link between amyloid β (Aβ) accumulation and synaptic degradation in Alzheimer's disease (AD) is known, the consequences of this pathology on population coding remain unknown. We found that the entropy, a measure of the diversity of network firing patterns, was lower in the dorsal CA1 region in the APP/PS1 mouse model of Aβ pathology, relative to controls, thereby reducing the population's coding capacity. Our results reveal a network level signature of the deficits Aβ accumulation causes to the computations performed by neural circuits.

Sex differences in head-fixed voluntary running behavior in C57BL/6J mice.

Sex differences in running behaviors between female and male mice occur naturally in the wild. Recent experiments using head-fixed mice on a voluntary running wheel have exploited analogous locomotor activity to gain insight into the neural underpinnings of a number of behaviors ranging from spatial navigation to decision-making. It is however largely unknown if sex differences exist between females and males in a head-fixed experimental paradigm.

Species-specific maturation profiles of human, chimpanzee and bonobo neural cells.

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex.

Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping.

Neuronal activity in sensory regions can be modulated by attention, behavioral state, motor output, learning, and memory. This is often done through direct feedback or centrifugal projections originating from higher processing areas. Though, functionally important, the identity and organization of these feedback connections remain poorly characterized.

Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro.

Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus.

Diverse Representations of Olfactory Information in Centrifugal Feedback Projections.

Unlabelled: Although feedback or centrifugal projections from higher processing centers of the brain to peripheral regions have long been known to play essential functional roles, the anatomical organization of these connections remains largely unknown. Using a virus-based retrograde labeling strategy and 3D whole-brain reconstruction methods, we mapped the spatial organization of centrifugal projections from two olfactory cortical areas, the anterior olfactory nucleus (AON) and the piriform cortex, to the granule cell layer of the main olfactory bulb in the mouse. Both regions are major recipients of information from the bulb and are the largest sources of feedback to the bulb, collectively constituting circuits essential for olfactory coding and olfactory behavior.

Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.

Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size.

An Empirical Model for Reliable Spiking Activity.

Understanding a neuron's transfer function, which relates a neuron's inputs to its outputs, is essential for understanding the computational role of single neurons. Recently, statistical models, based on point processes and using generalized linear model (GLM) technology, have been widely applied to predict dynamic neuronal transfer functions. However, the standard version of these models fails to capture important features of neural activity, such as responses to stimuli that elicit highly reliable trial-to-trial spiking.

In vitro myelin formation using embryonic stem cells.

Myelination in the central nervous system is the process by which oligodendrocytes form myelin sheaths around the axons of neurons. Myelination enables neurons to transmit information more quickly and more efficiently and allows for more complex brain functions; yet, remarkably, the underlying mechanism by which myelination occurs is still not fully understood. A reliable in vitro assay is essential to dissect oligodendrocyte and myelin biology.

Disrupting information coding via block of 4-AP-sensitive potassium channels.

Recent interest has emerged on the role of intrinsic biophysical diversity in neuronal coding. An important question in neurophysiology is understanding which voltage-gated ion channels are responsible for this diversity and how variable expression or activity of one class of ion channels across neurons of a single type affects they way populations carry information. In mitral cells in the olfactory bulb of mice, we found that biophysical diversity was conferred in part by 4-aminopyridine (4-AP)-sensitive potassium channels and reduced following block of those channels.

A regenerative approach to the treatment of multiple sclerosis.

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis.

Intermediate intrinsic diversity enhances neural population coding.

Cell-to-cell variability in molecular, genetic, and physiological features is increasingly recognized as a critical feature of complex biological systems, including the brain. Although such variability has potential advantages in robustness and reliability, how and why biological circuits assemble heterogeneous cells into functional groups is poorly understood. Here, we develop analytic approaches toward answering how neuron-level variation in intrinsic biophysical properties of olfactory bulb mitral cells influences population coding of fluctuating stimuli.