Comparative Physiology and Morphology of BLA-Projecting NBM/SI Cholinergic Neurons in Mouse and Macaque.

Cholinergic projection neurons of the nucleus basalis and substantia innominata (NBM/SI) densely innervate the basolateral amygdala (BLA) and have been shown to contribute to the encoding of fundamental and life-threatening experiences. Given the vital importance of these circuits in the acquisition and retention of memories that are essential for survival in a changing environment, it is not surprising that the basic anatomical organization of the NBM/SI is well conserved across animal classes as diverse as teleost and mammal. What is not known is the extent to which the physiology and morphology of NBM/SI neurons have also been conserved.

Neuregulin1 Nuclear Signaling Influences Adult Neurogenesis and Regulates a Schizophrenia Susceptibility Gene Network within the Mouse Dentate Gyrus.

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al.

Comparative physiology and morphology of BLA-projecting NBM/SI cholinergic neurons in mouse and macaque.

Cholinergic projection neurons of the nucleus basalis and substantia innominata (NBM/SI) densely innervate the basolateral amygdala (BLA) and have been shown to contribute to the encoding of fundamental and life-threatening experiences. Given the vital importance of these circuits in the acquisition and retention of memories that are essential for survival in a changing environment, it is not surprising that the basic anatomical organization of the NBM/SI is well conserved across animal classes as diverse as teleost and mammal. What is not known is the extent to which the physiology and morphology of NBM/SI neurons have also been conserved.

A simple MATLAB toolbox for analyzing calcium imaging data in vitro and in vivo.

Background: Fluorescence imaging of calcium dynamics in neuronal populations is powerful because it offers a way of relating the activity of individual cells to the broader population of nearby cells. The method's growth across neuroscience has particularly been driven by the introduction of sophisticated mathematical techniques related to motion correction, image registration, cell detection, spike estimation, and population characterization. However, for many researchers, making good use of these techniques has been difficult because they have been devised by different workers and impose differing - and sometimes stringent - technical requirements on those who seek to use them.

Distinct subpopulations of ventral pallidal cholinergic projection neurons encode valence of olfactory stimuli.

To better understand the function of cholinergic projection neurons in the ventral pallidum (VP), we examined behavioral responses to appetitive (APP) and aversive (AV) odors that elicited approach or avoidance, respectively. Exposure to each odor increased cFos expression and calcium signaling in VP cholinergic neurons. Activity and Cre-dependent viral vectors selectively labeled VP cholinergic neurons that were activated and reactivated in response to either APP or AV odors, but not both, identifying two non-overlapping populations of VP cholinergic neurons differentially activated by the valence of olfactory stimuli.

Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons.

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SI) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically-encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can "learn" the association between a naïve tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24h later (recall). In the NBM/SI cholinergic neurons express the immediate early gene, Fos following both training and memory recall.

Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons.

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SI) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can 'learn' the association between a naive tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24 hr later (recall). In the NBM/SI cholinergic neurons express the immediate early gene, Fos following both training and memory recall.

Distinct subpopulations of ventral pallidal cholinergic projection neurons encode valence of olfactory stimuli.

The ventral pallidum (VP) mediates motivated behaviors largely via the action of VP GABA and glutamatergic neurons. In addition to these neuronal subtypes, there is a population of cholinergic projection neurons in the VP, whose functional significance remains unclear. To understand the functional role of VP cholinergic neurons, we first examined behavioral responses to an appetitive (APP) odor that elicited approach, and an aversive (AV) odor that led to avoidance.

Basal forebrain cholinergic signalling: development, connectivity and roles in cognition.

Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition.

Seq'ing the origins of cells in the developing spinal cord.

In the developing central nervous system, neurogenesis precedes gliogenesis; however, when and how progenitors are specified for a neuronal versus glial fate and the temporal regulation of this process is unclear. Progenitors within the motor neuron progenitor domain in the developing spinal cord give rise to cholinergic motor neurons and cells of the oligodendroglial lineage sequentially. In a recent study, Xing et al.

Axonal α7* nicotinic acetylcholine receptors modulate glutamatergic signaling and synaptic vesicle organization in ventral hippocampal projections.

Modulation of the release of glutamate by activation of presynaptic nicotinic acetylcholine receptors (nAChRs) is one of the most prevalent mechanism of nicotinic facilitation of glutamatergic transmission in cortico-limbic circuits. By imaging gene chimeric co-cultures from mouse, we examined the role of α7* nAChRs mediated cholinergic modulation of glutamate release and synaptic vesicle organization in ventral hippocampal projections. We directly visualized exogenous and endogenous cholinergic facilitation of glutamate release in this specialized preparation of circuits .

NeuRegenerate: A Framework for Visualizing Neurodegeneration.

Recent advances in high-resolution microscopy have allowed scientists to better understand the underlying brain connectivity. However, due to the limitation that biological specimens can only be imaged at a single timepoint, studying changes to neural projections over time is limited to observations gathered using population analysis. In this article, we introduce NeuRegenerate, a novel end-to-end framework for the prediction and visualization of changes in neural fiber morphology within a subject across specified age-timepoints.

NeuroConstruct: 3D Reconstruction and Visualization of Neurites in Optical Microscopy Brain Images.

We introduce NeuroConstruct, a novel end-to-end application for the segmentation, registration, and visualization of brain volumes imaged using wide-field microscopy. NeuroConstruct offers a Segmentation Toolbox with various annotation helper functions that aid experts to effectively and precisely annotate micrometer resolution neurites. It also offers an automatic neurites segmentation using convolutional neuronal networks (CNN) trained by the Toolbox annotations and somas segmentation using thresholding.

Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances the learning of cue-reward contingency.

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency.

Deletion from Cholinergic Neurons Selectively Impairs Recognition Memory and Disrupts Cholinergic Modulation of the Perirhinal Cortex.

Rett Syndrome is a neurological disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) and characterized by severe intellectual disability. The cholinergic system is a critical modulator of cognitive ability and is affected in patients with Rett Syndrome. To better understand the importance of MeCP2 function in cholinergic neurons, we studied the effect of selective deletion from cholinergic neurons in mice.

Specific Basal Forebrain-Cortical Cholinergic Circuits Coordinate Cognitive Operations.

Based on recent molecular genetics, as well as functional and quantitative anatomical studies, the basal forebrain (BF) cholinergic projections, once viewed as a diffuse system, are emerging as being remarkably specific in connectivity. Acetylcholine (ACh) can rapidly and selectively modulate activity of specific circuits and ACh release can be coordinated in multiple areas that are related to particular aspects of cognitive processing. This review discusses how a combination of multiple new approaches with more established techniques are being used to finally reveal how cholinergic neurons, together with other BF neurons, provide temporal structure for behavior, contribute to local cortical state regulation, and coordinate activity between different functionally related cortical circuits.

Visualization of Neuronal Structures in Wide-Field Microscopy Brain Images.

Wide-field microscopes are commonly used in neurobiology for experimental studies of brain samples. Available visualization tools are limited to electron, two-photon, and confocal microscopy datasets, and current volume rendering techniques do not yield effective results when used with wide-field data. We present a workflow for the visualization of neuronal structures in wide-field microscopy images of brain samples.

A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies.

The neurotransmitter acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body. Despite its importance, cholinergic transmission in the majority of tissues and organs remains poorly understood owing primarily to the limitations of available ACh-monitoring techniques. We developed a family of ACh sensors (GACh) based on G-protein-coupled receptors that has the sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo.

Reduced type III neuregulin 1 expression does not modulate the behavioural sensitivity of mice to acute Δ-tetrahydrocannabinol (D-THC).

Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ-tetrahydrocannabinol (D-THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia.

Electrophysiological properties of basal forebrain cholinergic neurons identified by genetic and optogenetic tagging.

Recent developments in the generation of neuronal population-specific, genetically modified mouse lines have allowed precise identification and selective stimulation of cholinergic neurons in vivo. Although considerably less laborious than studies conducted with post hoc identification of cholinergic neurons by immunostaining, it is not known whether the genetically based labeling procedures that permit in vivo identification are electrophysiologically benign. In this study, we use mice carrying a bacterial artificial chromosome transgene that drives expression of a tau-green fluorescent fusion protein specifically in cholinergic neurons.

Parent-of-origin effects on schizophrenia-relevant behaviours of type III neuregulin 1 mutant mice.

A robust, disease-relevant phenotype is paramount to the validity of genetic mouse models, which are an important tool in understanding complex diseases. Recent evidence from genome-wide association studies suggests the genetic contribution of parents to offspring is not equivalent. Despite this, few studies to date have examined the potential impact of parent genotype (i.

Axonal Type III Nrg1 Controls Glutamate Synapse Formation and GluA2 Trafficking in Hippocampal-Accumbens Connections.

Altered neuregulin 1 (Nrg1)/ErbB signaling and glutamatergic hypofunction have been implicated in the pathophysiology of schizophrenia. Here, we employed gene chimeric ventral hippocampus (vHipp)-nucleus accumbens (nAcc) coculture from mouse, electrophysiology, immunocytochemistry, FM1-43 vesicle fusion, and electron microscopy techniques to examine the pre- and postsynaptic mechanisms of genetic deficits in Nrg1/ErbB signaling-induced glutamatergic dysfunctions. Reduced presynaptic type III Nrg1 expression along vHipp axons decreases the number of glutamate synapses and impairs GluA2 trafficking in the postsynaptic nAcc neurons, resulting in decreased frequency and amplitude of miniature EPSCs (mEPSCs).

A RET-ER81-NRG1 Signaling Pathway Drives the Development of Pacinian Corpuscles.

Unlabelled: Axon-Schwann cell interactions are crucial for the development, function, and repair of the peripheral nervous system, but mechanisms underlying communication between axons and nonmyelinating Schwann cells are unclear. Here, we show that ER81 is functionally required in a subset of mouse RET mechanosensory neurons for formation of Pacinian corpuscles, which are composed of a single myelinated axon and multiple layers of nonmyelinating Schwann cells, and Ret is required for the maintenance of Er81 expression. Interestingly, Er81 mutants have normal myelination but exhibit deficient interactions between axons and corpuscle-forming nonmyelinating Schwann cells.

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline.

Recent work continues to place cholinergic circuits at center stage for normal executive and mnemonic functioning and provides compelling evidence that the loss of cholinergic signaling and cognitive decline are inextricably linked. This Review focuses on the last few years of studies on the mechanisms by which cholinergic signaling contributes to circuit activity related to cognition. We attempt to identify areas of controversy, as well as consensus, on what is and is not yet known about how cholinergic signaling in the CNS contributes to normal cognitive processes.