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Molecular Psychiatry Dec 2023Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders...
Although clinical reports have highlighted association of the deacetylase sirtuin 1 (SIRT1) gene with anxiety, its exact role in the pathogenesis of anxiety disorders remains unclear. The present study was designed to explore whether and how SIRT1 in the mouse bed nucleus of the stria terminalis (BNST), a key limbic hub region, regulates anxiety. In a chronic stress model to induce anxiety in male mice, we used site- and cell-type-specific in vivo and in vitro manipulations, protein analysis, electrophysiological and behavioral analysis, in vivo MiniScope calcium imaging and mass spectroscopy, to characterize possible mechanism underlying a novel anxiolytic role for SIRT1 in the BNST. Specifically, decreased SIRT1 in parallel with increased corticotropin-releasing factor (CRF) expression was found in the BNST of anxiety model mice, whereas pharmacological activation or local overexpression of SIRT1 in the BNST reversed chronic stress-induced anxiety-like behaviors, downregulated CRF upregulation, and normalized CRF neuronal hyperactivity. Mechanistically, SIRT1 enhanced glucocorticoid receptor (GR)-mediated CRF transcriptional repression through directly interacting with and deacetylating the GR co-chaperone FKBP5 to induce its dissociation from the GR, ultimately downregulating CRF. Together, this study unravels an important cellular and molecular mechanism highlighting an anxiolytic role for SIRT1 in the mouse BNST, which may open up new therapeutic avenues for treating stress-related anxiety disorders.
Topics: Animals; Male; Sirtuin 1; Corticotropin-Releasing Hormone; Mice; Anxiety; Tacrolimus Binding Proteins; Septal Nuclei; Stress, Psychological; Signal Transduction; Mice, Inbred C57BL; Disease Models, Animal; Receptors, Glucocorticoid; Neurons; Anxiety Disorders
PubMed: 37386058
DOI: 10.1038/s41380-023-02144-6 -
Neuron Jun 2020The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional...
The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.
Topics: Animals; Avoidance Learning; Central Amygdaloid Nucleus; Escape Reaction; Mice; Neural Pathways; Neurons, Efferent; Nociception; Optogenetics; Pain; Parabrachial Nucleus; Periaqueductal Gray; Septal Nuclei; Ventromedial Hypothalamic Nucleus
PubMed: 32289251
DOI: 10.1016/j.neuron.2020.03.014 -
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 -
Biological Psychiatry Apr 2024The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood.
BACKGROUND
The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood.
METHODS
We combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and electrophysiological recording to investigate the involvement of specific extended amygdala circuits in different fear memory.
RESULTS
We identified the projections from central lateral amygdala (CeL) protein kinase C δ (PKCδ)-positive neurons and somatostatin (SST)-positive neurons to GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons in the ventral part of the bed nucleus of stria terminalis (vBNST). Prolonged optogenetic activation or inhibition of the PKCδ pathway specifically reduced context fear memory, whereas the SST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδ neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SST neurons could bidirectionally regulate both context and tone fear memory. We subsequently demonstrated the presence of δ and κ opioid receptor protein expression within the CeL-vBNST circuits, potentially accounting for the discrepancy between prolonged activation of GABAergic circuits and inhibition of downstream vBNST neurons. Finally, administration of an opioid receptor antagonist cocktail on the PKCδ or SST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits.
CONCLUSIONS
Together, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear.
Topics: Mice; Animals; Septal Nuclei; Central Amygdaloid Nucleus; Neurons; Fear; Basolateral Nuclear Complex
PubMed: 37678543
DOI: 10.1016/j.biopsych.2023.08.022 -
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 -
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 Neuroscience Research Jul 2022The lateral septum (LS) is a structure in the midline of the brain that is interconnected with areas associated with stress and feeding. This review highlights the role... (Review)
Review
The lateral septum (LS) is a structure in the midline of the brain that is interconnected with areas associated with stress and feeding. This review highlights the role of the LS in anxiety, depression, and eating disorders and their comorbidity. There is a prevailing view that the LS is anxiolytic. This review finds that the LS is both anxiolytic and anxiogenic. Furthermore, the LS can promote and inhibit feeding. Given these shared roles, the LS represents a common site for the comorbidity of neuropsychiatric disorders, and therefore a potential pharmacological target. This is crucial since currently available treatments are not always effective. Corticotrophin-releasing factor 2 antagonists are potential drugs for the treatment of anxiety and anorexia and require further research. Furthermore, other drugs currently in trials for binge eating, such as alpha-adrenergic agonists, may in fact promote food intake. It is hoped that the advancements in chemo- and optogenetic techniques will allow future studies to profile the specific neural connections of the LS and their function. This information could facilitate our understanding of the underlying mechanisms, and therefore pharmacological targets, of these psychiatric conditions.
Topics: Anti-Anxiety Agents; Anxiety; Optogenetics
PubMed: 35443088
DOI: 10.1002/jnr.25052 -
Neurobiology of Disease Apr 2022Acute injuries or insults to the cortex, such as trauma, subarachnoid hemorrhage, lobar hemorrhage, can cause seizures or status epilepticus(SE). Neocortical SE is...
OBJECTIVES
Acute injuries or insults to the cortex, such as trauma, subarachnoid hemorrhage, lobar hemorrhage, can cause seizures or status epilepticus(SE). Neocortical SE is associated with coma, worse prognosis, delayed recovery, and the development of epilepsy. The anatomical structures progressively recruited during neocortical-onset status epilepticus (SE) is unknown. Therefore, we constructed large-scale maps of brain regions active during neocortical SE.
METHODS
We used a neocortical injury-induced SE mouse model. We implanted cobalt (Co) in the right supplementary motor cortex (M2). We 16 h later administered a homocysteine injection (845 mg/kg, intraperitoneal) to C57Bl/6 J mice to induce SE and monitored it by video and EEG. We harvested animals for 1 h (early-stage) and 2 h (late-stage) following homocysteine injections. To construct activation maps, we immunolabeled whole-brain sections for cFos and NeuN, imaged them using a confocal microscope and quantified cFos immunoreactivity (IR).
RESULTS
SE in the early phase consisted of discrete, focal intermittent seizures, which became continuous and bilateral in the late stage. In this early stage, cFos IR was primarily observed in the right hemisphere, ipsilateral to the Co lesion, specifically in the motor cortex, retrosplenial cortex, somatosensory cortex, anterior cingulate cortex, lateral and medial septal nuclei, and amygdala. We observed bilateral cFos IR in brain regions during the late stage, indicating the bilateral spread of focal seizures. We found increased cFOS IR in the bilateral somatosensory cortex and the motor cortex and subcortical regions, including the amygdala, thalamus, and hypothalamus. There was noticeably different, intense cFos IR in the bilateral hippocampus compared to the early stage. In addition, there was higher activity in the cortex ipsilateral to the seizure focus during the late stage compared with the early one.
CONCLUSION
We present a large-scale, high-resolution map of seizure spread during neocortical injury-induced SE. Cortico-cortical and cortico subcortical re-entrant circuits sustain neocortical SE. Neuronal loss following neocortical SE, distant from the neocortical focus, may result from seizures.
Topics: Animals; Hippocampus; Mice; Neocortex; Neurons; Seizures; Status Epilepticus
PubMed: 35065250
DOI: 10.1016/j.nbd.2022.105633 -
Annals of Clinical and Translational... Dec 2023Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases. (Review)
Review
OBJECTIVE
Further understanding of the function and regulatory mechanism of cholinergic neural circuits and related neurodegenerative diseases.
METHODS
This review summarized the research progress of the central cholinergic nervous system, especially for the cholinergic circuit of the medial septal nucleus-hippocampus, vertical branch of diagonal band-hippocampus, basal nucleus of Meynert-cerebral cortex cholinergic loop, amygdala, pedunculopontine nucleus, and striatum-related cholinergic loops.
RESULTS
The extensive and complex fiber projection of cholinergic neurons form the cholinergic neural circuits, which regulate several nuclei in the brain through neurotransmission and participate in learning and memory, attention, emotion, movement, etc. The loss of cholinergic neurotransmitters, the reduction, loss, and degeneration of cholinergic neurons or abnormal theta oscillations and cholinergic neural circuits can induce cognitive disorders such as AD, PD, PDD, and DLB.
INTERPRETATION
The projection and function of cholinergic fibers in some nuclei and the precise regulatory mechanisms of cholinergic neural circuits in the brain remain unclear. Further investigation of cholinergic fiber projections in various brain regions and the underlying mechanisms of the neural circuits are expected to open up new avenues for the prevention and treatment of senile neurodegenerative diseases.
Topics: Humans; Central Nervous System; Hippocampus; Cerebral Cortex; Neurodegenerative Diseases; Cholinergic Agents
PubMed: 37846148
DOI: 10.1002/acn3.51920 -
Clinical Parkinsonism & Related... 2022Parkinson's disease (PD) mainly affects basal ganglia including septal nuclei. Septal nuclei have extensive cholinergic connections with thalamus and brain stem nuclei....
OBJECTIVE
Parkinson's disease (PD) mainly affects basal ganglia including septal nuclei. Septal nuclei have extensive cholinergic connections with thalamus and brain stem nuclei. We hypothesized that the degeneration of septal nuclei has an impact on dopaminergic (motor) and non-dopaminergic (cognitive) symptoms in PD.
METHOD
Clinical and MRI data of 80 patients with Parkinson's disease and 20 healthy controls (HC) with a structural magnetic resonance imaging (MRI) were selected from their first visit from PPMI database. Septal nuclei were manually segmented from T1W images according to previously established anatomical criteria. In addition, subcortical structures such as thalamus, amygdala, hippocampus, caudate, putamen, pallidum and accumbens were automatically segmented.
RESULTS
Volume of septal nuclei in the patients with PD was decreased in comparison with controls. These changes were independent of volume changes in other subcortical grey structure in PD. In addition, we found a correlation between motor components of unified Parkinson's disease rating scale (UPDRS) and volume of septal nuclei in PD. Other clinical measures such as olfactory test, upper extremity function (mobility) performance, total UPDRS, lower extremity function (mobility) performance, and cognitive function were significantly more in PD group than in control. No correction was found between cognitive function and volume of septal nuclei.
CONCLUSION
We concluded that septal nuclei is distinctly affected in PD and is strongly associated with motor impairment. This may be a modulatory effect of cholinergic system on dopaminergic and glutamergic system. It is suggested that volume of septal nuclei may be a useful biomarker in PD diagnosis and monitoring.
PubMed: 36338824
DOI: 10.1016/j.prdoa.2022.100171