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Brain Structure & Function Sep 2022The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate...
The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate the PVT and evidence shows that the PVT regulates appetitive and aversive responses. The brainstem is a source of afferents to the PVT and the present study was done to determine if the lateral parabrachial nucleus (LPB) is a relay for inputs to the PVT. Retrograde tracing experiments with cholera toxin B (CTB) demonstrate that the LPB contains more PVT projecting neurons than other regions of the brainstem including the catecholamine cell groups. The hypothesis that the LPB is a relay for signals to the PVT was assessed using an intersectional monosynaptic rabies tracing approach. Sources of inputs to LPB included the reticular formation; periaqueductal gray (PAG); nucleus cuneiformis; and superior and inferior colliculi. Distinctive clusters of input cells to LPB-PVT projecting neurons were also found in the dorsolateral bed nucleus of the stria terminalis (BSTDL) and the lateral central nucleus of the amygdala (CeL). Anterograde viral tracing demonstrates that LPB-PVT neurons densely innervate all regions of the PVT in addition to providing collateral innervation to the preoptic area, lateral hypothalamus, zona incerta and PAG but not the BSTDL and CeL. The paper discusses the anatomical evidence that suggests that the PVT is part of a network of interconnected neurons involved in arousal, homeostasis, and the regulation of behavioral states with forebrain regions potentially providing descending modulation or gating of signals relayed from the LPB to the PVT.
Topics: Animals; Brain Stem; Midline Thalamic Nuclei; Neurons; Paraventricular Hypothalamic Nucleus; Prosencephalon; Rats; Rats, Sprague-Dawley; Thalamus
PubMed: 35838792
DOI: 10.1007/s00429-022-02534-6 -
ELife Mar 2022A new brain circuit that contributes to aversive states, such as fear or anxiety, has been characterized in mice.
A new brain circuit that contributes to aversive states, such as fear or anxiety, has been characterized in mice.
Topics: Affect; Animals; Anxiety; Brain; Emotions; Fear; Mice
PubMed: 35297762
DOI: 10.7554/eLife.77550 -
Peptides Aug 2021Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic polypeptide that can activate G protein-coupled PAC1, VPAC1, and VPAC2 receptors, and has... (Review)
Review
Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic polypeptide that can activate G protein-coupled PAC1, VPAC1, and VPAC2 receptors, and has been implicated in stress signaling. PACAP and its receptors are widely distributed throughout the nervous system and other tissues and can have a multitude of effects. Human and animal studies suggest that PACAP plays a role responding to a variety of threats and stressors. Here we review the roles of PACAP in several regions of the central nervous system (CNS) as they relate to several behavioral functions. For example, in the bed nucleus of the stria terminalis (BNST), PACAP is upregulated following chronic stress and may drive anxiety-like behavior. PACAP can also influence both the consolidation and expression of fear memories, as demonstrated by studies in several fear-related areas, such as the amygdala, hippocampus, and prefrontal cortex. PACAP can also mediate the emotional component of pain, as PACAP in the central nucleus of the amygdala (CeA) is able to decrease pain sensitivity thresholds. Outside of the central nervous system, PACAP may drive glucocorticoid release via enhanced hypothalamic-pituitary-adrenal axis activity and may participate in infection-induced stress responses. Together, this suggests that PACAP exerts effects on many stress-related systems and may be an important driver of emotional behavior.
Topics: Animals; Humans; Mental Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide; Stress, Psychological
PubMed: 33865930
DOI: 10.1016/j.peptides.2021.170554 -
Frontiers in Neuroscience 2021The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide...
The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide (CGRP)-expressing neurons that play a key role. The receptor for the orexigenic hormone ghrelin (the growth hormone secretagogue receptor, GHSR) is also abundantly expressed in the lPBN and ghrelin delivery to this site has recently been shown to increase food intake and alter food choice. Here we sought to explore whether GHSR-expressing cells in the lPBN (GHSR cells) contribute to feeding control, food choice and body weight gain in mice offered an obesogenic diet, involving studies in which GHSR cells were silenced. We also explored the neurochemical identity of GHSR cells. To silence GHSR cells, male mice were bilaterally injected intra-lPBN with a Cre-dependent viral vector expressing tetanus toxin-light chain. Unlike control wild-type littermates that significantly increased in body weight on the obesogenic diet (i.e., high-fat high-sugar free choice diet comprising chow, lard and 9% sucrose solution), the heterozygous mice with silenced GHSR cells were resistant to diet-induced weight gain with significantly lower food intake and fat weight. The lean phenotype appeared to result from a decreased food intake compared to controls and caloric efficiency was unaltered. Additionally, silencing the GHSR cells altered food choice, significantly reducing palatable food consumption. RNAscope and immunohistochemical studies of the lPBN revealed considerable co-expression of GHSR with glutamate and pituitary adenylate cyclase-activating peptide (PACAP), and much less with neurotensin, substance P and CGRP. Thus, the GHSR cells are important for diet-induced weight gain and adiposity, as well as in the regulation of food intake and food choice. Most GHSR cells were found to be glutamatergic and the majority (76%) do not belong to the well-characterized anorexigenic CGRP cell population.
PubMed: 33658910
DOI: 10.3389/fnins.2021.633018 -
Frontiers in Endocrinology 2024Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However,...
Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control.
Topics: Animals; Astrocytes; Male; Female; Rats; Eating; Parabrachial Nucleus; Anorexia; Feeding Behavior; Rats, Sprague-Dawley; Glutamic Acid; Receptors, N-Methyl-D-Aspartate
PubMed: 38887265
DOI: 10.3389/fendo.2024.1389589 -
Frontiers in Neuroscience 2023Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and... (Review)
Review
Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and can exert serious effects on a patient's physical and mental health. According to modeling stimulation protocols, the current animal models of visceral pain mainly include the mechanical dilatation model, the ischemic model, and the inflammatory model. Acupuncture can exert analgesic effects by integrating and interacting input signals from acupuncture points and the sites of pain in the central nervous system. The brain nuclei involved in regulating visceral pain mainly include the nucleus of the solitary tract, parabrachial nucleus (PBN), locus coeruleus (LC), rostral ventromedial medulla (RVM), anterior cingulate cortex (ACC), paraventricular nucleus (PVN), and the amygdala. The neural circuits involved are PBN-amygdala, LC-RVM, amygdala-insula, ACC-amygdala, claustrum-ACC, bed nucleus of the stria terminalis-PVN and the PVN-ventral lateral septum circuit. Signals generated by acupuncture can modulate the central structures and interconnected neural circuits of multiple brain regions, including the medulla oblongata, cerebral cortex, thalamus, and hypothalamus. This analgesic process also involves the participation of various neurotransmitters and/or receptors, such as 5-hydroxytryptamine, glutamate, and enkephalin. In addition, acupuncture can regulate visceral pain by influencing functional connections between different brain regions and regulating glucose metabolism. However, there are still some limitations in the research efforts focusing on the specific brain mechanisms associated with the effects of acupuncture on the alleviation of visceral pain. Further animal experiments and clinical studies are now needed to improve our understanding of this area.
PubMed: 38027491
DOI: 10.3389/fnins.2023.1243232 -
Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.Science Advances May 2023The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic...
The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic signatures of cell types and their links to function remain poorly understood. Using single-nucleus RNA sequencing, we describe nine CeA cell clusters, of which four are mostly associated with appetitive and two with aversive behaviors. To analyze the activation mechanism of appetitive CeA neurons, we characterized serotonin receptor 2a (Htr2a)-expressing neurons (CeA) that comprise three appetitive clusters and were previously shown to promote feeding. In vivo calcium imaging revealed that CeA neurons are activated by fasting, the hormone ghrelin, and the presence of food. Moreover, these neurons are required for the orexigenic effects of ghrelin. Appetitive CeA neurons responsive to fasting and ghrelin project to the parabrachial nucleus (PBN) causing inhibition of target PBN neurons. These results illustrate how the transcriptomic diversification of CeA neurons relates to fasting and hormone-regulated feeding behavior.
Topics: Transcriptome; Ghrelin; Fasting; Central Amygdaloid Nucleus; Neurons
PubMed: 37224253
DOI: 10.1126/sciadv.adf6521 -
NPJ Parkinson's Disease May 2023The presence of central neuropathic pain in Parkinson's disease suggests that the brain circuits that allow us to process pain could be dysfunctional in the disorder....
The presence of central neuropathic pain in Parkinson's disease suggests that the brain circuits that allow us to process pain could be dysfunctional in the disorder. However, there is to date no clear pathophysiological mechanism to explain these symptoms. In this work, we present evidence that the dysfunction of the subthalamic nucleus and/or substantia nigra pars reticulata may impact nociceptive processing in the parabrachial nucleus (PBN), a low level primary nociceptive structure in the brainstem, and induce a cellular and molecular neuro-adaptation in this structure. In rat models of Parkinson's disease with a partial dopaminergic lesion in the substantia nigra compacta, we found that the substantia nigra reticulata showed enhanced nociceptive responses. Such responses were less impacted in the subthalamic nucleus. A total dopaminergic lesion produced an increase in the nociceptive responses as well as an increase of the firing rate in both structures. In the PBN, inhibited nociceptive responses and increased expression of GABA receptors were found following a total dopaminergic lesion. However, neuro-adaptations at the level of dendritic spine density and post-synaptic density were found in both dopaminergic lesion groups. These results suggest that the molecular changes within the PBN following a larger dopaminergic lesion, such as increased GABA expression, is a key mechanism to produce nociceptive processing impairment, whilst other changes may protect function after smaller dopaminergic lesions. We also propose that these neuro-adaptations follow increased inhibitory tone from the substantia nigra pars reticulata and may represent the mechanism generating central neuropathic pain in Parkinson's disease.
PubMed: 37236965
DOI: 10.1038/s41531-023-00516-x -
Current Opinion in Physiology Jun 2020Sleep-wake control is dependent upon multiple brain areas widely distributed throughout the neural axis. Historically, the monoaminergic and cholinergic neurons of the...
Sleep-wake control is dependent upon multiple brain areas widely distributed throughout the neural axis. Historically, the monoaminergic and cholinergic neurons of the ascending arousal system were the first to be discovered, and it was only relatively recently that GABAergic and glutamatergic wake- and sleep-promoting populations have been identified. Contemporary advances in molecular-genetic tools have revealed both the complexity and heterogeneity of GABAergic NREM sleep-promoting neurons as well as REM sleep-regulating populations in the brainstem such as glutamatergic neurons in the sublaterodorsal nucleus. The sleep-wake cycle progresses from periods of wakefulness to non-rapid eye movement (NREM) sleep and subsequently rapid eye movement (REM) sleep. Each vigilance stage is controlled by multiple neuronal populations, via a complex regulation that is still incompletely understood. In recent years the field has seen a proliferation in the identification and characterization of new neuronal populations involved in sleep-wake control thanks to newer, more powerful molecular genetic tools that are able to reveal neurophysiological functions via selective activation, inhibition and lesion of neuroanatomically defined sub-types of neurons that are widespread in the brain, such as GABAergic and glutamatergic neurons..
PubMed: 32647777
DOI: 10.1016/j.cophys.2019.12.012 -
Progress in Neurobiology Jan 2021Hemispheric asymmetries within the brain have been identified across taxa and have been extensively studied since the early 19th century. Here, we discuss lateralization... (Review)
Review
Hemispheric asymmetries within the brain have been identified across taxa and have been extensively studied since the early 19th century. Here, we discuss lateralization of a brain structure, the amygdala, and how this lateralization is reshaping how we understand the role of the amygdala in pain processing. The amygdala is an almond-shaped, bilateral brain structure located within the limbic system. Historically, the amygdala was known to have a role in the processing of emotions and attaching emotional valence to memories and other experiences. The amygdala has been extensively studied in fear conditioning and affect but recently has been shown to have an important role in processing noxious information and impacting pain. The amygdala is composed of multiple nuclei; of special interest is the central nucleus of the amygdala (CeA). The CeA receives direct nociceptive inputs from the parabrachial nucleus (PBN) through the spino-parabrachio-amygdaloid pathway as well as more highly processed cortical and thalamic input via the lateral and basolateral amygdala. Although the amygdala is a bilateral brain region, most data investigating the amygdala's role in pain have been generated from the right CeA, which has an overwhelmingly pro-nociceptive function across pain models. The left CeA has often been characterized to have no effect on pain modulation, a dampened pro-nociceptive function, or most recently an anti-nociceptive function. This review explores the current literature on CeA lateralization and the hemispheres' respective roles in the processing and modulation of different forms of pain.
Topics: Animals; Arthralgia; Central Amygdaloid Nucleus; Functional Laterality; Humans; Neuralgia; Nociceptive Pain; Visceral Pain
PubMed: 32730859
DOI: 10.1016/j.pneurobio.2020.101891