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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 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 -
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 -
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 -
Nature Aug 2023Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid...
Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVH neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVH neurons.
Topics: Agouti-Related Protein; Corticotropin-Releasing Hormone; Fasting; GABAergic Neurons; gamma-Aminobutyric Acid; Hypothalamo-Hypophyseal System; Neurons; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Presynaptic Terminals; Septal Nuclei
PubMed: 37495689
DOI: 10.1038/s41586-023-06358-0 -
Science (New York, N.Y.) Feb 2023Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the...
Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that the ejaculation experience selectively activated estrogen receptor 2 ()-expressing neurons in the bed nucleus of the stria terminalis (BNST)-BNST-and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNST elicited fast mating recovery in satiated mice of both sexes. In males, such hyperexcitability reduced mating motivation and was partially mediated by larger HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Thus, BNST not only encode a specific mating action but also represent a persistent state of sexual satiety, and alterations in a neuronal ion channel contribute to sexual experience-dependent long-term changes to mating drive.
Topics: Animals; Female; Male; Mice; Motivation; Neurons; Satiation; Septal Nuclei; Sexual Behavior, Animal; Ejaculation; Estrogen Receptor beta
PubMed: 36758107
DOI: 10.1126/science.abl4038 -
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 -
Aging Jan 2019
Topics: Alzheimer Disease; Basal Forebrain; Cell Cycle; Humans; Septal Nuclei
PubMed: 30668543
DOI: 10.18632/aging.101777 -
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 -
Nature Sep 2021The hippocampus has previously been implicated in both cognitive and endocrine functions. We simultaneously measured electrophysiological activity from the hippocampus...
The hippocampus has previously been implicated in both cognitive and endocrine functions. We simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats to identify an activity pattern that may link these disparate functions of the hippocampus. Here we report that clusters of sharp wave-ripples recorded from the hippocampus reliably predicted a decrease in peripheral glucose concentrations within about 10 min. This correlation was not dependent on circadian, ultradian or meal-triggered fluctuations, could be mimicked with optogenetically induced ripples in the hippocampus (but not in the parietal cortex) and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum, which is the major conduit between the hippocampus and the hypothalamus. Our findings demonstrate that a function of the sharp wave-ripple is to modulate peripheral glucose homeostasis, and offer a mechanism for the link between sleep disruption and blood glucose dysregulation in type 2 diabetes.
Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Hippocampus; Homeostasis; Hypothalamus; Optogenetics; Pharmacogenetics; Rats; Rats, Long-Evans; Septal Nuclei; Sleep; Time Factors
PubMed: 34381214
DOI: 10.1038/s41586-021-03811-w