Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold.

BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.

Early-life and chronic exposure to high-fat diet alters noradrenergic and glutamatergic neurotransmission in the male rat amygdala and hippocampus under cognitive challenges.

Childhood obesity increases the risk of health and cognitive disorders in adulthood. Consuming high-fat diets (HFD) during critical neurodevelopmental periods, like childhood, impairs cognition and memory in humans and animals, affecting the function and connectivity of brain structures related to emotional memory. However, the underlying mechanisms of such phenomena need to be better understood. This study aimed to investigate the neurochemical profile of the amygdala and hippocampus, brain structures involved in emotional memory, during the acquisition of conditioned odor aversion in male rats that consumed a HFD from weaning to adulthood. The rats gained weight, experienced metabolic changes, and reduced insulin sensitivity and glucose tolerance. Rats showed enhanced odor aversion memory, contrary to the expected cognitive impairments. This memory enhancement was accompanied by increased noradrenergic and glutamatergic neurotransmission in the amygdala and hippocampus. Importantly, this upregulation was specific to stimuli exposure, as basal neurotransmitter levels remained unaltered by the HFD. Our results suggest that HFD modifies cognitive function by altering neurochemical signaling, in this case, upregulating neurotransmitter levels rendering a stronger memory trace, demonstrating that metabolic dysfunctions do not only trigger exclusively detrimental plasticity processes but also render enhanced plastic effects depending on the type of information.

Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats.

RATIONALE: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. OBJECTIVES: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. RESULTS: We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. CONCLUSIONS: These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.

Efficacy and safety of terlipressin and albumin vs. noradrenaline and albumin in adult patients with hepatorenal syndrome: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and safety compared to albumin and noradrenaline in adult hepatorenal disease patients. MATERIALS AND METHODS: Clinical trials from four databases were included. Cochrane's approach for calculating bias risk was utilized. We rated the quality evaluation by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included the following outcomes: serum creatinine (mg/dl), urine output (ml/24 h), mean arterial pressure (mmHg), reversal rate of HRS, mortality rate, blood plasma renin activity (ng/ml/h), plasma aldosterone concentration (pg/ml), urine sodium (mEq/l), and creatinine clearance (ml/min). RESULTS: Our analysis of nine clinical studies revealed that the noradrenaline group was associated with higher creatinine clearance (MD = 4.22 [0.40, 8.05]), (P = 0.03). There were no significant differences in serum creatinine levels (MD = 0.03 [-0.07, 0.13]), urinary sodium (MD = -1.02 [-5.15, 3.11]), urine output (MD = 32.75 [-93.94, 159.44]), mean arterial pressure (MD = 1.40 [-1.17, 3.96]), plasma renin activity (MD = 1.35 [-0.17, 2.87]), plasma aldosterone concentration (MD = 55.35 [-24.59, 135.29]), reversal rate of HRS (RR = 1.15 [0.96, 1.37]), or mortality rate (RR = 0.87 [0.74, 1.01]) between the two groups (p-values > 0.05). CONCLUSIONS: Noradrenaline is a safe alternative medical therapy for HRS.

Maternal and neonatal cortisol and catecholamines throughout vaginal eutocia and C-section in dogs.

Increased fetal cortisol is associated with catecholamine release, a primary factor for neonatal adaptive responses. However, relationship between canine peripartum cortisol and catecholamine is unknown. We aimed to compare serum adrenaline, noradrenaline and cortisol during peripartum in bitches and neonates of distinct obstetric conditions and to assess amniotic fluid cortisol concentration. Twenty females and maximum of three puppies per litter were allocated into Vaginal Eutocia (10 females; 17 neonates) and Elective C-section (10 females; 20 neonates) groups. Amniotic fluid was collected at delivery for cortisol concentration. Maternal and neonatal blood were collected prepartum, intrapartum, postpartum and 1h postpartum, and at birth, 30 and 60min, 12hs and 24hs, respectively, for cortisol, adrenaline and noradrenaline assessment. C-section determined higher noradrenaline throughout delivery and cortisol concentration from intrapartum through 1h postpartum, compared to vaginal birth. C-section maternal cortisol showed progressive increase from intrapartum onwards, while neonatal cortisol remained unchanged. No difference of maternal cortisol concentration occurred along whelping, whereas a significant decrease was verified for vaginal delivery puppies from birth until the 12hs. Puppies delivered vaginally had higher cortisol concentration at birth and 30min, compared to c-section puppies. There was a higher concentration of amniotic fluid cortisol in vaginal eutocia. In conclusion, c-section induces higher maternal stress during and after surgery, whilst vaginal delivery is a more neonatal physiologically stressful condition, contributing to better adaptation during transition.

Traumatic brain injury extending to the striatum alters autonomic thermoregulation and hypothalamic monoamines in recovering rats.

The brain cortex is the structure that is typically injured in traumatic brain injury (TBI) and is anatomically connected with other brain regions, including the striatum and hypothalamus, which are associated in part with motor function and the regulation of body temperature, respectively. We investigated whether a TBI extending to the striatum could affect peripheral and core temperatures as an indicator of autonomic thermoregulatory function. Moreover, it is unknown whether thermal modulation is accompanied by hypothalamic and cortical monoamine changes in rats with motor function recovery. The animals were allocated into three groups: the sham group (sham), a TBI group with a cortical contusion alone (TBI alone), and a TBI group with an injury extending to the dorsal striatum (TBI + striatal injury). Body temperature and motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, rats were euthanized to measure the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) levels using high-performance liquid chromatography (HPLC). We observed that TBI with an injury extending to the dorsal striatum increased core and peripheral temperatures. These changes were accompanied by a sustained motor deficit lasting for 14 days. Furthermore, there were notable increases in NA and 5-HT levels in the brain cortex and hypothalamus both 3 and 20 days after injury. In contrast, rats with TBI alone showed no changes in peripheral temperatures and achieved motor function recovery by the 7th day post-injury. In conclusion, our results suggest that TBI with an injury extending to the dorsal striatum elevates both core and peripheral temperatures, causing a delay in functional recovery and increasing hypothalamic monoamine levels. The aftereffects can be attributed to the injury site and changes to the autonomic thermoregulatory functions.

Acute physical exercise improves recognition memory via locus coeruleus activation but not via ventral tegmental area activation.

Both animals and humans have been studied to explore the impact of acute physical exercise (PE) on memory. In rats, a single session of PE enhances the persistence of novel object recognition (NOR) memory, which depends on dopamine and noradrenaline activity in the hippocampus. However, limited research has examined the involvement of other brain regions in this phenomenon. In this study, we investigated the role of the ventral tegmental area (VTA) and locus coeruleus (LC) in modulating the persistence of NOR memory induced by acute PE. After NOR training, some animals underwent a 30 min treadmill PE session, followed by infusion of either vehicle (VEH) or muscimol (MUS) in either the VTA or LC. Other animals did not undergo PE and only received VEH, MUS, or NMDA within the same time window. We evaluated memory recall 1, 7, and 14 days later. Acute PE promoted memory persistence for up to 14 days afterward, similar to NMDA glutamatergic stimulation of the VTA or LC. Moreover, only the LC region was required for the memory improvement induced by acute PE since blocking this region with MUS impaired NOR encoding. Our findings suggest that acute PE can improve learning within a closed time window, and this effect depends on LC, but not VTA, activity.

Multisensory Stimulation Reverses Memory Impairment in Adrß3KO Male Mice.

Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrß: ß1, ß2 and ß3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrß3 (Adrß3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrß3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrß3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrß3KO mice. In the AMY of Adrß3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrß3KO animals and indicates that the control of neuroinflammation mediates this response.

Sirtuin 1 and Vascular Function in Healthy Women and Men: A Randomized Clinical Trial Comparing the Effects of Energy Restriction and Resveratrol.

Background: Sirtuin 1 (SIRT1) has been associated with longevity and protection against cardiometabolic diseases, but little is known about how it influences human vascular function. Therefore, this study evaluated the effects of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adults. Methods: A randomized trial allocated 48 healthy adults (24 women and 24 men), aged 55 to 65 years, to resveratrol supplementation or energy restriction for 30 days. Blood lipids, glucose, insulin, C-reactive protein, noradrenaline, SIRT1 (circulating and gene expression), and flow-mediated vasodilation (FMD) and nitrate-mediated vasodilation (NMD) were measured. Results: Both interventions increased circulating SIRT1 (p < 0.001). Pre- and post-tests changes of plasma noradrenaline were significant for both groups (resveratrol: p = 0.037; energy restriction: p = 0.008). Baseline circulating SIRT1 was inversely correlated with noradrenaline (r = -0.508; p < 0.01), and post-treatment circulating SIRT1 was correlated with NMD (r = 0.433; p < 0.01). Circulating SIRT1 was a predictor of FMD in men (p = 0.045), but not in women. SIRT1 was an independent predictor of NMD (p = 0.026) only in the energy restriction group. Conclusions: Energy restriction and resveratrol increased circulating SIRT1 and reduced sympathetic activity similarly in healthy adults. SIRT1 was independently associated with NMD only in the energy restriction group.

Superior mesenteric ganglion via ovarian plexus nerve involved in the cross-talk between noradrenaline and GnRH in rat ovaries.

There is evidence of the existence of an intraovarian gonadotropin-releasing hormone (GnRH) system. There are also reports about the influence of extrinsic ovarian innervation in gonadal function. Therefore, it is interesting to study the relationship between ovarian sympathetic innervation and GnRH to shed light on possible physiological and pathophysiological implications. This work aimed to investigate whether noradrenergic stimulation of the superior mesenteric ganglion (SMG) can modify the levels of ovarian GnRH and cause functional and morphological changes in the gonad through the ovarian plexus nerve (OPN), during estrus and diestrus II in rats. The SMG-OPN-Ovary system and an ovary without extrinsic innervation were removed from Holtzman rats in estrus and diestrus II stages and placed in specially designed cuvettes containing Krebs-Ringer buffer. In the experimental groups, SMGs and denervated ovaries were stimulated with 10-6 M noradrenaline (NA). GnRH and progesterone levels (in the ovarian incubation medium) and the mRNA expression of 3beta-hydroxysteroid dehydrogenase (Hsd3b3), 20alpha-hydroxysteroid dehydrogenase (Akr1c18), Bax, and Bcl2 were analyzed. Histological studies of the ovaries were performed. In estrus, NA decreased GnRH levels in both experimental schemes. Furthermore, progesterone levels increased while the Akr1c18 expression and Bax/Bcl2 ratio decreased, without causing changes in ovarian morphology. In diestrus, the noradrenergic stimulation of the ganglion increased GnRH levels, decreased progesterone levels, and increased Akr1c18 expression and Bax/Bcl2 ratio. Follicles with histoarchitecture alterations and corpus luteum with signs of cell death were observed. In denervated ovaries, NA increased the levels of GnRH and progesterone. Furthermore, NA decreased the Bax/Bcl2 ratio and histological studies revealed signs compatible with a possible atretogenic effect. In conclusion, noradrenergic stimulation of the SMG-OPN pathway regulates ovarian cyclicity. The SMG modulates the cross-talk between NA and ovarian GnRH, protecting the ovary from atretogenic effects and luteal apoptosis during estrus while inducing luteal regression in the diestrus II.

Norepinephrine modulation of heat dissipation in female rats lacking estrogen.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine-ß-hydroxylase (DBH)-immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH-ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2-adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes.

Prior aerobic physical training modulates neuropeptide expression and central thermoregulation after ovariectomy in the rat.

This study compared the effects of aerobic physical training and estradiol (E2) replacement on central pathways involved with thermoregulation in ovariectomized rats. Rats were assigned to untrained ovariectomized treated with placebo (UN-OVX), untrained ovariectomized treated with E2 (E2-OVX), and trained ovariectomized (TR-OVX) groups. Tail skin temperature (TST), internal temperature (Tint), and basal oxygen consumption (VO2) were recorded. Neuronal activity, brain expression of Kiss1, NKB and Prodyn, and central norepinephrine (NE) levels were measured. UN-OVX had the highest TST. Compared to UN-OVX rats, TR-OVX and E2-OVX had lower Fos expression in the paraventricular and arcuate (ARC) nuclei, and lower double labeling for Tyrosine Hydroxylase and Fos in the brainstem. Compared to UN-OVX, only TR-OVX group exhibited lower kisspeptin (Kiss1), neurokinin B (NKB), and prodynorphin expression in the ARC and higher central NE levels. Aerobic physical training before menopause may prevent the heat dissipation imbalance induced by reduction of E2, through central NE release, modulation of Kiss1, NKB and prodynorphin expression in neurons from ARC nucleus.

Molecular basis of Period 1 regulation by adrenergic signaling in the heart.

The cardiac circadian clock is responsible for the modulation of different myocardial processes, and its dysregulation has been linked to disease development. How this clock machinery is regulated in the heart remains an open question. Because noradrenaline (NE) can act as a zeitgeber in cardiomyocytes, we tested the hypothesis that adrenergic signaling resets cardiac clock gene expression in vivo. In its anti-phase with Clock and Bmal1, cardiac Per1 abundance increased during the dark phase, concurrent with the rise in heart rate and preceded by an increase in NE levels. Sympathetic denervation altered Bmal1 and Clock amplitude, while Per1 was affected in both amplitude and oscillatory pattern. We next treated mice with a ß-adrenergic receptor (ß-AR) blocker. Strikingly, the ß-AR blockade during the day suppressed the nocturnal increase in Per1 mRNA, without altering Clock or Bmal1. In contrast, activating ß-AR with isoproterenol (ISO) promoted an increase in Per1 expression, demonstrating its responsiveness to adrenergic input. Inhibitors of ERK1/2 and CREB attenuated ISO-induced Per1 expression. Upstream of ERK1/2, PI3Kγ mediated ISO induction of Per1 transcription, while activation of ß2-AR, but not ß1-AR induced increases in ERK1/2 phosphorylation and Per1 expression. Consistent with the ß2-induction of Per1 mRNA, ISO failed to activate ERK1/2 and elevate Per1 in the heart of ß2-AR-/- mice, whereas a ß2-AR antagonist attenuated the nocturnal rise in Per1 expression. Our study established a link between NE/ß2-AR signaling and Per1 oscillation via the PI3Ky-ERK1/2-CREB pathway, providing a new framework for understanding the physiological mechanism involved in resetting cardiac clock genes.

Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes.

The authors previously demonstrated that newborn llama (NBLL) express high levels of α1 adrenergic receptors, which provide a potent vasoconstriction response when compared with newborn sheep (NBSH) gestated at sea level. However, data regarding the impact of chronic gestational hypobaric hypoxia on α-adrenergic vasoconstriction in the neonatal life has not been studied. We evaluated if gestation under chronic hypobaric hypoxia modifies α1-adrenergic vasoconstrictor function in NBLL and NBSH. We compared the vasoconstrictor response induced by potassium and α-adrenergic stimuli in isolated small femoral arteries of NBLL and NBSH gestated at high altitude (HA; 3,600 m) or low altitude (LA; 580 m). The maximal contraction (R MAX) and potency (EC50) to potassium, noradrenaline (NA), and phenylephrine (PHE) were larger in HA-NBLL than LA-NBLL. R MAX to potassium, NA, and PHE were lower in HA-NBSH when compared with LA-NBSH and potency results were similar. Competitive blockade with prazosin showed that RNLL LA/HA have a similar pA2. In contrast, NBSH had increased pA2 values in HA when compared with LA. Finally, small femoral arteries denudated or treated with LNAME in LA and HA lacked NO or endothelium participation in response to PHE stimulation. In contrast, NBSH displayed that denudation or blockade with LNAME support NO or endothelium participation in response to PHE activation. In conclusion, HA chronic hypoxia enhances α1 adrenergic receptor activity in small femoral arteries in NBLL to a higher degree than NBSH, implying a higher vasoconstriction function.

Structural Features of the Human Connectome That Facilitate the Switching of Brain Dynamics via Noradrenergic Neuromodulation.

The structural connectivity of human brain allows the coexistence of segregated and integrated states of activity. Neuromodulatory systems facilitate the transition between these functional states and recent computational studies have shown how an interplay between the noradrenergic and cholinergic systems define these transitions. However, there is still much to be known about the interaction between the structural connectivity and the effect of neuromodulation, and to what extent the connectome facilitates dynamic transitions. In this work, we use a whole brain model, based on the Jasen and Rit equations plus a human structural connectivity matrix, to find out which structural features of the human connectome network define the optimal neuromodulatory effects. We simulated the effect of the noradrenergic system as changes in filter gain, and studied its effects related to the global-, local-, and meso-scale features of the connectome. At the global-scale, we found that the ability of the network of transiting through a variety of dynamical states is disrupted by randomization of the connection weights. By simulating neuromodulation of partial subsets of nodes, we found that transitions between integrated and segregated states are more easily achieved when targeting nodes with greater connection strengths-local feature-or belonging to the rich club-meso-scale feature. Overall, our findings clarify how the network spatial features, at different levels, interact with neuromodulation to facilitate the switching between segregated and integrated brain states and to sustain a richer brain dynamics.

Hypertension in Prenatally Undernourished Young-Adult Rats Is Maintained by Tonic Reciprocal Paraventricular-Coerulear Excitatory Interactions.

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular-coerulear excitatory interactions in prenatally undernourished young-adult rats.

Cerebrospinal Fluid Neurotransmitters, Cytokines, and Chemokines in Alzheimer's and Lewy Body Diseases.

BACKGROUND: Alzheimer's disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. OBJECTIVE: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. METHODS: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). RESULTS: Among neurotransmitters, noradrenaline (NA) was increased in AD CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. CONCLUSIONS: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts.

Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial.

Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction (ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021-1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.

Post-traumatic stress disorder increases pain sensitivity by reducing descending noradrenergic and serotoninergic modulation.

Exposure to stress might influence pain sensitivity; however, little is known about whether post-traumatic stress disorder (PTSD)-like symptoms alter pain sensitivity and how it can happen. Male rats were exposed to the inescapable footshock paired with either social isolation or a control condition (not exposed to footshock but subjected to social isolation). After 7, 14, or 21 days, memory retention was evaluated. In the following three days, animals underwent the following tests: open-field, social interaction and formalin tests. Another group of animals were subjected to the object recognition test and to von Frey filaments. In other cohorts of animals, saline, fluoxetine, or desipramine were injected intrathecally and immunohistochemistry was performed to investigate whether PTSD-like symptoms alter the expression of c-Fos in serotonergic and noradrenergic neurons. Inescapable footshock induced the development of PTSD-like symptoms. Animals with PTSD-like symptoms showed an increase in the number of flinches in the formalin test and a reduction in mechanical threshold in the von Frey test at both retention intervals. The social interaction was negatively correlated with the nociceptive response in the formalin test. Fluoxetine or desipramine prevented the nociceptive response to chemical stimulus in the formalin test. In addition, in animals with PTSD-like symptoms, there was a reduction in c-Fos expression in serotonergic and noradrenergic neurons. Our results are important for the association of increased sensitivity to pain as one of the clinical manifestations that are present in the development of PTSD, and a possible treatment for increased pain sensitivity in male individuals with PTSD.

Medial prefrontal cortical control of reward- and aversion-based behavioral output: Bottom-up modulation.

How does the brain guide our actions? This is a complex issue, where the medial prefrontal cortex (mPFC) plays a crucial role. The mPFC is essential for cognitive flexibility and decision making. These functions are related to reward- and aversion-based learning, which ultimately drive behavior. Though, cortical projections and modulatory systems that may regulate those processes in the mPFC are less understood. How does the mPFC regulate approach-avoidance behavior in the case of conflicting aversive and appetitive stimuli? This is likely dependent on the bottom-up neuromodulation of the mPFC projection neurons. In this review, we integrate behavioral-, pharmacological-, and viral-based circuit manipulation data showing the involvement of mPFC dopaminergic, noradrenergic, cholinergic, and serotoninergic inputs in reward and aversion processing. Given that an incorrect balance of reward and aversion value could be a key problem in mental diseases such as substance use disorders, we discuss outstanding questions for future research on the role of mPFC modulation in reward and aversion.