Nucleus Of The Tractus Solitarius Research Articles

GABAergic and glutamatergic inputs to the medulla oblongata and locus coeruleus noradrenergic pathways are critical for seizures and postictal antinociception neuromodulation

We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonic‒clonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures. The effects of LC neurotoxic lesions caused by DSP-4, followed by NTS-NMDA receptor activation, on both tonic‒clonic seizures and postictal antinociception were also investigated. The NTS is connected to lPGi neurons that send outputs to the LC. Glutamatergic vesicles were found on dendrites and perikarya of GABAergic interneurons in the NTS. Both tonic‒clonic seizures and postictal antinociception are partially dependent on glutamatergic-mediated neurotransmission in the NTS of seizing rats in addition to the integrity of the noradrenergic system since NMDA receptor blockade in the NTS and intrathecal administration of DSP-4 decrease the postictal antinociception. The GABAA receptor activation in the NTS decreases both seizure severity and postictal antinociception. These findings suggest that glutamatergic inputs to NTS-GABAergic interneurons, in addition to ascending and descending noradrenergic pathways from the LC, are critical for the control of both seizures and postictal antinociception.

Adolescent alcohol disrupts development of noradrenergic neurons in the nucleus of the tractus solitarius and enhances stress behaviors in adulthood in mice in a sex specific manner

Alcohol use disorders (AUDs) are common mental health issues worldwide and can lead to other chronic diseases. Stress is a major factor in the development and continuation of AUDs, and adolescent alcohol exposure can lead to enhanced stress-responsivity and increased risk for AUD development in adulthood. The exact mechanisms behind the interaction between adolescence, stress, and alcohol are not fully understood and require further research. In this regard, the nucleus of the tractus solitarius (NTS) provides dense norepinephrine projections to the extended amygdala, providing a key pathway for stress-related alcohol behaviors. While NTS norepinephrine neurons are known to be alcohol sensitive, whether adolescent alcohol disrupts NTS-norepinephrine neuron development and if this is related to altered stress-sensitivity and alcohol preference in adulthood has not previously been examined. Here, we exposed male and female C57Bl/6J mice to the commonly used adolescent intermittent ethanol (AIE) vapor model during postnatal day 28-42 and examined AIE effects on: 1) tyrosine hydroxylase (TH) mRNA expression in the NTS across various ages (postnatal day 21-90), 2) behavioral responses to acute stress in the light/dark box test in adulthood, 3) NTS TH neuron responses to acute stress and ethanol challenges in adulthood, and 4) ethanol conditioned place preference behavior in adulthood. Overall the findings indicate that AIE alters NTS TH mRNA expression and increases anxiety-like behaviors following acute stress exposure in a sex-dependent manner. These mRNA expression and behavioral changes occur in the absence of AIE-induced changes in NTS TH neuron sensitivity to either acute stress or acute alcohol exposure or changes to ethanol conditioned place preference.

Temporal dysregulation of hypothalamic integrative and metabolic nuclei in rats fed during the rest phase

ABSTRACT Temporal coordination of organisms according to the daytime allows a better performance of physiological processes. However, modern lifestyle habits, such as food intake during the rest phase, promote internal desynchronization and compromise homeostasis and health. The hypothalamic suprachiasmatic nucleus (SCN) synchronizes body physiology and behavior with the environmental light–dark cycle by transmitting time information to several integrative hypothalamic nuclei, such as the paraventricular nucleus (PVN), dorsomedial hypothalamic nucleus (DMH) and median preoptic area (MnPO). The SCN receives metabolic information mainly via Neuropeptide Y (NPY) inputs from the intergeniculate nucleus of the thalamus (IGL). Nowadays, there is no evidence of the response of the PVN, DMH and MnPO when the animals are subjected to internal desynchronization by restricting food access to the rest phase of the day. To explore this issue, we compared the circadian activity of the SCN, PVN, DMH and MnPO. In addition, we analyzed the daily activity of the satiety centers of the brainstem, the nucleus of the tractus solitarius (NTS) and area postrema (AP), which send metabolic information to the SCN, directly or via the thalamic intergeniculate leaflet (IGL). For that, male Wistar rats were assigned to three meal protocols: fed during the rest phase (Day Fed); fed during the active phase (Night Fed); free access to food (ad libitum). After 21 d, the daily activity patterns of these nuclei were analyzed by c-Fos immunohistochemistry, as well as NPY immunohistochemistry, in the SCN. The results show that eating during the rest period produces a phase advance in the activity of the SCN, changes the daily activity pattern in the MnPO, NTS and AP and flattens the c-Fos rhythm in the PVN and DMH. Altogether, these results validate previous observations of circadian dysregulation that occurs within the central nervous system when meals are consumed during the rest phase, a behavior that is involved in the metabolic alterations described in the literature.

Fluoroquinolones-Associated Disability: It Is Not All in Your Head

Fluoroquinolones (FQs) are a broad class of antibiotics typically prescribed for bacterial infections, including infections for which their use is discouraged. The FDA has proposed the existence of a permanent disability (Fluoroquinolone Associated Disability; FQAD), which is yet to be formally recognized. Previous studies suggest that FQs act as selective GABAA receptor inhibitors, preventing the binding of GABA in the central nervous system. GABA is a key regulator of the vagus nerve, involved in the control of gastrointestinal (GI) function. Indeed, GABA is released from the Nucleus of the Tractus Solitarius (NTS) to the Dorsal Motor Nucleus of the vagus (DMV) to tonically regulate vagal activity. The purpose of this review is to summarize the current knowledge on FQs in the context of the vagus nerve and examine how these drugs could lead to dysregulated signaling to the GI tract. Since there is sufficient evidence to suggest that GABA transmission is hindered by FQs, it is reasonable to postulate that the vagal circuit could be compromised at the NTS-DMV synapse after FQ use, possibly leading to the development of permanent GI disorders in FQAD.

Mapping of the Substrate for Production of Swallow and Cough Within the Rostral Nucleus of the Tractus Solitarius (NTS)/Paramedian Reticular Nucleus by Electrical Stimulation

Swallow and cough are airway protective behaviors which are regulated via overlapping networks in the brainstem. However, it is not known if there are locations in the caudal brainstem which are capable of centrally stimulating both behaviors. To this end, a craniotomy was performed in sodium-pentobarbital anesthetized freely-breathing animals (n = 8). Electromyograms were recorded from upper airway and respiratory muscles to confirm swallow, cough, breathing, and other airway protective behaviors. Using a concentric monopolar electrode, a series of stimulations were performed across the dorsal brainstem. The electrode was systematically placed at points ranging laterally from 0.6 to 3.4 mm, and rostrally from 0 to 2.6 mm away from obex with a depth ranging from 0.5 to 4.0 mm from the surface of the brainstem. We were able to elicit swallow at 63 loci. Visual inspection of the receptive field indicated 2 sub-populations, and a k-means clustering analysis of these points centered them at stereotaxic coordinates (Lateral, Rostral, Depth) of [2.72, 1.82, 1.82] and [1.07, 0.78, 2.46]. In contrast, cough was only elicited in 1 animal at 8 locations in and around the NTS/paramedian reticular nucleus, with a cluster centered around [0.85, 0.53, 2.63]; these locations also elicited swallowing. These results are consistent with and extend early work of Sherrington (1915) and Markwald (1886). The neural substrate responsible for the production of swallow in this region of the medulla appears to be more expansive than that for cough. Our limited success in inducing cough with electrical stimulation in these areas is consistent with: a) a more anatomically distributed cough network relative to that for swallow, and/or b) more complex local synaptic mechanisms for induction of coughing that are resistant to actuation by electrical stimulation. An example of such a mechanism is selective inhibition of some neuron populations that are required to bring cough to threshold. In this case, frank excitation of these populations by electrical stimulation would have a limited effect in eliciting coughing.

Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions.

The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.

Central Neurocircuits Regulating Food Intake in Response to Gut Inputs-Preclinical Evidence.

The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.

SARS-CoV-2, an Underestimated Pathogen of the Nervous System

Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Additionally, transmembrane serine protease 2 (TMPRSS2) and furin facilitate virus entry into the host. Besides, the probable routes of virus entry into the nervous system include the hematogenic pathway, through the vagus, the olfactory nerve, or the enteric nervous system. However, the trajectory of SARS-CoV-2 to the brain needs investigation. Furthermore, a Th17-mediated cytokine storm is seen in COVID-19 cases with higher levels of IL-1β/2/7/8/9/10/17, GM-CSF, IFN-γ, TNF-α, CXCL-10, MCP1, and MIP1α/β. Some cytokines can cross the blood-brain barrier and activate the brain’s immune cells to produce neural cytokines, leading to neuronal dysfunctions. Nonetheless, most of the neurological conditions developed due to viral infections may not have effective and registered treatments. Although, some antivirals may inhibit the virus-mediated pathogenesis and prove to be suitable in COVID-19 treatment. Therefore, clinicians’ and researchers’ collective expertise may unravel the potential of SARS-CoV-2 infection to prevent short-term and long-term CNS damage.

Anxiolytic Activity and Brain Modulation Pattern of the α-Casozepine-Derived Pentapeptide YLGYL in Mice.

α-Casozepine (α-CZP) is an anxiolytic-like bioactive decapeptide derived from bovine αs1-casein. The N-terminal peptide YLGYL was previously identified after proteolysis of the original peptide in an in vitro digestion model. Its putative anxiolytic-like properties were evaluated in a Swiss mice model using a light/dark box (LDB) after an intraperitoneal injection (0.5 mg/kg). The effect of YLGYL on c-Fos expression in brain regions linked to anxiety regulation was afterwards evaluated via immunofluorescence and compared to those of α-CZP and diazepam, a reference anxiolytic benzodiazepine. YLGYL elicited some anxiolytic-like properties in the LDB, similar to α-CZP and diazepam. The two peptides displayed some strong differences compared with diazepam in terms of c-Fos expression modulation in the prefontal cortex, the amygdala, the nucleus of the tractus solitarius, the periaqueductal grey, and the raphe magnus nucleus, implying a potentially different mode of action. Additionally, YLGYL modulated c-Fos expression in the amygdala and in one of the raphe nuclei, displaying a somewhat similar pattern of activation as α-CZP. Nevertheless, some differences were also spotted between the two peptides, making it possible to formulate the hypothesis that these peptides could act differently on anxiety regulation. Taken together, these results showed that YLGYL could contribute to the in vivo overall action of α-CZP.

SPARC‐Network‐Scale Interactions Among Simultaneously Recorded Brainstem Neurons In The Dorsal Medulla, Ventrolateral Medulla, And Pons: A Substrate For Central Autonomic Control And Processing Of Cardiovascular Afferent Feedback

The central autonomic control system provides parasympathetic and sympathetic drive to peripheral ganglia that regulate a host of visceral functions. Detailed knowledge of the network scale organization of this central circuit is incomplete. We hypothesized that functional synaptic interactions between many simultaneously recorded neurons in and around the nucleus of the tractus solitarius (NTS), the retrotrapezoid nucleus (RTN), ventral respiratory column (VRC) and pons would yield information about the network‐scale strategy that is employed by this system to regulate autonomic drive. Experiments were conducted in 73 decerebrated, paralyzed, and artificially ventilated cats. Multi‐electrode arrays including up to 100 channels were placed in the areas of the NTS, RTN, and VRC. A total of 2,643 neurons were challenged with alterations in blood pressure (BP) and cardiac modulation was assessed in 3,531 neurons. The spike activity patterns of many simultaneously recorded single neurons were evaluated during breathing, the cardiac cycle, increased activation of baroreceptors by inflation of a balloon in the abdominal aorta and unloading of baroreceptors by inflation of a balloon in the vena cava. There was no apparent anatomical segregation of neurons in these areas with regard to cardiac or BP modulation based on stereotaxic coordinates. Cross correlation analysis revealed robust excitatory and inhibitory functional interactions between neurons in the areas of the NTS, VRC, RTN, and pons. Plots customized to reveal patterns of information transfer between neurons in different areas provided evidence that units in the RTN and VRC were predominantly exciting those in the NTS area, while these same NTS neurons were exciting and inhibiting different neurons in the RTN and VRC. Specific evidence was found for putative intermediate ventrolateral medulla (iVLM) neurons that were excited by BP and involved in inhibitory interactions with putative rostral ventrolateral medulla (RVLM) neurons that were inhibited by increased BP. However, this mechanism was a low frequency feature of the dataset. Evidence for synaptic inhibition between neurons that responded to increased BP was a predominant finding. Among neurons that responded to decreased BP, evidence for synaptic excitation was more common. These results support differential organization of brainstem networks that mediate autonomic responses to increased BP relative to those that mediate decreased BP. The brainstem network that mediates sympatho‐inhibition in response to increased blood pressure is sparsely excitatory and may depend on abundant inhibitory mechanisms to enhance signal/noise ratios in support of information transmission from baroreceptors.Support or Funding InformationSupported by 3OT2OD023854

Voltage-sensitive dye recording of glossopharyngeal nerve-related synaptic networks in the embryonic mouse brainstem

The glossopharyngeal nerve (N.IX) transfers motor and sensory information related to visceral and somatic functions, such as salivary secretion, gustation and the control of blood pressure. N.IX-related neural circuits are indispensable for these essential functions. Compared with the strenuous analysis of morphogenesis, we are only just starting to elucidate the functiogenesis of these neural circuits during ontogenesis. In the present study, we applied voltage-sensitive dye recording to the embryonic mouse brainstem, and examined the functional development of the N.IX-related neural circuits. First, we optically identified the motor nucleus (the inferior salivatory nucleus (ISN)) and the first-order sensory nucleus (the nucleus of the tractus solitarius (NTS)). We also succeeded in recording optical responses in the second/higher-order sensory nuclei via the NTS, including the parabrachial nucleus. Second, we pursued neuronal excitability and the onset of synaptic function in the N.IX-related nuclei. The neurons in the ISN were excitable at least at E11, and functional synaptic transmission in the NTS was first expressed at E12. In the second/higher-order sensory nuclei, synaptic function emerged at around E12-13. Third, by mapping optical responses to N.IX and vagus nerve (N.X) stimulation, we showed that the distribution patterns of neural activity in the NTS were different between the N.IX and the N.X from the early stage of ontogenesis. We discuss N.IX-related neural circuit formation in the brainstem, in comparison with our previous results obtained from chick and rat embryos.

A voltage-dependent depolarization induced by low external glucose in neurons of the nucleus of the tractus solitarius: interaction with KATP channels.

Neurons from the brainstem nucleus of the tractus solitarius (NTS) participate in the counter-regulatory mechanisms in response to hypoglycaemia. ATP-sensitive potassium (KATP ) channels are expressed in NTS neurons, and are partially open at rest in normoglycaemic 5mM glucose. In normoglycaemic conditions, most NTS neurons depolarize in response to low external glucose (0.5mM), via a voltage-dependent mechanism. Conversely, most NTS neurons incubated in hyperglycaemic 10mM glucose do not respond to low glucose due to a more positive resting membrane potential caused by the closure of KATP channels following increased intracellular metabolic ATP. Our findings show that in hyperglycaemic conditions, NTS neurons failed to sense rapid changes in external glucose, which could be related to hypoglycaemia-associated autonomic failure. The nucleus of the tractus solitarius (NTS) is an integrative centre for autonomic counter-regulatory responses to hypoglycaemia. KATP channels link the metabolic status of the neuron to its excitability. Here we investigated the influence of KATP channels on the membrane potential of NTS neurons in normo- and hyperglycaemic external glucose concentrations, and after switching to a hypoglycaemic concentration, using in vitro electrophysiological recordings in brainstem slices. We found that in normoglycaemic (5mM) glucose, tolbutamide, a KATP channel antagonist, depolarized the membrane of most neurons, and this effect was observed in more hyperpolarized neurons. All neurons hyperpolarized after pharmacological activation of KATP channels. Most NTS neurons depolarized in the presence of low glucose (0.5mM), and this effect was only seen in hyperpolarized neurons. The effect of glucose was caused by a cationic current with a reversal potential around -50mV. In the presence of hyperglycaemic glucose (10mM), neurons were more depolarized, and fewer neurons responded to KATP blockage. Application of 0.5mM glucose solution to these neurons depolarized the membrane only in more hyperpolarized neurons. We conclude that NTS neurons present with KATP channels open at rest in normoglycaemic conditions, and their membrane potential is affected by extracellular glucose. Moreover, NTS neurons depolarize the membrane in response to the application of a low glucose solution, but this effect is occluded by membrane depolarization triggered by KATP blockage. Our data suggest a homeostatic regulation of the membrane potential by external glucose, and a possible mechanism related to the hypoglycaemia-associated autonomic failure.

Impact of Adolescent Intermittent Ethanol on Noradrenergic Development

In clinical populations, adolescent alcohol drinking has been shown to increase stress sensitivity and the likelihood of developing alcohol use disorders (AUDs) in adulthood. These findings suggest pathways mediating stress‐relating behaviors are impacted by developmental exposure to alcohol, contributing to a greater risk for alcoholism and potentially stress‐induced relapse following treatment. Animal models indicate tyrosine hydroxylase (TH) neurons in the A2 region of the nucleus of the tractus solitarius (NTS) contribute to stress‐induced relapse through enhanced norepinephrine signaling, subsequently increasing neuronal activity in the bed nucleus of the stria terminalus (BNST). Previous research suggests NTS TH expression undergoes developmental changes during adolescence that may make this neuronal population susceptible to modulation by alcohol during this age. We hypothesized adolescent intermittent ethanol (AIE) exposure in mice, a standard preclinical model of adolescent binge drinking, will impact NTS TH neuron development, ultimately altering the NTS‐BNST circuitry resulting in a higher risk of AUDs in adulthood. NTS TH mRNA expression in male and female C57Bl6/J mice exposed to AIE (postnatal day [PND] 28–42) or used as air controls was quantified via qRT‐PCR at different time points (PND29, PND36, PND43, PND49, PND70). Immunohistochemistry methods were implemented to determine the impact of AIE on NTS TH neuronal activity following an ethanol challenge in adulthood (PND70). Results showed a significant increase in TH mRNA in males one day after beginning AIE (PND29) relative to air controls, while females exhibited the greatest TH expression after their first week of exposure to ethanol (PND36). In both sexes, heightened TH mRNA expression occurred earlier than expected during normal development. Surprisingly, compared to adult ethanol naïve mice, AIE decreased the ability of ethanol at doses of 2g/kg and 4g/kg to alter NTS TH neuron cFos expression at PND70 compared to control. Together, these findings suggest an enhancement of NTS TH activity early in development and reduction of ethanol sensitivity in adulthood. Studies are in progress to further delineate the mechanisms by which AIE reduces adult ethanol sensitivity and how this may alter stress‐related behaviors.Support or Funding InformationAA22937AA017823This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Central Circuits Inhibiting Skeletal Muscle Shivering

BackgroundSkeletal muscle shivering is the most important source of thermogenesis in the human cold‐defensive maintenance of core body temperature (Tcore) and the elevated Tcore during fever. We have described the thermoregulatory reflex pathway through which skin and core cooling, or injection of prostaglandin E2 into the preoptic area of the hypothalamus, leads to activation of skeletal muscle shivering (J Physiol 589.14: 3641–3658, 2011). Here we describe brain regions containing neurons that can provide an inhibitory regulation of shivering.ResultsEMG activities in masseter, neck and gastrocnemius muscles were recorded in Inactin‐anesthetized rats during cold exposure or injection of PGE2 into the preoptic hypothalamus. Cold‐evoked and febrile shivering EMGs were eliminated by activation of neurons in the ventral part of the lateral preoptic nucleus (vLPO), or by increasing the discharge of neurons in the paraventricular hypothalamus, in the nucleus of the tractus solitarii, or in the ventrolateral medulla. Inhibiting neuronal discharge or blocking glutamate receptors in the vLPO elicited a sustained increase in shivering EMGs in warm rats.ConclusionThese results indicate the strong, tonic inhibitory influence of neurons in the vLPO on skeletal muscle shivering, likely through a GABAergic input to shivering premotor neurons in the rostral raphe pallidus. The discovery of the vLPO and other neuronal populations capable of inhibiting shivering supports the potential for the therapeutic control of shivering in the settings of neurogenic fever, brain injury, or induction of hypothermia.Support or Funding InformationSupported by NIH grants NS040987 and NS091066This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Differential Ascending Projections From the Male Rat Caudal Nucleus of the Tractus Solitarius: An Interface Between Local Microcircuits and Global Macrocircuits.

To integrate and broadcast neural information, local microcircuits and global macrocircuits interact within certain specific nuclei of the central nervous system. The structural and functional architecture of this interaction was determined for the caudal nucleus of the tractus solitarius (NTS) at the level of the area postrema (AP), a relay station of peripheral viscerosensory information that is processed and conveyed to brain regions concerned with autonomic-affective and other interoceptive reflexive functions. Axon collaterals of most small NTS cells (soma <150 μm2) establish excitatory or inhibitory local microcircuits likely to control the activity of nearby NTS cells and to transfer peripheral signals to efferent projection neurons. At least two types of cells that constitute efferent pathways from the caudal NTS (cNTS) were distinguished: (1) a greater numbers of small cells, seemingly forming local excitatory microcircuits via recurrent axon collaterals, that project specifically and unidirectionally to the lateral parabrachial nucleus; and (2) a much smaller numbers of cells likely to establish multiple global connections, mostly via the medial forebrain bundle (MFB) or the dorsal longitudinal fascicle (DLF), with a wide range of brain regions, including the ventrolateral medulla (VLM), hypothalamus, central nucleus of the amygdala (ACe), bed nucleus of the stria terminalis (BNST), spinal cord dorsal horn, brainstem reticular formation, locus coeruleus (LC), periaqueductal gray (PAG) and periventricular diencephalon (including the epithalamus). The evidence presented here suggests that distinct cNTS cell types distinguished by projection pattern and related structural and functional features participate differentially in the computation of viscerosensory information and coordination of global macro-networks in a highly organized manner.

Current Concepts of Pathophysiology of Vasovagal Syncope and its Evaluation and Management: A Review

ABSTRACTVasovagal syncope (VVS) with a sudden, temporary loss of consciousness (LoC) is a common phenomenon in the young and the elderly. Though generally described as innocuous, it may lead to serious consequences in special category of people (pilots), or in the elderly in whom LoC may lead to a fall and serious injury. The topic has been copiously researched upon and discussed in medical literature over the last few decades, but the exact mechanisms which lead to the disability have yet to be fully agreed upon. Changes in cardiovascular baroreceptor sensitivity, aberrations in the complex interaction amongst the nucleus of the tractus solitarius and the nuclei around it, inability of the peripheral circulation to respond to autonomic vasoconstrictors, or excess production of vasodilators such as nitric oxide produced locally have been considered in its pathophysiology. Various extraneous situations like dehydration, exposure to heat stress, medications, psychological factors may adversely stress regulatory physiological responses and promote occasional episodes of VVS. More complex dysautonomia could be a reason for the recurrent VVS. Differences between brain structure of VVS sufferers and normal subjects have been proposed. Head-up tilt table (HUT) test is the most widely applied investigation for evaluating VVS episodes. Lower body negative pressure (LBNP) has also been used. Enhancement of the orthostatic stress may be done by simultaneous use of both, or with peripheral vasodilators. As to whether such an enhancement is necessary is debatable. Management with increased salt and fluid intake, corticosteroids, beta adrenergic receptor blockers, alpha adrenergic receptor stimulants, selective serotonin reuptake inhibitors, and nitric oxide synthase inhibitors have been tried with variable success.

Incubation of NTS Neurons in High Glucose Decreases the Sensitivity to a Low Glucose Challenge: Role of KATP Channels

The brainstem nucleus of the tractus solitarius (NTS) is an integrative center for the counterregulatory responses to hypoglycemia, and recent evidences have showed that NTS neurons can directly sense extracellular glucose fluctuations via mechanisms that rely on glucose metabolism. The ATP‐sensitive potassium (KATP) channels play a key role in linking metabolic status and electrical excitability in glucose‐sensing neurons, and KATP channels are expressed in NTS neurons. Therefore, this work aimed to investigate the effect of a low external glucose (0.5 mM) on the membrane properties of NTS neurons of rats, and its interaction with KATP channels, by whole‐cell patch‐clamp. We observed that low glucose induces a voltage‐dependent depolarization in most NTS neurons, i.e., the more negative the resting membrane potential (RMP) of neurons, the higher membrane potential amplitude response. KATP channels are opened at rest in NTS neurons maintained in 5 mM extracellular glucose, and contribute to the hyperpolarized RMP of neurons. Blockage of KATP channels with tolbutamide strongly depolarizes neurons and occludes the effect of low glucose, thus acting as modulators of low‐glucose sensing in NTS neurons. Membrane hyperpolarization after blockage of KATP channels restores the depolarizing effect of low glucose. Additionally, the incubation of NTS neurons in high‐glucose (10 mM) aCSF prior to electrophysiological recordings leads to more depolarized RMP, what contributes to increase the number of neurons unresponsive to a low‐glucose challenge. Again, membrane hyperpolarization restores the depolarization induced by low glucose, however, tolbutamide application did not produced the pronounced membrane depolarization in comparison to NTS neurons incubated in 5 mM glucose aCSF, confirming that KATP channels are closed in a high‐glucose environment. We conclude that (1) low‐glucose sensing in NTS neurons is a voltage‐dependent mechanism; (2) KATP channels influence the RMP of neurons, thus modulating the sensitivity of these neurons to low glucose; (3) incubation of NTS neurons in high‐glucose decrease the number of responsive neurons to low glucose, possibly by depolarization via inhibition of KATP channels following increased amounts of high glucose‐derived ATP levels; (4) this effect could be a permissive mechanism for the decreased brain response to hypoglycemia in individuals that experience recurrent episodes of hypoglycemia, such as insulin‐treated diabetic patients, and; (5) depolarization induced by low glucose might represent a form of homeostatic regulation of the RMP in order to avoid an excessive hyperpolarization by unblocking KATP channels under a hypoglycemia episode.Support or Funding InformationCAPES, CNPq, FAEPA, and FAPESP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Developmental roles of the spontaneous depolarization wave in synaptic network formation in the embryonic brainstem

One of the earliest activities expressed within the developing central nervous system is a widely propagating wave-like activity, which we referred to as the depolarization wave. Despite considerable consensus concerning the global features of the activity, its physiological role is yet to be clarified. The depolarization wave is expressed during a specific period of functional synaptogenesis, and this developmental profile has led to the hypothesis that the wave plays some roles in synaptic network organization. In the present study, we tested this hypothesis by inhibiting the depolarization wave in ovo and examining its effects on the development of functional synapses in vagus nerve-related brainstem nuclei of the chick embryo. Chronic inhibition of the depolarization wave had no significant effect on the developmental time course, amplitude, and spatial distribution of monosynaptic excitatory postsynaptic potentials in the first-order nuclei of the vagal sensory pathway (the nucleus of the tractus solitarius (NTS) and the contralateral non-NTS region), but reduced polysynaptic responses in the higher-order nucleus (the parabrachial nucleus). These results suggest that the depolarization wave plays an important role in the initial process of functional synaptic expression in the brainstem, especially in the higher-order nucleus of the cranial sensory pathway.

Abstract P386: The Paraventricular Nucleus in Control of Blood Pressure and Its Role in Hypertension

Rationale and objectives: In conscious mammals the importance of neural control over sympathetic tone in relation to cardiovascular (CV) function is well established. Neuro-CV dysregulation leads to increased sympathetic activity and neurogenic hypertension. The paraventricular nucleus (PVN) of the hypothalamus and both the rostral ventrolateral medulla (RVLM) and nucleus of the tractus solitarius (nTS) in the brainstem are currently viewed as key hubs for BP control and are implicated in producing or relaying the increased sympathetic tone in hypertension. We propose increased activity in the PVN, potentially through an upregulation of the renin angiotensin system, causes an increase in blood pressure. We test this theory by examining how stimulation or lesioning of the excitatory PVN neurons in conscious mice affects blood pressure and sympathetic activity. Methods: PVN and nearby glutamatergic neurons were unilaterally transduced with channelrhodopsin using an adeno-associated virus (CamKII-ChR2-eYFP-AAV) in wildtype mice. We then measured the effect of acute stimulation of excitatory PVN neurons on resting blood pressure (telemetry) and baroreflex in conscious mice. Additionally, in vGlut-cre mice glutamatergic neurons of the PVN were bilaterally lesioned utilizing a cre-dependent caspase (Dio-Caspase-AAV). We then recorded baseline resting blood pressure and baroreflex in conscious mice before and after DOCA-Salt hypertension. Finally, we measured nor-epinephrine levels as a quantification of sympathetic activity. Results and conclusions: Unilateral PVN excitation increased blood pressure from baseline by ~10 mmHg. Glutamatergic lesions of the PVN resulted in a blunted rise in BP when animals went through the DOCA-Salt protocol. These experiments demonstrate that the autonomic dysfunction seen in hypertension could be due to changes in the PVN. Overactivation of the PVN in hypertension is probably one of multiple factors that increase sympathetic drive resulting in an increased blood pressure.

Acute ethanol modulation of neurocircuit function in the nucleus of the tractus solitarius

The nucleus of the tractus solitarius (NTS) is a brain stem region critical to many physiologic processes and has been implicated in addiction to multiple classes of abused drugs, including alcohol (EtOH). That said, the mechanism by which EtOH modulates NTS neurocircuit activity is not well characterized and has yet to be examined utilizing electrophysiologic methods in mouse models of alcohol use disorders. To begin to address this gap in knowledge, we sought to use whole-cell and cell-attached recordings to determine the mechanism of acute EtOH action on GABAergic and glutamatergic neurotransmission, as well as on action potential firing in the NTS of adult male, EtOH naïve mice. Bath application of EtOH (50mM) significantly enhanced the frequency of spontaneous inhibitory postsynaptic current events, while increasing the amplitude of these events in half of the neurons tested. This finding suggests a presynaptic mechanism of EtOH action on GABAergic transmission in the NTS as well as a postsynaptic mechanism in subsets of NTS neurons. EtOH application was further associated with a significant decrease in action potential firing in most, but not all, NTS neurons tested. EtOH induced a small but significant decrease in spontaneous excitatory postsynaptic current frequency, indicating that EtOH may also inhibit NTS glutamatergic signaling to some degree. Intriguingly, in vivo EtOH exposure (4g/kg IP) enhanced c-FOS colocalization with tyrosine hydroxylase via immunohistochemical methods, indicating that NTS norepinephrine neurons may be activated by acute EtOH exposure. Although future work is needed, the current data indicate that acute EtOH may enhance GABAergic signaling in local NTS circuits resulting in disinhibition of NTS norepinephrine neurons. Such a finding has important implications in understanding the role of the NTS in the development of alcoholism.