RESUMO
BACKGROUND: Bipolar disorder (BD) is associated with marked functional impairments along with increased rate of suicide. Although there is ample evidence for the involvement of inflammatory processes and microglia activation in the pathophysiology of BD, the mechanisms that regulate these cells in BD patients, and particularly the role of microglia checkpoints, is still unclear. METHODS: Immunohistochemical analyses of hippocampal sections from post-mortem brains of 15 BD patients and 12 control subjects were used to assess microglia density, by staining the microglia-specific receptor P2RY12, and microglia activation, by staining the activation marker MHC II. Given recent findings on the involvement of LAG3, which interacts with MHC II and serves as a negative microglia checkpoint, in depression and electroconvulsive therapy, we assessed the levels of LAG3 expression and their correlations with microglia density and activation. RESULTS: There were no overall differences between BD patients and controls, but BD patients who committed suicide (N = 9) displayed a significant elevation in the overall microglia density and the density of MHC II-labeled microglia (but not other MHC II-labeled cells), compared with no suicide BD patients (N = 6) and controls. Furthermore, the percent of microglia expressing LAG3 was significantly reduced only in suicidal BD patients, with significant negative correlations between microglial LAG3 expression levels and the density of microglia, in general, and activated microglia, in particular. CONCLUSION: Suicidal BD patients exhibit microglia activation, which is possibly mediated by reduced LAG3 checkpoint expression, suggesting that anti-microglial therapeutics, including LAG3 modulators, may be beneficial for this subgroup of patients.
Assuntos
Transtorno Bipolar , Suicídio , Humanos , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismo , Linfócitos/metabolismoRESUMO
Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.
Assuntos
Transtorno Depressivo Maior , Microglia , Animais , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo/metabolismo , Camundongos , Microglia/metabolismo , Neurogênese/fisiologiaRESUMO
Clinical studies suggest that key genetic factors involved in stress resilience are related to the innate immune system. In the brain, this system includes microglia cells, which play a major role in stress responsiveness. Consistently, mice with deletion of the CX3CR1 gene (CX3CR1-/- mice), which in the brain is expressed exclusively by microglia, exhibit resilience to chronic stress. Here, we compared the emotional, cognitive, neurogenic and microglial responses to chronic unpredictable stress (CUS) between CX3CR1-/- and wild type (WT) mice. This was followed by hippocampal whole transcriptome (RNA-seq) analysis. We found that following CUS exposure, WT mice displayed reduced sucrose preference, impaired novel object recognition memory, and reduced neurogenesis, whereas CX3CR1-/- mice were completely resistant to these effects of CUS. CX3CR1-/- mice were also resilient to the memory-suppressive effect of a short period of unpredictable stress. Microglial somas were larger in CX3CR1-/- than in WT, but in both genotypes CUS induced a similar decline in hippocampal microglial density and processes length. RNA sequencing and pathway analysis revealed basal strain differences, particularly reduced expression of interferon (IFN)-regulated and MHC class I gene transcripts in CX3CR1-/- mice. Furthermore, while CUS exposure similarly altered neuronal gene transcripts (e.g. Arc, Npas4) in both strains, transcripts downstream of hippocampal estrogen receptor signaling (particularly Igf2 and Igfbp2) were altered only in CX3CR1-/- mice. These findings indicate that emotional and cognitive stress resilience involves CX3CR1-dependent basal and stress-induced alterations in hippocampal transcription, implicating inhibition of CX3CR1 signaling as a novel approach for promoting stress resilience.
Assuntos
Receptor 1 de Quimiocina CX3C/genética , Hipocampo/metabolismo , Microglia/metabolismo , Estresse Psicológico/metabolismo , Transcriptoma , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Masculino , Memória/fisiologia , Camundongos , Camundongos Knockout , Neurogênese/fisiologia , Neurônios/metabolismo , Resiliência Psicológica , Transdução de Sinais , Estresse Psicológico/genéticaRESUMO
Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α(2)nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra(Ast)(+/+) mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra(Ast)(+/+) mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.
Assuntos
Osso e Ossos/metabolismo , Interleucina-1/metabolismo , Sistema Nervoso Parassimpático/fisiologia , Acetilcolina/metabolismo , Animais , Apoptose , Densidade Óssea , Reabsorção Óssea , Encéfalo/metabolismo , Proliferação de Células , Coração/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Brometo de Piridostigmina/farmacologia , Transdução de SinaisRESUMO
Recent studies demonstrate that microglia play an important role in cognitive and neuroplasticity processes, at least partly via microglial CX3C receptor 1 (CX3CR1) signaling. Furthermore, microglia are responsive to environmental enrichment (EE), which modulates learning, memory and neurogenesis. In the present study we examined the role of microglial CX3CR1 signaling in hippocampal- and olfactory-bulb (OB)-related memory and neurogenesis in homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter (CX3CR1(-/-) mice), in which the CX3CR1 gene is functionally deleted, as well as heterozygous CX3CR1(+/-) and WT controls. We report that the CX3CR1-deficient mice displayed better hippocampal-dependent memory functioning and olfactory recognition, along with increased number and soma size of hippocampal microglia, suggestive of mild activation status, but no changes in OB microglia. A similar increase in hippocampal-dependent memory functioning and microglia number was also induced by pharmacological inhibition of CX3CR1 signaling, using chronic (2weeks) i.c.v. administration of CX3CR1 blocking antibody. In control mice, EE improved hippocampal-dependent memory and neurogenesis, and increased hippocampal microglia number and soma size, whereas odor enrichment (OE) improved olfactory recognition and OB neurogenesis without changing OB microglia status. In CX3CR1-deficient mice, EE and OE did not produce any further improvement in memory functioning or neurogenesis and had no effect on microglial status. These results support the notion that in the hippocampus microglia and their interactions with neurons via the CX3CR1 play an important role in memory functioning and neurogenesis, whereas in the OB microglia do not seem to be involved in these processes.
Assuntos
Hipocampo/citologia , Memória/fisiologia , Microglia/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurogênese/fisiologia , Bulbo Olfatório/citologia , Receptores de Quimiocinas/fisiologia , Animais , Receptor 1 de Quimiocina CX3C , Meio Ambiente , Genes Reporter , Hipocampo/imunologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Odorantes , Bulbo Olfatório/imunologia , Bulbo Olfatório/fisiologia , Estimulação Física , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/deficiência , Reconhecimento Psicológico/fisiologiaRESUMO
Neurons, astrocytes, and blood vessels are organized in functional "neurovascular units" in which the vasculature can impact neuronal activity and, in turn, dynamically adjust to its change. Here we explored different mechanisms by which VEGF, a pleiotropic factor known to possess multiple activities vis-à-vis blood vessels and neurons, may affect adult neurogenesis and cognition. Conditional transgenic systems were used to reversibly overexpress VEGF or block endogenous VEGF in the hippocampus of adult mice. Importantly, this was done in settings that allowed the uncoupling of VEGF-promoted angiogenesis, neurogenesis, and memory. VEGF overexpression was found to augment all three processes, whereas VEGF blockade impaired memory without reducing hippocampal perfusion or neurogenesis. Pertinent to the general debate regarding the relative contribution of adult neurogenesis to memory, we found that memory gain by VEGF overexpression and memory impairment by VEGF blockade were already evident at early time points at which newly added neurons could not yet have become functional. Surprisingly, VEGF induction markedly increased in vivo long-term potentiation (LTP) responses in the dentate gyrus, and VEGF blockade completely abrogated LTP. Switching off ectopic VEGF production resulted in a return to a normal memory and LTP, indicating that ongoing VEGF is required to maintain increased plasticity. In summary, the study not only uncovered a surprising role for VEGF in neuronal plasticity, but also suggests that improved memory by VEGF is primarily a result of increasing plasticity of mature neurons rather than the contribution of newly added hippocampal neurons.
Assuntos
Cognição/fisiologia , Giro Denteado/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Neurogênese/fisiologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
This NeuroView is intended for graduate students who are not sure how to choose or what to expect from a mentor as well as mentors who are uncertain what to give mentees. Two principal investigators and a current mentee will share their perspectives on this bidirectional relationship.
Assuntos
Tutoria , Mentores , Humanos , Avaliação de Programas e Projetos de Saúde , EstudantesRESUMO
Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1ß secretion. Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.
RESUMO
Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFα, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases.
Assuntos
Imunomodulação/fisiologia , Aprendizagem/fisiologia , Memória/fisiologia , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Comportamento/fisiologia , Comportamento Animal/fisiologia , Citocinas/fisiologia , Humanos , Imunidade Celular , Prostaglandinas/fisiologia , Linfócitos T/fisiologiaRESUMO
Recent studies indicate that astrocytes play an integral role in neural and synaptic functioning. To examine the implications of these findings for neurobehavioral plasticity we investigated the involvement of astrocytes in memory and long-term potentiation (LTP), using a mouse model of impaired learning and synaptic plasticity caused by genetic deletion of the interleukin-1 receptor type I (IL-1RI). Neural precursor cells (NPCs), derived from either wild type (WT) or IL-1 receptor knockout (IL-1rKO) neonatal mice, were labeled with bromodeoxyuridine (BrdU) and transplanted into the hippocampus of either IL-1rKO or WT adult host mice. Transplanted NPCs survived and differentiated into astrocytes (expressing GFAP and S100ß), but not to neurons or oligodendrocytes. The NPCs-derived astrocytes from WT but not IL-1rKO mice displayed co-localization of GFAP with the IL-1RI. Four to twelve weeks post-transplantation, memory functioning was examined in the fear-conditioning and the water maze paradigms and LTP of perforant path-dentate gyrus synapses was assessed in anesthetized mice. As expected, IL-1rKO mice transplanted with IL-1rKO cells or sham operated displayed severe memory disturbances in both paradigms as well as a marked impairment in LTP. In contrast, IL-1rKO mice transplanted with WT NPCs displayed a complete rescue of the impaired memory functioning as well as partial restoration of LTP. These findings indicate that astrocytes play a critical role in memory functioning and LTP, and specifically implicate astrocytic IL-1 signaling in these processes. The results suggest novel conceptualization and therapeutic targets for neuropsychiatric disorders characterized by impaired astrocytic functioning concomitantly with disturbed memory and synaptic plasticity.
Assuntos
Astrócitos/fisiologia , Hipocampo/fisiologia , Interleucina-1/fisiologia , Memória/fisiologia , Animais , Condicionamento Clássico/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Receptores Tipo I de Interleucina-1/fisiologiaRESUMO
Environmental enrichment (EE) was found to facilitate memory functioning and neural plasticity in normal and neurologically impaired animals. However, the ability of this manipulation to rescue memory and its biological substrate in animals with specific genetically based deficits in these functions has not been extensively studied. In the present study, we investigated the effects of EE in two mouse models of impaired memory functioning and plasticity. Previous research demonstrated that mice with a deletion of the receptor for the cytokine interleukin-1 (IL-1rKO), and mice with CNS-specific transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG) display impaired hippocampal memory and long-term potentiation (LTP). We report here a corrective effect of EE on spatial and contextual memory in IL-1rKO and IL-1raTG mice and reveal two mechanisms for this beneficial effect: Concomitantly with their disturbed memory functioning, LTP in IL-1rKO mice that were raised in a regular environment is impaired, and their dendritic spine size is reduced. Both of these impairments were corrected by environmental enrichment. No deficiencies in neurogenesis or hippocampal BDNF and vascular endothelial growth factor secretion were found in IL-1rKO mice that were raised in a regular environment, and both of these variables were increased to a similar degree in enriched IL-1rKO and wild-type mice. These findings suggest that exposure to an enriched environment may be beneficial for individuals with impaired learning and memory related to genetic impairments of IL-1 signaling (and possibly other genetic causes), by reversing impairments in dentate gyrus LTP and spine size and by promoting neurogenesis and trophic factors secretion.
Assuntos
Espinhas Dendríticas/ultraestrutura , Meio Ambiente , Potenciação de Longa Duração , Memória/fisiologia , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/fisiologia , Animais , Espinhas Dendríticas/patologia , Exposição Ambiental , Potenciais Pós-Sinápticos Excitadores/genética , Potenciação de Longa Duração/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-1/genética , Transdução de Sinais/genéticaRESUMO
Ample evidence demonstrates that the pro-inflammatory cytokine interleukin-1 (IL-1), produced following exposure to immunological and psychological challenges, plays an important role in the neuroendocrine and behavioral stress responses. Specifically, production of brain IL-1 is an important link in stress-induced activation of the hypothalamus-pituitary-adrenal axis and secretion of glucocorticoids, which mediate the effects of stress on memory functioning and neural plasticity, exerting beneficial effects at low levels and detrimental effects at high levels. Furthermore, IL-1 signaling and the resultant glucocorticoid secretion mediate the development of depressive symptoms associated with exposure to acute and chronic stressors, at least partly via suppression of hippocampal neurogenesis. These findings indicate that whereas under some physiological conditions low levels of IL-1 promote the adaptive stress responses necessary for efficient coping, under severe and chronic stress conditions blockade of IL-1 signaling can be used as a preventive and therapeutic procedure for alleviating stress-associated neuropathology and psychopathology.
Assuntos
Interleucina-1/fisiologia , Plasticidade Neuronal/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Interleucina-1/antagonistas & inibidores , Memória , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
An increasing number of studies suggest an association between depression and osteoporosis. In a mouse model, depression induces bone loss, mediated by brain-to-bone sympathetic signaling. Depression and bone antianabolic sympathetic tone are alleviated by increasing central serotonin (5-hydroxytryptamine, 5-HT) levels. However, selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressants, increase extracellular 5-HT levels but have deleterious skeletal effects. The skeletal serotonergic system consists of 5-HT receptors and the 5-HT transporter (5-HTT) in osteoblasts and osteocytes. 5-HTT is a transmembrane protein targeted by SSRIs. 5-HT restrains osteoblastic activity, thus leading to bone loss. Apparently, the negative skeletal effects of the peripheral SSRI-induced increase in 5-HT outweighs the skeletal benefits resulting from the enhanced central 5-HT antidepressant and antisympathetic activity. Overall, major depression appears as an important risk factor for osteoporosis. However, antidepressants, mainly SSRIs, should be evaluated in view of the causal relationship between depression and bone loss, and vis-à-vis their skeletal adverse effects. Patients with depressive disorders should undergo a routine skeletal evaluation and receive timely antiosteoporotic therapy, especially when SSRI treatment is prescribed.
Assuntos
Depressão/epidemiologia , Osteoporose/epidemiologia , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Causalidade , Comorbidade , Depressão/diagnóstico , Depressão/fisiopatologia , Humanos , Osteoporose/fisiopatologia , Osteoporose Pós-Menopausa/epidemiologia , Osteoporose Pós-Menopausa/fisiopatologia , Pós-Menopausa/fisiologia , Pré-Menopausa/fisiologia , Receptores de Serotonina/fisiologia , Fatores de Risco , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying molecular mechanisms are unknown. Given the neuro-modulatory role of acetylcholine, we sought behavioral-transcriptomic links in SB using TgR transgenic mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble 'readthrough' acetylcholinesterase-R splice variant AChE-R. TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion, intensified reaction to pilocarpine and reduced rearing in unfamiliar situations. Small-RNA sequencing revealed 36 differentially expressed (DE) microRNAs in TgR mice hippocampi, 8 of which target more than 5 cholinergic transcripts. Moreover, compared to FVB/N mice, TgR prefrontal cortices displayed individually variable changes in over 400 DE mRNA transcripts, primarily acetylcholine and glutamate-related. Furthermore, TgR brains presented c-fos over-expression in motor behavior-regulating brain regions and immune-labeled AChE-R excess in the basal ganglia, limbic brain nuclei and the brain stem, indicating a link with the observed behavioral phenotypes. Our findings demonstrate association of stress-induced SB to previously unknown microRNA-mediated perturbations of cholinergic/glutamatergic networks and underscore new therapeutic strategies for correcting stereotypic behaviors.
Assuntos
Colinérgicos/metabolismo , Ácido Glutâmico/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos TransgênicosRESUMO
We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.
Assuntos
Desenvolvimento Ósseo/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/fisiologia , Animais , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/metabolismo , Sequência de Bases , Osso e Ossos/metabolismo , Primers do DNA , Endocanabinoides , Feminino , Glicerídeos/administração & dosagem , Glicerídeos/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor CB1 de Canabinoide/genéticaRESUMO
The proinflammatory cytokine interleukin-1 (IL-1) within the brain is critically involved in mediating the memory impairment induced by acute inflammatory challenges and psychological stress. However, the role of IL-1 in memory impairment and suppressed neurogenesis induced by chronic stress exposure has not been investigated before now. We report here that mice that were isolated for 4 weeks displayed a significant elevation in hippocampal IL-1beta levels concomitantly with body weight loss, specific impairment in hippocampal-dependent memory, and decreased hippocampal neurogenesis. To examine the causal role of IL-1 in these effects, we developed a novel approach for long-term delivery of IL-1 receptor antagonist (IL-1ra) into the brain, using transplantation of neural precursor cells (NPCs), obtained from neonatal mice with transgenic overexpression of IL-1ra (IL-1raTG) under the glial fibrillary acidic protein promoter. Four weeks following intrahippocampal transplantation of IL-1raTG NPCs labeled with PKH-26, the transplanted cells were incorporated within the dentate gyrus and expressed mainly astrocytic markers. IL-1ra levels were markedly elevated in the hippocampus, but not in other brain regions, by 10 days and for at least 4 weeks post-transplantation. Transplantation of IL-1raTG NPCs completely rescued the chronic isolation-induced body weight loss, memory impairment, and suppressed hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham operated. The transplantation had no effect in group-housed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic isolation and suggest that transplantation of IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in chronic inflammatory and neurological conditions.
Assuntos
Proliferação de Células , Condicionamento Psicológico/fisiologia , Hipocampo/transplante , Proteína Antagonista do Receptor de Interleucina 1/genética , Transtornos da Memória/genética , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Comportamento Animal , Proteínas do Domínio Duplacortina , Medo , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neurofilamentos/metabolismo , Neuropeptídeos/metabolismo , Compostos Orgânicos/metabolismo , Transplante de Células-Tronco/métodos , Fatores de TempoRESUMO
Medically ill patients present with a high prevalence of non-specific comorbid symptoms including pain, sleep disorders, fatigue and cognitive and mood alterations that is a leading cause of disability. However, despite major advances in the understanding of the immune-to-brain communication pathways that underlie the pathophysiology of these symptoms in inflammatory conditions, little has been done to translate this newly acquired knowledge to the clinics and to identify appropriate therapies. In a multidisciplinary effort to address this problem, clinicians and basic scientists with expertise in areas of inflammation, psychiatry, neurosciences and psychoneuroimmunology were brought together in a specialized meeting organized in Bordeaux, France, on May 28-29, 2007. These experts considered key questions in the field, in particular those related to identification and quantification of the predominant symptoms associated with inflammation, definition of systemic and central markers of inflammation, possible domains of intervention for controlling inflammation-associated symptoms, and relevance of animal models of inflammation-associated symptoms. This resulted in a number of recommendations that should improve the recognition and management of inflammation-associated symptoms in medically ill patients.
Assuntos
Encéfalo/imunologia , Doença Crônica , Inflamação/diagnóstico , Neuroimunomodulação/fisiologia , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/terapiaRESUMO
Both early-life stress and immune system activation in adulthood have been linked independently to depression in a number of studies. However, the relationship between early-life infection, which may be considered a "stressor", and later-life depression has not been explored. We have reported that neonatal bacterial infection in rats leads to exaggerated brain cytokine production, as well as memory impairments, to a subsequent peripheral immune challenge in adulthood, and therefore predicted that stressor-induced depressive-like symptoms would be more severe in these rats as well. Rats treated on postnatal day 4 with PBS or Escherichia coli were as adults exposed to inescapable tailshock stress (IS), and then tested for sucrose preference, social exploration with a juvenile, and overall activity, 1, 3, 5, and 7 days following the stressor. Serum corticosterone and extracellular 5-HT within the basolateral amygdala were measured in a second group of rats in response to the IS. IS resulted in profound depressive-like behaviors in adult rats, but, surprisingly, rats that suffered a bacterial infection early in life had blunted corticosterone responses to the stressor and were remarkably protected from the depressive symptoms compared to controls. These data suggest that early-life infection should be considered within a cost/benefit perspective, in which outcomes in adulthood may be differentially protected or impaired. These data also suggest that the immune system likely plays a previously unsuspected role in "homeostatic" HPA programming and brain development, which may ultimately lend insight into the often-contradictory literature on cytokines, inflammation, and depression.