RESUMO
Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulfate proteoglycans (CSPGs), which preferentially encase parvalbumin-containing (PV+) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase ABC (chABC)-mediated PNN removal requires intact signaling by the neurotrophin receptor TRKB in PV+ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates brain-derived neurotrophic factor (BDNF)-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase σ (PTPσ, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTPσ deletion increases phosphorylation of TRKB in vitro and in vivo in male and female mice, and juvenile-like plasticity is retained in the visual cortex of adult PTPσ-deficient mice (PTPσ+/-). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTPσ by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV+ neurons through inhibition of TRKB dephosphorylation by the PTPσ-CSPG complex.SIGNIFICANCE STATEMENT Critical period-like plasticity can be reactivated in the adult visual cortex through disruption of perineuronal nets (PNNs) by chondroitinase treatment, or by chronic antidepressant treatment. We now show that the effects of both chondroitinase and fluoxetine are mediated by the neurotrophin receptor TRKB in parvalbumin-containing (PV+) interneurons. We found that chondroitinase-induced visual cortical plasticity is dependent on TRKB in PV+ neurons. Protein tyrosine phosphatase σ (PTPσ, PTPRS), a receptor for PNNs, interacts with TRKB and inhibits its phosphorylation, and chondroitinase treatment or deletion of PTPσ increases TRKB phosphorylation. Antidepressant fluoxetine disrupts the interaction between TRKB and PTPσ, thereby increasing TRKB phosphorylation. Thus, juvenile-like plasticity induced by both chondroitinase and antidepressant treatment is mediated by TRKB activation in PV+ interneurons.
Assuntos
Antidepressivos/farmacologia , Condroitinases e Condroitina Liases/farmacologia , Glicoproteínas de Membrana/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Parvalbuminas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologiaRESUMO
Elevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.
Assuntos
Interneurônios , Plasticidade Neuronal , Córtex Visual , Animais , Interneurônios/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Parvalbuminas/metabolismo , Transmissão Sináptica , Sinaptotagmina II/metabolismo , Córtex Visual/metabolismoRESUMO
The activation of tropomyosin receptor kinase B (TrkB), the receptor of brain-derived neurotrophic factor (BDNF), plays a key role in induced juvenile-like plasticity (iPlasticity), which allows restructuring of neural networks in adulthood. Optically activatable TrkB (optoTrkB) can temporarily and spatially evoke iPlasticity, and recently, optoTrkB (E281A) was developed as a variant that is highly sensitive to light stimulation while having lower basal activity compared to the original optoTrkB. In this study, we validate optoTrkB (E281A) activated in alpha calcium/calmodulin-dependent protein kinase type II positive (CKII+) pyramidal neurons or parvalbumin-positive (PV+) interneurons in the mouse visual cortex by immunohistochemistry. OptoTrkB (E281A) was activated in PV+ interneurons and CKII+ pyramidal neurons with blue light (488 nm) through the intact skull and fur, and through a transparent skull, respectively. LED light stimulation significantly increased the intensity of phosphorylated ERK and CREB even through intact skull and fur. These findings indicate that the highly sensitive optoTrkB (E281A) can be used in iPlasticity studies of both inhibitory and excitatory neurons, with flexible stimulation protocols in behavioural studies.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Córtex Visual , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio , Camundongos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Receptor trkB/metabolismo , Tropomiosina/metabolismo , Córtex Visual/metabolismoRESUMO
The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile-like plasticity comparable to that observed during developmental critical periods: Such critical-period-like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug-induced state of juvenile-like plasticity 'iPlasticity.' A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain-derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Humanos , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Receptor trkB/fisiologiaRESUMO
Inputs to sensory cortices are known to compete for target innervation through an activity-dependent mechanism during critical periods. To investigate whether this principle also applies to association cortices such as the medial prefrontal cortex (mPFC), we produced a bilateral lesion during early development to the ventral hippocampus (vHC), an input to the mPFC, and analyzed the intensity of the projection from another input, the basolateral amgydala (BLA). We found that axons from the BLA had a higher density of "en passant" boutons in the mPFC of lesioned animals. Furthermore, the density of neurons labeled with retrograde tracers was increased, and neurons projecting from the BLA to the mPFC showed increased expression of FosB. Since neonatal ventral hippocampal lesion has been used as an animal model of schizophrenia, we investigated its effects on behavior and found a negative correlation between the density of retrogradely labeled neurons in the BLA and the reduction of the startle response in the prepulse inhibition test. Our results not only indicate that the inputs from the BLA and the vHC compete for target innervation in the mPFC during postnatal development but also that subsequent abnormal rewiring might underlie the pathophysiology of neuropsychiatric disorders such as schizophrenia.
Assuntos
Complexo Nuclear Basolateral da Amígdala/citologia , Hipocampo/citologia , Neurônios/citologia , Córtex Pré-Frontal/citologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Ácido Ibotênico , Imuno-Histoquímica , Microscopia Confocal , Vias Neurais/citologia , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Long-Evans , Filtro Sensorial/fisiologiaRESUMO
Cell adhesion molecules play important roles in the development of the nervous system. Among the contactin-associated protein (Caspr; also known as Cntnap) family, which belongs to the neurexin superfamily of proteins, Caspr and Caspr2 are indispensable for the formation and maintenance of myelinated nerves. In contrast, a physiological role for Caspr3 remains to be elucidated. This study examines the expression and localization of Caspr3 in the mouse brain using newly generated Caspr3 antibodies. Caspr3 was expressed abundantly between the first and the second postnatal weeks. During this period, Caspr3 was localized especially to the basal ganglia, including the striatum, external segment of the globus pallidus, and substantia nigra, and no gross abnormalities were apparent in the basal ganglia of Caspr3 knockout mice. In the striatum, Caspr3 was expressed by a subpopulation of medium spiny neurons that constitute the direct and indirect pathways. Caspr3 immunostaining was observed as punctate around the cell bodies as well as in the soma. These Caspr3 signals did not, however, overlap with those of synaptic markers. Our findings suggest that Caspr3 may play an important role in basal ganglia development during early postnatal stages.
Assuntos
Gânglios da Base/crescimento & desenvolvimento , Gânglios da Base/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Células Cultivadas , Corpo Estriado/citologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The L-type calcium channel blocker nimodipine improves clinical outcome produced by delayed cortical ischemia or vasospasm associated with subarachnoid hemorrhage. While vasoactive mechanisms are strongly implicated in these therapeutic actions of nimodipine, we sought to test whether nimodipine might also regulate neurotrophic and neuroplastic signaling events associated with TrkB neurotrophin receptor activation. Adult male mice were acutely treated with vehicle or nimodipine (10 mg/kg, s.c., 1.5 h) after which the phosphorylation states of TrkB, cyclic-AMP response element binding protein (CREB), protein kinase B (Akt), extracellular regulated kinase (ERK), mammalian target of rapamycin (mTor) and p70S6 kinase (p70S6k) from prefrontal cortex and hippocampus were assessed. Nimodipine increased the phosphorylation of the TrkB catalytic domain and the phosphoslipase-Cγ1 (PLCγ1) domain, whereas phosphorylation of the TrkB Shc binding site remained unaltered. Nimodipine-induced TrkB phosphorylation was associated with increased phosphorylation levels of Akt and CREB in the prefrontal cortex and the hippocampus whereas phosphorylation of ERK, mTor and p70S6k remained unaltered. Nimodipine-induced TrkB signaling was not associated with changes in BDNF mRNA or protein levels. These nimodipine-induced changes on TrkB signaling mimic those produced by antidepressant drugs and thus propose common mechanisms and long-term functional consequences for the effects of these medications. This work provides a strong basis for investigating the role of TrkB-associated signaling underlying the neuroprotective and neuroplastic effects of nimodipine in translationally relevant animal models of brain trauma or compromised synaptic plasticity.
Assuntos
Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Nimodipina/farmacologia , Córtex Pré-Frontal/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Nimodipina/administração & dosagem , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacosRESUMO
BACKGROUND: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type. METHODS: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1ß, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA). RESULTS: Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p < 0.05, FDR corrected). Twenty-three microRNAs were commonly DE across all brain injury groups when comparing favorable and unfavorable outcomes (p < 0.05). LDA of four microRNAs targeting the studied proteins showed high prognostic accuracy (OR 11.7; AUC = 94.1%, p = 0.016). CONCLUSIONS: The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.
Assuntos
Biomarcadores , MicroRNA Circulante , Plasticidade Neuronal , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Biomarcadores/sangue , MicroRNA Circulante/sangue , Idoso , Plasticidade Neuronal/fisiologia , Adulto , Hemorragia Subaracnóidea/sangue , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/diagnóstico , Estudos de Coortes , Doenças Neuroinflamatórias/sangue , AVC Isquêmico/sangue , Receptores de Fator de Crescimento Neural/sangue , Receptores de Fator de Crescimento Neural/genética , Recuperação de Função Fisiológica/fisiologia , Prognóstico , Proteínas do Tecido Nervoso , Proteínas Adaptadoras de Transporte VesicularRESUMO
BACKGROUND: Copy number variation (CNV), an important source of diversity in genomic structure, is frequently found in clusters called CNV regions (CNVRs). CNVRs are strongly associated with segmental duplications (SDs), but the composition of these complex repetitive structures remains unclear. RESULTS: We conducted self-comparative-plot analysis of all mouse chromosomes using the high-speed and large-scale-homology search algorithm SHEAP. For eight chromosomes, we identified various types of large SD as tartan-checked patterns within the self-comparative plots. A complex arrangement of diagonal split lines in the self-comparative-plots indicated the presence of large homologous repetitive sequences. We focused on one SD on chromosome 13 (SD13M), and developed SHEPHERD, a stepwise ab initio method, to extract longer repetitive elements and to characterize repetitive structures in this region. Analysis using SHEPHERD showed the existence of 60 core elements, which were expected to be the basic units that form SDs within the repetitive structure of SD13M. The demonstration that sequences homologous to the core elements (>70% homology) covered approximately 90% of the SD13M region indicated that our method can characterize the repetitive structure of SD13M effectively. Core elements were composed largely of fragmented repeats of a previously identified type, such as long interspersed nuclear elements (LINEs), together with partial genic regions. Comparative genome hybridization array analysis showed that whereas 42 core elements were components of CNVR that varied among mouse strains, 8 did not vary among strains (constant type), and the status of the others could not be determined. The CNV-type core elements contained significantly larger proportions of long terminal repeat (LTR) types of retrotransposon than the constant-type core elements, which had no CNV. The higher divergence rates observed in the CNV-type core elements than in the constant type indicate that the CNV-type core elements have a longer evolutionary history than constant-type core elements in SD13M. CONCLUSIONS: Our methodology for the identification of repetitive core sequences simplifies characterization of the structures of large SDs and detailed analysis of CNV. The results of detailed structural and quantitative analyses in this study might help to elucidate the biological role of one of the SDs on chromosome 13.
Assuntos
Variações do Número de Cópias de DNA/genética , Duplicação Gênica/genética , Genômica/métodos , Algoritmos , Animais , Análise por Conglomerados , Camundongos , Hibridização de Ácido Nucleico , Sequências Repetitivas de Ácido Nucleico/genética , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Especificidade da EspécieRESUMO
Expanding knowledge about the cellular composition of subcortical brain regions demonstrates large heterogeneity and differences from the cortical architecture. Previously we described three subtypes of somatostatin-expressing (Sst) neurons in the mouse ventral tegmental area (VTA) and showed their local inhibitory action on the neighboring dopaminergic neurons (Nagaeva et al., 2020). Here, we report that Sst+ neurons especially from the anterolateral part of the mouse VTA also project far outside the VTA and innervate forebrain regions that are mainly involved in the regulation of emotional behavior, including the ventral pallidum, lateral hypothalamus, the medial part of the central amygdala, anterolateral division of the bed nucleus of stria terminalis, and paraventricular thalamic nucleus. Deletion of these VTASst neurons in mice affected several behaviors, such as home cage activity, sensitization of locomotor activity to morphine, fear conditioning responses, and reactions to the inescapable stress of forced swimming, often in a sex-dependent manner. Together, these data demonstrate that VTASst neurons have selective projection targets distinct from the main targets of VTA dopamine neurons. VTASst neurons are involved in the regulation of behaviors primarily associated with the stress response, making them a relevant addition to the efferent VTA pathways and stress-related neuronal network.
Assuntos
Neurônios Dopaminérgicos , Área Tegmentar Ventral , Camundongos , Animais , Área Tegmentar Ventral/metabolismo , Vias Eferentes/metabolismo , Neurônios Dopaminérgicos/metabolismo , Região Hipotalâmica Lateral , Somatostatina/metabolismoRESUMO
Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.
Assuntos
Parvalbuminas , Reversão de Aprendizagem , Camundongos , Animais , Parvalbuminas/metabolismo , Fluoxetina/farmacologia , Receptor trkB/metabolismo , Interneurônios/fisiologia , Medo , Antidepressivos/farmacologia , Antidepressivos/metabolismoRESUMO
Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS.
Assuntos
Síndrome do Cromossomo X Frágil , Células-Tronco Pluripotentes Induzidas , Masculino , Animais , Camundongos , Humanos , Síndrome do Cromossomo X Frágil/genética , Astrócitos , Metabolismo dos Lipídeos , Citocinas , HomeostaseRESUMO
Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB has for a long time been recognized as a critical mediator of the antidepressant drug action, but BDNF signaling has been considered to be activated indirectly through the action of typical and rapid-acting antidepressants through monoamine transporters and glutamate NMDA receptors, respectively. However, recent findings demonstrate that both typical and the fast-acting antidepressants directly bind to TrkB and thereby allosterically potentiate BDNF signaling, suggesting that TrkB is the direct target for antidepressant drugs. Increased TrkB signaling particularly in the parvalbumin-expressing interneurons orchestrates iPlasticity, a state of juvenile-like enhanced plasticity in the adult brain. iPlasticity sensitizes neuronal networks to environmental influences, enabling rewiring of networks miswired by adverse experiences. These findings have dramatically changed the position of TrkB in the antidepressant effects and they propose a new end-to-end model of the antidepressant drug action. This model emphasizes the enabling role of antidepressant treatment and the active participation of the patient in the process of recovery from mood disorders.
RESUMO
Ultradian periodicities in physiological processes have been reported for a wide variety of organisms and may appear as bouts in locomotor activity. In some instances, this temporal organization can be related to some ethological strategy. In mice, however, ultradian rhythms have been reported largely in animals with circadian pacemakers disrupted either by genetic or surgical manipulation. Using analysis techniques capable of resolving periodicities in the ultradian range in the presence of strong diel periodicity, we found unequivocal evidence of ultradian rhythms in mice entrained to an light:dark cycle. We collected locomotor activity data of individuals from 11 genetically disparate strains of mice whose activity was recorded in 12 h:12 h L:D photoperiods for 3 days. Data were subjected to maximum entropy spectral analysis and autocorrelation, both before and after filtering to remove the 24-h periodicity. We found that every strain had a majority of individuals with strong ultradian rhythms ranging from ~3 to ~5 h. These periodicities were commonly visible in individual animals both in high-pass-filtered and in unfiltered data. Furthermore, when all raw data from a given strain were pooled to get a 24-h ensemble average across all animals and days, the rhythms continued to be discernable. We fitted Fourier series to these form estimates to model the frequency structure of each strain and found significant effects of strain and an interaction between period and strain indicating significant genetic variation for rhythmicity in the ultradian range. The techniques employed in this study should have wider use in a range of organisms and fields.
Assuntos
Ciclos de Atividade/fisiologia , Atividade Motora/fisiologia , Animais , Camundongos , Análise EspectralRESUMO
The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA). Both areas are well-known regulators of the reward-based decision-making process and hence likely to be involved in processes like evidence integration, impulsivity or addiction biology, but also in helping us to predict the valence of our future actions: i.e., what is "good" and what is "bad." Here we propose a hypothesis of a critical period, during which the inputs of the mPFC compete for target innervation, establishing specific prefrontal network configurations in the adult brain. We discuss how these different prefrontal configurations are linked to brain diseases such as addiction or neuropsychiatric disorders, and especially how drug abuse and other events during early life stages might lead to the formation of more vulnerable prefrontal network configurations. Finally, we show different promising pharmacological approaches that, when combined with the appropriate stimuli, will be able to re-establish these functional prefrontocortical configurations during adulthood.
RESUMO
P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p < 0.05, false discovery rate corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.
Assuntos
Algoritmos , Lesões Encefálicas , Mineração de Dados , Redes Reguladoras de Genes , Redes e Vias Metabólicas , Proteínas do Tecido Nervoso , Doenças Neurodegenerativas , Receptores de Fator de Crescimento Neural , Transdução de Sinais , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , PubMed , Receptores de Fator de Crescimento Neural/genética , Receptores de Fator de Crescimento Neural/metabolismoRESUMO
NETO2 is an auxiliary subunit for kainate-type glutamate receptors that mediate normal cued fear expression and extinction. Since the amygdala is critical for these functions, we asked whether Neto2-/- mice have compromised amygdala function. We measured the abundance of molecular markers of neuronal maturation and plasticity, parvalbumin-positive (PV+), perineuronal net-positive (PNN+), and double positive (PV+PNN+) cells in the Neto2-/- amygdala. We found that Neto2-/- adult, but not postnatal day (P)23, mice had 7.5% reduction in the fraction of PV+PNN+ cells within the total PNN+ population, and 23.1% reduction in PV staining intensity compared with Neto2+/+ mice, suggesting that PV interneurons in the adult Neto2-/- amygdala remain in an immature state. An immature PV inhibitory network would be predicted to lead to stronger amygdalar excitation. In the amygdala of adult Neto2-/- mice, we identified increased glutamatergic and reduced GABAergic transmission using whole-cell patch-clamp recordings. This was accompanied by increased spine density of thin dendrites in the basal amygdala (BA) compared with Neto2+/+ mice, indicating stronger glutamatergic synapses. Moreover, after fear acquisition Neto2-/- mice had a higher number of c-Fos-positive cells than Neto2+/+ mice in the lateral amygdala (LA), BA, and central amygdala (CE). Altogether, our findings indicate that Neto2 is involved in the maturation of the amygdala PV interneuron network. Our data suggest that this defect, together with other processes influencing amygdala principal neurons, contribute to increased amygdalar excitability, higher fear expression, and delayed extinction in cued fear conditioning, phenotypes that are common in fear-related disorders, including the posttraumatic stress disorder (PTSD).
Assuntos
Medo , Receptores de Ácido Caínico , Tonsila do Cerebelo/metabolismo , Animais , Interneurônios/metabolismo , Proteínas de Membrana , Camundongos , Parvalbuminas/metabolismo , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismoRESUMO
BACKGROUND: A variety of mouse strains exhibit diversity in spontaneous activity consistent with an important genetic contribution. To date, many studies have defined spontaneous home-cage activity as total distance or total counts of activity within a test period. However, spontaneous activity is, in fact, a composite of elements of 'temporal' and 'intensity' that is similar to 'velocity'. Here, we report on quantitative trait loci for different components of spontaneous activity, an important step towards dissection of the underlying genetic mechanisms. RESULTS: In the analysis of total home-cage activity (THA) after habituation in female mice, KJR strain exhibit higher activity than C57BL/6J (B6). In this study, THA was partitioned into two components: active time (AT) was an index of the 'temporal element' of THA, average activity during active time (AA) was an index of 'intensity'. Correlation analysis using B6xKJR F2 female mice indicated that AA is a major component of THA, whereas AA and AT were associated to a lesser degree. To explore the genetic basis of the activity differences, we conducted quantitative trait loci (QTL) analysis on data of THA and its components, AT and AA. Three significant QTL affecting variation of different components of home cage activity were identified, two linked QTL Hylaq1 and Hylaq2 on Chr 2, and Hylaq3 on Chr 10. Chromosomal positions of these QTL were previously implicated in locomotor activity (Chr 2) or open-field ambulation (Chr 10). The results indicated that Hylaq1 influences AT, Hylaq2, AA, while Hylaq3 is associated with both AA and AT. CONCLUSION: Through this study, we found that variation in total home cage activity over a 3 day period is affected by variation in active time and intensity of activity. The latter two variables are distinct components of home cage activity with only partially overlapping genetic architecture.
Assuntos
Camundongos Endogâmicos C57BL/genética , Atividade Motora/genética , Locos de Características Quantitativas , Animais , Mapeamento Cromossômico , Cristalização , Feminino , Genótipo , Camundongos , Repetições de Microssatélites , Análise de Sequência de DNARESUMO
Bipolar disorder is a major mental illness characterized by severe swings in mood and activity levels which occur with variable amplitude and frequency. Attempts have been made to identify mood states and biological features associated with mood changes to compensate for current clinical diagnosis, which is mainly based on patients' subjective reports. Here, we used infradian (a cycle > 24 h) cyclic locomotor activity in a mouse model useful for the study of bipolar disorder as a proxy for mood changes. We show that metabolome patterns in peripheral blood could retrospectively predict the locomotor activity levels. We longitudinally monitored locomotor activity in the home cage, and subsequently collected peripheral blood and performed metabolomic analyses. We then constructed cross-validated linear regression models based on blood metabolome patterns to predict locomotor activity levels of individual mice. Our analysis revealed a significant correlation between actual and predicted activity levels, indicative of successful predictions. Pathway analysis of metabolites used for successful predictions showed enrichment in mitochondria metabolism-related terms, such as "Warburg effect" and "citric acid cycle." In addition, we found that peripheral blood metabolome patterns predicted expression levels of genes implicated in bipolar disorder in the hippocampus, a brain region responsible for mood regulation, suggesting that the brain-periphery axis is related to mood-change-associated behaviors. Our results may serve as a basis for predicting individual mood states through blood metabolomics in bipolar disorder and other mood disorders and may provide potential insight into systemic metabolic activity in relation to mood changes.
Assuntos
Afeto , Transtorno Bipolar/sangue , Transtorno Bipolar/metabolismo , Metaboloma , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/metabolismo , Ritmo Infradiano/genética , Masculino , Camundongos , Mitocôndrias/metabolismo , Atividade Motora/genéticaRESUMO
AIM: Maturation abnormalities of the brain cells have been suggested in several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, and epilepsy. In this study, we examined the expression patterns of neuronal maturation markers in the brain of a mouse model of dementia with Lewy body-linked mutant ß-synuclein (ßS), especially in the hippocampus, to explore whether such brain abnormalities occur in neurodegenerative disorders as well. METHODS: Quantitative PCR (qPCR) and immunohistochemical analyses were performed using the hippocampus of 14-month-old P123H ßS transgenic (Tg) mice to evaluate the expression of molecular markers for maturation of dentate granule cells. RESULTS: Based on qPCR results, expression of Tdo2 and Dsp (markers of mature granule cells) was decreased and that of Drd1a (a marker of immature granule cells) was increased in the hippocampus of P123H ßS Tg mice compared to that in wild-type controls. Immunohistochemical analysis revealed decreased expression of mature granule cell markers Calb1 and Gria1, along with increased expression of the microglial marker Iba1, in the hippocampal dentate gyrus region of P123H ßS Tg mice. P123H ßS Tg mice exhibited immature-like neuronal molecular expression patterns and microgliosis in the hippocampus. Pseudo-immaturity of dentate granule cells, associated with neuroinflammation, may be a shared endophenotype in the brains of at least a subgroup of patients with neuropsychiatric disorders and neurodegenerative diseases.