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Nature Communications Feb 2023As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in...
Electroacupuncture improves swallowing function in a post-stroke dysphagia mouse model by activating the motor cortex inputs to the nucleus tractus solitarii through the parabrachial nuclei.
As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in dysphagia. However, little is known about the neurological mechanism by which this peripheral stimulation approach treats for dysphagia. Here, we first identified a cluster of excitatory neurons in layer 5 (L5) of the primary motor cortex (M1) that can regulate swallowing function in male mice by modulating mylohyoid activity. Moreover, we found that focal ischemia in the M1 mimicked the post-stroke dysphagia (PSD) pathology, as indicated by impaired water consumption and electromyographic responses in the mylohyoid. This dysfunction could be rescued by electroacupuncture (EA) stimulation at the CV23 acupoint (EA-CV23) in a manner dependent on the excitatory neurons in the contralateral M1 L5. Furthermore, neuronal activation in both the parabrachial nuclei (PBN) and nucleus tractus solitarii (NTS), which was modulated by the M1, was required for the ability of EA-CV23 treatment to improve swallowing function in male PSD model mice. Together, these results uncover the importance of the M1-PBN-NTS neural circuit in driving the protective effect of EA-CV23 against swallowing dysfunction and thus reveal a potential strategy for dysphagia intervention.
Topics: Male; Mice; Animals; Solitary Nucleus; Deglutition; Deglutition Disorders; Electroacupuncture; Motor Cortex; Stroke
PubMed: 36781899
DOI: 10.1038/s41467-023-36448-6 -
Respiration; International Review of... 2023Voluntary breath-holding (BH) triggers responses from central neural control and respiratory centers in order to restore breathing. Such responses can be observed using...
BACKGROUND
Voluntary breath-holding (BH) triggers responses from central neural control and respiratory centers in order to restore breathing. Such responses can be observed using functional MRI (fMRI).
OBJECTIVES
We used this paradigm in healthy volunteers with the view to develop a biomarker that could be used to investigate disorders of the central control of breathing at the individual patient level.
METHOD
In 21 healthy human subjects (mean age±SD, 32.8 ± 9.9 years old), fMRI was used to determine, at both the individual and group levels, the physiological neural response to expiratory and inspiratory voluntary apneas, within respiratory control centers in the brain and brainstem.
RESULTS
Group analysis showed that expiratory BH, but not inspiratory BH, triggered activation of the pontine respiratory group and raphe nuclei at the group level, with a significant relationship between the levels of activation and drop in SpO2. Using predefined ROIs, expiratory BH, and to a lesser extent, inspiratory BH were associated with activation of most respiratory centers. The right ventrolateral nucleus of the thalamus, right pre-Bötzinger complex, right VRG, right nucleus ambiguus, and left Kölliker-Fuse-parabrachial complex were only activated during inspiratory BH. Individual analysis identified activations of cortical/subcortical and brainstem structures related to respiratory control in 19 out of 21 subjects.
CONCLUSION
Our study shows that BH paradigm allows to reliably trigger fMRI response from brainstem and cortical areas involved in respiratory control at the individual level, suggesting that it might serve as a clinically relevant biomarker to investigate conditions associated with an altered central control of respiration.
Topics: Humans; Young Adult; Adult; Respiratory Center; Breath Holding; Respiration; Magnetic Resonance Imaging; Brain
PubMed: 36750046
DOI: 10.1159/000529388 -
Molecular Pain 2023The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of...
The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping - a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.
Topics: Rats; Male; Female; Animals; Mice; Rats, Sprague-Dawley; Carrageenan; Hot Temperature; Avoidance Learning; Pain; Morphine; Pain Threshold
PubMed: 36717755
DOI: 10.1177/17448069231156657 -
Frontiers in Pharmacology 2022The parabrachial nucleus (PBN) is an important structure regulating the sleep-wake behavior and general anesthesia. Astrocytes in the central nervous system modulate...
The parabrachial nucleus (PBN) is an important structure regulating the sleep-wake behavior and general anesthesia. Astrocytes in the central nervous system modulate neuronal activity and consequential behavior. However, the specific role of the parabrachial nucleus astrocytes in regulating the sleep-wake behavior and general anesthesia remains unclear. We used chemogenetic approach to activate or inhibit the activity of PBN astrocytes by injecting AAV-GFAabc1d-hM3Dq-eGFP or AAV-GFAabc1d-hM4Di-eGFP into the PBN. We investigated the effects of intraperitoneal injection of CNO or vehicle on the amount of wakefulness, NREM sleep and REM sleep in sleep-wake behavior, and on the time of loss of righting reflex, time of recovery of righting reflex, sensitivity to isoflurane, electroencephalogram (EEG) power spectrum and burst suppression ratio (BSR) in isoflurane anesthesia. The activation of PBN astrocytes increased wakefulness amount for 4 h, while the inhibition of PBN astrocytes decreased total amount of wakefulness during the 3-hour post-injection period. Chemogenetic activation of PBN astrocytes decreased isoflurane sensitivity and shortened the emergence time from isoflurane-induced general anesthesia. Cortical EEG recordings revealed that PBN astrocyte activation decreased the EEG delta power and BSR during isoflurane anesthesia. Chemogenetic Inhibition of PBN astrocytes increased the EEG delta power and BSR during isoflurane anesthesia. PBN astrocytes are a key neural substrate regulating wakefulness and emergence from isoflurane anesthesia.
PubMed: 36712675
DOI: 10.3389/fphar.2022.991238 -
BioRxiv : the Preprint Server For... Jan 2023In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural...
In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.
PubMed: 36712030
DOI: 10.1101/2023.01.19.524823 -
Nature Neuroscience Mar 2023Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral...
Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral nerve injury, cholinergic neurons in the anterior nucleus basalis (aNB) of the basal forebrain are increasingly active during nonrapid eye movement (NREM) sleep in a mouse model of neuropathic pain. These neurons directly activate vasoactive intestinal polypeptide-expressing interneurons in the primary somatosensory cortex (S1), causing disinhibition of pyramidal neurons and allodynia. The hyperactivity of aNB neurons is caused by the increased inputs from the parabrachial nucleus (PB) driven by the injured peripheral afferents. Inhibition of this pathway during NREM sleep, but not wakefulness, corrects neuronal hyperactivation and alleviates pain. Our results reveal that the PB-aNB-S1 pathway during sleep is critical for the generation and maintenance of chronic pain. Inhibiting this pathway during the sleep phase could be important for treating neuropathic pain.
Topics: Animals; Mice; Chronic Pain; Sleep; Sleep, Slow-Wave; Neuralgia; Cholinergic Neurons
PubMed: 36690899
DOI: 10.1038/s41593-022-01250-y -
Nutrients Jan 2023Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated... (Review)
Review
Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin-angiotensin-aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.
Topics: Sodium; Oxytocin; Homeostasis; Kidney; Angiotensin II
PubMed: 36678265
DOI: 10.3390/nu15020395 -
The Journal of Neuroscience : the... Feb 2023Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice...
Recent findings from our laboratory demonstrated that the rostral nucleus of the solitary tract (rNST) retains some responsiveness to sugars in double-knock-out mice lacking either the T1R1+T1R3 (KO1+3) or T1R2+T1R3 (KO2+3) taste receptor heterodimers. Here, we extended these findings in the parabrachial nucleus (PBN) of male and female KO1+3 mice using warm stimuli to optimize sugar responses and employing additional concentrations and pharmacological agents to probe mechanisms. PBN T1R-independent sugar responses, including those to concentrated glucose, were more evident than in rNST. Similar to the NST, there were no "sugar-best" neurons in KO1+3 mice. Nevertheless, 1000 mm glucose activated nearly 55% of PBN neurons, with responses usually occurring in neurons that also displayed acid and amiloride-insensitive NaCl responses. In wild-type (WT) mice, concentrated sugars activated the same electrolyte-sensitive neurons but also "sugar-best" cells. Regardless of genotype, phlorizin, an inhibitor of the sodium-glucose co-transporter (SGLT), a component of a hypothesized alternate glucose-sensing mechanism, did not diminish responses to 1000 mm glucose. The efficacy of concentrated sugars for driving neurons broadly responsive to electrolytes implied an origin from Type III taste bud cells. To test this, we used the carbonic anhydrase (CA) inhibitor dorzolamide (DRZ), previously shown to inhibit amiloride-insensitive sodium responses arising from Type III taste bud cells. Dorzolamide had no effect on sugar-elicited responses in WT sugar-best PBN neurons but strongly suppressed them in WT and KO1+3 electrolyte-generalist neurons. These findings suggest a novel T1R-independent mechanism for hyperosmotic sugars, involving a CA-dependent mechanism in Type III taste bud cells. Since the discovery of receptors for sugars and artificial sweeteners, evidence has accrued that mice lacking these receptors maintain some behavioral, physiological, and neural responsiveness to sugars. But the substrate(s) has remained elusive. Here, we recorded from parabrachial nucleus (PBN) taste neurons and identified T1R-independent responses to hyperosmotic sugars dependent on carbonic anhydrase (CA) and occurring primarily in neurons broadly responsive to NaCl and acid, implying an origin from Type III taste bud cells. The effectiveness of different sugars in driving these T1R-independent responses did not correlate with their efficacy in driving licking, suggesting they evoke a nonsweet sensation. Nevertheless, these salient responses are likely to comprise an adequate cue for learned preferences that occur in the absence of T1R receptors.
Topics: Animals; Female; Male; Mice; Amiloride; Glucose; Mice, Knockout; Sodium Chloride; Sugars; Taste; Taste Buds
PubMed: 36623875
DOI: 10.1523/JNEUROSCI.1760-22.2023 -
Neuroscience Bulletin Aug 2023The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity....
The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity. Phenotypically-characterized NTS neurons have been implicated in the differential regulation of blood pressure (BP). Here, we investigated whether phenylethanolamine N-methyltransferase (PNMT)-expressing NTS (NTS) neurons contribute to the control of BP. We demonstrate that photostimulation of NTS neurons has variable effects on BP. A depressor response was produced during optogenetic stimulation of NTS neurons projecting to the paraventricular nucleus of the hypothalamus, lateral parabrachial nucleus, and caudal ventrolateral medulla. Conversely, photostimulation of NTS neurons projecting to the rostral ventrolateral medulla produced a robust pressor response and bradycardia. In addition, genetic ablation of both NTS neurons and those projecting to the rostral ventrolateral medulla impaired the arterial baroreflex. Overall, we revealed the neuronal phenotype- and circuit-specific mechanisms underlying the contribution of NTS neurons to the regulation of BP.
Topics: Solitary Nucleus; Blood Pressure; Phenylethanolamine N-Methyltransferase; Neurons; Paraventricular Hypothalamic Nucleus
PubMed: 36588135
DOI: 10.1007/s12264-022-01008-3