More than meets the eye: A conserved sensorimotor reflex helps unravel the circuit mechanisms of ASD.

Animal models are instrumental to understanding the mechanisms underlying autism spectrum disorder, yet translating human behavioral phenotypes remains challenging. Wang et al. leverage a conserved sensorimotor reflex to elucidate synaptic deficits in Scn2a haploinsufficiency and pilot novel rescue strategies.

Neuroendocrine cells initiate protective upper airway reflexes.

Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5'-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.

Sentinels of the airways.

Epithelial cells in the larynx and trachea sense harmful cues and trigger protective reflexes.

Electrodermal and central measures of the tonic orienting reflex (OR).

Sokolov described both phasic and tonic aspects of the Orienting Reflex (OR), but subsequent research and theory development has focussed primarily on the phasic OR at the expense of the tonic OR. The present study used prestimulus skin conductance level (SCL) during a dishabituation paradigm to model the tonic OR, examining its amplitude patterning over repeated standard stimulus presentations and a change stimulus. We expected sensitisation (increased amplitude) following the initial and change trials, and habituation (decrement) over the intervening trials. Prestimulus EEG alpha level was explored as a potential central measure of the tonic OR (as an inverse correlate), examining its pattern over stimulus repetition and change in relation to the SCL model. We presented a habituation series of innocuous auditory stimuli to two groups (each N = 20) at different ISIs (Long 13-15 s and Short 5-7 s) and recorded electrodermal and EEG data during two counterbalanced conditions; Indifferent: no task requirements; Significant: silent counting. Across groups and conditions, prestimulus SCLs and alpha amplitudes generally showed the expected trials patterns, confirming our main hypotheses. Findings have important implications for including the assessment of Sokolov's tonic OR in modelling central and autonomic nervous system interactions of fundamental attention and learning processes.

Effects of different types of induced neonatal inflammation on development and behavior of C57BL/6 and BTBR mice.

Neuroinflammation in the early postnatal period can disturb trajectories of the completion of normal brain development and can lead to mental illnesses, such as depression, anxiety disorders, and personality disorders later in life. In our study, we focused on evaluating short- and long-term effects of neonatal inflammation induced by lipopolysaccharide, poly(I:C), or their combination in female and male C57BL/6 and BTBR mice. We chose the BTBR strain as potentially more susceptible to neonatal inflammation because these mice have behavioral, neuroanatomical, and physiological features of autism spectrum disorders, an abnormal immune response, and several structural aberrations in the brain. Our results indicated that BTBR mice are more sensitive to the influence of the neonatal immune activation (NIA) on the formation of neonatal reflexes than C57BL/6 mice are. In these experiments, the injection of lipopolysaccharide had an effect on the formation of the cliff aversion reflex in female BTBR mice. Nonetheless, NIA had no delayed effects on either social behavior or anxiety-like behavior in juvenile and adolescent BTBR and C57BL/6 mice. Altogether, our data show that NIA has mimetic-, age-, and strain-dependent effects on the development of neonatal reflexes and on exploratory activity in BTBR and C57BL/6 mice.

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.

Cyclooxygenase products contribute to the exaggerated exercise pressor reflex evoked by static muscle contraction in male UCD-type 2 diabetes mellitus rats.

Cyclooxygenase (COX) products of arachidonic acid metabolism, specifically prostaglandins, play a role in evoking and transmitting the exercise pressor reflex in health and disease. Individuals with type 2 diabetes mellitus (T2DM) have an exaggerated exercise pressor reflex; however, the mechanisms for this exaggerated reflex are not fully understood. We aimed to determine the role played by COX products in the exaggerated exercise pressor reflex in T2DM rats. The exercise pressor reflex was evoked by static muscle contraction in unanesthetized, decerebrate, male, adult University of California Davis (UCD)-T2DM (n = 8) and healthy Sprague-Dawley (n = 8) rats. Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) during muscle contraction were compared before and after intra-arterial injection of indomethacin (1 mg/kg) into the contracting hindlimb. Data are presented as means ± SD. Inhibition of COX activity attenuated the exaggerated peak MAP (Before: Δ32 ± 13 mmHg and After: Δ18 ± 8 mmHg; P = 0.004) and blood pressor index (BPi) (Before: Δ683 ± 324 mmHg·s and After: Δ361 ± 222 mmHg·s; P = 0.006), but not HR (Before: Δ23 ± 8 beats/min and After Δ19 ± 10 beats/min; P = 0.452) responses to muscle contraction in T2DM rats. In healthy rats, COX activity inhibition did not affect MAP, HR, or BPi responses to muscle contraction. Inhibition of COX activity significantly reduced local production of prostaglandin E2 in T2DM and healthy rats. We conclude that peripheral inhibition of COX activity attenuates the pressor response to muscle contraction in T2DM rats, suggesting that COX products partially contribute to the exaggerated exercise pressor reflex in those with T2DM.NEW & NOTEWORTHY We compared the pressor and cardioaccelerator responses to static muscle contraction before and after inhibition of cyclooxygenase (COX) activity within the contracting hindlimb in decerebrate, unanesthetized type 2 diabetic mellitus (T2DM) and healthy rats. The pressor responses to muscle contraction were attenuated after peripheral inhibition of COX activity in T2DM but not in healthy rats. We concluded that COX products partially contribute to the exaggerated pressor reflex in those with T2DM.

Dysphoric milk ejection reflex among Japanese mothers: a self-administered survey.

BACKGROUND: The dysphoric milk ejection reflex (D-MER) is a reflex that causes temporary discomfort during milk ejection. D-MER develops due to the effects of hormones involved in lactation, and it has been reported that it is a physiological symptom different from postpartum depression, but the actual situation is unknown in Japan. METHODS: This study was conducted using a self-administered, anonymous survey of mothers of children who had undergone health checkups at three years of age at five health centers in Kagoshima city and aimed to clarify the reality and perceptions of mothers regarding D-MER. The survey period was from May to September, 2022. The questionnaires were distributed to 389 mothers, and 216 (55.5% recovery rate) responses were received, of which 202 (valid response rate 93.5%) were included in the analysis. RESULTS: Regarding the experience of D-MER, 202 mothers in the study population had given birth to a total of 403 children and experienced D-MER when breastfeeding 62 children (15.4%). Of the 202 mothers included in the analysis, 47 (23.3%) answered that they had experienced D-MER with at least one child while breastfeeding. Sixty-six mothers (32.7%) knew about D-MER. Compared to those who had not experienced D-MER, those who had experienced D-MER had significantly higher scores on the items related to having had trouble breastfeeding (odds ratio (OR]: 3.78; 95% confidence interval (CI]: 1.57, 9.09) and knowing about D-MER (OR 2.41; 95% CI 1.20, 4.84). Regarding symptoms, irritability (n = 24, 51.1%), anxiety (n = 22, 46.8%), and sadness (n = 18, 38.3%) ranked high. Coping strategies included distraction, focusing on the child, and, in some cases, cessation of breastfeeding. Thirty mothers (63.8%) answered that they did not consult anyone, citing reasons such as a belief that no one would be likely to understand their symptoms, and that they could not sufficiently explain their symptoms. CONCLUSION: The low level of awareness of D-MER suggests that it is necessary to inform and educate mothers and the public about the physiological symptoms of D-MER. Moreover, it is necessary to listen to the feelings of mothers with D-MER and support them in coping with their symptoms.

The feasibility and technical aspects of trigemino-cervical reflex elicitation in humans under general anesthesia.

OBJECTIVE: To analyze the feasibility, neurophysiological aspects, stimulation patterns, and topographic distribution of trigemino-cervical reflex (TCR) components in humans under general anesthesia. METHODS: This prospective observational study enrolled 20 participants who underwent posterior fossa surgery, surgical proceduresin thecraniovertebral junction,or spinal cord surgery. TCR responses were simultaneously recorded in the sternocleidomastoid (SCM) and trapezius muscles after electrical stimulation of the supraorbital and infraorbital nerves. TCR responses were recorded preoperatively and intraoperatively using single-pulse and multipulse (trains of 2-7 electrical stimuli) stimulation, respectively. Two stimulus duration patterns were evaluated: 0.2-0.5 ms and 0.5-1.0 ms. RESULTS: Intraoperatively, short- and long-latency TCR components were obtained in the SCM ipsilateral to the stimulation with variable recordability. Short-latency responses were the most commonly recorded components. A longer stimulus duration (0.5-1.0 ms) seems to favor the elicitation of TCR responses under general anesthesia. CONCLUSIONS: Short-latency components recorded in the SCM ipsilateral to the stimulation could be regularly elicited under general anesthesia when a larger stimulus duration (0.5-1.0 ms) was applied. SIGNIFICANCE: This is the first study to demonstrate the elicitation of TCR components in humans under general anesthesia. This neurophysiological technique can potentially optimize intraoperative neurophysiological monitoring during brainstem surgery.

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex.

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

A vagal reflex evoked by airway closure.

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering-Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation3,4, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone.

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control (n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion (n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats (n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level (n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control (n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused (n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex.NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

Primitive reflexes and dementia in older adults: a meta-analysis of observational and cohort studies.

Primitive reflexes (PRs) are clinical signs that indicate diffuse cerebral dysfunction and frontal lesions. We aimed to present a comprehensive analysis of the prevalence and risk of PRs in patients with dementia. English-language articles published from January 1990 to April 2021 were searched in PubMed, ScienceDirect, Cochrane, and Web of Science with keywords. The titles and abstracts of the identified articles were screened to identify potentially relevant papers. Odds ratios and risk ratios were extracted with 95% confidence intervals and combined using the random-effects model after logarithmic transformation. The prevalence in dementia patients was also combined using the random-effects model. This meta-analysis involved 29 studies. The snout reflex (48% of cases) was the most prevalent. It was found that the risk of PRs in individuals with dementia was significantly elevated, ranging from 13.94 to 16.38 times higher than in healthy controls. The grasp reflex exhibited the highest risk for dementia. This meta-analysis showed that the prevalence and the risk of PRs is high in older patients with dementia. Therefore, PRs, especially the grasp reflex, should be carefully assessed as a part of routine physical examination in the diagnostic process for dementia.

Dysphoric Milk Ejection Reflex in Human Lactation: An Integrative Literature Review.

BACKGROUND: Dysphoric Milk Ejection Reflex is an understudied condition of lactation involving emotional dysregulation during letdown or milk ejection. Affected individuals may experience transient feelings of helplessness, melancholy, and general unhappiness. RESEARCH AIM: To evaluate the scope of published literature on Dysphoric Milk Ejection Reflex. METHOD: Whittemore and Knafl's methodology guided this integrative review. Five databases were searched for primary research, summaries, and editorials on Dysphoric Milk Ejection Reflex in lactating individuals. Literature searched also included websites, pamphlets, and conference proceedings via Google and Google Scholar. A total of 11 articles, from five different countries, met inclusion criteria for review. RESULTS: Studies on Dysphoric Milk Ejection Reflex and negative emotional sensations during lactation were synthesized under five conceptual umbrellas: (1) Experiences, Sensations, and Symptom Management; (2) Biological Underpinnings; (3) Influence on Maternal Role and Breastfeeding Self-Efficacy; (4) Support, Understanding, and Awareness; and (5) Reduction and Cessation of Breastfeeding. CONCLUSION: Dysphoric Milk Ejection Reflex is a neurobiological condition characterized by low mood and negative feelings during milk ejection throughout lactation. Dysphoric Milk Ejection Reflex is linked to maternal psychological distress and breastfeeding discontinuation. Priority areas for future research include biological origins and interventions aimed at prevention, symptom control, and greater awareness of the condition on a more international scope.

The blink reflex and its modulation - Part 2: Pathophysiology and clinical utility.

The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes.

Distinguishing reflex from non-reflex responses elicited by transcutaneous spinal stimulation targeting the lumbosacral cord in healthy individuals.

Transcutaneous spinal stimulation (TSS) studies rely on the depolarization of afferent fibers to provide input to the spinal cord; however, this has not been routinely ascertained. Thus, we aimed to characterize the types of responses evoked by TSS and establish paired-pulse ratio cutoffs that distinguish posterior root reflexes, evoked by stimulation of afferent nerve fibers, from motor responses, evoked by stimulation of efferent nerve fibers. Twelve neurologically intact participants (six women) underwent unipolar TSS (cathode over T11-12 spinal processes, anode paraumbilically) while resting supine. In six participants, unipolar TSS was repeated 2-3 months later and also compared to a bipolar TSS configuration (cathode 2.5 cm below T11-12, anode 5 cm above cathode). EMG signals were recorded from 16 leg muscles. A paired-pulse paradigm was applied at interstimulus intervals (ISIs) of 25, 50, 100, 200, and 400 ms. Responses were categorized by three assessors into reflexes, motor responses, or their combination (mixed responses) based on the visual presence/absence of paired-pulse suppression across ISIs. The paired-pulse ratio that best discriminated between response types was derived for each ISI. These cutoffs were validated by repeating unipolar TSS 2-3 months later and with bipolar TSS. Unipolar TSS evoked only reflexes (90%) and mixed responses (10%), which were mainly recorded in the quadriceps muscles (25-42%). Paired-pulse ratios of 0.51 (25-ms ISI) and 0.47 (50-ms ISI) best distinguished reflexes from mixed responses (100% sensitivity, > 99.2% specificity). These cutoffs performed well in the repeated unipolar TSS session (100% sensitivity, > 89% specificity). Bipolar TSS exclusively elicited reflexes which were all correctly classified. These results can be utilized in future studies to ensure that the input to the spinal cord originates from the depolarization of large afferents. This knowledge can be applied to improve the design of future neurophysiological studies and increase the fidelity of neuromodulation interventions.

Technical Aspects of Eliciting Trigeminocervical and Trigeminospinal Reflexes in Humans: A Scoping Review.

SUMMARY: This scoping review aims to summarize the technical strategies for obtaining trigeminocervical reflex (TCR) and trigeminospinal reflex (TSR) responses. Studies published on TCR or TSR elicitation in humans through electrical stimulation of trigeminal nerve branches were eligible for this scoping review. The data of interest included stimulation parameters, site of stimulation, recording parameters, and the feasibility of TCR and TSR elicitation, in healthy participants. Short-latency TCR responses were regularly obtained in both anterior and posterior neck muscles after electrical stimulation of the supraorbital and infraorbital nerves under voluntary muscle activation. However, without voluntary muscle activation, we found evidence of elicitation of short-latency TCR components only in the posterior neck muscles after supraorbital or infraorbital nerve stimulation. Long-latency TCR responses were regularly obtained in the anterior and posterior neck muscles in studies that evaluated this technique, regardless of the trigeminal branch stimulation or muscle activation status. Short-latency TSR components were not obtained in the included studies, whereas long-latency TSR responses were regularly recorded in proximal upper limb muscles. This scoping review revealed key heterogeneity in the techniques used for TCR and TSR elicitation. By summarizing all the methodological procedures used for TCR and TSR elicitation, this scoping review can guide researchers in defining optimized technical approaches for different research and clinical scenarios.