Electroacupuncture Alleviates Memory Deficits in APP/PS1 Mice by Targeting Serotonergic Neurons in Dorsal Raphe Nucleus

Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impairment in individuals with AD.However,the underlying mechanisms remains poorly understood.This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD.Methods APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu(BL 23)and Baihui(GV 20).Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus(DRN).Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests.Golgi staining,western blot,and immunostaining were utilized to determine EA-induced neuroprotection.Results EA at Shenshu(BL 23)and Baihui(GV 20)effectively ameliorated learning and memory impairments in APP/PS1 mice.EA attenuated dendritic spine loss,increased the expression levels of PSD95,synaptophysin,and brain-derived neurotrophic factor in hippocampus.Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B.Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory.Conclusion EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN.Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.

Semaphorin7A:its role in the control of serotonergic circuits and functional recovery following spinal cord injury

Serotonin is a monoamine neurotransmitter synthetized in various populations of brainstem neurons.In the spinal cord,descending serotonergic projections regulate postural muscle tone,locomotion and rhythm and coordination of movements via the Central Pattern Generator.Following a spinal cord injury,serotonergic projections to the lumbar spinal cord,where the Central Pattern Generators are located,are interrupted resulting in devastating locomotor impairments and changes in the expression and activation of serotonin and its spinal receptors.The molecular cues that control the precise patterning and targeting of serotonergic inputs onto Central Pattern Generator networks in healthy animals or after injury are still unknown.In our recent research work,we have been particularly interested in Semaphorin7A,which belongs to the Semaphorins family involved in guiding growing axons and controlling plasticity of synaptic connections.In this review,we discuss the role of Semaphorin7A signaling as an important molecular actor that instructs the patterning of serotonin inputs to spinal Central Pattern Generator networks.We show that Semaphorin7A controls the wiring of descending serotonin axons in the spinal cord.Our results reveal that mistargetting of serotonin fibers in the spinal cord is compensated in healthy uninjured Semaphorin7A deficient mice so that their gross locomotion proceeds accurately.We also demonstrate that when the system is challenged with a spinal lesion,the pattern of post-injury serotonin expression is significantly altered in Semaphorin7A deficient mice with specific ectopic targeting of serotonin fibers in the lumbar spinal cord.Compensatory mechanisms in place in uninjured Semaphorin7A deficient mice are lost and injured Semaphorin7A deficient mice exhibit a worsening of their post-injury locomotor abilities.Our findings identify Semaphorin7A as a critical determinant of serotonergic circuit formation in healthy or spinal cord injured mice.

How do serotonergic psychedelics treat depression:The potential role of neuroplasticity

Depression is a common mental disorder and one of the leading causes of disability around the world.Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients.This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants.One such novel antidepressant is ketamine,which has demonstrated both clinically promising results and contributed to new explanatory models of depression,including the potential role of neuroplasticity in depression.Early clinical trials are now showing promising results of serotonergic psychedelics for depression;however,their mechanism of action remains poorly understood.This paper seeks to review the effect of depression,classic antidepressants,ketamine,and serotonergic psychedelics on markers of neuroplasticity at a cellular,molecular,electrophysiological,functional,structural,and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.

Intrauterine Exposure to Chronic 22 kHz Sound Affects Inhibitory Avoidance and Serotonergic Parameters in Forebrain Areas of Dams and Rat Offspring

In the present study we evaluated the effects of chronic exposure to sounds at 22 kHz during pregnancy on the central serotonergic and behavioral parameters in Wistar rat dams after the suckling period and on their male rat offspring. In addition, we also assessed the effects of an acute 22 kHz sound, associated with the chronic intrauterine exposure, on the emotional responses of adult offspring. The primary hypothesis was that experiencing 22 kHz stimuli during an early stage of development would interfere with brain serotonergic parameters and, later, with the adult rat’s defensive responses. The corollary question was whether a 22 kHz sound exposure would differentially affect inhibitory avoidance and escape responses and central serotonergic parameters. Female rats were divided into four groups: non-pregnant control;non-pregnant chronic exposure;pregnant control;and pregnant chronic exposure. Male offspring were divided into four groups: chronic intrauterine sound exposure;acute sound exposure in adulthood;chronic intrauterine exposure with acute exposure in adulthood;and no exposure. Chronic sound exposure affected inhibitory avoidance and serotonergic parameters in female rats. For offspring, there was an interaction between chronic and acute sound exposure effects on inhibitory avoidance response but not on escape response. There were significant effects of chronic intrauterine exposure on serotonin turnover in the hippocampus and PFC of females. For offspring, the turnover was increased by chronic exposure only in PFC, and in amygdala it was increased by acute exposure. These results illuminate the potential of an early acoustic sound exposure for causing central serotonergic and emotional behavioral changes that can persist into later periods of life.

Cecal microbiota transplantation:unique influence of cecal microbiota from divergently selected inbred donor lines on cecal microbial profile,serotonergic activity,and aggressive behavior of recipient chickens

Background Accumulating evidence from human trials and rodent studies has indicated that modulation of gut microbiota affects host physiological homeostasis and behavioral characteristics.Similarly,alterations in gut micro-biota could be a feasible strategy for reducing aggressive behavior and improving health in chickens.The study was conducted to determine the effects of early-life cecal microbiota transplantation(CMT)on cecal microbial composi-tion,brain serotonergic activity,and aggressive behavior of recipient chickens.Methods Chicken lines 63 and 72 with nonaggressive and aggressive behavior,respectively,were used as donors and a commercial strain Dekalb XL was used as recipients for CMT.Eighty-four 1-d-old male chicks were randomly assigned to 1 of 3 treatments with 7 cages per treatment and 4 chickens per cage(n=7):saline(control,CTRL),cecal solution of line 6_(3)(6_(3)-CMT),and cecal solution of line 7_(2)(7_(2)-CMT).Transplantation was conducted via oral gavage once daily from d 1 to 10,and then boosted once weekly from week 3 to 5.At weeks 5 and 16,home-cage behavior was recorded,and chickens with similar body weights were assigned to paired aggression tests between the treat-ments.Samples of blood,brain,and cecal content were collected from the post-tested chickens to detect CMT-induced biological and microbiota changes.Results 63-CMT chickens displayed less aggressive behavior with a higher hypothalamic serotonergic activity at week 5.Correspondingly,two amplicon sequence variants(ASVs)belonging to Lachnospiraceae and one Ruminococ-caceae UCG-005 ASV were positively correlated with the levels of brain tryptophan and serotonin,respectively.7_(2)-CMT chickens had lower levels of brain norepinephrine and dopamine at week 5 with higher levels of plasma serotonin and tryptophan at week 16.ASVs belonging to Mollicutes RF39 and GCA-900066225 in 7_(2)-CMT chickens were nega-tively correlated with the brain 5-hydroxyindoleacetic acid(5-HIAA)at week 5,and one Bacteroides ASV was negatively correlated with plasma serotonin at week 16.Conclusion Results indicate that CMT at an early age could regulate aggressive behavior via modulating the cecal microbial composition,together with central serotonergic and catecholaminergic systems in recipient chickens.The selected CMT could be a novel strategy for reducing aggressive behavior through regulating signaling along the microbiota-gut-brain axis.

Molecular signaling of 5-HT_1Aand presence of serotonergic cells in the fetal cerebral cortex

Early appearance of the serotonergic system in the fetal brain and the various effects of serotonin (5-HT) on brain morphogenesis, have given support to a neurotrophic role of serotonin. This function of serotonin is accomplished through a system of serotonin nerve terminals in the target regions that involves various 5-HT receptors. In visual, auditory and somatosensory cortex an early and intense serotonergic innervation is particularly important. The neuronal somata of these terminals are normally located in the mesencephalon and they have not been observed in the maturing cerebral cortex, neither in the adult brain. By using immunolabeling techniques, fluorescence and confocal microscopy, we observe the presence of both, 5-HT terminals and 5-HT cells in mesencephalon (Me, E17) and in the neopallium (Np, E13-E16) cocultures. Cells immunopositive to 5-HT and to tryptophan-5-hydroxilase are also observed in the Np on day 12 of culture. These results concerning the unexpected presence of serotonergic cells in the fetal cerebral cortex are interesting and may be of importance in corticogenesis. As it happens with other elements of the serotonergic system, the presence of these phenotypically serotonergic cells in the early cerebral cortex may be transitory and probably supporting cortex maturation processes. The molecular signaling path of the 5-HT1A receptor has also been identified.

Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies

Irritable bowel syndrome(IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patients suffer from the constipation subtype of IBS(IBS-C), most commonly afflicting older individuals and those with a lower socioeconomic status. Conventional pharmacologic and nonpharmacologic treatment options have limited efficacies and/or significant adverse events, which lead to increased long-term health care expenditures. Failure to effectively treat IBS-C patients over the past decades has largely been due to a poor understanding of disease pathophysiology, lack of a global view of the patient, and an inappropriate selection of patients and treatment endpoints in clinical trials. In recent years, however, more effective and safer drugs have been developed for the treatment of IBS-C. The advancement in the area of pharmacologic treatment is based on new knowledge of the pathophysiologic basis of IBS-C and the development of drugs with increased selectivity within pharmacologic classes with recognized efficacies. This narrative review covers the spectrum of available drugs and their mechanisms of action, as well as the efficacy and safety profiles of each as determined in relevant clinical trials that have investigated treatment options for IBS-C and chronic constipation. A brief summary of laxative-based treatment options is presented, followed by up-to-date assessments for three classes of drugs: prokinetics, prosecretory agents, and bile acid modulators.

Chronic serotonin syndrome:A retrospective study

BACKGROUND Serotonin syndrome(SS)is an underdiagnosed drug-induced clinical syndrome resulting from the excess intrasynaptic concentration of serotonin.Very limited information is available about chronic SS.AIM To evaluate the epidemiological,clinical,and other aspects of the insidious onset SS.METHODS We retrospectively evaluated 14 consecutive adult patients(>18 years)who had complaints for more than 6 wk at the time of consultation and met the Hunter criteria for SS.RESULTS The mean age was 41.1 years(range:21-61 years),with a male preponderance(64%).Although tremors were observed in all patients,this was a presenting complaint in only 43%of patients.Generalized body pain,insomnia,and restlessness were common presenting features(50%each).Other common clinical features were stiffness of the limbs(43%),diaphoresis(43%),gait disturbances(36%),bowel disturbances(36%),dizziness(29%),sexual dysfunctions(21%),incoordination(14%),and fatigue(14%)The mean duration of symptoms before the diagnosis of SS was 13.5±5.8 wk(range:6-24 wk).Amitriptyline was the most common drug(n=6,43%),followed by tramadol(n=5,36%)and sodium valproate(n=5,36%).All patients received cyproheptadine,a 5-hydroxytryptamine2A antagonist,as treatment and noted an excellent response CONCLUSION This study represents the largest study on chronic SS.We suggest that patients receiving serotonergic drugs should be physically examined for the presence of SS upon the development of new symptoms.

An inherent acceleratory effect of insulin on small intestinal transit and its pharmacological characterization in normal mice

AIM： To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS： Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose （BG） levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit （SIT）. Charcoal meal was administered （0.3 mL） intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine （1 mg/kg）, clonidine （0.1 mg/kg）, ondansetron （1 mg/kg）, naloxone （5 mg/kg）, verapamil （8 mg/kg） and glibenclamide （10 mg/kg）, were administered intravenously 10 min prior to the administration of insulin （2 μU/kg）. RESULTS： The lower doses of insulin （2 μU/kg and 2 mU/kg） produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels （P〈0.01）, while the highest dose of insulin （2 U/kg） produced a fall in blood glucose levels which was also associated with significant acceleration of SIT （P〈0.01）. After pretreatment of insulin （2 μU/kg） group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle ＋ insulintreated group, i.e. from 74.7% to 27.7% （P〈0.01）. In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT （23.5%）. In naloxone-pretreated group, insulin administration could significantly reverse the inhibition of SIT produced by naloxone when compared with naloxoneperse group, i.e. from 32.3% to 53.9% （P〈0.01）. In verapamil-pretreated group, insulin administration could only partially reverse the inhibition （65%）. In glibenclamide-pretreated group, insulin administration produced further acceleration of SIT （12.2%）. CONCLUSION： Insulin inherently possesses an acceleratory effect on SIT in normal mice. Adrenergic and cholinergic systems can play a significant role. Calcium channels and opioidergic system can play a supportive role; in addition, enhancement of endogenous insulin release can augment the effect of exogenously administered insulin on SIT.