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Behavioural Brain Research Jan 2015Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked... (Review)
Review
Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (α-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs.
Topics: Animals; Eating; Feeding Behavior; Humans; Obesity; Receptors, Serotonin; Satiety Response; Serotonin
PubMed: 25217810
DOI: 10.1016/j.bbr.2014.08.065 -
Frontiers in Psychiatry 2023In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and...
In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and sympathetic activities. Repeated stress responses play an essential role in the pathogenesis of psychiatric diseases and sleep disorders. However, the underlying mechanism of sleep changes and anxiety disorders in response to acute stress is not well established. In the current study, the effects of restraint stress (RS) on anxiety and sleep-wake cycles in mice were investigated. We found that after RS, the mice showed anxiety-like behavior after RS manipulation and increased the amounts of both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in the dark period. The increase in sleep time was mainly due to the increased number of episodes of NREM and REM sleep during the dark period. In addition, the mice showed an elevation of the EEG power spectrum of both NREM and REM sleep 2 h after RS manipulation. There was a significant reduction in the EEG power spectrum of both NREM and REM sleep during the darkperiod in the RS condition. The expression of the c-Fos protein was significantly increased in the parabrachial nucleus, bed nucleus of the stria terminalis, central amygdala, and paraventricular hypothalamus by RS manipulation. Altogether, the findings from the present study indicated that neural circuits from the parabrachial nucleus might regulate anxiety and sleep responses to acute stress, and suggest a potential therapeutic target for RS induced anxiety and sleep alterations.
PubMed: 37124267
DOI: 10.3389/fpsyt.2023.1090420 -
The Journal of Neuroscience : the... Oct 2019The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive... (Review)
Review
The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.
Topics: Animals; Body Temperature Regulation; Humans; Neural Pathways; Neurons; Nociception; Pain; Parabrachial Nucleus; Taste
PubMed: 31619491
DOI: 10.1523/JNEUROSCI.1162-19.2019 -
Frontiers in Neuroscience 2019Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway... (Review)
Review
Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway collapse, followed by brief arousals that help re-establish the airway patency. These repetitive arousals which can occur hundreds of times during the course of a night are the cause of the sleep-disruption, which in turn causes cognitive impairment as well as cardiovascular and metabolic morbidities. To prevent this potential outcome, it is important to target preventing the arousal from sleep while preserving or augmenting the increase in respiratory drive that reinitiates breathing, but will require understanding of the neural circuits that regulate the cortical and respiratory responses to apnea. The parabrachial nucleus (PB) is located in rostral pons. It receives chemosensory information from medullary nuclei that sense increase in CO2 (hypercapnia), decrease in O2 (hypoxia) and mechanosensory inputs from airway negative pressure during apneas. The PB area also exerts powerful control over cortical arousal and respiration, and therefore, is an excellent candidate for mediating the EEG arousal and restoration of the airway during sleep apneas. Using various genetic tools, we dissected the neuronal sub-types responsible for relaying the stimulus for cortical arousal to forebrain arousal circuits. The present review will focus on the circuitries that regulate waking-up from sleep in response to hypercapnia.
PubMed: 31080401
DOI: 10.3389/fnins.2019.00401 -
Nature Communications Jul 2022Both rodents and primates have evolved to orchestrate food intake to maintain thermal homeostasis in coping with ambient temperature challenges. However, the mechanisms...
Both rodents and primates have evolved to orchestrate food intake to maintain thermal homeostasis in coping with ambient temperature challenges. However, the mechanisms underlying temperature-coordinated feeding behavior are rarely reported. Here we find that a non-canonical feeding center, the anteroventral and periventricular portions of medial preoptic area (apMPOA) respond to altered dietary states in mice. Two neighboring but distinct neuronal populations in apMPOA mediate feeding behavior by receiving anatomical inputs from external and dorsal subnuclei of lateral parabrachial nucleus. While both populations are glutamatergic, the arcuate nucleus-projecting neurons in apMPOA can sense low temperature and promote food intake. The other type, the paraventricular hypothalamic nucleus (PVH)-projecting neurons in apMPOA are primarily sensitive to high temperature and suppress food intake. Caspase ablation or chemogenetic inhibition of the apMPOA→PVH pathway can eliminate the temperature dependence of feeding. Further projection-specific RNA sequencing and fluorescence in situ hybridization identify that the two neuronal populations are molecularly marked by galanin receptor and apelin receptor. These findings reveal unrecognized cell populations and circuits of apMPOA that orchestrates feeding behavior against thermal challenges.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Feeding Behavior; In Situ Hybridization, Fluorescence; Mice; Paraventricular Hypothalamic Nucleus; Temperature
PubMed: 35869064
DOI: 10.1038/s41467-022-31917-w -
Journal of Translational Medicine Dec 2023Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological...
BACKGROUND
Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood.
METHODS
We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits.
RESULTS
Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain.
CONCLUSIONS
Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.
Topics: Mice; Animals; Male; Parabrachial Nucleus; Freund's Adjuvant; Mice, Inbred C57BL; Neurons; Chronic Pain; Attention
PubMed: 38072957
DOI: 10.1186/s12967-023-04583-9 -
Neuroscience Bulletin Apr 2023The parabrachial nucleus (PBN) integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,...
The parabrachial nucleus (PBN) integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing, emotion, and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem. However, the precise identity and function of distinct PBN subpopulations are still largely unknown. Here, we leveraged molecular characterization, retrograde tracing, optogenetics, chemogenetics, and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain, rather than the medulla. Their activation induces freezing and anxiety-like behaviors, which in turn result in tachypnea. In addition, optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture. We propose that these neurons comprise a PBN subpopulation with specific gene expression, connectivity, and function, which play essential roles in behavioral and physiological regulation.
Topics: Parabrachial Nucleus; Wakefulness; Neurons; Emotions; Sleep
PubMed: 36522525
DOI: 10.1007/s12264-022-00994-8 -
Brain : a Journal of Neurology Apr 2021Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been...
Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n = 63), pedunculopontine nucleus (n = 48), ventral tegmental area (n = 22), substantia nigra (n = 9), mesencephalic reticular formation (n = 7), medial forebrain bundle (n = 8), superior cerebellar peduncles (n = 3), red nucleus (n = 3), parabrachial complex (n = 2), and locus coeruleus (n = 1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.
Topics: Brain Stem; Deep Brain Stimulation; Humans
PubMed: 33313788
DOI: 10.1093/brain/awaa374 -
Proceedings of the National Academy of... Oct 2023Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory...
Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia, and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS-related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate -expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment.
Topics: Animals; Mice; Motion Sickness; Movement; Neurons; Vestibular Nuclei; Vestibule, Labyrinth
PubMed: 37847729
DOI: 10.1073/pnas.2304933120 -
The Journal of Pain Sep 2023Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately...
Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) in the brainstem plays a key role in pain and emotional processing; yet, the effects of opioids on synaptic plasticity in this area remain unexplored. Using patch-clamp recordings in acute brainstem slices from male and female Sprague Dawley rats, we demonstrate a concentration-dependent, bimodal effect of opioids on excitatory synaptic transmission in the LPBN. While a lower concentration of DAMGO (0.5 µM) induced a long-term depression of synaptic strength (low-DAMGO LTD), abrupt termination of a higher concentration (10 µM) induced a long-term potentiation (high-DAMGO LTP) in a subpopulation of cells. LTD involved a metabotropic glutamate receptor (mGluR)-dependent mechanism; in contrast, LTP required astrocytes and N-methyl-D-aspartate receptor (NMDAR) activation. Selective optogenetic activation of spinal and periaqueductal gray matter (PAG) inputs to the LPBN revealed that, while LTD was expressed at all parabrachial synapses tested, LTP was restricted to spino-parabrachial synapses. Thus, we uncovered previously unknown forms of opioid-induced long-term plasticity in the parabrachial nucleus that potentially modulate some adverse effects of opioids. PERSPECTIVE: We found a previously unrecognized site of opioid-induced plasticity in the lateral parabrachial nucleus, a key region for pain and emotional processing. Unraveling opioid-induced adaptations in parabrachial function might facilitate the identification of new therapeutic measures for addressing adverse effects of opioid discontinuation such as hyperalgesia and aversion.
Topics: Rats; Male; Female; Animals; Analgesics, Opioid; Rats, Sprague-Dawley; Pain Clinics; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Neuronal Plasticity; Brain Stem; Pain
PubMed: 37150382
DOI: 10.1016/j.jpain.2023.05.001