Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.

Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

The Role of Acupuncture in the Management of Insomnia as a Major or Residual Symptom Among Patients With Active or Previous Depression: A Systematic Review and Meta-Analysis.

Background: Due to concerns about risks associated with antidepressants and/or hypnotics, complementary therapies such as acupuncture have been sought by patients with active or previous depression to manage insomnia. This systematic review aimed to clarify if acupuncture is effective and safe enough to be recommended as an alternative or adjuvant therapy to standard care in ameliorating concomitant or residual insomnia, two types of insomnia associated with depression. Methods: Randomized controlled trials (RCTs) of depression-related insomnia (DI) treatment via acupuncture vs. waitlist-control or placebo-/sham-acupuncture and RCTs of DI treatment via acupuncture alone or combined with standard care [Western pharmacotherapy and/or cognitive-behavioral therapy (CBT)] vs. standard care alone were searched for from seven databases from inception to December 2021. Cochrane criteria were followed. Results: Twenty-one studies involving 1,571 participants were analyzed. For insomnia as a major symptom of active depression, meta-analyses suggested that acupuncture significantly reduced the global scores of both the Pittsburg Sleep Quality Index (PSQI) [MD = -3.12, 95% CI (-5.16, -1.08), p < 0.01] and Hamilton Depression Scale (HAMD) [SMD = -2.67, 95% CI (-3.51, -1.84), p < 0.01], in comparison with placebo-acupuncture. When compared with conventional pharmacotherapy (antidepressants and/or hypnotics), the results favored acupuncture in decreasing PSQI [MD = -1.17, 95% CI (-2.26, -0.08), p = 0.03] and HAMD [SMD = -0.47, 95% CI (-0.91, -0.02), p = 0.04]. Acupuncture was comparable to conventional pharmacotherapy in reducing scores of each domain of PSQI. For insomnia as a residual symptom of previous or partially remitted depression, acupuncture conferred a very limited, non-significant therapeutic advantage against sham-/placebo-acupuncture. Whether acupuncture has an add-on effect to conventional pharmacotherapy in this type of insomnia has not been investigated. Also, no study was available to address the efficacy differences between acupuncture and CBT or the synergistic effect of these two therapies. Conclusions: There is a low to moderate level of evidence supporting acupuncture as a safe and effective remedy alternative to or adjuvant to conventional pharmacotherapy (antidepressant and/or hypnotic) in improving insomnia and other depression symptoms among patients with active depression. Furthermore, the patients' complaint of disrupted sleep continuity is most likely to benefit from acupuncture. The benefit of acupuncture on residual insomnia associated with previous or partially remitted depression is limited. Future acupuncture studies need to consider applying optimal dosage and addressing deficiencies in trial quality.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021269880, PROSPERO, identifier: CRD42021269880.

Acupuncture: A Promising Approach for Comorbid Depression and Insomnia in Perimenopause.

Comorbid depression and insomnia are ubiquitous mental complaints among women going through the perimenopausal stage of life and can result in major decline in quality of life. Antidepressive agents combined with/without hypnotics, and/or hormone therapy are currently the most common treatment for perimenopausal depression (PMD) and insomnia (PMI). Balancing the benefits of these pharmacotherapies against the risk of adverse events (AEs) is a difficult task for both clinicians and women. There has been a growing body of research regarding the utilization of acupuncture for treatment of PMD or PMI, whereas no studies of acupuncture for comorbid PMD and PMI have appeared. In this review, we summarize the clinical and preclinical evidence of acupuncture as a treatment for PMD or PMI, and then discuss the potential mechanisms involved and the role of acupuncture in helping women during this transition. Most clinical trials indicate that acupuncture ameliorates not only PMD/PMI but also climacteric symptoms with minimal AEs. It also regulates serum hormone levels. The reliability of trials is however limited due to methodological flaws in most studies. Rodent studies suggest that acupuncture prolongs total sleep time and reduces depression-like behavior in PMI and PMD models, respectively. These effects are possibly mediated through multiple mechanisms of action, including modulating sex hormones, neurotransmitters, hypothalamic-pituitary-adrenal axis/hypothalamic-pituitary-ovary axis, oxidative stress, signaling pathways, and other cellular events. In conclusion, acupuncture is a promising therapeutic strategy for comorbid depression and insomnia during perimenopause. Neuroendocrine modulation is likely to play a major role in mediating those effects. High-quality trials are required to further validate acupuncture's effectiveness.

Emerging roles of extracellular vesicles in the intercellular communication for exercise-induced adaptations.

Complex organisms rely heavily on intercellular communication. The rapidly expanding field of extracellular vesicle biology has made it clear that the necessary intercellular communication occurs partly through their paracrine and endocrine actions. Extracellular vesicles are nanoscale lipid membranes (30-2,000 nm in diameter) that shuttle functional biological material between cells. They are released from numerous tissues and are isolated from nearly all biofluids and cell cultures. Although their biogenesis, cell targeting, and functional roles are incompletely understood, they appear to have crucial roles in physiological and disease processes. Their enormous potential to serve as sensitive biomarkers of disease and also new therapeutic interventions for diseases have gained them considerable attention in recent years. Regular physical exercise training confers systemic health benefits and consequently prevents many age-related degenerative diseases. Many of the molecular mechanisms responsible for the salubrious effects of exercise are known, yet a common underlying mechanism potentially responsible for the holistic health benefits of exercise has only recently been explored (i.e., via extracellular vesicle transport of biological material). Here, we provide an overview of extracellular vesicle biology before outlining the current evidence on the capacity for a single bout and chronic exercise to elicit changes in extracellular vesicle content and modulate their molecular cargo (e.g., small RNAs). We highlight areas for future research and emphasize their potential utility as biomarkers and therapeutic strategies of disease and its prevention.

Psychoneuroimmunology goes East: Development of the PNIRSChina affiliate and its expansion into PNIRSAsia-Pacific.

The Psychoneuroimmunology Research Society (PNIRS) created an official Chinese regional affiliate in 2012, designated PNIRSChina. Now, just eight years later, the program has been so successful in advancing the science of psychoneuroimmunology that it has expanded to the whole of Asia-Oceania. In 2017, PNIRSChina became PNIRSAsia-Pacific. Between 2012 and 2019, this outreach affiliate of PNIRS organized seven symposia at major scientific meetings in China as well as nine others in Taiwan, Japan, South Korea, Australia and New Zealand. This paper summarizes the remarkable growth of PNIRSAsia-Pacific. Here, regional experts who have been instrumental in organizing these PNIRSAsia-Pacific symposia briefly review and share their views about the past, present and future state of psychoneuroimmunology research in China, Taiwan, Australia and Japan. The newest initiative of PNIRSAsia-Pacific is connecting Asia-Pacific laboratories with those in Western countries through a simple web-based registration system. These efforts not only contribute to the efforts of PNIRS to serve a truly global scientific society but also to answer the imperative call of increasing diversity in our science.

High Maternal Omega-3 Supplementation Dysregulates Body Weight and Leptin in Newborn Male and Female Rats: Implications for Hypothalamic Developmental Programming.

Maternal diet is critical for offspring development and long-term health. Here we investigated the effects of a poor maternal diet pre-conception and during pregnancy on metabolic outcomes and the developing hypothalamus in male and female offspring at birth. We hypothesised that offspring born to dams fed a diet high in fat and sugar (HFSD) peri-pregnancy will have disrupted metabolic outcomes. We also determined if these HFSD-related effects could be reversed by a shift to a healthier diet post-conception, in particular to a diet high in omega-3 polyunsaturated fatty acids (ω3 PUFAs), since ω3 PUFAs are considered essential for normal neurodevelopment. Unexpectedly, our data show that there are minimal negative effects of maternal HFSD on newborn pups. On the other hand, consumption of an ω3-replete diet during pregnancy altered several developmental parameters. As such, pups born to high-ω3-fed dams weighed less for their length, had reduced circulating leptin, and also displayed sex-specific disruption in the expression of hypothalamic neuropeptides. Collectively, our study shows that maternal intake of a diet rich in ω3 PUFAs during pregnancy may be detrimental for some metabolic developmental outcomes in the offspring. These data indicate the importance of a balanced dietary intake in pregnancy and highlight the need for further research into the impact of maternal ω3 intake on offspring development and long-term health.

Obesity after neonatal overfeeding is independent of hypothalamic microgliosis.

The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippocampal microglia that are hyper-responsive to an immune challenge in adulthood. However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippocampus. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity.

Chronic predator stress in female mice reduces primordial follicle numbers: implications for the role of ghrelin.

Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist (d-Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.

Conditional microglial depletion in rats leads to reversible anorexia and weight loss by disrupting gustatory circuitry.

Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy individuals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.

Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production.

BACKGROUND: It is well established that lung pathology and inflammation are more severe during respiratory infections complicated by the presence of both bacteria and viruses. Whilst co-infection can result in invasive pneumococcal disease and systemic inflammation, the neuroinflammatory consequences of co-infection are poorly characterised. METHODS: In this study, we utilised a mouse co-infection model involving Streptococcus pneumoniae (S. pneumoniae) and influenza A virus (IAV) lung infection, and we also isolated microglia for ex vivo stimulation with pneumococcus or serum amyloid A (SAA). RESULTS: Co-infection but not S. pneumoniae or IAV alone significantly increased the number of amoeboid-shaped microglia and expression of pro-inflammatory cytokines including tumour necrosis factor α (TNFα), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and C-C motif chemokine ligand-2 (CCL-2) in the hypothalamus. Pneumococcus was only detected in the hypothalamus of co-infected mice. In addition, the systemic inflammatory cytokines TNFα, IL-1ß and IL-6 were not elevated in co-infected mice relative to IAV-infected mice, whereas SAA levels were markedly increased in co-infected mice (p < 0.05). SAA and its functional receptor termed formyl peptide receptor 2 (Fpr2) transcript expression were also increased in the hypothalamus. In mouse primary microglia, recombinant SAA but not S. pneumoniae stimulated TNFα, IL-1ß, IL-6 and CCL-2 expression, and this response was completely blocked by the pro-resolving Fpr2 agonist aspirin-triggered resolvin D1 (AT-RvD1). CONCLUSIONS: In summary, lung co-infection increased the number of 'activated' amoeboid-shaped microglia and inflammatory cytokine expression in the hypothalamus. Whilst persistent pneumococcal brain infection was observed, SAA proved to be a much more potent stimulus of microglia than pneumococci, and this response was potently suppressed by the anti-inflammatory AT-RvD1. Targeting Fpr2 with pro-resolving eicosanoids such as AT-RvD1 may restore microglial homeostasis during severe respiratory infections.

Acylated ghrelin suppresses the cytokine response to lipopolysaccharide and does so independently of the hypothalamic-pituitary-adrenal axis.

Ghrelin, one of the major metabolic hormones involved in controlling energy balance, has recently been shown to have other properties including regulating the hypothalamic-pituitary-adrenal (HPA) axis response to psychological stress and being a potent anti-inflammatory agent. Ghrelin's HPA axis and anti-inflammatory actions have previously been identified as principally due to the acylated form (AG). However, our recent work has also suggested a role for des-acylated ghrelin (DAG) in these functions. Here we hypothesized ghrelin's anti-inflammatory activity is mediated by the HPA axis and this effect is differentially executed by AG and DAG. We gave adult male Wistar rats a concomitant injection of AG or DAG and lipopolysaccharide (LPS) and measured their effects on circulating cytokines, stress hormones and neuronal activation of the paraventricular nucleus of the hypothalamus (PVN). AG, but not DAG significantly suppressed the pro- and anti-inflammatory cytokine response induced by LPS in vivo. DAG also had no effects on any components of the HPA axis. AG, despite stimulating neuronal activation in the PVN in vivo and stimulating ACTH release from the pituitary in vitro, did not affect the HPA axis response to LPS. These findings suggest AG's anti-inflammatory effects are independent of its actions on the HPA axis and have implications for the potential use of this peptide for treatment of inflammatory conditions without compromising HPA axis activity.

Hormonal and nutritional regulation of postnatal hypothalamic development.

The hypothalamus is a key centre for regulation of vital physiological functions, such as appetite, stress responsiveness and reproduction. Development of the different hypothalamic nuclei and its major neuronal populations begins prenatally in both altricial and precocial species, with the fine tuning of neuronal connectivity and attainment of adult function established postnatally and maintained throughout adult life. The perinatal period is highly susceptible to environmental insults that, by disrupting critical developmental processes, can set the tone for the establishment of adult functionality. Here, we review the most recent knowledge regarding the major postnatal milestones in the development of metabolic, stress and reproductive hypothalamic circuitries, in the rodent, with a particular focus on perinatal programming of these circuitries by hormonal and nutritional influences. We also review the evidence for the continuous development of the hypothalamus in the adult brain, through changes in neurogenesis, synaptogenesis and epigenetic modifications. This degree of plasticity has encouraging implications for the ability of the hypothalamus to at least partially reverse the effects of perinatal mal-programming.

Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent.

Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.

Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation.

Adolescence is a period of significant brain plasticity that can be affected by environmental factors, including the degree of physical activity. Here we hypothesized that adolescent rats would be more sensitive to the beneficial metabolic and anti-inflammatory effects of voluntary exercise than adult rats, whose more mature brains have less capacity for plasticity. We tested this by giving adolescent and adult Wistar rats four weeks' voluntary access to running wheels. At the end of this period we assessed metabolic effects, including weight and circulating leptin and ghrelin, as well as performance in a novel object recognition test of memory and central changes in neuronal proliferation, survival, synaptic density, and inflammatory markers in hippocampus. We found exercise reduced fat mass and circulating leptin levels in both adults and adolescents but suppressed total weight gain and lean mass in adults only. Exercise stimulated neuronal proliferation in the suprapyramidal blade of the dentate gyrus in both adults and adolescents without altering the number of mature neurons during this time frame. Exercise also increased dentate microglial numbers in adolescents alone and microglial numbers in this region were inversely correlated with performance in the novel object recognition test. Together these data suggest that adolescent hippocampal microglia are more sensitive to the effects of exercise than those of adults, but this leads to no apparent improvement in recognition memory. © 2016 Wiley Periodicals, Inc.

Obesity and neuroinflammation: a pathway to cognitive impairment.

Obesity is a growing problem worldwide and is associated with a range of comorbidities, including cognitive dysfunction. In this review we will address the evidence that obesity and high fat feeding can lead to cognitive dysfunction. We will also examine the idea that obesity-associated systemic inflammation leads to inflammation within the brain, particularly the hypothalamus, and that this is partially responsible for these negative cognitive outcomes. Thus, obesity, and high fat feeding, lead to systemic inflammation and excess circulating free fatty acids. Circulating cytokines, free fatty acids and immune cells reach the brain at the level of the hypothalamus and initiate local inflammation, including microglial proliferation. This local inflammation likely causes synaptic remodeling and neurodegeneration within the hypothalamus, altering internal hypothalamic circuitry and hypothalamic outputs to other brain regions. The result is disruption to cognitive function mediated by regions such as hippocampus, amygdala, and reward-processing centers. Central inflammation is also likely to affect these regions directly. Thus, central inflammation in obesity leads not just to disruption of hypothalamic satiety signals and perpetuation of overeating, but also to negative outcomes on cognition.

Preweaning over- and underfeeding alters onset of puberty in the rat without affecting kisspeptin.

The perinatal nutritional environment can permanently influence body weight, potentially leading to changes in puberty onset and reproductive function. We hypothesized that perinatal under- or overfeeding would alter puberty onset and influence concentrations of a neuropeptide crucial for successful puberty, kisspeptin. We manipulated Wistar rat litter sizes to derive small (SL), control (CL), and large (LL) litters containing 4, 12, and 20 rat pups respectively. This manipulation results in an overweight phenotype in SL rats and a lean phenotype in LL that persists throughout life. To investigate whether successful puberty onset is affected by neonatal under- or overfeeding, we examined indices of growth and development, including the onset of puberty, as well as the central expression of Kiss1 mRNA in these pups. Male LL rats reached puberty later than those from CL. These males also had reduced plasma testosterone and elevated 17beta-estradiol concentrations at puberty. The age at puberty onset was not affected in SL males despite accelerated growth. In females, puberty onset was not significantly delayed by having a lean phenotype, and steroid hormones were not affected. The age at onset was, however, younger in the SL females. Kiss1 mRNA in the hypothalamus was not affected by neonatal nutrition either at puberty or 7 days later. Our findings show early life underfeeding in males and overfeeding in females significantly affects puberty onset, altering steroid hormone concentrations in males, but this is not related to changes in hypothalamic kisspeptin.

Early life programming of obesity: the impact of the perinatal environment on the development of obesity and metabolic dysfunction in the offspring.

It is now well accepted that early life events can contribute substantially to the likelihood of an individual becoming obese, although many of the mechanisms for this are not well understood. Maternal over- and under-nutrition as well as the postnatal nutritional environment can contribute significantly to obesity throughout life. This review will provide an overview of early life events associated with neuroendocrine programming of obesity and metabolic dysfunction. In particular this review will focus on the long-term impact of perinatal nutrition, as well as the perinatal role of leptin, insulin, and glucocorticoids in programming the hypothalamic circuitry responsible for appropriate regulation of feeding and metabolism throughout life.

Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways.

A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E(2) that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.

Neonatal overfeeding alters adult anxiety and stress responsiveness.

The neonatal nutritional environment is critical for programming the systems regulating body weight, and an inappropriate nutritional environment in early life can lead to overweight or obesity later on. In this study we demonstrate that changes to the neonatal nutritional environment, induced by changing the litter size in which the animal is raised, can alter not only body weight into adulthood, but also anxiety behaviours and stress responsiveness. These effects appear to be somewhat sex-dependent, affecting female rats more strongly than males. Thus, Wistar rats raised in small litters, where they have greater access to their mothers' milk, weigh more in adulthood than those raised in large litters. Females from these small litters show enhanced exploratory behaviour and reduced anxiety in the elevated plus maze, entering the open arms more often. They also display enhanced central responses to restraint stress including greater activation of the paraventricular nucleus of the hypothalamus and paraventricular nucleus of the thalamus, possibly indicating that the changes we see are related to enhanced arousal. Thus, while neonatal litter size affects long-term body weight regulation, it can also alter long-term activity, anxiety and stress responsiveness, and the degree to which it does so appears to be sex-dependent.

Long term alterations in neuroimmune responses of female rats after neonatal exposure to lipopolysaccharide.

Male and female rats display significant gender-associated differences in their responses to an immune challenge, and gender-specific alterations in many aspects of physiology are seen after a variety of interventions during the neonatal period. It is well-established that neonatal exposure to an immune challenge can alter centrally mediated inflammatory responses in adult male rats and yet little is known about female responses after a similar challenge. We therefore asked if neonatal exposure to lipopolysaccharide (LPS) would alter febrile and hypothalamic cyclooxygenase (COX)-2 responses to an adult immune challenge in female rats. Female Sprague-Dawley rats were administered a single injection of the bacterial endotoxin LPS at postnatal day 14 and were examined as adults for febrile, COX-2 and activity changes to LPS, as well as responses to interleukin (IL)-1beta. Adult female rat responses were similar to those we have seen previously for the males in that febrile and hypothalamic COX-2 responses to adult LPS were attenuated in neonatally LPS-treated animals. Responses to adult IL-1beta were unaffected. Interestingly, females did not display the elevated basal hypothalamic COX-2 that was previously seen in males. Thus we demonstrate that, like in the males, neonatal exposure to LPS has a powerful effect on adult responses to further LPS challenge in the female rats.