Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 401
Filtrar
1.
Nat Commun ; 11(1): 4669, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938940

RESUMO

The prefrontal cortex and striatum form a recurrent network whose spiking activity encodes multiple types of learning-relevant information. This spike-encoded information is evident in average firing rates, but finer temporal coding might allow multiplexing and enhanced readout across the connected network. We tested this hypothesis in the fronto-striatal network of nonhuman primates during reversal learning of feature values. We found that populations of neurons encoding choice outcomes, outcome prediction errors, and outcome history in their firing rates also carry significant information in their phase-of-firing at a 10-25 Hz band-limited beta frequency at which they synchronize across lateral prefrontal cortex, anterior cingulate cortex and anterior striatum when outcomes were processed. The phase-of-firing code exceeds information that can be obtained from firing rates alone and is evident for inter-areal connections between anterior cingulate cortex, lateral prefrontal cortex and anterior striatum. For the majority of connections, the phase-of-firing information gain is maximal at phases of the beta cycle that were offset from the preferred spiking phase of neurons. Taken together, these findings document enhanced information of three important learning variables at specific phases of firing in the beta cycle at an inter-areally shared beta oscillation frequency during goal-directed behavior.


Assuntos
Corpo Estriado/fisiologia , Giro do Cíngulo/fisiologia , Aprendizagem/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Análise por Conglomerados , Corpo Estriado/citologia , Sincronização de Fases em Eletroencefalografia , Eletrofisiologia/métodos , Eletrofisiologia/estatística & dados numéricos , Giro do Cíngulo/citologia , Macaca mulatta , Masculino , Rede Nervosa , Córtex Pré-Frontal/citologia , Recompensa
2.
Proc Natl Acad Sci U S A ; 117(11): 6196-6204, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132213

RESUMO

Previous research has focused on the anterior cingulate cortex (ACC) as a key brain region in the mitigation of the competition that arises from two simultaneously active signals. However, to date, no study has demonstrated that ACC is necessary for this form of behavioral flexibility, nor have any studies shown that ACC acts by modulating downstream brain regions such as the dorsal medial striatum (DMS) that encode action plans necessary for task completion. Here, we performed unilateral excitotoxic lesions of ACC while recording downstream from the ipsilateral hemisphere of DMS in rats, performing a variant of the STOP-signal task. We show that on STOP trials lesioned rats perform worse, in part due to the failure of timely directional action plans to emerge in the DMS, as well as the overrepresentation of the to-be-inhibited behavior. Collectively, our findings suggest that ACC is necessary for the mitigation of competing inputs and validates many of the existing theoretical predictions for the role of ACC in cognitive control.


Assuntos
Adaptação Psicológica/fisiologia , Comportamento Animal/fisiologia , Conflito Psicológico , Giro do Cíngulo/fisiologia , Animais , Mapeamento Encefálico/instrumentação , Sinais (Psicologia) , Eletrodos Implantados , Feminino , Giro do Cíngulo/citologia , Masculino , Neurônios/fisiologia , Ratos , Técnicas Estereotáxicas/instrumentação
3.
Nat Commun ; 11(1): 1017, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094367

RESUMO

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Potenciais de Ação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Dendritos/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Feminino , Giro do Cíngulo/citologia , Giro do Cíngulo/patologia , Humanos , Interneurônios/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Células Piramidais/metabolismo , Somatostatina/metabolismo , Técnicas Estereotáxicas , Tálamo/citologia , Tálamo/metabolismo
4.
Anat Histol Embryol ; 49(1): 150-156, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31603577

RESUMO

The rabbit midcingulate cortex that enclosed four cortical areas was immunohistochemically studied using a calcium-binding protein, parvalbumin, as a neurochemical marker. The distribution of parvalbumin-immunopositive somata and fibres was similar across all four areas, where they were present mainly in layers 2/3 and 5. However, there were a slightly greater number of the immunopositive structures in the two ventral areas than the two dorsal areas. Similarity in the distribution of parvalbumin-immunopositive structures across the four areas suggests that neurons expressing parvalbumin may be involved in similar functions across the constituent areas of the rabbit midcingulate cortex.


Assuntos
Calbindina 2/metabolismo , Giro do Cíngulo/citologia , Neurônios/metabolismo , Parvalbuminas/metabolismo , Coelhos , Animais , Giro do Cíngulo/metabolismo , Imuno-Histoquímica , Coelhos/anatomia & histologia
5.
J Anat ; 235(3): 651-669, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31435943

RESUMO

Von Economo neurons (VENs) are modified pyramidal neurons characterized by an extremely elongated rod-shaped soma. They are abundant in layer V of the anterior cingulate cortex (ACC) and fronto-insular cortex (FI) of the human brain, and have long been described as a human-specific neuron type. Recently, VENs have been reported in the ACC of apes and the FI of macaque monkeys. The first description of the somato-dendritic morphology of VENs in the FI by Cajal in 1899 (Textura del Sistema Nervioso del Hombre y de los Vertebrados, Tomo II. Madrid: Nicolas Moya) strongly suggested that they were a unique neuron subtype with specific morphological features. It is surprising that a clarification of this extremely important observation has not yet been attempted, especially as possible misidentification of other oval or fusiform cells as VENs has become relevant in many recently published studies. Here, we analyzed sections of Brodmann area 24 (ACC) stained with rapid Golgi and Golgi-Cox in five adult human specimens, and confirmed Cajal's observations. In addition, we established a comprehensive morphological description of VENs. VENs have a distinct somato-dendritic morphology that allows their clear distinction from other modified pyramidal neurons. We established that VENs have a perpendicularly oriented, stick-shaped core part consisting of the cell body and two thick extensions - an apical and basal stem. The perpendicular length of the core part was 150-250 µm and the thickness was 10-21 µm. The core part was characterized by a lack of clear demarcation between the cell body and the two extensions. Numerous thin, spiny and horizontally oriented side dendrites arose from the cell body. The basal extension of the core part typically ended by giving numerous smaller dendrites with a brush-like branching pattern. The apical extension had a topology typical for apical dendrites of pyramidal neurons. The dendrites arising from the core part had a high dendritic spine density. The most distinct feature of VENs was the distant origin site of the axon, which arose from the ending of the basal extension, often having a common origin with a dendrite. Quantitative analysis found that VENs could be divided into two groups based on total dendritic length - small VENs with a peak total dendritic length of 1500-2500 µm and large VENs with a peak total dendritic length of 5000-6000 µm. Comparative morphological analysis of VENs and other oval and fusiform modified pyramidal neurons showed that on Nissl sections small VENs might be difficult to identify, and that oval and fusiform neurons could be misidentified as VENs. Our analysis of Golgi slides of Brodmann area 9 from a total of 32 adult human subjects revealed only one cell resembling VEN morphology. Thus, our data show that the numerous recent reports on the presence of VENs in non-primates in other layers and regions of the cortex need further confirmation by showing the dendritic and axonal morphology of these cells. In conclusion, our study provides a foundation for further comprehensive morphological and functional studies on VENs between different species.


Assuntos
Giro do Cíngulo/citologia , Células Piramidais/citologia , Adolescente , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem
6.
J Neurosci ; 39(34): 6668-6683, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31217329

RESUMO

The cingulate cortex contributes to complex, adaptive behaviors, but the exact nature of its contributions remains unresolved. Proposals from previous studies, including evaluating past actions or selecting future ones, have been difficult to distinguish in part because of an incomplete understanding of the task-relevant variables that are encoded by individual cingulate neurons. In this study, we recorded from individual neurons in parts of both the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) in 2 male rhesus monkeys performing a saccadic reward task. The task required them to use adaptive, feedback-driven strategies to infer the spatial location of a rewarded saccade target in the presence of different forms of uncertainty. We found that task-relevant, spatially selective feedback signals were encoded by the activity of individual neurons in both brain regions, with stronger selectivity for spatial choice and reward-target signals in PCC and stronger selectivity for feedback in ACC. Moreover, neurons in both regions were sensitive to sequential effects of feedback that partly reflected sequential behavioral patterns. However, neither brain region exhibited systematic modulations by the blockwise conditions that governed the reliability of the trial-by-trial feedback and drove adaptive behavioral patterns. There was also little evidence that single-neuron responses in either brain region directly predicted the extent to which feedback and contextual information were used to inform choices on the subsequent trial. Thus, certain cingulate neurons encode diverse, evaluative signals needed for adaptive, feedback-driven decision-making, but those signals may be integrated elsewhere in the brain to guide actions.SIGNIFICANCE STATEMENT Effective decision-making in dynamic environments requires adapting to changes in feedback and context. The anterior and posterior cingulate cortex have been implicated in adaptive decision-making, but the exact nature of their respective roles remains unresolved. Here we compare patterns of task-driven activity of subsets of individual neurons from parts of the two brain regions in monkeys performing a saccadic task with dynamically changing reward locations. We find evidence for regional specializations in neural representations of choice and feedback, including task-relevant modulations of activity that could be used for performance monitoring. However, we find little evidence that these neural representations are used directly to adjust choice behavior, which thus likely requires integration of these signals elsewhere in the brain.


Assuntos
Tomada de Decisões/fisiologia , Giro do Cíngulo/fisiologia , Neurônios/fisiologia , Autoimagem , Adaptação Psicológica/fisiologia , Animais , Comportamento de Escolha/fisiologia , Condicionamento Operante , Eletroencefalografia , Retroalimentação Psicológica , Giro do Cíngulo/citologia , Macaca mulatta , Masculino , Recompensa , Movimentos Sacádicos
7.
Mol Cell Neurosci ; 98: 19-31, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059774

RESUMO

EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of Epac2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered expression of vesicular GABA transporter (VGAT) but not vesicular glutamate transporter 1 (VGluT1), indicating an altered ratio of excitatory and inhibitory synapses onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that loss of EPAC2 enhances the stability of excitatory synapses and increases the number of inhibitory inputs.


Assuntos
Espinhas Dendríticas/fisiologia , Fatores de Troca do Nucleotídeo Guanina/genética , Potenciais Pós-Sinápticos Inibidores , Sinapses/fisiologia , Animais , Caderinas/genética , Caderinas/metabolismo , Células Cultivadas , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Potenciais Pós-Sinápticos Excitadores , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Giro do Cíngulo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
8.
J Neurosci ; 39(19): 3676-3686, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30842247

RESUMO

Stimulation and functional imaging studies have revealed the existence of a large network of cortical regions involved in the regulation of heart rate. However, very little is known about the link between cortical neural firing and cardiac-cycle duration (CCD). Here, we analyze single-unit and multiunit data obtained in humans at rest, and show that firing rate covaries with CCD in 16.7% of the sample (25 of 150). The link between firing rate and CCD was most prevalent in the anterior medial temporal lobe (entorhinal and perirhinal cortices, anterior hippocampus, and amygdala), where 36% (18 of 50) of the units show the effect, and to a lesser extent in the mid-to-anterior cingulate cortex (11.1%, 5 of 45). The variance in firing rate explained by CCD ranged from 0.5 to 11%. Several lines of analysis indicate that neural firing influences CCD, rather than the other way around, and that neural firing affects CCD through vagally mediated mechanisms in most cases. These results show that part of the spontaneous fluctuations in firing rate can be attributed to the cortical control of the cardiac cycle. The fine tuning of the regulation of CCD represents a novel physiological factor accounting for spontaneous variance in firing rate. It remains to be determined whether the "noise" introduced in firing rate by the regulation of CCD is detrimental or beneficial to the cognitive information processing carried out in the parahippocampal and cingulate regions.SIGNIFICANCE STATEMENT Fluctuations in heart rate are known to be under the control of cortical structures, but spontaneous fluctuations in cortical firing rate, or "noise," have seldom been related to heart rate. Here, we analyze unit activity in humans at rest and show that spontaneous fluctuations in neural firing in the medial temporal lobe, as well as in the mid-to-anterior cingulate cortex, influence heart rate. This phenomenon was particularly pronounced in the entorhinal and perirhinal cortices, where it could be observed in one of three neurons. Our results show that part of spontaneous firing rate variability in regions best known for their cognitive role in spatial navigation and memory corresponds to precise physiological regulations.


Assuntos
Potenciais de Ação/fisiologia , Giro do Cíngulo/fisiologia , Frequência Cardíaca/fisiologia , Neurônios/fisiologia , Giro Para-Hipocampal/fisiologia , Descanso/fisiologia , Adulto , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletrocardiografia/métodos , Feminino , Giro do Cíngulo/citologia , Humanos , Masculino , Giro Para-Hipocampal/citologia
9.
Cereb Cortex ; 29(4): 1473-1495, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29697775

RESUMO

Area 10, located in the frontal pole, is a unique specialization of the primate cortex. We studied the cortical connections of area 10 in the New World Cebus monkey, using injections of retrograde tracers in different parts of this area. We found that injections throughout area 10 labeled neurons in a consistent set of areas in the dorsolateral, ventrolateral, orbital, and medial parts of the frontal cortex, superior temporal association cortex, and posterior cingulate/retrosplenial region. However, sites on the midline surface of area 10 received more substantial projections from the temporal lobe, including clear auditory connections, whereas those in more lateral parts received >90% of their afferents from other frontal areas. This difference in anatomical connectivity reflects functional connectivity findings in the human brain. The pattern of connections in Cebus is very similar to that observed in the Old World macaque monkey, despite >40 million years of evolutionary separation, but lacks some of the connections reported in the more closely related but smaller marmoset monkey. These findings suggest that the clearer segregation observed in the human frontal pole reflects regional differences already present in early simian primates, and that overall brain mass influences the pattern of cortico-cortical connectivity.


Assuntos
Evolução Biológica , Lobo Frontal/citologia , Vias Aferentes/citologia , Animais , Cebus , Feminino , Giro do Cíngulo/citologia , Masculino , Técnicas de Rastreamento Neuroanatômico , Neurônios/citologia , Lobo Temporal/citologia
10.
Anat Rec (Hoboken) ; 301(11): 1871-1881, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30289208

RESUMO

Relatively little neuroscience research has been focused on artiodactyls. Recent observations of complex social interactions in domestic and wild species suggest that analyses of artiodactyl brain anatomy would be of comparative value. In this study, we examined how the distribution of cortical neuropil space (a proxy for connectivity) varies across representative members of this diverse clade. Using image analysis techniques, we quantified the neuropil space in the anterior cingulate cortex (ACC) and the occipital (putative primary visual) cortex (OC) of 12 artiodactyl species from adult specimens. Additionally, we conducted a preliminary investigation of variation in ACC neuropil space in a developmental series of five white-tailed deer (Odocoileus virginianus). Results indicate a consistent pattern of greater neuropil space in the ACC in comparison to the OC among all species, and a gradual increase in ACC neuropil space toward maturity in the white-tailed deer. Given the taxa that have the greatest cortical neuropil space, we hypothesize that such enhanced connectivity might be needed to support behaviors such as group foraging and attentiveness to conspecifics. These results help advance a broader understanding of diversity in neural circuitry in artiodactyls and point to the need for more in-depth comparisons of cortical neuron morphology and organization in this relatively understudied taxonomic group. Anat Rec, 301:1871-1881, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Giro do Cíngulo/citologia , Neurópilo/citologia , Lobo Occipital/citologia , Animais , Artiodáctilos , Giro do Cíngulo/fisiologia , Neurópilo/fisiologia , Lobo Occipital/fisiologia , Filogenia
11.
Nat Commun ; 9(1): 3526, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166546

RESUMO

Alcohol is a traditional social-bonding reinforcer; however, the neural mechanism underlying ethanol-driven social behaviors remains elusive. Here, we report that ethanol facilitates observational fear response. Observer mice exhibited stronger defensive immobility while observing cagemates that received repetitive foot shocks if the observer mice had experienced a brief priming foot shock. This enhancement was associated with an observation-induced recruitment of subsets of anterior cingulate cortex (ACC) neurons in the observer mouse that were responsive to its own pain. The vicariously activated ACC neurons projected their axons preferentially to the basolateral amygdala. Ethanol shifted the ACC neuronal balance toward inhibition, facilitated the preferential ACC neuronal recruitment during observation, and enhanced observational fear response, independent of an oxytocin signaling pathway. Furthermore, ethanol enhanced socially evoked fear response in autism model mice.


Assuntos
Giro do Cíngulo/citologia , Neurônios/citologia , Dor/metabolismo , Animais , Eletrofisiologia , Etanol , Feminino , Giro do Cíngulo/fisiologia , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Dor/fisiopatologia
12.
PLoS One ; 13(7): e0200567, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001424

RESUMO

Somatostatin-expressing (SOM+), inhibitory interneurons represent a heterogeneous group of cells and given their remarkable diversity, classification of SOM+ interneurons remains a challenging task. Electrophysiological, morphological and neurochemical classes of SOM+ interneurons have been proposed in the past but it remains unclear as to what extent these classes are congruent. We performed whole-cell patch-clamp recordings from 127 GFP-labeled SOM+ interneurons ('GIN') of the superficial cingulate cortex with subsequent biocytin-filling and immunocytochemical labeling. Principal component analysis followed by k-means clustering predicted two putative subtypes of SOM+ interneurons, which we designated as group I and group II GIN. A key finding of our study is the fact that these electrophysiologically and morphologically distinct groups of SOM+ interneurons can be correlated with two neurochemical subtypes of SOM+ interneurons described recently in our laboratory. In particular, all SOM+ interneurons expressing calbindin but no calretinin could be classified as group I GIN, whereas all but one neuropeptide Y- and calretinin-positive interneurons were found in group II.


Assuntos
Neurônios GABAérgicos , Giro do Cíngulo , Interneurônios , Somatostatina/biossíntese , Animais , Calbindinas/biossíntese , Neurônios GABAérgicos/classificação , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Interneurônios/classificação , Interneurônios/citologia , Interneurônios/metabolismo , Camundongos , Neuropeptídeo Y/biossíntese
13.
Mol Pain ; 14: 1744806918783478, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956582

RESUMO

Background Chronic pain is a persistent unpleasant sensation that produces pathological synaptic plasticity in the central nervous system. Both human imaging study and animal studies consistently demonstrate that the anterior cingulate cortex is a critical cortical area for nociceptive and chronic pain processing. Thus far, the mechanisms of excitatory synaptic transmission and plasticity have been well characterized in the anterior cingulate cortex for various models of chronic pain. By contrast, the potential contribution of inhibitory synaptic transmission in the anterior cingulate cortex, in models of chronic pain, is not fully understood. Methods Chronic inflammation was induced by complete Freund adjuvant into the adult mice left hindpaw. We performed in vitro whole-cell patch-clamp recordings from layer II/III pyramidal neurons in two to three days after the complete Freund adjuvant injection and examined if the model could cause plastic changes, including transient and tonic type A γ-aminobutyric acid (GABAA) receptor-mediated inhibitory synaptic transmission, in the anterior cingulate cortex. We analyzed miniature/spontaneous inhibitory postsynaptic currents, GABAA receptor-mediated tonic currents, and evoked inhibitory postsynaptic currents. Finally, we studied if GABAergic transmission-related proteins in the presynapse and postsynapse of the anterior cingulate cortex were altered. Results The complete Freund adjuvant model reduced the frequency of both miniature and spontaneous inhibitory postsynaptic currents compared with control group. By contrast, the average amplitude of these currents was not changed between two groups. Additionally, the complete Freund adjuvant model did not change GABAA receptor-mediated tonic currents nor the set of evoked inhibitory postsynaptic currents when compared with control group. Importantly, protein expression of vesicular GABA transporter was reduced within the presynpase of the anterior cingulate cortex in complete Freund adjuvant model. In contrast, the complete Freund adjuvant model did not change the protein levels of GABAA receptors subunits such as α1, α5, ß2, γ2, and δ. Conclusion Our results suggest that the induction phase of inflammatory pain involves spontaneous GABAergic plasticity at presynaptic terminals of the anterior cingulate cortex.


Assuntos
Dor Crônica/complicações , Dor Crônica/patologia , Giro do Cíngulo/patologia , Inflamação/etiologia , Plasticidade Neuronal/fisiologia , Limiar da Dor/fisiologia , Ácido gama-Aminobutírico/metabolismo , Anestésicos Locais/farmacologia , Anestésicos Locais/uso terapêutico , Animais , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Adjuvante de Freund/toxicidade , Antagonistas de Receptores de GABA-A/farmacologia , Giro do Cíngulo/citologia , Técnicas In Vitro , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Estimulação Física/efeitos adversos , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/fisiologia , Tetrodotoxina/farmacologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
14.
BMC Genomics ; 19(1): 340, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29739336

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are a novel class of endogenous, non-coding RNAs that form covalently closed continuous loops and that are both highly conserved and abundant in the mammalian brain. A role for circRNAs in sponging microRNAs (miRNAs) has been proposed, but the circRNA-miRNA-mRNA interaction networks in human brain cells have not been defined. Therefore, we identified circRNAs in RNA sequencing data previously generated from astrocytes microdissected from the posterior cingulate (PC) of Alzheimer's disease (AD) patients (N = 10) and healthy elderly controls (N = 10) using four circRNA prediction algorithms - CIRI, CIRCexplorer, find_circ and KNIFE. RESULTS: Overall, utilizing these four tools, we identified a union of 4438 unique circRNAs across all samples, of which 70.3% were derived from exonic regions. Notably, the widely reported CDR1as circRNA was detected in all samples across both groups by find_circ. Given the putative miRNA regulatory function of circRNAs, we identified potential miRNA targets of circRNAs, and further, delineated circRNA-miRNA-mRNA networks using in silico methods. Pathway analysis of the genes regulated by these miRNAs identified significantly enriched immune response pathways, which is consistent with the known function of astrocytes as immune sensors in the brain. CONCLUSIONS: In this study, we performed circRNA detection on cell-specific transcriptomic data and identified potential circRNA-miRNA-mRNA regulatory networks in PC astrocytes. Given the known function of astrocytes in cerebral innate immunity and our identification of significantly enriched immune response pathways, the circRNAs we identified may be associated with such key functions. While we did not detect recurrent differentially expressed circRNAs in the context of healthy controls or AD, we report for the first time circRNAs and their potential regulatory impact in a cell-specific and region-specific manner in aged subjects. These predicted regulatory network and pathway analyses may help provide new insights into transcriptional regulation in the brain.


Assuntos
Doença de Alzheimer/genética , Astrócitos/metabolismo , Redes Reguladoras de Genes , Marcadores Genéticos , Giro do Cíngulo/metabolismo , RNA/genética , Idoso , Doença de Alzheimer/patologia , Astrócitos/citologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Giro do Cíngulo/citologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , MicroRNAs/genética , RNA Circular , RNA Mensageiro/genética
15.
J Neurosci ; 38(15): 3823-3839, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29540548

RESUMO

Itch is an unpleasant sensation that initiates scratching behavior. The itch-scratch reaction is a complex phenomenon that implicates supraspinal structures required for regulation of sensory, emotional, cognitive, and motivational aspects. However, the central mechanisms underlying the processing of itch and the interplay of the supraspinal regions and spinal cord in regulating itch-scratch processes are poorly understood. Here, we have shown that the neural projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a critical circuit element for regulating itch-related behaviors in the brains of male C57BL/6J mice. Moreover, we demonstrate that ACC-DMS projections selectively modulate histaminergic, but not nonhistaminergic, itch-related behavior. Furthermore, photoactivation of ACC-DMS projections has also no significant effects on pain behavior induced by thermal, mechanical, and chemical stimuli except for a relief on inflammatory pain evoked by formalin and complete Freund's adjuvant. We further demonstrate that the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons, which represent a population of spinal inhibitory interneurons that mediate the inhibition of itch. Therefore, this study presents the first evidence that the ACC-DMS projections modulate histaminergic itch-related behavior and reveals an interplay between the supraspinal and spinal levels in histaminergic itch regulation.SIGNIFICANCE STATEMENT This study reveals that the projections from anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) constitute a supraspinal circuit for modulation of histaminergic, but not nonhistaminergic, itch. Manipulation of ACC-DMS projections has no effect on acute pain sensation. Furthermore, the dorsal spinal cord exerts an inhibitory effect on itch signal from ACC-DMS projections through B5-I neurons. Understanding the supraspinal itch circuits is of great significance in the development of new therapies for chronic itch-related intractable diseases.


Assuntos
Corpo Estriado/fisiologia , Giro do Cíngulo/fisiologia , Histamina/metabolismo , Neurônios/fisiologia , Prurido/fisiopatologia , Animais , Corpo Estriado/citologia , Giro do Cíngulo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Nociceptividade
16.
eNeuro ; 5(1)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29527569

RESUMO

To understand the hippocampus, it is necessary to understand the subiculum. Unlike other hippocampal subfields, the subiculum projects to almost all distal hippocampal targets, highlighting its critical importance for external networks. The present studies, in male rats and mice, reveal a new category of dorsal subiculum neurons that innervate both the mammillary bodies (MBs) and the retrosplenial cortex (RSP). These bifurcating neurons comprise almost half of the hippocampal cells that project to RSP. The termination of these numerous collateral projections was visualized within the medial mammillary nucleus and the granular RSP (area 29). These collateral projections included subiculum efferents that cross to the contralateral MBs. Within the granular RSP, the collateral projections form a particularly dense plexus in deep Layer II and Layer III. This retrosplenial termination site colocalized with markers for VGluT2 and neurotensin. While efferents from the hippocampal CA fields standardly collateralize, subiculum projections often have only one target site. Consequently, the many collateral projections involving the RSP and the MBs present a relatively unusual pattern for the subiculum, which presumably relates to how both targets have complementary roles in spatial processing. Furthermore, along with the anterior thalamic nuclei, the MBs and RSP are key members of a memory circuit, which is usually described as both starting and finishing in the hippocampus. The present findings reveal how the hippocampus simultaneously engages different parts of this circuit, so forcing an important revision of this network.


Assuntos
Giro do Cíngulo/citologia , Hipocampo/citologia , Corpos Mamilares/citologia , Neurônios/citologia , Animais , Núcleos Anteriores do Tálamo/citologia , Masculino , Camundongos Endogâmicos C57BL , Vias Neurais/citologia , Técnicas de Rastreamento Neuroanatômico , Ratos , Especificidade da Espécie
17.
Behav Brain Res ; 344: 120-131, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29444449

RESUMO

Memory consolidation is a dynamic process that involves a sequential remodeling of hippocampal-cortical circuits. Although synaptic events underlying memory consolidation are well assessed, fine molecular events controlling this process deserve further characterization. To this aim, we challenged male C57BL/6N mice in a contextual fear conditioning (CFC) paradigm and tested their memory 24 h, 7 days or 36 days later. Mice displayed a strong fear response at all time points with an increase in dendritic spine density and protein levels of the cell adhesion factor EphrinB2 in CA1 hippocampal neurons 24 h and 7 days post conditioning (p.c.), and in anterior cingulate cortex (ACC) neurons 36 days p.c. We then investigated whether the formation of remote memory and neuronal modifications in the ACC would depend on p.c. protein synthesis in hippocampal neurons. Bilateral intrahippocampal infusions with the protein synthesis inhibitor anisomycin administered immediately p.c. decreased fear response, neuronal spine growth and EphrinB2 protein levels of hippocampal and ACC neurons 24 h and 36 days p.c., respectively. Anisomycin infusion 24 h p.c. had no effects on fear response, increase in spine density and in EphrinB2 protein levels in ACC neurons 36 days p.c. Our results thus confirm that early but not late p.c. hippocampal protein synthesis is necessary for the formation of remote memory and provide the first evidence of a possible involvement of EphrinB2 in neuronal plasticity in the ACC.


Assuntos
Região CA1 Hipocampal/metabolismo , Espinhas Dendríticas/fisiologia , Efrina-B2/metabolismo , Medo/fisiologia , Giro do Cíngulo/fisiologia , Memória/fisiologia , Animais , Anisomicina/farmacologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Medo/efeitos dos fármacos , Giro do Cíngulo/citologia , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Inibidores da Síntese de Proteínas/farmacologia , Receptor EphA4/metabolismo , Fatores de Tempo
18.
Cell Rep ; 22(1): 84-95, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29298436

RESUMO

Cognitive abilities, such as volitional attention, operate under top-down, executive frontal cortical control of hierarchically lower structures. The circuit mechanisms underlying this process are unresolved. The claustrum possesses interconnectivity with many cortical areas and, thus, is hypothesized to orchestrate the cortical mantle for top-down control. Whether the claustrum receives top-down input and how this input may be processed by the claustrum have yet to be formally tested, however. We reveal that a rich anterior cingulate cortex (ACC) input to the claustrum encodes a preparatory top-down information signal on a five-choice response assay that is necessary for optimal task performance. We further show that ACC input monosynaptically targets claustrum inhibitory interneurons and spiny glutamatergic projection neurons, the latter of which amplify ACC input in a manner that is powerfully constrained by claustrum inhibitory microcircuitry. These results demonstrate ACC input to the claustrum is critical for top-down control guiding action.


Assuntos
Gânglios da Base , Giro do Cíngulo , Interneurônios , Animais , Gânglios da Base/citologia , Gânglios da Base/fisiologia , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Camundongos , Camundongos Transgênicos
19.
J Neurosci ; 38(7): 1788-1801, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29335357

RESUMO

Continuation of spiking after a stimulus ends (i.e. persistent spiking) is thought to support working memory. Muscarinic receptor activation enables persistent spiking among synaptically isolated pyramidal neurons in anterior cingulate cortex (ACC), but a detailed characterization of that spiking is lacking and the underlying mechanisms remain unclear. Here, we show that the rate of persistent spiking in ACC neurons is insensitive to the intensity and number of triggers, but can be modulated by injected current, and that persistent spiking can resume after several seconds of hyperpolarization-imposed quiescence. Using electrophysiology and calcium imaging in brain slices from male rats, we determined that canonical transient receptor potential (TRPC) channels are necessary for persistent spiking and that TRPC-activating calcium enters in a spike-dependent manner via voltage-gated calcium channels. Constrained by these biophysical details, we built a computational model that reproduced the observed pattern of persistent spiking. Nonlinear dynamical analysis of that model revealed that TRPC channels become fully activated by the small rise in intracellular calcium caused by evoked spikes. Calcium continues to rise during persistent spiking, but because TRPC channel activation saturates, firing rate stabilizes. By calcium rising higher than required for maximal TRPC channel activation, TRPC channels are able to remain active during periods of hyperpolarization-imposed quiescence (until calcium drops below saturating levels) such that persistent spiking can resume when hyperpolarization is discontinued. Our results thus reveal that the robust intrinsic bistability exhibited by ACC neurons emerges from the nonlinear positive feedback relationship between spike-dependent calcium influx and TRPC channel activation.SIGNIFICANCE STATEMENT Neurons use action potentials, or spikes, to encode information. Some neurons can store information for short periods (seconds to minutes) by continuing to spike after a stimulus ends, thus enabling working memory. This so-called "persistent" spiking occurs in many brain areas and has been linked to activation of canonical transient receptor potential (TRPC) channels. However, TRPC activation alone is insufficient to explain many aspects of persistent spiking such as resumption of spiking after periods of imposed quiescence. Using experiments and simulations, we show that calcium influx caused by spiking is necessary and sufficient to activate TRPC channels and that the ensuing positive feedback interaction between intracellular calcium and TRPC channel activation can account for many hitherto unexplained aspects of persistent spiking.


Assuntos
Sinalização do Cálcio/fisiologia , Giro do Cíngulo/citologia , Giro do Cíngulo/fisiologia , Neurônios/fisiologia , Canais de Receptores Transientes de Potencial/fisiologia , Algoritmos , Animais , Canais de Cálcio/fisiologia , Simulação por Computador , Fenômenos Eletrofisiológicos/fisiologia , Retroalimentação Psicológica , Masculino , Dinâmica não Linear , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley
20.
Cortex ; 99: 69-77, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29175073

RESUMO

BACKGROUND: Throughout the human aging lifespan, neurons acquire an unusually high burden of wear and tear; this is likely why age is considered the strongest risk factor for the development of Alzheimer's Disease (AD). Von Economo neurons (VENs) are rare, spindle-shaped cells mostly populated in anterior cingulate cortex. In a prior study, "SuperAgers" (individuals older than 80 years of age with outstanding memory ability) showed higher VEN densities compared to elderly controls with average memory, and those with amnestic Mild Cognitive Impairment (aMCI). The intrinsic vulnerabilities of these neurons are unclear, and their contribution to neurodegeneration is unknown. The current study investigated the influence of age and the severity of Alzheimer's disease (AD) on VEN density. METHODS: VEN and total neuronal densities were quantitated using unbiased stereological methods in the anterior cingulate cortex of postmortem samples from the following subject groups: younger controls (age 20-60), SuperAgers, cognitively average elderly controls (age 65+), individuals diagnosed antemortem with aMCI, and individuals diagnosed antemortem with dementia of AD (N = 5, per group). RESULTS: The AD group showed significantly lower VEN density compared to younger and older controls (p < .05), but not compared to the aMCI group, and VENs bearing neurofibrillary tangles were discovered in AD cases. The aMCI group showed lower VEN density than elderly controls, but this was not significant. There was a significant negative correlation between VEN density and Braak stages of AD (p < .001). Consistent with prior findings, SuperAgers showed highest mean VEN density, even when compared to younger cases. CONCLUSIONS: VENs in human anterior cingulate cortex are vulnerable to AD pathology, particularly in later stages of pathogenesis. Their densities do not change throughout aging in individuals with average cognition, and they are more numerous in SuperAgers.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Giro do Cíngulo/patologia , Neurônios/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Contagem de Células , Feminino , Giro do Cíngulo/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...