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Cell Jun 2019Defining cell types requires integrating diverse single-cell measurements from multiple experiments and biological contexts. To flexibly model single-cell datasets, we... (Comparative Study)
Comparative Study
Defining cell types requires integrating diverse single-cell measurements from multiple experiments and biological contexts. To flexibly model single-cell datasets, we developed LIGER, an algorithm that delineates shared and dataset-specific features of cell identity. We applied it to four diverse and challenging analyses of human and mouse brain cells. First, we defined region-specific and sexually dimorphic gene expression in the mouse bed nucleus of the stria terminalis. Second, we analyzed expression in the human substantia nigra, comparing cell states in specific donors and relating cell types to those in the mouse. Third, we integrated in situ and single-cell expression data to spatially locate fine subtypes of cells present in the mouse frontal cortex. Finally, we jointly defined mouse cortical cell types using single-cell RNA-seq and DNA methylation profiles, revealing putative mechanisms of cell-type-specific epigenomic regulation. Integrative analyses using LIGER promise to accelerate investigations of cell-type definition, gene regulation, and disease states.
Topics: Adolescent; Adult; Aged; Animals; DNA Methylation; Female; Gene Expression Regulation; Humans; Male; Mice; Middle Aged; Septal Nuclei; Sequence Analysis, RNA; Single-Cell Analysis; Substantia Nigra
PubMed: 31178122
DOI: 10.1016/j.cell.2019.05.006 -
Nature Nov 2021Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group. The dorsal CA2 (dCA2) and...
Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group. The dorsal CA2 (dCA2) and ventral CA1 (vCA1) subregions of the hippocampus, and their projection targets, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours, but also social memory, by influencing distinct target structures.
Topics: Animals; CA2 Region, Hippocampal; Female; Glutamic Acid; Male; Memory; Mice; Neural Pathways; Neuronal Plasticity; Optogenetics; Pyramidal Cells; Receptor, Serotonin, 5-HT1B; Septal Nuclei; Serotonin; Social Behavior; Synapses
PubMed: 34616037
DOI: 10.1038/s41586-021-03956-8 -
Nature Jan 2023In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social...
In humans, traumatic social experiences can contribute to psychiatric disorders. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NT) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NT neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NT neurons that occlude social reward processing.
Topics: Animals; Female; Male; Mice; Brain; Calcium; Mice, Inbred C57BL; Neural Pathways; Neurons; Neurotensin; Optogenetics; Psychological Trauma; Reward; Septal Nuclei; Social Behavior; Stress, Psychological
PubMed: 36450985
DOI: 10.1038/s41586-022-05484-5 -
Cell and Tissue Research Sep 2018The septo-hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum,... (Review)
Review
The septo-hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum, cholinergic, glutamatergic and GABAergic neurons form a highly interconnected local network. Neurons of these three classes project to glutamatergic pyramidal neurons and different subsets of GABAergic neurons in the hippocampal CA1 region. From there, GABAergic neurons project back to the medial septum and form a feedback loop between the two remote brain areas. In vivo, the firing of GABAergic medial septal neurons is theta modulated, while theta modulation is not observed in cholinergic neurons. One prominent feature of glutamatergic neurons is the correlation of their firing rates to the animals running speed. The cellular diversity, the high local interconnectivity and different activity patterns of medial septal neurons during different behaviors complicate the functional dissection of this network. New technical advances help to define specific functions of individual cell classes. In this review, we seek to highlight recent findings and elucidate functional implications of the septo-hippocampal connectivity on the microcircuit scale.
Topics: Animals; Behavior; Cholinergic Neurons; GABAergic Neurons; Hippocampus; Humans; Locomotion; Memory; Models, Neurological; Pyramidal Cells; Septal Nuclei; Theta Rhythm
PubMed: 29250747
DOI: 10.1007/s00441-017-2745-2 -
Science Advances Apr 2022The comorbidity of chronic pain and mental dysfunctions such as depression and anxiety disorders has long been recognized, but the underlying mechanisms remain poorly...
The comorbidity of chronic pain and mental dysfunctions such as depression and anxiety disorders has long been recognized, but the underlying mechanisms remain poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated neuronal plasticity in the bed nucleus of the stria terminalis (BNST), which plays a critical role in chronic pain-induced maladaptive anxiety. Electrophysiology demonstrated that chronic pain increased inhibitory inputs to lateral hypothalamus (LH)-projecting BNST neurons. Chemogenetic manipulation revealed that sustained suppression of LH-projecting BNST neurons played a crucial role in chronic pain-induced anxiety. Furthermore, using a molecular genetic approach, we demonstrated that chronic pain elevated the excitability of a specific subpopulation of BNST neurons, which express cocaine- and amphetamine-regulated transcript (CART). The elevated excitability of CART-positive neurons caused the increased inhibitory inputs to LH-projecting BNST neurons, thereby inducing anxiety-like behavior. These findings shed light on how chronic pain induces psychiatric disorders, characterized by maladaptive anxiety.
Topics: Anxiety; Anxiety Disorders; Chronic Pain; Humans; Neuronal Plasticity; Septal Nuclei
PubMed: 35476439
DOI: 10.1126/sciadv.abj5586 -
British Journal of Anaesthesia May 2023Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission...
BACKGROUND
Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections.
METHOD
Lipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-μm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP.
RESULTS
Intracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml to 382 [14] pg ml; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice.
CONCLUSIONS
Systemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.
Topics: Mice; Animals; Septal Nuclei; Acetylcholine; Lipopolysaccharides; Calcium; Hippocampus; Synaptic Transmission; Cognitive Dysfunction; Sepsis; Cognition; Cholinergic Agents
PubMed: 36813621
DOI: 10.1016/j.bja.2023.01.019 -
Aging Jan 2019
Topics: Alzheimer Disease; Basal Forebrain; Cell Cycle; Humans; Septal Nuclei
PubMed: 30668543
DOI: 10.18632/aging.101777 -
Sleep Medicine Reviews Apr 2012The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus... (Review)
Review
The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus noradrenergic neurons has long-suggested a role of this system in the induction of an alert waking state. Work over the past two decades provides unambiguous evidence that the locus coeruleus, and likely other noradrenergic nuclei, exert potent wake-promoting actions via an activation of noradrenergic β- and α₁-receptors located within multiple subcortical structures, including the general regions of the medial septal area, the medial preoptic area and, most recently, the lateral hypothalamus. Conversely, global blockade of β- and α₁-receptors or suppression of norepinephrine release results in profound sedation. The wake-promoting action of central noradrenergic neurotransmission has clinical implications for treatment of sleep/arousal disorders, such as insomnia and narcolepsy, and clinical conditions associated with excessive arousal, such as post-traumatic stress disorder.
Topics: Adrenergic Neurons; Animals; Arousal; Humans; Locus Coeruleus; Norepinephrine; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, beta; Septal Nuclei; Wakefulness
PubMed: 22296742
DOI: 10.1016/j.smrv.2011.12.003 -
Neuropharmacology Oct 2021Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral... (Review)
Review
Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral assays. This is reflected in the heterogeneous neuronal populations within the PBN to the extended amygdala (EA) circuits which encompass the bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) circuitry, as they differentially modulate aspects of behavior in response to diverse threat-like contexts necessary for survival. Here we review how the PBN→CeA and PBN→BNST pathways differentially modulate fear-like behavior, innate and conditioned, through unique changes in neurotransmission in response to stress-inducing contexts. Furthermore, we hypothesize how in specific instances the PBN→CeA and PBN→BNST circuits are redundant and in part intertwined with their respective reciprocal projections. By deconstructing the interoceptive and exteroceptive components of affect- and stress related behavioral paradigms, evidence suggests that the PBN→CeA circuit modulates innate response to physical stimuli and fear conditioning. Conversely, the PBN→BNST circuit modulates distress-like stress in unpredictable contexts. Thereby, the PBN provides a pathway for alarming interoceptive and exteroceptive stimuli to be processed and relayed to the EA to induce stress-relevant affect. Additionally, we provide a framework for future studies to detail the cell-type specific intricacies of PBN→EA circuits in mediating behavioral responses to threats, and the relevance of the PBN in drug-use as it relates to threat and negative reinforcement. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.
Topics: Affect; Amygdala; Animals; Fear; Humans; Parabrachial Nucleus; Septal Nuclei; Stress, Psychological
PubMed: 34461068
DOI: 10.1016/j.neuropharm.2021.108757 -
Journal of Cognitive Neuroscience Apr 2019During real-life situations, multiple factors interact dynamically to determine threat level. In the current fMRI study involving healthy adult human volunteers, we...
During real-life situations, multiple factors interact dynamically to determine threat level. In the current fMRI study involving healthy adult human volunteers, we investigated interactions between proximity, direction (approach vs. retreat), and speed during a dynamic threat-of-shock paradigm. As a measure of threat-evoked physiological arousal, skin conductance responses were recorded during fMRI scanning. Some brain regions tracked individual threat-related factors, and others were also sensitive to combinations of these variables. In particular, signals in the anterior insula tracked the interaction between proximity and direction where approach versus retreat responses were stronger when threat was closer compared with farther. A parallel proximity-by-direction interaction was also observed in physiological skin conductance responses. In the right amygdala, we observed a proximity by direction interaction, but intriguingly in the opposite direction as the anterior insula; retreat versus approach responses were stronger when threat was closer compared with farther. In the right bed nucleus of the stria terminalis, we observed an effect of threat proximity, whereas in the right periaqueductal gray/midbrain we observed an effect of threat direction and a proximity by direction by speed interaction (the latter was detected in exploratory analyses but not in a voxelwise fashion). Together, our study refines our understanding of the brain mechanisms involved during aversive anticipation in the human brain. Importantly, it emphasizes that threat processing should be understood in a manner that is both context-sensitive and dynamic.
Topics: Adult; Amygdala; Anticipation, Psychological; Brain Mapping; Cerebral Cortex; Fear; Galvanic Skin Response; Humans; Magnetic Resonance Imaging; Periaqueductal Gray; Septal Nuclei; Young Adult
PubMed: 30513044
DOI: 10.1162/jocn_a_01363