Showing papers on "Solitary tract published in 2022"

A brainstem map for visceral sensations

Abstract: The nervous system uses various coding strategies to process sensory inputs. For example, the olfactory system uses large receptor repertoires and is wired to recognize diverse odours, whereas the visual system provides high acuity of object position, form and movement1-5. Compared to external sensory systems, principles that underlie sensory processing by the interoceptive nervous system remain poorly defined. Here we developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives vagal and other inputs from the body. Focusing on gut and upper airway stimuli, we observed that individual NTS neurons are tuned to detect signals from particular organs and are topographically organized on the basis of body position. Moreover, some mechanosensory and chemosensory inputs from the same organ converge centrally. Sensory inputs engage specific NTS domains with defined locations, each containing heterogeneous cell types. Spatial representations of different organs are further sharpened in the NTS beyond what is achieved by vagal axon sorting alone, as blockade of brainstem inhibition broadens neural tuning and disorganizes visceral representations. These findings reveal basic organizational features used by the brain to process interoceptive inputs.

Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour

Abstract: Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2-4. Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS-AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS-AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection. Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.

Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations

Abstract: The paraventricular nucleus of hypothalamus (PVN), an integrative center in the brain, orchestrates a wide range of physiological and behavioral responses. While the PVN melanocortin 4 receptor (MC4R) signaling (PVNMC4R+) is involved in feeding regulation, the neuroanatomical organization of PVNMC4R+ connectivity and its role in other physiological regulations are incompletely understood. Here we aimed to better characterize the input-output organization of PVNMC4R+ neurons and test their physiological functions beyond feeding.Using a combination of viral tools, we mapped PVNMC4R+ circuits and tested the effects of chemogenetic activation of PVNMC4R+ neurons on thermoregulation, cardiovascular control, and other behavioral responses beyond feeding.We found that PVNMC4R+ neurons innervate many different brain regions that are known to be important not only for feeding but also for neuroendocrine and autonomic control of thermoregulation and cardiovascular function, including but not limited to the preoptic area, median eminence, parabrachial nucleus, pre-locus coeruleus, nucleus of solitary tract, ventrolateral medulla, and thoracic spinal cord. Contrary to these broad efferent projections, PVNMC4R+ neurons receive monosynaptic inputs mainly from other hypothalamic nuclei (preoptic area, arcuate and dorsomedial hypothalamic nuclei, supraoptic nucleus, and premammillary nucleus), the circumventricular organs (subfornical organ and vascular organ of lamina terminalis), the bed nucleus of stria terminalis, and the parabrachial nucleus. Consistent with their broad efferent projections, chemogenetic activation of PVNMC4R+ neurons not only suppressed feeding but also led to an apparent increase in heart rate, blood pressure, and brown adipose tissue temperature. These physiological changes accompanied acute transient hyperactivity followed by hypoactivity and resting-like behavior.Our results elucidate the neuroanatomical organization of PVNMC4R+ circuits and shed new light on the roles of PVNMC4R+ pathways in autonomic control of thermoregulation, cardiovascular function, and biphasic behavioral activation.

The ins and outs of the caudal nucleus of the solitary tract: An overview of cellular populations and anatomical connections

Abstract: The body and brain are in constant two‐way communication. Driving this communication is a region in the lower brainstem: the dorsal vagal complex. Within the dorsal vagal complex, the caudal nucleus of the solitary tract (cNTS) is a major first stop for incoming information from the body to the brain carried by the vagus nerve. The anatomy of this region makes it ideally positioned to respond to signals of change in both emotional and bodily states. In turn, the cNTS controls the activity of regions throughout the brain that are involved in the control of both behaviour and physiology. This review is intended to help anyone with an interest in the cNTS. First, I provide an overview of the architecture of the cNTS and outline the wide range of neurotransmitters expressed in subsets of neurons in the cNTS. Next, in detail, I discuss the known inputs and outputs of the cNTS and briefly highlight what is known regarding the neurochemical makeup and function of those connections. Then, I discuss one group of cNTS neurons: glucagon‐like peptide‐1 (GLP‐1)‐expressing neurons. GLP‐1 neurons serve as a good example of a group of cNTS neurons, which receive input from varied sources and have the ability to modulate both behaviour and physiology. Finally, I consider what we might learn about other cNTS neurons from our study of GLP‐1 neurons and why it is important to remember that the manipulation of molecularly defined subsets of cNTS neurons is likely to affect physiology and behaviours beyond those monitored in individual experiments.

Inflammatory Stress Induced by Intraperitoneal Injection of LPS Increases Phoenixin Expression and Activity in Distinct Rat Brain Nuclei

Abstract: Due to phoenixin’s role in restraint stress and glucocorticoid stress, as well as its recently shown effects on the inflammasome, we aimed to investigate the effects of lipopolysaccharide (LPS)-induced inflammatory stress on the activity of brain nuclei-expressing phoenixin. Male Sprague Dawley rats (n = 6/group) were intraperitoneally injected with either LPS or control (saline). Brains were processed for c-Fos and phoenixin immunohistochemistry and the resulting slides were evaluated using ImageJ software. c-Fos was counted and phoenixin was evaluated using densitometry. LPS stress significantly increased c-Fos expression in the central amygdaloid nucleus (CeM, 7.2-fold), supraoptic nucleus (SON, 34.8 ± 17.3 vs. 0.0 ± 0.0), arcuate nucleus (Arc, 4.9-fold), raphe pallidus (RPa, 5.1-fold), bed nucleus of the stria terminalis (BSt, 5.9-fold), dorsal motor nucleus of the vagus nerve (DMN, 89-fold), and medial part of the nucleus of the solitary tract (mNTS, 121-fold) compared to the control-injected group (p < 0.05). Phoenixin expression also significantly increased in the CeM (1.2-fold), SON (1.5-fold), RPa (1.3-fold), DMN (1.3-fold), and mNTS (1.9-fold, p < 0.05), leading to a positive correlation between c-Fos and phoenixin in the RPa, BSt, and mNTS (p < 0.05). In conclusion, LPS stress induces a significant increase in activity in phoenixin immunoreactive brain nuclei that is distinctively different from restraint stress.

Analysis of the distribution of vagal afferent projections from different peripheral organs to the nucleus of the solitary tract in rats

Abstract: Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno‐associated virus that transports retrogradely and exhibits selective tropism for vagal afferents, to map their soma location and central termination sites within the nucleus of the solitary tract (NTS). We examined the vagal sensory afferents innervating the trachea, duodenum, stomach, or heart, and in some animals, from two organs concurrently. We observed no obvious somatotopy in the somata distribution within the nodose ganglion. The central termination patterns of afferents from different organs within the NTS overlap substantially. Convergence of vagal afferent inputs from different organs onto single NTS neurons is observed. Abdominal and thoracic afferents terminate throughout the NTS, including in the rostral NTS, where the 7th cranial nerve inputs are known to synapse. To address whether the axonal labeling produced by viral transduction is so widespread because it fills axons traveling to their targets, and not just terminal fields, we labeled pre and postsynaptic elements of vagal afferents in the NTS . Vagal afferents form multiple putative synapses as they course through the NTS, with each vagal afferent neuron distributing sensory signals to multiple second‐order NTS neurons. We observe little selectivity between vagal afferents from different visceral targets and NTS neurons with common neurochemical phenotypes, with afferents from different organs making close appositions with the same NTS neuron. We conclude that specific viscerosensory information is distributed widely within the NTS and that the coding of this input is probably determined by the intrinsic properties and projections of the second‐order neuron.

Modulation of stress-related behaviour by hypothalamic engagement of preproglucagon neurons in the nucleus of the solitary tract

Abstract: Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Using an intersectional approach, we show that a corticotropin-releasing hormone (CRH)-rich input from the paraventricular nucleus of the hypothalamus (PVN) drives activation of both the cNTS as a whole and PPG neurons in particular in response to acute stress. Finally, we demonstrate that NTS-projecting PVN neurons are necessary for the ability of acute stress to suppress food intake. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

Abstract: Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the "overstimulated" renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.

Target-specific projections of amygdala somatostatin-expressing neurons to the hypothalamus and brainstem.

Abstract: Somatostatin neurons in the central nucleus of the amygdala (CeA/Sst) can be parsed into subpopulations that project either to the nucleus of the solitary tract (NST) or parabrachial nucleus (PBN). We have shown recently that inhibition of CeA/Sst-to-NST neurons increased the ingestion of a normally aversive taste stimulus, quinine HCl (QHCl). Because the CeA innervates other forebrain areas such as the lateral hypothalamus (LH) that also sends axonal projections to the NST, the effects on QHCl intake could be, in part, the result of CeA modulation of LH-to-NST neurons. To address these issues, the present study investigated whether CeA/Sst-to-NST neurons are distinct from CeA/Sst-to-LH neurons. For comparison purposes, additional experiments assessed divergent innervation of the LH by CeA/Sst-to-PBN neurons. In Sst-cre mice, two different retrograde transported flox viruses were injected into the NST and the ipsilateral LH or PBN and ipsilateral LH. The results showed that 90% or more of retrograde-labeled CeA/Sst neurons project either to the LH, NST, or PBN. Separate populations of CeA/Sst neurons projecting to these different regions suggest a highly heterogeneous population in terms of synaptic target and likely function.

Ultrastructure of Rat Rostral Nucleus of the Solitary Tract Terminals in the Parabrachial Nucleus and Medullary Reticular Formation

Abstract: Neurons in the rostral nucleus of the solitary tract (rNST) receive taste information from the tongue and relay it mainly to the parabrachial nucleus (PBN) and the medullary reticular formation (RF) through two functionally different neural circuits. To help understand how the information from the rNST neurons is transmitted within these brainstem relay nuclei in the taste pathway, we examined the terminals of the rNST neurons in the PBN and RF by use of anterograde horseradish peroxidase (HRP) labeling, postembedding immunogold staining for glutamate, serial section electron microscopy, and quantitative analysis. Most of the anterogradely labeled, glutamate-immunopositive axon terminals made a synaptic contact with only a single postsynaptic element in PBN and RF, suggesting that the sensory information from rNST neurons, at the individual terminal level, is not passed to multiple target cells. Labeled terminals were usually presynaptic to distal dendritic shafts in both target nuclei. However, the frequency of labeled terminals that contacted dendritic spines was significantly higher in the PBN than in the RF, and the frequency of labeled terminals that contacted somata or proximal dendrites was significantly higher in the RF than in the PBN. Labeled terminals receiving axoaxonic synapses, which are a morphological substrate for presynaptic modulation frequently found in primary sensory afferents, were not observed. These findings suggest that the sensory information from rNST neurons is processed in a relatively simple manner in both PBN and RF, but in a distinctly different manner in the PBN as opposed to the RF.

The Neural Code for Taste in the Nucleus of the Solitary Tract of Rats with Obesity Following Roux-En-Y Gastric Bypass Surgery

Abstract: Previous work has shown that taste responses in the nucleus tractus solitarius (NTS; the first central relay for gustation) are blunted in rats with diet-induced obesity (DIO). Here, we studied whether these effects could be reversed by Roux-en-Y gastric bypass (RYGB) surgery, an effective treatment for obesity. Rats were fed a high energy diet (60% kcal fat; HED) both before and after undergoing RYGB. Electrophysiological responses from NTS cells in unrestrained rats were recorded as they licked tastants from a lick spout. Sweet, salty, and umami tastes, as well as their naturalistic counterparts, were presented. Results were compared with those of lean rats from a previous study. As with DIO rats, NTS cells in RYGB rats were more narrowly tuned, showed weaker responses, and less lick coherence than those in lean rats. Both DIO and RYGB rats licked at a slower rate than lean rats and paused more often during a lick bout. However, unlike DIO rats, the proportion of taste cells in RYGB rats was similar to that in lean rats. Our data show that, despite being maintained on a HED after surgery, RYGB can induce a partial recovery of the deficits seen in the NTS of DIO rats.

Morphological Relationships between the Cholinergic and Somatostatin-28(1-12) Systems in the Alpaca (Lama pacos) Brainstem

Abstract: In the alpaca brainstem, the distribution of the cholinergic system by the immunohistochemical detection of the enzyme choline acetyltransferase (ChAT) has been described, and its relationship with the distribution of somatostatin-28(1-12) is analyzed by double-immunostaining techniques. Overlapping distribution patterns for both substances were observed in many brainstem regions, suggesting that interactions between them may occur in the reticular formation, nucleus ambiguus or laterodorsal tegmental nucleus. Colocalization of the two substances in the same cell bodies was only observed in restricted areas, such as the nucleus of the solitary tract, reticular formation and nucleus ambiguus. In addition, in several regions, an apparent high innervation of the peptidergic fibers on cholinergic neurons has been observed. The results suggest that chemospecific interactions could be crucial for the control of specific cardiorespiratory and/or digestive functions in alpacas. These interactions may represent brain-adaptive mechanisms to particular environments and have a potential therapeutic use in respiratory disorders.

Ticking and talking in the brainstem satiety centre: Circadian timekeeping and interactions in the diet-sensitive clock of the dorsal vagal complex

Abstract: The dorsal vagal complex (DVC) is a key hub for integrating blood-borne, central, and vagal ascending signals that convey important information on metabolic and homeostatic state. Research implicates the DVC in the termination of food intake and the transition to satiety, and consequently it is considered a brainstem satiety centre. In natural and laboratory settings, animals have distinct times of the day or circadian phases at which they prefer to eat, but if and how circadian signals affect DVC activity is not well understood. Here, we evaluate how intrinsic circadian signals regulate molecular and cellular activity in the area postrema (AP), nucleus of the solitary tract (NTS), and dorsal motor nucleus of the vagus (DMV) of the DVC. The hierarchy and potential interactions among these oscillators and their response to changes in diet are considered a simple framework in which to model these oscillators and their interactions is suggested. We propose possible functions of the DVC in the circadian control of feeding behaviour and speculate on future research directions including the translational value of knowledge of intrinsic circadian timekeeping the brainstem.

210-LB: Central Regulation of Peripheral Adiposity by Nos1PVHNeurons

Abstract: Within the CNS, the paraventricular nucleus of the hypothalamus (PVH) is critical for energy homeostasis, as developmental or mechanical lesions targeting the PVH lead to massive obesity. The PVH is composed of multiple cell types expressing an assortment of neuropeptides, receptors, and enzymes, including a subset of neurons expressing nitric oxide synthase-1 (Nos1PVH) . Nos1PVH neurons project to the nucleus of the solitary tract and the intermediolateral column of the spinal cord suggesting a neural substrate through which Nos1PVH neurons might directly modulate sympathetic output and energy balance [1]. To understand the necessity of Nos1PVH neurons in basal energy balance regulation, we bilaterally injected the PVH of Nos1-iCre mice with an AAV expressing a Cre-dependent tetanus toxin (Nos1TT) . Chronic silencing of the Nos1PVH resulted in acute onset of subcutaneous and visceral obesity without changes in food intake. Surprisingly, metabolic analyses indicated no significant changes in energy expenditure, although Nos1TT treated animals preferred to utilize fat as the predominant fuel source. Pair feeding experiments also confirmed that the obesity observed in Nos1TT animals was not secondary to increased caloric intake. Adipose tissues receive input from CNS cell groups that are part of the general SNS outflow from the brain [2, 3]. Analysis of subcutaneous white adipose tissue of Nos1TT animals revealed a significant decrease in tyrosine hydroxylase (TH) immunoactivity within WAT suggesting decreased capacity for sympathetic activation of lipolysis. These data indicate that Nos1PVH neurons regulate energy homeostasis possibly through changes in peripheral aspects of energy balance without the influence of energy consumption. Therefore, the main goal of this project is to clarify the physiological roles of Nos1PVH neurons in the regulation of peripheral adiposity, which may lead to the development of more refined anti-obesity therapies. 1. PMID: 25392498 2. PMID: 9688991 3. PMID: 15142857 L. D. Faulkner: n/a. K. Lewis: None. T. H. Meek: Employee; Novo Nordisk. A. J. Mercer: Employee; Novo Nordisk. O. A. Macdougald: None. D. Olson: Research Support; AstraZeneca, Novo Nordisk A/S. American Diabetes Association (7-21-PMF-020) ; Novo Nordisk A/S; National Institutes of Health (5R01DK104999-05)

Perinatal High Fat Diet Decreases Oxytocinergic Innervation to the Brainstem

Abstract: Perinatal high fat diet (pHFD) exposure is known to increase anxiety in offspring, and reduce stress resilience, however the mechanism that causes this functional change is unknown. Oxytocin is the prototypical anti‐stress peptide, and the paraventricular nucleus of the hypothalamus (PVN) provides descending inputs to the dorsal vagal complex (DVC) within the brainstem. The DVC provides parasympathetic extrinsic control over the gastrointestinal tract. The present study was designed to investigate the hypothesis that changes in oxytocin hypothalamic‐brainstem innervation may be partially responsible for the lack of stress resilience observed following a pHFD.

Glutamatergic Activity in the Nucleus of the Solitary Tract contributes to the Circadian Regulation of Blood Pressure

Abstract: Cardiorespiratory parameters including blood pressure are governed by a 24‐hour circadian rhythm. Blood pressure follows a circadian cycle and dips during the resting/sleeping period while peaking during the active/awake period. During sleep blood pressure is 10%‐20% lower than average daytime blood pressure, a phenomenon described as “dipping”. The brain regions and mechanisms by which the circadian rhythm of blood pressure is controlled are not fully understood. To address this knowledge gap, we examined the nucleus of the solitary tract (nTS). The nTS is the first central site for integration and modulation of reflexes including the baroreflex. The nTS receives sensory information through glutamate release from baroreceptors that sense changes in blood pressure, eliciting reflex responses in the nTS to maintain BP homeostasis. Previous studies have shown that injections of glutamate or increases of extracellular glutamate decrease blood pressure. Due to its integral role in the autonomic system, we hypothesized that the nTS is involved in circadian blood pressure regulation through alterations in glutamate. Specifically, the present study sought to identify if decreased glutamate raised blood pressure during the active period and if increased glutamate reduced blood pressure in the inactive period. To address this, we used 7‐week‐old male Sprague Dawley rats and a combination of electrophysiology, molecular methods, immunohistochemistry, and 24/7 telemetry. Rats acclimated for 2 weeks prior to telemetry recordings. Measurements were compared at four different time points in one day (6 hours apart) except for electrophysiological recordings which were taken 12 hours apart. During the active period, blood pressure significantly increased in comparison to the inactive period. We next examined the relationship between changes in blood pressure and changes in glutamatergic activity. We first determined if activation of glutamatergic neurons differed across the 4 time periods. We took 30 µm of coronal slices containing the nTS (at the level of area postrema) from perfused animals. Active glutamatergic neurons (denoted by cFos expression) significantly decreased during the active period in comparison to the inactive period. To examine if this increase in glutamatergic neuronal cFos expression correlated with channel expression, we used western blot and found that the expression of AMPA receptors (GluA1 subunit) also decreased during the active period. During the active period, the resting membrane potential of nTS neurons were hyperpolarized in comparison to the inactive period. This lead to a significant decrease in spontaneous excitatory post‐synaptic currents in nTS neurons during the active period. The data indicate that glutamatergic activity decreased during the active period when blood pressure was higher in comparison to the inactive period. Taken together, these results suggest that nTS glutamatergic activity may have a circadian pattern and may contribute to the circadian blood pressure rhythm.

Identification of the brain network controlling systemic inflammatory signals

Abstract: Systemic inflammatory conditions are finely controlled not only by the immune system but also by the neuronal system in the body. While the vagus nerve is the key neuronal pathway to control the peripheral immune system, known as the inflammatory reflex, it is largely unknown how the brain regulates the reflex. The purpose of this study is to clarify the brain network response to systemic inflammatory signals. Transgenic targeted-recombination-in-active-populations (TRAP2) mice that expressed tamoxifen-inducible Cre under control of an activity-dependent c-Fos promoter were crossed with a Cre-dependent tdTomato reporter line. These mice (TRAP2/tdTomato mice) were injected with 4-OHT (an active form of Tamoxifen) to induce Cre recombination and tdTomato expression. 30 min later, TNF was administered intraperitoneally to these mice and the brains were collected 7 days after the induction. Nucleus of the solitary tract (NTS), where vagal afferents ascending from peripheral tissues synapse on neurons, showed the increased number of tdTomato-expressing cells. In addition, TNF stimulation reinforced the tdTomato expression in the paraventricular nucleus (PVN) and the bed nuclei of the stria terminalis (BNST). Interestingly, many tdTomato-expressing cells colocalized with the sub-nuclei of PKC delta-positive neurons within the BNST. Systemic TNF signals are transmitted to the brain regions through the vagus nerve, including NTS, PVN, and BNST. Furthermore, the specific neuronal population within the BNST may play a role in the modulation of systemic inflammatory condition. This experiment is supported by grant from NIH to KJT and SSC Supported by grants from NIH (R01GM132672, R35GM118182-01)

Glycemic challenge is associated with the rapid cellular activation of the locus ceruleus and nucleus of solitary tract: Circumscribed spatial analysis of phosphorylated MAP kinase immunoreactivity

Abstract: Abstract Rodent studies indicate that impaired glucose utilization or hypoglycemia is associated with cellular activation of neurons in the medulla ( Winslow, 1733 ) (MY) believed to control feeding behavior and glucose counterregulation. However, such activation has been tracked primarily within hours of the challenge, rather than sooner, and has been poorly mapped within standardized brain atlases. Here, we report that within 15 min of receiving 2-deoxy-D-glucose (2-DG; 250 mg/kg, i.v.), which can trigger glucoprivic feeding behavior, marked elevations were observed in the numbers of rhombic brain ( His, 1893 ) (RB) neuronal cell profiles immunoreactive for the cellular activation marker(s), phosphorylated p44/42 MAP kinases (phospho-ERK1/2), some of which were also catecholaminergic. We mapped their distributions within an open-access rat brain atlas and found that 2-DG-treated rats (compared to their saline-treated controls) displayed greater numbers of phospho-ERK1/2 + neurons in the locus ceruleus ( Wenzel & Wenzel, 1812 ) (LC) and the nucleus of solitary tract (>1840) (NTS). Thus, 2-DG-activation of certain RB neurons is more rapid than perhaps previously realized, engaging neurons that serve multiple functional systems and are of varying cellular phenotypes. Mapping these populations within standardized brain atlas maps streamlines their targeting and/or comparable mapping in preclinical rodent models of disease.

Characteristics and Impact of the rNST GABA Network on Neural and Behavioral Taste Responses

Abstract: Abstract The rostral nucleus of the solitary tract (rNST), the initial CNS site for processing gustatory information, is comprised of two major cell types, glutamatergic excitatory and GABAergic inhibitory neurons. Although many investigators have described taste responses of rNST neurons, the phenotypes of these cells were unknown. To directly compare the response characteristics of both inhibitory and noninhibitory neurons, we recorded from mice expressing Channelrhodopsin-2 (ChR2) under the control of GAD65, a synthetic enzyme for GABA. We observed that chemosensitive profiles of GABAergic taste neurons (G+ TASTE ) were similar to non-GABA taste neurons (G- TASTE ) but had much lower response rates. We further observed a novel subpopulation of GABA cells located more ventrally in the nucleus that were unresponsive to taste stimulation (G+ UNR ), suggesting pathways for inhibition initiated by centrifugal sources. This preparation also allowed us to determine how optogenetic activation of the rNST GABA network impacted the taste responses of G- TASTE neurons. Activating rNST inhibitory circuitry suppressed gustatory responses of G- TASTE neurons across all qualities and chemosensitive types of neurons. Although the tuning curves of identified G- TASTE were modestly sharpened, the overall shape of response profiles and the ensemble pattern remained highly stable. These neurophysiological effects were consistent with the behavioral consequences of activating GAD65-expressing inhibitory neurons using DREADDs. In a brief-access licking task, concentration-response curves to both palatable (sucrose, maltrin) and unpalatable (quinine) stimuli were shifted to the right when GABA neurons were activated. Thus, the rNST GABAergic network is poised to modulate taste intensity across the qualitative and hedonic spectrum.