Area Postrema Lesions Research Articles

Clinico-radiologic Spectrum and Outcome of Pediatric Acquired Demyelinating Disorders of Central Nervous System: A Retrospective Indian Tertiary Care Hospital Cohort.

Pediatric acquired demyelinating syndrome (ADS) constitutes a group of treatable disorders with acute neurologic dysfunction. Neuroimaging has played a significant role in diagnosis of ADS. We describe clinico-radiologic spectrum, outcomes, and comparison of the groups: acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder (NMOSD), clinically isolated syndrome (CIS), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). Retrospective review of 70 children with ADS at a tertiary care hospital over 15 years (2008-2023) was performed. Diagnosis was assigned as per International Pediatric Multiple Sclerosis Study Group criteria 2016. Fisher's exact and chi-square tests were applied. Thirty-nine boys and 31 girls aged 8.2 ± 4.0 years with CIS (n = 27), ADEM (n = 16), NMOSD (n = 13), MS (n = 1), and MOGAD (n = 13) were included. Clinical syndromes with positive significant association included polyfocal symptoms, encephalopathy in ADEM, optic neuritis (ON) in MOGAD, brainstem, area postrema syndrome in NMOSD. MOGAD presented with atypical presentations like prolonged fever (PF; 76.9%) and aseptic meningitis (23%). Seropositivity for myelin oligodendrocyte glycoprotein immunoglobulin-G was 62% and for NMO-IgG 2.6%. Neuroimaging of MOGAD showed lesions predominantly in basal ganglia/thalami (69.2%), optic nerve (46.2%), and cerebellum (46.2%). Imaging patterns between ADEM and MOGAD were comparable except for more ON (p = 0.004), spinal cord (p = 0.01), and cerebellar lesions (p = 0.03) in MOGAD. Area postrema lesion was unique to NMOSD. All patients received immunotherapy, of whom 91.4% (n = 64) had good recovery, 8.6% (n = 6) had functional limitation on modified Rankin scale at discharge, and 12 (17.1%) relapsed. The largest group was CIS. Seropositivity of MOG was high with atypical presentations like PF and aseptic meningitis. Specific neuroimaging patterns correlated with ADS categories. Short-term outcome with immunotherapy was favorable in spite of relapses.

Advances in the long-term treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neuroinflammatory disorder with a prevalence of 1-5/100,000 globally, characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent relapses. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved relapse prevention and quality of life remain a goal in the field. A better understanding of the underlying pathophysiology of NMOSD over the last 10years has led to newer, more specific approaches in treatment, culminating in the first FDA approved treatments in the disease. In this review, we will discuss the seminal trials of PREVENT or Eculizumab in the treatment of aquaporin-4 (AQP4)-IgG positive NMOSD, N-Momentum or Inebilizumab in the study of NMOSD (both AQP4-IgG positive and negative) and SAkura Sky and SAkuraStar which studied satralizumab in AQP4-IgG seropositive and seronegative NMOSD patients. We will also discuss the extension trials of each of these medications and what lead to their approval in AQP4-IgG seropositive NMOSD patients. We will then examine treatments in the pipeline for adult and pediatric NMOSD patients and conclude with discussions on treatment considerations in pregnant patients and how to approach treatment of NMOSD patients during COVID.

Teaching NeuroImages: Cortical damage with leptomeningeal enhancement in neuromyelitis optica spectrum disorder

A 27-year-old woman presented with headache, weakness, and numbness in both lower extremities for 2 weeks. Two years ago, she had refractory hiccups and vomiting with associated area postrema lesions on MRI (figure, A–C). Workup for infectious disease was negative. Serum aquaporin-4–immunoglobulin G was positive. Recent MRI showed cortical damage adjacent to the cerebral falx with leptomeningeal enhancement (figure, D–F). Treatment with immunoglobulin and high-dose methylprednisolone produced a significant improvement of the symptoms and the follow-up MRI (figure, G–I). This patient's case is unusual, as neuromyelitis optica spectrum disorders rarely involve the cortex and pia mater.1,2

Symptomatic care of late-onset Alexander disease presenting with area postrema-like syndrome with prednisolone; a case report

BackgroundAlexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone.Case presentationA normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting.ConclusionsThis study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.

Peripherally administered amylin inhibits stress-like behaviors and enhances cognitive performance

Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizophrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in rodent-based behavioral assays sensitive to neuropsychiatric drugs, including anxiolytic, antidepressant, antipsychotic, and cognitive enhancing drugs: stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), forced swim test (FST), pre-pulse inhibition, and phencyclidine-induced locomotion. To assess the neural underpinnings of amylin's anxiolytic-like effects, we examined the effect of amylin on SIH after lesioning the area postrema (AP), which mediates amylin's metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10mg/kg) significantly (P<0.05) decreased SIH (97% below vehicle) and AP lesions inhibited this effect. Amylin also reduced marble burying (72% below vehicle), but had no effect in the EPM. Together, these effects suggest anxiolytic-like activity or potential. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by implanted osmotic pumps, amylin (300mg/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3mg/kg/d) reduced the time immobile in the FST (P<0.05; 30% below vehicle), suggesting antidepressant-like potential. Although further testing is needed, our findings support a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.

Effects of area postrema lesions and bilateral subdiaphragmatic afferent vagotomy on emetine-induced conditioned taste avoidance in rats.

We investigated the effect of area postrema lesions and selective vagotomy of afferent fibers on emetine-induced nausea in rats. We evaluated the acquisition of the conditioned taste avoidance (CTA) to 0.1% saccharin solution after conditioning with emetine dihydrochloride (5.54 mg/kg, i.p., 1% BW). The CTA was measured in three groups of rats: a bilateral subdiaphragmatic afferent vagotomy group, an area postrema lesion group, and a sham lesion group. The bilateral vagotomy and sham groups of rats showed acquisition of CTA within 2 days of the test date. Taste avoidance was never conditioned in the area postrema lesion group. These results indicate that the area postrema plays a crucial role in the induction of emetine-induced nausea.

The role of the area postrema in belching

Introduction: The primary reflex involved with belching is associated with the activation of neurons in the area postrema (AP), therefore, we investigated the role of the AP in the activation of belching. Methods: The effects of mechanical lesions of the dorsal brainstem on activation of belching, esophago-UES contractile reflex (EUCR), and the pharyngeal swallow (PS) were determined in 13 decerebrate cats. Discussion: Bilateral lesions of the dorsal brain stem which included the rostral AP significantly (P&lt; 0.05, N = 7) blocked belching, but not the other reflexes. Bilateral lesions of the rostral AP only blocked belching (N=2). When belching was blocked, the same belch stimulus activated EUCR (in 6 out of 7 animals). Unilateral lesions of the AP (N = 3) did not block belching. Conclusions: The rostral AP is essential for activation of belching. We hypothesize that the AP serves an inhibitory function to prevent reflexes that promote orthograde transport, e.g. PS, and reflexes that prevent supra-esophageal reflux, e.g. EUCR, thereby, facilitating retrograde transport. Keywords: Belching; brain stem; area postrema.

Multiple sclerosis with intractable vomiting and atypical area postrema lesion

BackgroundArea postrema syndrome is considered as one of the most typical presentations of neuromyelitis optica spectrum disorders (NMOSDs) (Wingerchuk et al., 2015). The involvement of area postrema is rarely seen in multiple sclerosis (MS). We are here report a case of a young woman with multiple sclerosis, presented with intractable vomiting, and her MRI brain showed acute T2 hyperintense signal over the area postrema. Case presentationA 36-year-old Asian woman who is known to have schizophrenia and multiple sclerosis since 2012. She was noted to have spastic gait, and the MRI brain in 2012 showed multiple perpendicular periventricular T2 lesions suggestive of multiple sclerosis (MS). However, she defaulted her neurologist follow-up and was not on any treatment for MS. She was admitted in 2016 with intractable vomiting, and her MRI brain showed T2 hyperintense signal over area postrema with focal contrast enhancement. Her MRI cervical spine was normal. The visual evoked potential study showed bilateral prolonged P100 latencies. Oligoclonal bands were detected in her CSF analysis. Both the serum aquaporin-4 IgG (AQP4 IgGs) antibody and myelin oligodendrocyte glycoprotein (MOG-IgGs) were negative. Her intractable vomiting resolved after a short course of intravenous methylprednisolone. She was treated as MS with interferon-beta 1a. She has been in remission since 2016, and her functional status also improved from the expanded disability status scale (EDSS) of 2.0 (in 2016) to 1.0 (in 2020). ConclusionWe proposed that although area postrema lesion is typically seen in NMOSDs, it may also be seen in MS. Current MRI criteria for MS and NMOSDs are not sufficiently specific, and the diagnostic criteria should only be used in the appropriate clinical context.

Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis.

Increased cardiac sympathetic nerve activity (CSNA) is a key feature of heart failure (HF) and is associated with poor outcome. There is evidence that central angiotensinergic mechanisms contribute to the increased CSNA in HF, but the central sites involved are unknown. In an ovine, rapid pacing model of HF, we investigated the contribution of the lamina terminalis and area postrema to the increased CSNA and also the responses to fourth ventricular infusion of the angiotensin type 1 receptor antagonist losartan. Ablation of the area postrema or sham lesion (n = 6/group), placement of lamina terminalis lesion electrodes (n = 5), and insertion of a cannula into the fourth ventricle (n = 6) were performed when ejection fraction was ~ 50%. When ejection fraction was < 40%, recording electrodes were implanted, and after 3days, resting CSNA and baroreflex control of CSNA were measured before and following lesion of the lamina terminalis, in groups with lesion or sham lesion of the area postrema and before and following infusion of losartan (1.0mg/h for 5h) into the fourth ventricle. In conscious sheep with HF, lesion of the lamina terminalis did not significantly change CSNA (91 ± 2 vs. 86 ± 3 bursts/100 heart beats), whereas CSNA was reduced in the group with lesion of the area postrema (89 ± 3 to 45 ± 10 bursts/100 heart beats, P < 0.01) and following fourth ventricular infusion of losartan (89 ± 3 to 48 ± 8 bursts/100 heartbeats, P < 0.01). These findings indicate that the area postrema and brainstem angiotensinergic mechanisms may play an important role in determining the increased CSNA in HF.

Case report of multiple sclerosis with atypical presentation of intractable vomiting and area postrema lesion

Case report of multiple sclerosis with atypical presentation of intractable vomiting and area postrema lesion

Suspected bacterial meningomyelitis: The first presenting clinical feature of neuromyelitis optica spectrum disorder

A rare case of neuromyelitis optica spectrum disorder, suspected to be bacterial meningomyelitis as the initial manifestation, is reported. The patient presented with initial symptoms of meningomyelitis and fever. Cerebrospinal fluid analysis revealed pleocytosis (1280×106/L [98% lymphocytes]) and glucose level of 1.8mmol/L. Magnetic resonance imaging revealed >3 vertebral, longitudinally extensive transverse myelitis and area postrema lesions. Right optic neuritis was experienced 20months after the first attack. Serum anti-aquaporin-4 antibody was positive, and a diagnosis of neuromyelitis optica spectrum disorder was made, supporting the hypothesis that the pathogenesis of neuromyelitis optica is triggered by infection.

Role of the area postrema in the hypophagic effects of oleoylethanolamide

The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg−1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA’s behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA’s central effects that sustain its pro-satiety action.

The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc)

The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic ‘reward’ pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats.Amylin (50μg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50μg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake.

Different Phenotypes at Onset in Neuromyelitis Optica Spectrum Disorder Patients with Aquaporin-4 Autoimmunity.

Although rare, brain abnormalities without optic neuritis (ON) or transverse myelitis (TM) diagnosed with neuromyelitis optica spectrum disorder (NMOSD) have been reported in patients positive for the aquaporin-4 (AQP4) antibody. To analyze demographic and clinical differences among NMOSD patients without ON or TM, those with either ON or TM, and patients with simultaneous ON and TM at disease onset. In this retrospective study, patients who were positive for the AQP4 antibody, as detected using a cell-based assay, at the Second Affiliated Hospital of Guangzhou Medical University in China were recruited. Demographic and clinical data were obtained from each patient's medical record. A total of 292 patients were included in this study and were divided into four subgroups based on their initial manifestations: (i) NMOSD without ON or TM (NMOSD-ON-TM-, n = 70); (ii) NMOSD with ON (NMOSD-ON+, n = 95); (iii) NMOSD with TM (NMOSD-TM+, n = 116); and (iv) simultaneous ON and TM [neuromyelitis optica (NMO), n = 11]. We found that age at onset was lower in the NMOSD-ON-TM- group than that in the other groups. The interval from the first episode to relapse was shorter in the NMOSD-ON-TM- group than that in NMOSD-TM+ group. Cerebral spinal fluid white cell counts and protein levels were significantly higher in the NMOSD-ON-TM- group than those in the other groups. Lower Expanded Disability Status Scale scores were observed in the NMOSD-ON-TM- group. Brain abnormalities, including in area postrema and hemisphere lesions, were more frequent in the NMOSD-ON-TM- group. Kaplan-Meier analysis showed that patients in the NMOSD-ON-TM- group experienced earlier relapse than those in other groups. Conversion to NMO in the NMOSD-ON+ group was greater than that in the other groups. Only 14 patients (4.8%, 14/292) had pure brain abnormalities, of which 12 had disease duration of several more years and 8 (57.1%) experienced relapses. NMOSD patients with different initial manifestations present with significant differences in clinical features during follow-up. Patients with long-term AQP4 autoimmunity in the brain in the absence of ON or TM are not common.

Differentiation of neuromyelitis optica spectrum disorders from ultra-longitudinally extensive transverse myelitis in a cohort of Chinese patients

This study aimed to differentiate neuromyelitis optica spectrum disorders (NMOSD) from other causes in cases of ultra-longitudinally extensive transverse myelitis (uLETM). We retrospectively analyzed thirty-three Chinese patients with uLETM hospitalized in the China–Japan Friendship Hospital. The patients were divided into NMOSD (n=21) and non-NMOSD (n=12) groups. The NMOSD group exhibited significantly more comorbidity compared with the non-NMOSD group; moreover, the NMOSD group uniquely exhibited intractable vomiting and hiccups (IVH). The prevalence rates of cervicothoracic, area postrema (AP), and other circumventricular organ (CVO) lesions were significantly increased in the NMOSD group compared with the non-NMOSD group. Moreover, uLETM was strongly associated with NMOSD. These novel findings indicate that CVO lesions, including AP, and particularly when combined with clinical IVH, may represent a useful discriminator to differentiate NMOSD.

In heart failure, lesion of the area postrema reduces cardiac sympathoexcitation and improves cardiac function

Heart Failure (HF) is associated with increased cardiac sympathetic nerve activity (CSNA), but the mechanisms causing this are unclear. The area postrema (AP), a brainstem circumventricular organ, plays an important role in controlling SNA. We hypothesized that lesioning the AP would reduce CSNA and attenuate the decline in cardiac function. In sheep with pacing-induced HF, lesion of the AP or sham lesion (n = 6/group) was performed when ejection fraction (EF) had fallen to ~50%. In conscious sheep, blood pressure, heart rate and CSNA were recorded when EF had decreased to b40%. Compared with heathy sheep, sheep with HF had a large increase in CSNA (34 ± 4 vs. 89 ± 3 bursts/100 heartbeats, respectively), which was significantly reduced in HF sheep with lesion of the AP (45 ± 10 bursts/100 heartbeats, P b 0.01). In rats, AP lesion or sham lesion (n= 18/group) was performed before HF was induced by myocardial infarction. Eight weeks later, left ventricular end-diastolic pressure in anaesthetised ratswas significantly lower in theAP lesiongroup compared with the sham lesion group (9± 2 vs 16 ± 2mmHg, respectively, P b 0.05) and ejection fraction was higher. These findings suggest that the AP plays a critical role in setting the high level of CSNA in HF and indicate that lesion of the AP reduces the decline in cardiac function postmyocardial infarction, possibly due to the reduction in CSNA.

Cardiocirculatory effects of the selective 5-HT1A agonist NLX-112 on heart failure in rats

Heart Failure (HF) is associated with increased cardiac sympathetic nerve activity (CSNA), but the mechanisms causing this are unclear. The area postrema (AP), a brainstem circumventricular organ, plays an important role in controlling SNA. We hypothesized that lesioning the AP would reduce CSNA and attenuate the decline in cardiac function. In sheep with pacing-induced HF, lesion of the AP or sham lesion (n = 6/group) was performed when ejection fraction (EF) had fallen to ~50%. In conscious sheep, blood pressure, heart rate and CSNA were recorded when EF had decreased to b40%. Compared with heathy sheep, sheep with HF had a large increase in CSNA (34 ± 4 vs. 89 ± 3 bursts/100 heartbeats, respectively), which was significantly reduced in HF sheep with lesion of the AP (45 ± 10 bursts/100 heartbeats, P b 0.01). In rats, AP lesion or sham lesion (n= 18/group) was performed before HF was induced by myocardial infarction. Eight weeks later, left ventricular end-diastolic pressure in anaesthetised ratswas significantly lower in theAP lesiongroup compared with the sham lesion group (9± 2 vs 16 ± 2mmHg, respectively, P b 0.05) and ejection fraction was higher. These findings suggest that the AP plays a critical role in setting the high level of CSNA in HF and indicate that lesion of the AP reduces the decline in cardiac function postmyocardial infarction, possibly due to the reduction in CSNA.

Abstracts From the 36th Annual Scientific Meeting of the HBPRCA

### CONTRIBUTION OF THE AREA POSTREMA TO THE INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN OVINE HEART FAILURE Abukar Y, Ramchandra R, May CN The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Background : Heart failure (HF) is associated with an increase in cardiac sympathetic nerve activity (CSNA), which is directly linked to mortality in HF patients. The mechanisms responsible for the elevated CSNA remain unclear. Previous studies indicate that the area postrema (AP), a circumventricular organ in the brainstem, plays a role in the control of sympathetic nerve activity. We hypothesized that the elevated CSNA in HF is mediated by the AP and lesioning this region would reduce the increased CSNA in sheep with HF. Aims : To determine the effect of sham lesion or lesion of the AP on CSNA and hemodynamics in conscious sheep with HF. Methods : Studies were conducted in 2 groups of sheep with pacing-induced HF: sham (n=6) and AP lesion (n=6) sheep. Mean arterial blood pressure (MAP), heart rate (HR) and CSNA were recorded simultaneously in conscious sheep at least 4 days after surgery. Results : Heart failure was associated with a significant decrease in ejection fraction (from 74±2 % to 38±1 %; P<0.001), which was similar in both groups. There was a significant reduction in CSNA burst incidence in the AP lesion group compared with the sham group (45±10 and 89±3 bursts/100 heartbeats, respectively; P<0.01). Conclusions : In sheep with HF, the group with lesion of the AP had a significantly lower CSNA compared with the sham group. These data suggest that the AP plays a role in setting the detrimental high levels of CSNA in HF. ### G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING IMPROVES STROKE OUTCOME IN FEMALE MICE Broughton BRS, Jansen GL, Sobey CG Department of Pharmacology, Monash University, Clayton, Victoria, Australia Background: Estrogen has been assumed to provide neuroprotection following stroke entirely via classical estrogen receptors. Interestingly, there is recent evidence that activation of a novel G …

The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: behavioral and neuronal phenotyping

Amylin reduces meal size by activating noradrenergic neurons in the area postrema (AP). Neurons in the AP also mediate the eating-inhibitory effects of salmon calcitonin (sCT), a potent amylin agonist, but the phenotypes of the neurons mediating its effect are unknown. Here we investigated whether sCT activates similar neuronal populations to amylin, and if its anorectic properties also depend on AP function. Male rats underwent AP lesion (APX) or sham surgery. Meal patterns were analysed under ad libitum and post-deprivation conditions. The importance of the AP in mediating the anorectic action of sCT was examined in feeding experiments of dose-response effects of sCT in APX vs. sham rats. The effect of sCT to induce Fos expression was compared between surgery groups, and relative to amylin. The phenotype of Fos-expressing neurons in the brainstem was examined by testing for the co-expression of dopamine beta hydroxylase (DBH) or tryptophan hydroxylase (TPH). By measuring the apposition of vesicular glutamate transporter-2 (VGLUT2)-positive boutons, potential glutamatergic input to amylin- and sCT-activated AP neurons was compared. Similar to amylin, an intact AP was necessary for sCT to reduce eating. Further, co-expression between Fos activation and DBH after amylin or sCT did not differ markedly, while co-localization of Fos and TPH was minor. Approximately 95% of neurons expressing Fos and DBH after amylin or sCT treatment were closely apposed to VGLUT2-positive boutons. Our study suggests that the hindbrain pathways engaged by amylin and sCT share many similarities, including the mediation by AP neurons.

Circulating Glucagon-like Peptide-1 (GLP-1) Inhibits Eating in Male Rats by Acting in the Hindbrain and Without Inducing Avoidance

To address the neural mediation of the eating-inhibitory effect of circulating glucagon-like peptide-1 (GLP-1), we investigated the effects of 1) intra-fourth ventricular infusion of the GLP-1 receptor antagonist exendin-9 or 2) area postrema lesion on the eating-inhibitory effect of intrameal hepatic portal vein (HPV) GLP-1 infusion in adult male rats. To evaluate the physiological relevance of the observed effect we examined 3) the influence of GLP-1 on flavor acceptance in a 2-bottle conditioned flavor avoidance test, and 4) measured active GLP-1 in the HPV and vena cava (VC) in relation to a meal and in the VC after HPV GLP-1 infusion. Intrameal HPV GLP-1 infusion (1 nmol/kg body weight-5 min) specifically reduced ongoing meal size by almost 40% (P < .05). Intra-fourth ventricular exendin-9 (10 μg/rat) itself did not affect eating, but attenuated (P < .05) the satiating effect of HPV GLP-1. Area postrema lesion also blocked (P < .05) the eating-inhibitory effect of HPV GLP-1. Pairing consumption of flavored saccharin solutions with HPV GLP-1 infusion did not alter flavor acceptance, indicating that HPV GLP-1 can inhibit eating without inducing malaise. A regular chow meal transiently increased (P < .05) HPV, but not VC, plasma active GLP-1 levels, whereas HPV GLP-1 infusion caused a transient supraphysiological increase (P < .01) in VC GLP-1 concentration 3 minutes after infusion onset. The results implicate hindbrain GLP-1 receptors and the area postrema in the eating-inhibitory effect of circulating GLP-1, but question the physiological relevance of the eating-inhibitory effect of iv infused GLP-1 under our conditions.