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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 -
Neuroscience and Biobehavioral Reviews Jun 2024The lateral septum (LS) is involved in controlling anxiety, aggression, feeding, and other motivated behaviors. Lesion studies have also implicated the LS in various... (Review)
Review
The lateral septum (LS) is involved in controlling anxiety, aggression, feeding, and other motivated behaviors. Lesion studies have also implicated the LS in various forms of caring behaviors. Recently, novel experimental tools have provided a more detailed insight into the function of the LS, including the specific role of distinct cell types and their neuronal connections in behavioral regulations, in which the LS participates. This article discusses the regulation of different types of maternal behavioral alterations using the distributions of established maternal hormones such as prolactin, estrogens, and the neuropeptide oxytocin. It also considers the distribution of neurons activated in mothers in response to pups and other maternal activities, as well as gene expressional alterations in the maternal LS. Finally, this paper proposes further research directions to keep up with the rapidly developing knowledge on maternal behavioral control in other maternal brain regions.
Topics: Maternal Behavior; Animals; Septal Nuclei; Female; Humans; Oxytocin
PubMed: 38649125
DOI: 10.1016/j.neubiorev.2024.105683 -
Neuroscience Letters Feb 2019Anxiety disorders impose a staggering burden on public health, underscoring the need to develop a deeper understanding of the distributed neural circuits underlying... (Review)
Review
Anxiety disorders impose a staggering burden on public health, underscoring the need to develop a deeper understanding of the distributed neural circuits underlying extreme fear and anxiety. Recent work highlights the importance of the central extended amygdala, including the central nucleus of the amygdala (Ce) and neighboring bed nucleus of the stria terminalis (BST). Anatomical data indicate that the Ce and BST form a tightly interconnected unit, where different kinds of threat-relevant information can be integrated to assemble states of fear and anxiety. Neuroimaging studies show that the Ce and BST are engaged by a broad spectrum of potentially threat-relevant cues. Mechanistic work demonstrates that the Ce and BST are critically involved in organizing defensive responses to a wide range of threats. Studies in rodents have begun to reveal the specific molecules, cells, and microcircuits within the central extended amygdala that underlie signs of fear and anxiety, but the relevance of these tantalizing discoveries to human experience and disease remains unclear. Using a combination of focal perturbations and whole-brain imaging, a new generation of nonhuman primate studies is beginning to close this gap. This work opens the door to discovering the mechanisms underlying neuroimaging measures linked to pathological fear and anxiety, to understanding how the Ce and BST interact with one another and with distal brain regions to govern defensive responses to threat, and to developing improved intervention strategies.
Topics: Animals; Anxiety; Brain Mapping; Central Amygdaloid Nucleus; Fear; Humans; Models, Animal; Models, Neurological; Neural Pathways; Neuroimaging; Prefrontal Cortex; Primates; Septal Nuclei
PubMed: 29195911
DOI: 10.1016/j.neulet.2017.11.056 -
Proceedings of the National Academy of... Dec 2017Feeding behavior is controlled by diverse neurons and neural circuits primarily concentrated in the hypothalamus and hindbrain in mammals. In this study, by using...
Feeding behavior is controlled by diverse neurons and neural circuits primarily concentrated in the hypothalamus and hindbrain in mammals. In this study, by using chemo/optogenetic techniques along with feeding assays, we investigate how neurons within the medial septal complex (MSc), a brain area implicated in emotion and cognition, contribute to food intake. We find that chemo/optogenetic activation of MSc glutamatergic neurons profoundly reduces food intake during both light and dark periods of the rodent light cycle. Furthermore, we find that selective activation of MSc glutamatergic projections in paraventricular hypothalamus (PVH) reduces food intake, suggesting that MSc glutamatergic neurons suppress feeding by activating downstream neurons in the PVH. Open-field behavioral assays reveal that these neurons do not overtly affect anxiety levels and locomotion. Collectively, our findings demonstrate that septal glutamatergic neurons exert anorexigenic effects by projecting to the PVH without affecting anxiety and physical activities.
Topics: Animals; Appetite Regulation; Eating; Female; Locomotion; Male; Mice; Mice, Transgenic; Neurons; Septal Nuclei
PubMed: 29229861
DOI: 10.1073/pnas.1707228114 -
Neuropharmacology Aug 2017The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states.... (Review)
Review
The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components. Such recent developments are largely owed to methodological advances, which have made possible efforts previously deemed intractable, such as tracing of long-range cell-type specific projections and identifying functional efferent and afferent connections. In this review, we integrate earlier foundational work with more recent and advanced studies to construct a broad overview of the molecular neurocircuitry of the BNST in drug-associated behavior and affect. This article is part of the Special Issue entitled "Alcoholism".
Topics: Alcohol Drinking; Alcoholism; Animals; Drug-Seeking Behavior; Humans; Neural Pathways; Septal Nuclei
PubMed: 28351600
DOI: 10.1016/j.neuropharm.2017.03.028 -
The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies.Frontiers in Neural Circuits 2021The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal... (Review)
Review
The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain.
Topics: Animals; Brain; Brain Diseases; Brain Waves; Deep Brain Stimulation; Epilepsy; Humans; Mental Disorders; Septal Nuclei; Treatment Outcome
PubMed: 34305537
DOI: 10.3389/fncir.2021.701080 -
Psychoneuroendocrinology Mar 2018A network of interconnected cell groups in the limbic forebrain regulates hypothalamic-pituitary-adrenal (HPA) axis activation and behavioral responses to emotionally... (Review)
Review
A network of interconnected cell groups in the limbic forebrain regulates hypothalamic-pituitary-adrenal (HPA) axis activation and behavioral responses to emotionally stressful experiences, and chronic disruption of these systems chronically is implicated in the pathogenesis of psychiatric illnesses. A significant challenge has been to unravel the circuitry and mechanisms providing for regulation of HPA activity, as these limbic forebrain regions do not provide any direct innervation of HPA effector cell groups in the paraventricular hypothalamus (PVH). Moreover, information regarding how endocrine and behavioral responses are integrated has remained obscure. Here we summarize work from our laboratory showing that anteroventral (av) bed nuclei of the stria terminalis (BST) acts as a point of convergence between the limbic forebrain and PVH, receiving and coordinating upstream influences, and restraining HPA axis output in response to inescapable stressors. Recent studies highlight a more expansive modulatory role for avBST as one that coordinates HPA-inhibitory influences while concurrently suppressing passive behavioral responses via divergent pathways. avBST is uniquely positioned to convey endocrine and behavioral alterations resulting from chronic stress exposure, such as HPA axis hyperactivity and increased passive coping strategies, that may result from synaptic reorganization in upstream limbic cortical regions. We discuss how these studies give new insights into understanding the systems-level organization of stress response circuitry, the neurobiology of coping styles, and BST circuit dysfunction in stress-related psychiatric disorders.
Topics: Adaptation, Psychological; Animals; Humans; Hypothalamo-Hypophyseal System; Limbic Lobe; Mental Disorders; Nerve Net; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Psychophysiologic Disorders; Septal Nuclei; Stress, Physiological; Stress, Psychological; Thalamus
PubMed: 29395488
DOI: 10.1016/j.psyneuen.2017.12.005 -
Cold Spring Harbor Perspectives in... Apr 2013The extended amygdala is a series of interconnected, embryologically similar series of nuclei in the brain that are thought to play key roles in aspects of alcohol... (Review)
Review
The extended amygdala is a series of interconnected, embryologically similar series of nuclei in the brain that are thought to play key roles in aspects of alcohol dependence, specifically in stress-induced increases in alcohol-seeking behaviors. Plasticity of excitatory transmission in these and other brain regions is currently an intense area of scrutiny as a mechanism underlying aspects of addiction. N-methyl-D-aspartate (NMDA) receptors (NMDARs) play a critical role in plasticity at excitatory synapses and have been identified as major molecular targets of ethanol. Thus, this article will explore alcohol and NMDAR interactions first at a general level and then focusing within the extended amygdala, in particular on the bed nucleus of the stria terminalis (BNST).
Topics: Amygdala; Animals; Anxiety; Central Nervous System Depressants; Ethanol; Humans; Rats; Receptors, N-Methyl-D-Aspartate; Septal Nuclei; Stress, Psychological; Synapses
PubMed: 23426579
DOI: 10.1101/cshperspect.a012161 -
Human Brain Mapping Jun 2021While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white...
While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.
Topics: Adult; Adult Survivors of Child Abuse; Adverse Childhood Experiences; Affective Symptoms; Diffusion Tensor Imaging; Female; Fornix, Brain; Humans; Male; Medial Forebrain Bundle; Psychosocial Deprivation; Septal Nuclei; Socioeconomic Factors; Stress, Psychological; White Matter; Young Adult
PubMed: 33739544
DOI: 10.1002/hbm.25378 -
Neurobiology of Aging Jan 2010Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum...
Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid beta peptide (Abeta) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Abeta 1-40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Abeta 1-40 treated tissue. Additionally, glutamatergic terminals were significantly less in Abeta treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Abeta 1-40 treated tissue. Abeta also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Abeta alters the anatomy and physiology of the medial septum contributing to septo-hippocampal dysfunction. The Abeta induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients.
Topics: Acetylcholine; Action Potentials; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinergic Fibers; Disease Models, Animal; Glutamic Acid; Hippocampus; Male; Nerve Degeneration; Neural Pathways; Neurons; Peptide Fragments; Rats; Rats, Sprague-Dawley; Septal Nuclei; Theta Rhythm
PubMed: 18547680
DOI: 10.1016/j.neurobiolaging.2008.05.006