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Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.
Assuntos
Envelhecimento/patologia , Corpo Estriado/patologia , Doença de Huntington/patologia , Aprendizagem , Potenciais de Ação , Animais , Comportamento Animal , Biomarcadores/metabolismo , Corpo Estriado/fisiopatologia , Aprendizagem por Discriminação , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Interneurônios/patologia , Camundongos Transgênicos , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Parvalbuminas/metabolismo , Fotometria , Recompensa , Análise e Desempenho de TarefasRESUMO
In neurons, fast axonal transport (FAT) of vesicles occurs over long distances and requires constant and local energy supply for molecular motors in the form of adenosine triphosphate (ATP). FAT is independent of mitochondrial metabolism. Indeed, the glycolytic machinery is present on vesicles and locally produces ATP, as well as nicotinamide adenine dinucleotide bonded with hydrogen (NADH) and pyruvate, using glucose as a substrate. It remains unclear whether pyruvate is transferred to mitochondria from the vesicles as well as how NADH is recycled into NAD+ on vesicles for continuous glycolysis activity. The optimization of a glycolytic activity test for subcellular compartments allowed the evaluation of the kinetics of vesicular glycolysis in the brain. This revealed that glycolysis is more efficient on vesicles than in the cytosol. We also found that lactate dehydrogenase (LDH) enzymatic activity is required for effective vesicular ATP production. Indeed, inhibition of LDH or the forced degradation of pyruvate inhibited ATP production from axonal vesicles. We found LDHA rather than the B isoform to be enriched on axonal vesicles suggesting a preferential transformation of pyruvate to lactate and a concomitant recycling of NADH into NAD+ on vesicles. Finally, we found that LDHA inhibition dramatically reduces the FAT of both dense-core vesicles and synaptic vesicle precursors in a reconstituted cortico-striatal circuit on-a-chip. Together, this shows that aerobic glycolysis is required to supply energy for vesicular transport in neurons, similar to the Warburg effect.
Assuntos
Glicólise , NAD , NAD/metabolismo , Glicólise/fisiologia , Axônios/metabolismo , Trifosfato de Adenosina/metabolismo , Piruvatos/metabolismoRESUMO
Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.
Assuntos
Córtex Motor , Córtex Sensório-Motor , Humanos , Corpo Estriado/diagnóstico por imagem , Neostriado , Córtex Motor/diagnóstico por imagem , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/métodos , Imageamento por Ressonância MagnéticaRESUMO
The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.
Assuntos
Lobo Frontal , Camundongos Transgênicos , Córtex Motor , Vias Neurais , Córtex Somatossensorial , Animais , Córtex Motor/fisiologia , Masculino , Feminino , Camundongos , Córtex Somatossensorial/fisiologia , Lobo Frontal/fisiologia , Vias Neurais/fisiologia , Lateralidade Funcional/fisiologia , Corpo Estriado/fisiologiaRESUMO
The assembly of functional neuronal circuits requires appropriate numbers of distinct classes of neurons, but the mechanisms through which their relative proportions are established remain poorly defined. Investigating the mouse striatum, we found that the two most prominent subtypes of striatal interneurons, parvalbumin-expressing (PV+) GABAergic and cholinergic (ChAT+) interneurons, undergo extensive programmed cell death between the first and second postnatal weeks. Remarkably, the survival of PV+ and ChAT+ interneurons is regulated by distinct mechanisms mediated by their specific afferent connectivity. While long-range cortical inputs control PV+ interneuron survival, ChAT+ interneuron survival is regulated by local input from the medium spiny neurons. Our results identify input-specific circuit mechanisms that operate during the period of programmed cell death to establish the final number of interneurons in nascent striatal networks.
Assuntos
Corpo Estriado , Interneurônios , Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , ParvalbuminasRESUMO
Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.
Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Núcleo Subtalâmico , Ratos , Animais , Neurônios Dopaminérgicos/metabolismo , Dopamina/metabolismo , Glutamina/metabolismo , Transtornos Parkinsonianos/metabolismo , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , Glutamatos/metabolismo , Oxidopamina/farmacologiaRESUMO
The value associated with reward is sensitive to external factors, such as the time between the choice and reward delivery as classically manipulated in temporal discounting tasks. Subjective preference for two reward options is dependent on objective variables of reward magnitude and reward delay. Single neuron correlates of reward value have been observed in regions, including ventral striatum, orbital, and medial prefrontal cortex. Brain imaging studies show cortico-striatal-limbic network activity related to subjective preferences. To explore how oscillatory dynamics represent reward processing across brain regions, we measured local field potentials of rats performing a temporal discounting task. Our goal was to use a data-driven approach to identify an electrophysiological marker that correlates with reward preference. We found that reward-locked oscillations at beta frequencies signaled the magnitude of reward and decayed with longer temporal delays. Electrodes in orbitofrontal/medial prefrontal cortex, anterior insula, ventral striatum, and amygdala individually increased power and were functionally connected at beta frequencies during reward outcome. Beta power during reward outcome correlated with subjective value as defined by a computational model fit to the discounting behavior. These data suggest that cortico-striatal beta oscillations are a reward signal correlated, which may represent subjective value and hold potential to serve as a biomarker and potential therapeutic target.
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Huntington's disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.
Assuntos
Corpo Estriado , Modelos Animais de Doenças , Vesículas Extracelulares , Doença de Huntington , Aprendizagem , Destreza Motora , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/genética , Animais , Vesículas Extracelulares/metabolismo , Destreza Motora/fisiologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Aprendizagem/fisiologia , Camundongos , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BLRESUMO
The diagnosis of obsessive-compulsive disorder (OCD) has been linked with changes in frontostriatal resting-state connectivity. However, replication of prior findings is lacking, and the mechanistic understanding of these effects is incomplete. To confirm and advance knowledge on changes in frontostriatal functional connectivity in OCD, participants with OCD and matched healthy controls underwent resting-state functional, structural and diffusion neuroimaging. Functional connectivity changes in frontostriatal systems were here replicated in individuals with OCD (n = 52) compared with controls (n = 45). OCD participants showed greater functional connectivity (t = 4.3, PFWE = 0.01) between the nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC) but lower functional connectivity between the dorsal putamen and lateral prefrontal cortex (t = 3.8, PFWE = 0.04) relative to controls. Computational modelling suggests that NAcc-OFC connectivity changes reflect an increased influence of NAcc over OFC activity and reduced OFC influence over NAcc activity (posterior probability, Pp > 0.66). Conversely, dorsal putamen showed reduced modulation over lateral prefrontal cortex activity (Pp > 0.90). These functional deregulations emerged on top of a generally intact anatomical substrate. We provide out-of-sample replication of opposite changes in ventro-anterior and dorso-posterior frontostriatal connectivity in OCD and advance the understanding of the neural underpinnings of these functional perturbations. These findings inform the development of targeted therapies normalizing frontostriatal dynamics in OCD.
Assuntos
Imageamento por Ressonância Magnética , Transtorno Obsessivo-Compulsivo , Humanos , Córtex Pré-Frontal/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Núcleo Accumbens , Putamen/diagnóstico por imagem , Mapeamento EncefálicoRESUMO
OBJECTIVE: The development of novel treatments for anorexia nervosa (AN) requires a detailed understanding of the biological underpinnings of specific, commonly occurring symptoms, including compulsive exercise. There is considerable bio-behavioral overlap between AN and obsessive-compulsive disorder (OCD), therefore it is plausible that similar mechanisms underlie compulsive behavior in both populations. While the association between these conditions is widely acknowledged, defining the shared mechanisms for compulsive behavior in AN and OCD requires a novel approach. METHODS: We present an argument that a better understanding of the neurobiological mechanisms that underpin compulsive exercise in AN can be achieved in two critical ways. First, by applying a framework of the neuronal control of OCD to exercise behavior in AN, and second, by taking better advantage of the activity-based anorexia (ABA) rodent model to directly test this framework in the context of feeding pathology. RESULTS: A cross-disciplinary approach that spans preclinical, neuroimaging, and clinical research as well as compulsive neurocircuitry and behavior can advance our understanding of when, why, and how compulsive exercise develops in the context of AN and provide targets for novel treatment strategies. DISCUSSION: In this article, we (i) link the expression of compulsive behavior in AN and OCD via a transition between goal-directed and habitual behavior, (ii) present disrupted cortico-striatal circuitry as a key substrate for the development of compulsive behavior in both conditions, and (iii) highlight the utility of the ABA rodent model to better understand the mechanisms of compulsive behavior relevant to AN. PUBLIC SIGNIFICANCE: Individuals with AN who exercise compulsively are at risk of worse health outcomes and have poorer responses to standard treatments. However, when, why, and how compulsive exercise develops in AN remains inadequately understood. Identifying whether the neural circuitry underlying compulsive behavior in OCD also controls hyperactivity in the activity-based anorexia model will aid in the development of novel eating disorder treatment strategies for this high-risk population.
Assuntos
Anorexia Nervosa , Transtorno Obsessivo-Compulsivo , Anorexia Nervosa/terapia , Anorexia Nervosa/fisiopatologia , Humanos , Animais , Transtorno Obsessivo-Compulsivo/terapia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Exercício Compulsivo , Modelos Animais de Doenças , Comportamento Compulsivo/fisiopatologiaRESUMO
AIM: The effective connectivity between the striatum and cerebral cortex has not been fully investigated in attention-deficit/hyperactivity disorder (ADHD). Our objective was to explore the interaction effects between diagnosis and age on disrupted corticostriatal effective connectivity and to represent the modulation function of altered connectivity pathways in children and adolescents with ADHD. METHODS: We performed Granger causality analysis on 300 participants from a publicly available Attention-Deficit/Hyperactivity Disorder-200 dataset. By computing the correlation coefficients between causal connections between striatal subregions and other cortical regions, we estimated the striatal inflow and outflow connection to represent intermodulation mechanisms in corticostriatal pathways. RESULTS: Interactions between diagnosis and age were detected in the superior occipital gyrus within the visual network, medial prefrontal cortex, posterior cingulate gyrus, and inferior parietal lobule within the default mode network, which is positively correlated with hyperactivity/impulsivity severity in ADHD. Main effect of diagnosis exhibited a general higher cortico-striatal causal connectivity involving default mode network, frontoparietal network and somatomotor network in ADHD compared with comparisons. Results from high-order effective connectivity exhibited a disrupted information pathway involving the default mode-striatum-somatomotor-striatum-frontoparietal networks in ADHD. CONCLUSION: The interactions detected in the visual-striatum-default mode networks pathway appears to be related to the potential distraction caused by long-term abnormal information input from the retina in ADHD. Higher causal connectivity and weakened intermodulation may indicate the pathophysiological process that distractions lead to the impairment of motion planning function and the inhibition/control of this unplanned motion signals in ADHD.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Córtex Cerebral , Corpo Estriado , Imageamento por Ressonância Magnética , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Criança , Adolescente , Masculino , Feminino , Córtex Cerebral/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Corpo Estriado/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Rede de Modo Padrão/fisiopatologia , Rede de Modo Padrão/diagnóstico por imagem , Conectoma , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagemRESUMO
In Parkinson's disease patients and rodent models, dopaminergic neuron loss (DAN) results in severe motor disabilities. In contrast, general motility is preserved after early postnatal DAN loss in rodents. Here we used mice of both sexes to show that the preserved motility observed after early DAN loss depends on functional changes taking place in medium spiny neurons (MSN) of the dorsomedial striatum (DMS) that belong to the direct pathway (dMSN). Previous animal model studies showed that adult loss of dopaminergic input depresses dMSN response to cortical input, which likely contributes to Parkinson's disease motor impairments. However, the response of DMS-dMSN to their preferred medial PFC input is preserved after neonatal DAN loss as shown by in vivo studies. Moreover, their response to inputs from adjacent cortical areas is increased, resulting in reduced cortical inputs selectivity. Additional ex vivo studies show that membrane excitability increases in dMSN. Furthermore, chemogenetic inhibition of DMS-dMSN has a more marked inhibitory effect on general motility in lesioned mice than in their control littermates, indicating that expression of normal levels of locomotion and general motility depend on dMSN activity after early DAN loss. Contrastingly, DMS-dMSN inhibition did not ameliorate a characteristic phenotype of the DAN-lesioned animals in a marble burying task demanding higher behavioral control. Thus, increased dMSN excitability likely promoting changes in corticostriatal functional connectivity may contribute to the distinctive behavioral phenotype emerging after developmental DAN loss, with implications for our understanding of the age-dependent effects of forebrain dopamine depletion and neurodevelopment disorders.SIGNIFICANCE STATEMENT The loss of striatal dopamine in the adult brain leads to life-threatening motor impairments. However, general motility remains largely unaffected after its early postnatal loss. Here, we show that the high responsiveness to cortical input of striatal neurons belonging to the direct basal ganglia pathway, crucial for proper motor functioning, is preserved after early dopamine neuron loss, in parallel with an increase in these cells' membrane excitability. Chemogenetic inhibition studies show that the preserved motility depends on this direct pathway hyperexcitability/hyperconnectivity, while other phenotypes characteristic of this condition remained unaltered despite the dMSN inhibition. This insight has implications for our understanding of the mechanism underlying the behavioral impairments observed in neuropsychiatric conditions linked to early dopaminergic hypofunction.
Assuntos
Dopamina , Doença de Parkinson , Masculino , Feminino , Camundongos , Animais , Dopamina/metabolismo , Doença de Parkinson/patologia , Corpo Estriado/metabolismo , Gânglios da Base , Neurônios Dopaminérgicos/metabolismoRESUMO
Learning and recognition can be improved by sorting novel items into categories and subcategories. Such hierarchical categorization is easy when it can be performed according to learned rules (e.g., "if car, then automatic or stick shift" or "if boat, then motor or sail"). Here, we present results showing that human participants acquire categorization rules for new visual hierarchies rapidly, and that, as they do, corresponding hierarchical representations of the categorized stimuli emerge in patterns of neural activation in the dorsal striatum and in posterior frontal and parietal cortex. Participants learned to categorize novel visual objects into a hierarchy with superordinate and subordinate levels based on the objects' shape features, without having been told the categorization rules for doing so. On each trial, participants were asked to report the category and subcategory of the object, after which they received feedback about the correctness of their categorization responses. Participants trained over the course of a one-hour-long session while their brain activation was measured using functional magnetic resonance imaging. Over the course of training, significant hierarchy learning took place as participants discovered the nested categorization rules, as evidenced by the occurrence of a learning trial, after which performance suddenly increased. This learning was associated with increased representational strength of the newly acquired hierarchical rules in a corticostriatal network including the posterior frontal and parietal cortex and the dorsal striatum. We also found evidence suggesting that reinforcement learning in the dorsal striatum contributed to hierarchical rule learning.
Assuntos
Mapeamento Encefálico , Lobo Parietal , Humanos , Mapeamento Encefálico/métodos , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiologia , Aprendizagem/fisiologia , Encéfalo/fisiologia , Reforço Psicológico , Imageamento por Ressonância MagnéticaRESUMO
Tardive dyskinesia is a involuntary hyperkinetic disorder which usually occurs in older patients after long-term treatment with antipsychotic drugs. These dyskinesias are mostly irreversible and are frequently expressed in the tongue, cheeks, mandible, perioral area and other regions of the face. In this theoretical study we asked the question, why does tardive dyskinesia often have orofacial predominance? What might be the underlying neural network structure which contributes to this propensity? Graph analysis of high-level cortico-striato-thalamo-cortical network structure suggests a connectivity bottleneck. The number of walks of different lengths from the substantia nigra pars reticulata (SNr) to other vertices, as well as the returning cycles are the lowest in the network, which may indicate a higher damage susceptibility of this node. Analysis was also performed on published data from a recent high resolution histological study on cortico-striato-thalamo-cortical networks in rodents. Finer network partitioning and adjacency matrices demonstrated that the SNr has a heterogeneous connectivity structure and the number of local walks from nodes neighboring orofacial neural representation is higher, indicating possible early compensatory escape routes. However, with more extensive SNr damage the larger circuit compensation might be limited. This area of inquiry is important for future research, because identifying key vulnerable structures may provide more targeted therapeutical interventions.
Assuntos
Antipsicóticos , Discinesia Induzida por Medicamentos , Discinesia Tardia , Humanos , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/complicações , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Antipsicóticos/efeitos adversosRESUMO
Feedback projections from the secondary motor cortex (M2) to the primary motor and sensory cortices are essential for behavior selection and sensory perception. Intratelencephalic (IT) cells in layer 5 (L5) contribute feedback projections to diverse cortical areas. Here we show that L5 IT cells participating in feedback connections to layer 1 (L1) exhibit distinct projection patterns, genetic profiles, and electrophysiological properties relative to other L5 IT cells. An analysis of the MouseLight database found that L5 IT cells preferentially targeting L1 project broadly to more cortical regions, including the perirhinal and auditory cortices, and innervate a larger volume of striatum than the other L5 IT cells. We found experimentally that in upper L5 (L5a), ER81 (ETV1) was found more often in L1-preferring IT cells, and in IT cells projecting to perirhinal/auditory regions than those projecting to primary motor or somatosensory regions. The perirhinal region-projecting L5a IT cells were synaptically connected to each other and displayed lower input resistance than contra-M2 projecting IT cells including L1-preferring and nonpreferring cells. Our findings suggest that M2-L5a IT L1-preferring cells exhibit stronger ER81 expression and broader cortical/striatal projection fields than do cells that do not preferentially target L1.
Assuntos
Córtex Motor , Camundongos , Animais , Córtex Motor/fisiologia , Lobo Parietal , Fenômenos Eletrofisiológicos , Corpo Estriado , Vias Neurais/fisiologiaRESUMO
The neostriatum plays a central role in cortico-subcortical circuitry underlying goal-directed behavior. The adult mammalian neostriatum shows chemical and cytoarchitectonic compartmentalization in line with the connectivity. However, it is poorly understood how and when fetal compartmentalization (AChE-rich islands, nonreactive matrix) switches to adult (AChE-poor striosomes, reactive matrix) and how this relates to the ingrowth of corticostriatal afferents. Here, we analyze neostriatal compartments on postmortem human brains from 9 postconceptional week (PCW) to 18 postnatal months (PM), using Nissl staining, histochemical techniques (AChE, PAS-Alcian), immunohistochemistry, stereology, and comparing data with volume-growth of in vivo and in vitro MRI. We find that compartmentalization (C) follows a two-compartment (2-C) pattern around 10PCW and is transformed into a midgestational labyrinth-like 3-C pattern (patches, AChE-nonreactive perimeters, matrix), peaking between 22 and 28PCW during accelerated volume-growth. Finally, compartmentalization resolves perinatally, by the decrease in transient "AChE-clumping," disappearance of AChE-nonreactive, ECM-rich perimeters, and an increase in matrix reactivity. The initial "mature" pattern appears around 9 PM. Therefore, transient, a 3-C pattern and accelerated neostriatal growth coincide with the expected timing of the nonhomogeneous distribution of corticostriatal afferents. The decrease in growth-related AChE activity and transfiguration of corticostriatal terminals are putative mechanisms underlying fetal compartments reorganization. Our findings serve as normative for studying neurodevelopmental disorders.
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Gânglios da Base , Neostriado , Animais , Humanos , Encéfalo , Feto , Imuno-Histoquímica , Acetilcolinesterase , MamíferosRESUMO
Primary states of consciousness are conceived as phylogenetically older states of consciousness as compared to secondary states governed by sociocultural inhibition. The historical development of the concept in psychiatry and neurobiology is reviewed, along with its relationship to theories of consciousness. We suggest that primary states of consciousness are characterized by a temporary breakdown of self-control accompanied by a merging of action, communication, and emotion (ACE fusion), ordinarily segregated in human adults. We examine the neurobiologic basis of this model, including its relation to the phenomenon of neural dedifferentiation, the loss of modularity during altered states of consciousness, and increased corticostriatal connectivity. By shedding light on the importance of primary states of consciousness, this article provides a novel perspective on the role of consciousness as a mechanism of differentiation and control. We discuss potential differentiators underlying a gradient from primary to secondary state of consciousness, suggesting changes in thalamocortical interactions and arousal function. We also propose a set of testable, neurobiologically plausible working hypotheses to account for their distinct phenomenological and neural signatures.
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Estado de Consciência , Autocontrole , Adulto , Humanos , Estado de Consciência/fisiologia , Encéfalo/fisiologia , EmoçõesRESUMO
Binge eating (BE) is a maladaptive repetitive feeding behavior present across nearly all eating disorder diagnoses. Despite the substantial negative impact of BE on psychological and physiological health, its underlying neural mechanisms are largely unknown. Other repetitive behavior disorders (e.g., obsessive compulsive disorder) show dysfunction within corticostriatal circuitry. However, to date, no work has investigated the in vivo neural dynamics underlying corticostriatal activity during BE episodes. The aim of the current study was to longitudinally examine in vivo neural activity within corticostriatal regions - the infralimbic cortex (IL) and dorsolateral striatum (DLS)- in a robust pre-clinical model for BE. Female C57BL6/J mice (N = 32) were randomized to receive: 1) intermittent (daily, 2-h) binge-like access to palatable food (sweetened condensed milk) (BE), or 2) continuous, non-intermittent (24-h) access to palatable food (control). In vivo calcium imaging was performed via fiber photometry at baseline and after chronic (4 weeks) engagement in the model for BE. Specific consummatory behaviors (feeding bout onset/offset) during recordings were captured using lickometers which generated TTL outputs for precise alignment of behavior to neural data. IL showed no specific changes in neural activity related to BE. However, BE animals showed decreased DLS activity at feeding onset and offset at the chronic timepoint when compared to activity at the baseline timepoint. Additionally, BE mice had significantly lower DLS activity at feeding onset and offset at the chronic timepoint compared to control mice. These results point to a role for DLS hypofunction in chronic BE, highlighting a potential target for future treatment intervention.
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Transtorno da Compulsão Alimentar , Bulimia , Animais , Feminino , Camundongos , Transtorno da Compulsão Alimentar/psicologia , Bulimia/psicologia , Comportamento Alimentar/psicologia , AlimentosRESUMO
Anorexia nervosa (AN) typically emerges in adolescence. The cortico-striatal system (CSTS) and the default mode network (DMN) are brain circuits with a crucial development during this period. These circuits underlie cognitive functions that are impaired in AN, such as cognitive flexibility and inhibition, among others. Little is known about their involvement in adolescent AN and how weight and symptom improvement might modulate potential alterations in these circuits. Forty-seven adolescent females (30 AN, 17 healthy control) were clinically/neuropsychologically evaluated and scanned during a 3T-MRI resting-state session on two occasions, before and after a 6-month multidisciplinary treatment of the AN patients. Baseline and baseline-to-follow-up between-group differences in CSTS and DMN resting-state connectivity were evaluated, as well as their association with clinical/neuropsychological variables. Increased connectivity between the left dorsal putamen and the left precuneus was found in AN at baseline. At follow-up, body mass index and clinical symptoms had improved in the AN group. An interaction effect was found in the connectivity between the right dorsal caudate to right mid-anterior insular cortex, with lower baseline AN connectivity that improved at follow-up; this improvement was weakly associated with changes in neuropsychological (Stroop test) performance. These results support the presence of CSTS connectivity alterations in adolescents with AN, which improve with weight and symptom improvement. In addition, at the level of caudate-insula connectivity, they might be associated with inhibitory processing performance. Alterations in CSTS pathways might be involved in AN from the early stages of the disorder.
Assuntos
Anorexia Nervosa , Mapeamento Encefálico , Feminino , Humanos , Adolescente , Estudos Longitudinais , Anorexia Nervosa/diagnóstico por imagem , Anorexia Nervosa/terapia , Rede de Modo Padrão , Vias Neurais/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
It has been hypothesized that to perform sensorimotor transformations efficiently, somatosensory information being fed back to a particular motor circuit is organized in accordance with the mechanical loading patterns of the skin that result from the motor activity generated by that circuit. Rearrangements of sensory information to different motor circuits could in this respect constitute a key component of sensorimotor learning. We here explored whether the organization of tactile input from the plantar forepaw of the rat to cortical and striatal circuits is affected by a period of extensive sensorimotor training in a skilled reaching and grasping task. Our data show that the representation of tactile stimuli in terms of both temporal and spatial response patterns changes as a consequence of the training and that spatial changes particularly involve the primary motor cortex. Based on the observed reorganization, we propose that reshaping of the spatiotemporal representation of the tactile afference to motor circuits is an integral component of the learning process that underlies skill acquisition in reaching and grasping.NEW & NOTEWORTHY Sensorimotor transformations are fundamental to the function of the nervous system and determine how patterns of sensory input are converted into appropriate movements. We here investigated the extent to which experience-dependent processes can reshape the organization of somatosensory input feeding into cortico-basal ganglia motor structures. Our data point to a particularly important role for the primary motor cortex in the functional adaptions associated with skilled motor learning.