Brain insulin: regulation,mechanisms of action and functions

1. While many questions remain unanswered, it is now well documented that, contrary to earlier views, insulin is an important neuromodulator, contributing to neurobiological processes, in particular energy homeostasis and cognition. A specific role on cognitive functions related to feeding is proposed, and it is suggested that brain insulin from different sources might be involved in the above vital functions in health and disease.2. A molecule identical to pancreatic insulin, and specific insulin receptors, are found widely distributed in the central nervous system networks related to feeding, reproduction, or cognition.3. The actions of insulin in the central nervous system may be under both multilevel and multifactorial controls. The amount of blood insulin reaching the brain, brain insulin stores and secretion, potential local biosynthesis and degradation of the peptide, and insulin receptors and signal transduction can be affected by metabolic factors induced by nutrients, hormones, neurotransmitters, and regulatory peptides, peripherally or in the central nervous system.4. Glucose and serotonin regulate insulin directly in the hypothalamus and may be of importance for its biological effects. Central mechanisms regulating glucose-induced insulin secretion show some analogy with the mechanisms operating in the pancreas.5. A cross-talk between insulin and leptin receptors has been observed in the brain, and a regulation of central insulin actions, potentially via serotonin modulation, by leptin, galanin, melanocortins, and neuropeptide Y (NPY) is suggested.6. A more complete knowledge of the biological role of insulin in brain function and dysfunction, and of the regulatory mechanisms involved in these processes, constitutes a real advancement in the understanding of the pathophysiology of metabolic and mental diseases and could lead to important medical benefits.     

The Effects of NPY and Insulin on Food Intake Regulation in Fish

Recent abundant studies report that in rodents starvation inducesincreased neuropeptide Y (NPY) mRNA expression and peptide secretionin the hypothalamus which reduces autonomic nervous activityand promotes food intake, and intracerebroventricular (ICV)injection of NPY has potent orexigenic effects. Conversely,the effect of insulin in the central nervous system is to inhibitfood intake and NPY biosynthesis and secretion. In mammals bodyfatness is regulated and insulin acts as one intake inhibitorysignal related to fatness. In salmon (Oncorhynchus sp.) we havedemonstrated a rise in NPY-like mRNA expression and a coincidentdecrease in plasma insulin levels during 2 to 3 weeks of starvation.Additionally, experimentally manipulating body fatness withhigh and low fat diets has demonstrated that body fatness affectsfood intake in teleost fishes, raising the possibility thatNPY and insulin act to regulate their food intake. Therefore,we hypothesized that as in rodents, ICV treatment with NPY wouldstimulate food intake while ICV insulin would reduce food intake.Preliminary results suggest that ICV NPY administration doesstimulate food intake in channel catfish (Ictalurus punctatus),but central injection of insulin has no effect. Results of treatmentswith the sulfated octapeptide of cholecystokinin and the recombinantfragment of rat leptin 22–56 are also discussed.     

Neuropeptide Y administration acutely increases hypothalamic corticotropin-releasing factor immunoreactivity: lack of effect in other rat brain regions

The effect of acute central administration of Neuropeptide Y (NPY) to adult male rats on the brain content of corticotropin-releasing factor immunoreactivity (CRF-ir) was investigated. The brain regions studied included frontal cortex, hippocampus, medulla-pons, midbrain-thalamus, cerebellum, neurointermediate lobe of pituitary, median eminence and the remaining hypothalamus. CRF-ir was determined in each of these regions using a radioimmunoassay specific for rat CRF. CRF-ir was found to be significantly increased in the major site of CRF localization in the brain, the hypothalamus, in NPY-treated rats as compared to vehicle-treated controls either 15 minutes (p less than 0.025) or 45 minutes (p less than 0.005) post-injection. This increase was localized to the median eminence (p less than 0.05 after 15 minutes, p less than 0.01 after 45 minutes). No statistically significant differences were noted in any of the other brain regions assessed. Plasma adrenocorticotropin levels were also found to increase following NPY treatment, an effect which became significant after 45 minutes (p less than 0.05). These data show that NPY can alter the content of hypothalamic CRF and may play a role in its regulation.     

Unchanged hypothalamic neuropeptide Y concentrations in hyperphagic, hypoglycemic rats: evidence for specific metabolic regulation of hypothalamic NPY

Hypothalamic concentrations of neuropeptide Y (NPY), a potent central appetite stimulant, increase dramatically in food-restricted and insulin-deficient diabetic rats. This suggest that NPY may drive hyperphagia in these conditions, which are characterized by weight loss and insulin deficiency. To test the hypothesis that insulin deficiency and weight loss are specific stimuli to hypothalamic NPY, we measured NPY concentrations in individual hypothalamic regions in rats with hyperphagia caused by insulin-induced hypoglycemia. Groups of 8 male Wistar rats were injected with ultralente insulin (20-60 U/kg) to induce either acute hypoglycemia (7 h after a single injection) or chronic hypoglycemia (8 days with daily injections). In hypoglycemic rats, plasma insulin concentrations were increased 6- to 7-fold compared with saline-injected controls; food intake was significantly increased with acute and chronic hypoglycemia and weight gain was significantly increased in the chronically hypoglycemic group. NPY concentrations were measured by radioimmunoassay in 8 hypothalamic regions microdissected from fresh brain slices. NPY concentrations were not increased in any region in either acute or chronic hypoglycemia. NPY therefore seems unlikely to mediate hyperphagia in hyperinsulinemia-induced hypoglycemia, supporting the hypothesis that weight loss is a specific stimulus to hypothalamic NPY and that insulin deficiency may be the metabolic signal responsible.     

Neuropeptide Y: Direct and indirect action on insulin secretion in the rat

Neuropeptide Y (NPY) was tested for an ability to directly influence the release of insulin using an in vitro isolated rat pancreatic islet system. NPY, at doses ranging from 100 pg/ml to 1 μg/ml, had no significant effect on the basal release (5.5 mM glucose) of insulin. However, NPY treatment resulted in a significant, dose-dependent (1 ng/ml to 1 μg/ml) inhibition of glucose-stimulated (11 mM) insulin release. When tested in a perfused rat pancreas preparation in situ, NPY administration led to a marked inhibition of both basal and stimulated insulin release followed by a postinhibitory rebound which exceeded the control insulin levels by 3-fold. In contrast, the intracerebroventricular (ICV) microinjection of NPY (5 μg) produced a significant but delayed (30 min) elevation of circulating insulin. It is therefore suggested that the direct action of NPY on insulin release is inhibitory while the central action of NPY indirectly results in an increase in plasma insulin. Thus, NPY may be added to the growing list of peptidergic agents which may affect the endocrine pancreas by acting as neurotransmitters and/or neuromodulators.     

Minireview. Peptides and the blood-brain barrier

Most neuropeptides are known to occur both in the central nervous system and in blood. This, as well as the occurrence of central nervous peptide effects after peripheral administration, show the importance of studying the relationships between the peptides in the two compartments. For many peptides, such as the enkephalins, TRH, somatostatin and MIF-1, poor penetration of the blood-brain barrier was shown. In other cases, including beta-endorphin and angiotensin, peptides are rapidly degraded during or just after their entry into brain or cerebrospinal fluid. Some peptides, such as insulin, delta-sleep-inducing peptide, and the lipotropin-derived peptides, enter the cerebrospinal fluid to a slight or moderate extent in the intact form. Many peptide hormones, such as insulin, calcitonin and angiotensin, act directly on receptors in the circumventricular organs, where the blood-brain barrier is absent. Oxytocin, vasopressin, MSH, and an MSH-analog alter the properties of the blood-brain barrier, which may result in altered nutritient supply to the brain. In conclusion, the diffusion of most peptides across the brain vascular endothelium seems to be severely restricted. There are, however, several alternative routes for peripheral peptides to act on the central nervous system. The blood-brain barrier is a major obstacle for the development of pharmaceutically useful peptides, as in the case of synthetic enkephalin-analogs.     

Hypothalamic peptides: central nervous system control of visceral functions

Thyrotropin-releasing factor (TRF), somatostatin, and bombesin-like peptide are present in the brain and may be involved in central nervous system (CNS) control of visceral functions. All three peptides exert potent actions to modify animal thermoregulation. TRF and somatostatin or somatostatin analogs act within the brain to influence parasympathetic and sympathetic outflow resulting in changes of adrenal epinephrine secretion, gastric acid secretion, heart rate, and blood pressure. Bombesin acts within the brain to increase adrenal epinephrine secretion and to inhibit gastric acid secretion without influencing other sympathetic or parasympathetic activities. These peptides and others may be important physiological regulators of CNS information processing related to a variety of visceral systems.     

Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass

NPY is an important central orexigenic hormone, but little is known about its peripheral actions in human adipose tissue (AT) or its potential paracrine effects. Our objective was to examine NPY's role in AT, specifically addressing NPY protein expression, the effect of NPY on adipokine secretion, and the influence of insulin and rosiglitazone (RSG) on adipocyte-derived NPY in vitro. Ex vivo human AT was obtained from women undergoing elective surgery [age: 42.7 +/- 1.5 yr (mean +/- SE), BMI: 26.2 +/- 0.7 kg/m(2); n = 38]. Western blot analysis was used to determine NPY protein expression in AT depots. Abdominal subcutaneous (AbSc) adipocytes were isolated and treated with recombinant (rh) NPY, insulin, and RSG. NPY and adipokine levels were measured by ELISA. Our results were that NPY was localized in human AT and adipocytes and confirmed by immunohistochemistry. Depot-specific NPY expression was noted as highest in AbSc AT (1.87 +/- 0.23 ODU) compared with omental (Om; 1.03 +/- 0.15 ODU, P = 0.029) or thigh AT (Th; 1.0 +/- 0.29 ODU, P = 0.035). Insulin increased NPY secretion (control: 0.22 +/- 0.024 ng/ml; 1 nM insulin: 0.26 +/- 0.05 ng/ml; 100 nM insulin: 0.29 +/- 0.04 ng/ml; 1,000 nM insulin: 0.3 +/- 0.04 ng/ml; P < 0.05, n = 13), but cotreatment of RSG (10 nM) with insulin (100 nM) had no effect on NPY secretion. Furthermore, adipocyte treatment with rh-NPY downregulated leptin secretion (control: 6.99 +/- 0.89 ng/ml; 1 nmol/l rh-NPY: 4.4 +/- 0.64 ng/ml; 10 nmol/l rh-NPY: 4.3 +/- 0.61 ng/ml, 100 nmol/l rh-NPY: 4.2 +/- 0.67 ng/ml; P < 0.05, n = 10) but had no effect on adiponectin or TNF-alpha secretion. We conclude that NPY is expressed and secreted by human adipocytes. NPY secretion is stimulated by insulin, but this increment was limited by cotreatment with RSG. NPY's antilipolytic action may promote an increase in adipocyte size in hyperinsulinemic conditions. Adipose-derived NPY mediates reduction of leptin secretion and may have implications for central feedback of adiposity signals.     

Plasticity in the nucleus tractus solitarius and its influence on lung and airway reflexes.

The nucleus tractus solitarius (NTS) is the first central nervous system (CNS) site for synaptic contact of the primary afferent fibers from the lungs and airways. The signal processing at these synapses will determine the output of the sensory information from the lungs and airways to all downstream synapses in the reflex pathways. The second-order NTS neurons bring to bear their own intrinsic and synaptic properties to temporally and spatially integrate the sensory information with inputs from local networks, higher brain regions, and circulating mediators, to orchestrate a coherent reflex output. There is growing evidence that NTS neurons share the rich repertoire of forms of plasticity demonstrated throughout the CNS. This review focuses on existing evidence for plasticity in the NTS, potential targets for plasticity in the NTS, and the impact of this plasticity on lung and airway reflexes.     

Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance

The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes fos activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium currents, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS.     

Neuropeptide Y: anatomical distribution and possible function in mammalian nervous system

Neuropeptide Y (NYP) is a 36 amino acid peptide which shares considerable sequence homology with pancreatic polypeptide and peptide YY. NPY is widely distributed within neurons of the central and peripheral nervous systems, and occurs in mammalian brain in higher concentrations than all other peptides studied to date. Radioimmunoassay studies demonstrated high concentrations of NPY immunoreactivity within many regions of the hypothalamus and within the paraventricular thalamic nucleus, nucleus accumbens, the septum and medial amygdala. These findings correspond with the distribution of NPY containing terminals. Numerous cell bodies containing NPY are located within the cerebral cortex, caudate-putamen, hippocampus, hypothalamus, and nucleus tractus solitarius. Central administration of NPY causes a marked increase in ingestive behaviors, possibly related to the release of NPY from neurons in the arcuate nucleus that innervate the paraventricular nucleus of the hypothalamus. NPY projections from the arcuate nucleus to the medial preoptic area may be related to the central effects of NPY on luteinizing hormone release and sexual behavior. NPY immunoreactive terminals heavily innervated neurons within the amygdala and hypothalamus that are connected to the dorsal vagal complex, suggesting a role of NPY in central autonomic regulation. NPY terminals form a dense plexus around cerebral vessels and are probably responsible for NPY's potent vasoconstrictor effects in the cerebral cortex. Coronary vessels are also innervated heavily by NPY terminals, indicating a role for NPY in the pathogenesis of coronary vasospasm. NPY is present in pheochromocytomas and circulating levels of NPY may prove useful in the diagnosis of pheochromocytoma. Thus, anatomical and physiological studies suggest a varied, but important, function for NPY in mammalian nervous system.     

NPY L7P polymorphism and metabolic diseases

Neuropeptide Y (NPY) is an abundant and widespread peptide in mammalian nervous system, both in the central and peripheral nervous systems. NPY is a multifunctional neurotransmitter with multiple modulator effects in the regulation of physiological functions and responses in the body. NPY is a potent orexigenic peptide, which has effects on energy balance at the level of energy intake, expenditure, and partition. There are many association studies between the NPY gene variants and cardiovascular and metabolic disease. Most of them are done by using p.L7P substitution as a marker. At the moment it seems that the p.L7P substitution of preproNPY protein causes altered NPY secretion, which leads to haemodynamic disturbances caused by sympathetic hyperactivity and to various effects caused by altered local signalling by NPY. SNP association studies using p.L7P polymorphism suggest that this functional substitution may be a strong independent risk factor for various metabolic and cardiovascular diseases.     

Centrally administered bombesin modulates gastric motility

Intracerebroventricular bombesin alters arterial pressure and gastrointestinal transit in rats. In order to evaluate the influence of bombesin on arterial and gastric intraluminal pressure in a specific site in the central nervous system, we microinjected bombesin into the medial subnucleus of the nucleus tractus solitarius (mNTS) in 28 rats anesthetized with choralose. Bombesin (78 pmole in 25 nl), but not vehicle, caused an increase of tonic gastric intraluminal pressure (2.6 +/- 0.5 cm H2O) and of phasic gastric intraluminal pressures but did not acutely alter arterial pressure. The effect on tonic and phasic gastric intraluminal pressure was dose-dependent. The threshold dose was 7.8 pmole. Intravenous bombesin caused a similar dose-dependent rise in tonic gastric intraluminal pressure but did not significantly change the mean amplitude of phasic gastric intraluminal pressures. Transection of the cervical spinal cord and both cervical vagus nerves blocked the effect of centrally but not peripherally administered bombesin. We conclude that bombesin microinjected into the mNTS does not influence arterial pressure but does raise tonic and phasic gastric intraluminal pressures. Bombesin may act in the NTS as a central modulator of gastric motility.     

Mechanism of the induction of brain c-Fos-positive neurons by lipid absorption

Many gastrointestinal meal-related signals are transmitted to the central nervous system via the vagus nerve and thereby control changes in meal size. The c-Fos-positive neuron has been used as a marker of neuronal activation after lipid meals to examine the contribution of a selective macronutrient on brain neurocircuit activity. In rats fed Intralipid, the c-Fos-positive neurons were highly stimulated in the nucleus of the solitary tract (NTS) and in the hypothalamus, including the paraventricular nucleus (PVN), arcuate nucleus of the hypothalamus (ARC), and ventromedial hypothalamus at 4 h lipid feeding. However, c-Fos-like immunoreactivity was markedly attenuated in these brain regions when chylomicron formation/secretion was blocked by Pluronic L-81. After lymph was diverted from the lymph cannulated animals, the rats had a lower number of c-Fos-positive cells in the NTS and ARC. In contrast, the rats had higher c-Fos-positive neurons in PVN. The present study also revealed that c-Fos-positive neurons induced by feeding of Intalipid were abolished by CCK type 1 receptor antagonist, Lorglumide. We conclude that the formation and/or secretion of chylomicron are critical steps for initiating neuronal activation in the brain.     

Adenovirus-mediated gene transfer into the brain stem to examine cardiovascular function: role of nitric oxide and Rho-kinase

The central nervous system plays an important role in the regulation of blood pressure via the sympathetic nervous system. Abnormal regulation of the sympathetic nerve activity is involved in the pathophysiology of hypertension. In particular, the brain stem, including the nucleus tractus solitarii (NTS) and the rostral ventrolateral medulla (RVLM), is a key site that controls and maintains blood pressure via the sympathetic nervous system. Nitric oxide (NO) is a unique molecule that influences sympathetic nerve activity. Rho-kinase is a downstream effector of the small GTPase, Rho, and is implicated in various cellular functions. We developed a technique to transfer adenovirus vectors encoding endothelial nitric oxide synthase and dominant-negative Rho-kinase into the NTS or the RVLM of rats in vivo. We applied this technique to hypertensive rats to explore the physiological significance of NO and Rho-kinase.     

NPY-like peptides occur in the nervous system and midgut of the migratory locust, Locusta migratoria and in the brain of the grey fleshfly, Sarcophaga bullata

The distribution of the NPY-like substances in the nervous system and the midgut of the migratory locust, Locusta migratoria and in the brain of the grey fleshfly, Sarcophaga bullata was determined by immunocytochemistry using an antiserum directed against synthetic porcine NPY. The peroxidase-antiperoxidase procedure revealed that NPY immunoreactive cell bodies and nerve fibers were observed in the brain, optic lobes, corpora cardiaca, suboesophageal ganglion and ventral nerve cord of the locust and in the brain, optic lobes and suboesophageal ganglion of the fleshfly. In the locust midgut, numerous endocrine cells and nerve fibers penetrating the outer musculature contained NPY-like immunoreactivity. The concentrations of NPY immunoreactive material in acetic acid extracts of locust brain, optic lobes, thoracic ganglia, ovaries and midguts was measured using a specific radioimmunoassay technique. The dilution curves of the crude tissue extracts were parallel to the standard curve. The highest amount of NPY-like immunoreactivity was found in the locust ovary and midgut. Reverse-phase high-performance liquid chromatography (RP-HPLC) and radioimmunoassay were used to characterize the NPY-like substances in the locust brain and midgut. HPLC-analysis revealed that NPY-immunoreactivity in the locust brain eluted as three separate peaks. The major peak corresponded to a peptide less hydrophobic than synthetic porcine NPY. RP-HPLC analysis of midgut extracts revealed the presence of an additional NPY-immunoreactive peak which had a retention time similar to the porcine NPY standard. The present data show the existence of a widespread network of NPY immunoreactive neurons in the nervous system of the locust and the fleshfly. Characterization of the immunoreactive substances indicates that peptides similar but not identical to porcine NPY are present in the central nervous system and midgut of insects.     

The intriguing mission of neuropeptide Y in the immune system

For many years, the central nervous system and the immune system were considered two autonomous entities. However, extensive research in the field of neuroimmunomodulation during the past decades has demonstrated the presence of different neuropeptides and their respective receptors in the immune cells. More importantly, it has provided evidence for the direct effects of neuropeptides on the immune cell functions. Neuropeptide Y (NPY) is generally considered the most abundant peptide in the central and peripheral nervous system. However, it is also distinguished by exhibiting pleiotropic functions in many other physiological systems, including the immune system. NPY affects the functions of the cells of the adaptive and innate immunity. In this respect, NPY is known to modulate immune cell trafficking, T helper cell differentiation, cytokine secretion, natural killer cell activity, phagocytosis and the production of reactive oxygen species. The specific Y receptors have been found in immune cells, and their expression is amplified upon immune stimulation. Different Y receptor subtypes may mediate an opposite effect of NPY on the particular function, thus underlining its regulatory role. Since the immune cells are capable of producing NPY upon appropriate stimulation, this peptide can regulate immune cell functions in an autocrine/paracrine manner. NPY also has important implications in several immune-mediated disorders, which affirms the clear need for further investigation of its role in either the mechanisms of the disease development or its possible therapeutic capacity. This review summarises the key points of NPY’s mission throughout the immune system.     

Peptidergic regulation of gastrointestinal motility in rodents

Peptides involved in the endocrine and enteric nervous systems as well as in the central nervous system exert concerted action on gastrointestinal motility. Mechanical and chemical stimuli which induce peptide release from the epithelial endocrine cells are the earliest step in the initiation of peristaltic activities. Gut peptides exert hormonal effects, but peptide-containing stimulatory (Ach/substance P/tachykinin) and inhibitory (VIP/PACAP/NO) neurons are also involved in the induction of ascending contraction and descending relaxation, respectively. The dorsal vagal complex (DVC), located in the medulla of the brainstem, constitutes the basic neural circuitry of vago-vagal reflex control of gastrointestinal motility. Several gut peptides act on the DVC to modify vagal cholinergic reflexes directly (PYY and PP) or indirectly via afferent fibers in the periphery (CCK and GLP-1). The DVC is also a primary site of action of many neuropeptides (such as TRH and NPY) in mediating gastrointestinal motor activities. The identification over the last few years of a number of neuropeptide systems has greatly changed the field of feeding and body weight regulation. By exploring the brain and gut systems that employ recently identified peptidergic molecules, it will be possible to elaborate on the central and peripheral pathways involved in the regulation of gastrointestinal motility.     

An inhibitory role of beta-endorphin in central cardiovascular regulation

The cardiovascular effects of beta-endorphin after administration directly into the nucleus tractus solitarii (NTS) of urethane anaesthetised rats were investigated. Unilateral injection resulted in a dose related fall in mean arterial pressure and heart rate. No change in respiratory frequency was prevented and the bradycardia reduced by pretreatment with locally applied naloxone (10 ng). This dose of the opiate antagonist had no effect on mean arterial pressure or heart rate when administered alone. Antiserum to beta-endorphin (1:50 dilution) caused a rise in pressure and a tendency towards tachycardia on injection into the NTS, while it completely blocked the depressor response and bradycardia induced by beta-endorphin. These results are consistent with the view that a beta-endorphin-like peptide has a depressor role in the central nervous system. The hypotension may result from an effect within the central connections of the baroreceptor reflex arc, probably at the level of the NTS.     

Relationships between the brain and the immune system

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).