Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model.

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Neuron-Glia-Immune Triad and Cortico-Limbic System in Pathology of Pain.

Pain is an unpleasant sensation that alerts one to the presence of obnoxious stimuli or sensations. These stimuli are transferred by sensory neurons to the dorsal root ganglia-spinal cord and finally to the brain. Glial cells in the peripheral nervous system, astrocytes in the brain, dorsal root ganglia, and immune cells all contribute to the development, maintenance, and resolution of pain. Both innate and adaptive immune responses modulate pain perception and behavior. Neutrophils, microglial, and T cell activation, essential components of the innate and adaptive immune responses, can play both excitatory and inhibitory roles and are involved in the transition from acute to chronic pain. Immune responses may also exacerbate pain perception by modulating the function of the cortical-limbic brain regions involved in behavioral and emotional responses. The link between an emotional state and pain perception is larger than what is widely acknowledged. In positive psychological states, perception of pain along with other somatic symptoms decreases, whereas in negative psychological states, these symptoms may worsen. Sex differences in mechanisms of pain perception are not well studied. In this review, we highlight what is known, controversies, and the gaps in this field.

Clinical diagnosis of LGI1 antibody encephalitis in an 83-year-old woman.

An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.

Can't or Won't? Immunometabolic Constraints on Dopaminergic Drive.

Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can't) versus preference (won't) for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.

Can neuroimmune mechanisms explain the link between ultraviolet light (UV) exposure and addictive behavior?

High ultraviolet (UV) light exposure on the skin acts as a reinforcing stimulus, increasing sun-seeking behavior and even addiction-like sun seeking behavior. However, the physiological mechanisms that underlie this process remain to be defined. Here, we propose a novel hypothesis that neuroimmune signaling, arising from inflammatory responses in UV-damaged skin cells, causes potentiated signaling within the cortico-mesolimbic pathway, leading to increased sun-seeking behaviors. This hypothesized UV-induced, skin-to-brain signaling depends upon cell stress signals, termed alarmins, reaching the circulation, thereby triggering the activation of innate immune receptors, such as toll-like receptors (TLRs). This innate immune response is hypothesized to occur both peripherally and centrally, with the downstream signaling from TLR activation affecting both the endogenous opioid system and the mesolimbic dopamine pathway. As both neurotransmitter systems play a key role in the development of addiction behaviors through their actions at key brain regions, such as the nucleus accumbens (NAc), we hypothesize a novel connection between UV-induced inflammation and the activation of pathways that contribute to the development of addiction. This paper is a review of the existing literature to examine the evidence which suggests that chronic sun tanning resembles a behavioral addiction and proposes a novel pathway by which persistent sun-seeking behavior could affect brain neurochemistry in a manner similar to that of repeated drug use.

Correlation between neuronal antibodies and limbic encephalitis in Chinese Han subjects.

A variety of anti-neuronal cell membrane antibodies such as voltage-gated potassium channel antibody, N-methyl-D-aspartate-2B-antibody, and glutamic acid decarboxylase antibody, are correlated with limbic encephalitis (LE). In this study on patients with LE, the clinical manifestations, psychology Wechsler Adult Intelligence Scale, cerebrospinal fluid, electrophysiology, magnetic resonance imaging, and anti-immune therapy were studied and immunological determination was conducted; it was found that patients of Chinese Han nationality showed 2 types of clinical manifestations: simple and complex. Lesions could also be divided into focal and scalable lesions, and the clinical manifestations and lesions scopes were associated with various antibodies and antibody types. The prognosis may improve if early diagnosis is conducted and early anti-immune therapy is implemented in LE patients.

Current hypotheses on the mechanisms of alcoholism.

Chronic use of alcohol results in progressive changes to brain and behavior that often lead to the development of alcohol dependence and alcoholism. Although the mechanisms underlying the development of alcoholism remain to be fully elucidated, diminished executive functioning due to hypoactive prefrontal cortex executive control and hyperactive limbic system anxiety and negative emotion might contribute mechanistically to the shift from experimental use to alcoholism and dependence. In the chapter that follows, behavioral deficits associated with cortical dysfunction and neurodegeneration will be related to the behavioral characteristics of alcoholism (e.g., diminished executive function, impulsivity, altered limbic modulation). We will provide evidence that alterations in cyclic AMP-responsive element binding protein (CREB: neurotrophic) and NF-κB (neuroimmune) signaling contribute to the development and persistence of alcoholism. In addition, genetic predispositions and an earlier age of drinking onset will be discussed as contributing factors to the development of alcohol dependence and alcoholism. Overall chronic ethanol-induced neuroimmune gene induction is proposed to alter limbic and frontal neuronal networks contributing to the development and persistence of alcoholism.

Immunoglobulin-mediated neuro-cognitive impairment: new data and a comprehensive review.

Excessive influx of immunoglobulin (IgG) into the brain has been reported to induce central nervous system (CNS) dysfunction. Depressed patients may exhibit immune activation manifested by elevated inflammatory markers and pro-inflammatory cytokines. The brain and especially the limbic system contain high concentrations of high affinity Fc receptors. We reviewed the literature on this phenomena and present data on the behavioral effects of pooled normal IgG on the brain. Many disease states are associated with depression and we examined whether this may be linked to high IgG influx. Female Balb/C mice were injected intra-cerbroventricularly with human immunoglobulin whole molecule, or human IgG F(ab')2 or Fc fragments. Control mice were injected with saline. The four groups were subjected to behavioral (staircase, forced swimming test, and elevated plus maze) and cognitive tests (passive avoidance test). IgG-injected mice exhibited depression-like behavior as reflected by significantly higher immobility time in the forced swimming test (p < 0.05) and hyperactive behavior as reflected by higher number of stairs climbed in the staircase test compared to controls (p < 0.01). Fc-fragments-injected mice showed hyperactive behavior as reflected by both higher number of stairs climbed and rearing events in the staircase test compared to controls. The results indicate that high levels of normal IgG in the cerebrospinal fluid can cause hyperactivity and depression-like behavior. The mechanism involved in these CNS manifestations include possibly Fc receptor binding.

Attenuation of post-myocardial infarction depression in rats by n-3 fatty acids or probiotics starting after the onset of reperfusion.

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFA n-3 diet or the combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFA n-3 diet, combined or not with one billion live bacteria of L. helveticus and B. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2'-deoxyuridine, 5'-triphosphate (dUTP) nick-end labelling (TUNEL)-positive cells were decreased in the CA1, dentate gyrus (DG) and amygdala with the high-PUFA n-3 diet, as compared to the three other diets. Probiotics attenuated caspase-3 activity and TUNEL-positive cells in the DG and the medial amygdala. At 2 weeks post-MI, depression-like behaviour was observed in the low-PUFA n-3 diet without probiotics-group, and this behaviour was attenuated with the high-PUFA n-3 diet or/and probiotics. These results indicate that a high-PUFA n-3 diet or the administration of probiotics, starting after the onset of reperfusion, are beneficial to attenuate apoptosis in the limbic system and post-MI depression in the rat.

A developmental characterization of mesolimbocortical serotonergic gene expression changes following early immune challenge.

An immunogenic challenge during early postnatal development leads to long-term changes in behavioural and physiological measures reflecting enhanced emotionality and anxiety. Altered CNS serotonin (5-HT) signalling during the third postnatal week is thought to modify the developing neurocircuitry governing anxiety-like behaviour. Changes in 5-HT signalling during this time window may underlie increased emotionality reported in early immune challenge rodents. Here we examine both the spatial and temporal profile of 5-HT related gene expression, including 5HT1A, 2A, 2C receptors, the 5-HT transporter (5HTT), and tryptophan hydroxylase 2 (TPH2) during early development (postnatal day [P]14, P17, P21, P28) in mice challenged with lipopolysaccharide (LPS) during the first postnatal week. Expression levels were measured using in situ hybridization in regions associated with mediating emotive behaviours: the dorsal raphe (DR), hippocampus, amygdala, and prefrontal cortex (PFC). Increased TPH2 and 5HTT expression in the ventrolateral region of the DR of LPS-mice accompanied decreased expression of ventral DR 5HT1A and dorsal DR 5HTT. In the forebrain, 5HT1A and 2A receptors were increased, whereas 5HT2C receptors were decreased in the hippocampus. Decreased mRNA expression of 5HT2C was detected in the amygdala and PFC of LPS-treated pups; 5HT1A was increased in the PFC. The majority of these changes were restricted to P14-21. These transient changes in 5-HT expression coincide with the critical time window in which 5-HT disturbance leads to permanent modification of anxiety-related behaviours. This suggests that alterations in CNS 5-HT during development may underlie the enhanced emotionality associated with an early immune challenge.

Stress-induced changes of interleukin-1beta within the limbic system in the rat.

The aim of this study was to investigate the influence of two periods of life, namely P28 and P360, on the changes in interleukin-1beta (IL-1beta) immunoreactivity (-ir) in the hippocampus (CA1, CA3, DG) and amygdala (central-CeA, medial-MeA) caused by acute and repeated open field (OF), or by forced swim (FS) exposition. Rats were divided into groups: non-stressed, exposed to acute (one-time for 15 min) and chronic stressors (21 days for 15 min daily). We found IL-1beta-ir in the control group to be higher in P360 than in P28. In P28, under OF and FS exposure, IL-1beta-ir in the CeA remained unaltered but increased in the MeA and in the hippocampus after acute and chronic stress. In P360 no changes were observed in the IL-1beta-ir level after acute and chronic stimulation. These data demonstrate that only the levels of IL-1beta-ir in juvenile rat brains are affected by FS and OF. Additionally, there was no significant difference between FS and OF stimulation in IL-1beta-ir.

Autoantibodies to glutamate receptor GluRepsilon2 in a patient with limbic encephalitis associated with relapsing polychondritis.

Limbic encephalitis is a rare central nervous system (CNS) manifestation of relapsing polychondritis (RP). Vasculitis is assumed to be the cause of CNS involvement in RP. Several studies, however, have described CNS involvement in RP with no evidence of vasculitis but with a more nonspecific inflammatory picture. We report a patient with limbic encephalitis associated with RP who presented with anti-glutamate receptor (GluR) epsilon2 (NR2B) autoantibodies in his cerebrospinal fluid and sera. Brain MRI showed a high signal intensity lesion in the medial temporal lobe and progressive atrophy without multifocal abnormality on fluid-attenuated inversion recovery scanning. Our patient's results raise the interesting possibility that anti-GluRepsilon2 (NR2B) antibodies function in the development of limbic encephalitis in certain patients with RP.

Bilateral temporal glioma presenting as a paraneoplastic limbic encephalitis with pure cognitive impairment.

INTRODUCTION: Memory impairment caused by bilateral hippocampal primitive brain tumor is rarely reported. Clinical and MRI features can mimic paraneoplastic limbic encephalitis (PLE), and the differential diagnosis between these 2 entities may be difficult. CASE REPORT: We report the case of a 42-year-old woman presenting with amnesia without neurologic focal signs at clinical examination. The neuroimaging features consisted of bilateral limbic hyperintensities on T2-weighted and FLAIR brain MRI. Despite exhaustive biologic and radiologic investigations, no specific etiology was found. The diagnosis of paraneoplastic limbic encephalitis was suspected, although antineuronal antibodies were negative and no cancer was detected after the first evaluation. Eight months after onset, the memory complaint of the patient increased along with disability in activities of the daily living, the neurologic examination slightly changed with frontal neurologic signs and the brain MRI showed a new cystic lesion in the left hippocampus with enhancement after contrast administration. The left temporal tumor was resected and the neuropathological examination was consistent with gliomatosis cerebri with a focal high grade astrocytoma. CONCLUSIONS: This case highlights the need to consider the possibility of infiltrative gliomatosis in patients presenting with features of paraneoplastic limbic encephalitis.

Intra-VTA adenosine A1 receptor activation blocks morphine stimulation of motor behavior and cortical and limbic Fos immunoreactivity.

Drugs of abuse produce psychomotor stimulation as one of their characteristic behavioral effects. Single administration of opiates stimulates motor activity via effects on gamma-aminobutyric acid (GABA) and dopamine transmission in the ventral tegmental area (VTA). Adenosine A(1) receptor agonists inhibit VTA GABAergic and dopaminergic transmission and are predicted to alter the behavioral effects of opiates. This study examined the effects of intra-VTA administration of selective adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) on morphine-induced motor stimulation in C57BL/6 mice. It also examined the effects of CPA on morphine's activation of VTA neurons projecting to limbic and cortical regions including the nucleus accumbens (NAc), anterior cingulate cortex (ACg) and prelimbic cortex (PrL) via quantitation of immediate-early gene c-Fos protein in these regions. Mice received subcutaneous morphine and intra-VTA administration of CPA and then automated motor activity was measured. Morphine treatment induced both motor activity and Fos immunoreactivity in the NAc, ACg and PrL suggesting that behavioral stimulation is produced by neural activation in these regions. Intra-VTA CPA administration produced a dose-dependent inhibition of morphine-induced motor stimulation and blocked c-Fos induction in all three regions. Intra-VTA CPT treatment had no effects on motor activity or on morphine-induced motor stimulation. VTA adenosine A(1) agonist inhibition of morphine's effects on motor activity and of neural activation of VTA projections suggests that these neurons and their regulation are critical to morphine's stimulant effects. Adenosine A(1) receptor agonists and purinergic modulators may represent useful treatment approaches for blocking the behavioral effects of opiates.

Development of Isaacs' syndrome following complete recovery of voltage-gated potassium channel antibody-associated limbic encephalitis.

Autoantibodies against voltage-gated potassium channels (VGKC-Abs) are associated with acquired neuromyotonia (Isaacs' syndrome) and related disorders such as Morvan's syndrome and some cases of limbic encephalitis. The mechanisms underlying the various phenotypes induced by VGKC-Abs are not fully understood. Recently, we reported a case of LE with VGKC-Abs accompanied by severe intestinal pseudo-obstruction and thymoma. Thymectomy and immunosuppressive therapy induced dramatic clinical improvement of LE symptoms, and VGKC-Abs titers decreased from 1254 pM to 549 pM (normal>100 pM). Seventeen months later, the patient developed progressive generalized muscle cramping, paresthesias in his lower extremities, excessive sweating, and severe constipation. There was no recurrence of the LE. Electromyography showed fasciculation potentials and myokymic discharges, and the plasma VGKC-Abs titer was again elevated to 879 pM. Here we report a case of Isaacs' syndrome after complete remission of LE with VGKC-Abs that may provide an insight into a possible link among VGKC-Abs associated syndromes.

Limbic encephalitis - a review.

The clinical features of limbic encephalitis are diverse and early diagnosis of the disorder is frequently difficult. Four patients with limbic encephalitis are described. An antineuronal antibody was identified in three of these patients. Antibodies directed against voltage-gated potassium channels, the N-methyl-D-aspartate receptor and an unidentified neuropil antigen were each found in one patient. The fourth patient had multifocal paraneoplastic encephalitis associated with small cell lung cancer. The clinical and imaging findings associated with these antibodies and the other antineuronal antibodies described in patients with limbic encephalitis are reviewed. An approach to the diagnosis and management of limbic encephalitis is presented.

Focal cortical resection for complex partial status epilepticus due to a paraneoplastic encephalitis.

We report a 57-year-old female who presented with epilepsia partialis continua and rapidly progressed to refractory complex partial status epilepticus (CPSE) with brain magnetic resonance imaging revealing a focal cortical lesion on T2 sequences corresponding to the seizure focus on ictal electroencephalographic recordings. The patient underwent focal cortical resection of the seizure focus. Though clinical and electrographic seizure activity ceased, the patient remained unresponsive with repeat neuroimaging showing diffuse limbic and brainstem involvement. Serological tests revealed anti-Hu antibodies suggesting a paraneoplastic encephalitis. Chest computed tomography showed a 5-mm pulmonary nodule and resection of the pulmonary nodule confirmed the diagnosis of small cell lung cancer. Plasmapheresis was performed without clinical improvement. Focal resection can be effective in terminating refractory CPSE but evaluation for a paraneoplastic syndrome must be considered early in the diagnosis of epilepsia partialis continua and CPSE as these patients have a poor prognosis.

Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

OBJECTIVE: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection. METHODS: We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present. RESULTS: All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically). CONCLUSION: 1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.