RESUMO
How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolution of cognitive conflicts emerging when several strategies compete for behavioral control while adapting to environmental demands. Our findings may increase our understanding about the emergence of perseverative/compulsive traits in neuropsychiatric disorders with a reported SCIN reduction, such as Tourette and Williams syndromes.SIGNIFICANCE STATEMENT Selecting the best suited strategy to solve a problem is vital. Accordingly, available strategies must be compared across multiple dimensions, such as goal attainment effectiveness, cost-benefit trade-off, and cognitive load. The striatum is involved in strategy selection when strategies clearly diverge in their goal attainment capacity; however, its role whenever several strategies can be used for goal reaching-therefore making selection dependent on additional strategy dimensions-remains poorly understood. Here, we show that striatal cholinergic interneurons can signal strategy competition. Furthermore, they are required to adopt a given strategy whenever strategies with similar goal attainment capacity compete for behavioral control. Our study suggests that striatal cholinergic dysfunction may result in anomalous resolution of problems whenever complex cognitive valuations are required.
Assuntos
Neurônios Colinérgicos/fisiologia , Corpo Estriado/fisiologia , Interneurônios/fisiologia , Resolução de Problemas/fisiologia , Navegação Espacial/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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
Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.
Assuntos
Hipocampo/metabolismo , Interneurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Animais , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Masculino , Camundongos , Camundongos Knockout , Vias Neurais/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Transdução de Sinais/fisiologia , Ritmo Teta/fisiologiaRESUMO
The mechanisms underlying social dysfunction in neuropsychiatric conditions such as obsessive-compulsive disorder and Tourette syndrome remain uncertain. However, it is known that dysfunctions in basal ganglia, including a reduced number of striatal cholinergic interneurons (SCIN), are involved in their pathophysiology. To explore the role of SCIN in relation to perseverative behaviors, we characterized a new transgenic mouse model in which inducible ablation of SCIN is achieved with high efficiency in a cell-type- and region-specific manner. Mice were subjected to extensive behavioral testing, including assessment of social behaviors, and corticostriatal functional connectivity was evaluated in vivo Selective SCIN ablation leads to altered social interactions together with exacerbated spontaneously emitted repetitive behaviors. Lesioned mice showed normal motor coordination, balance, and general locomotion. Interestingly, only environmentally driven, but not self-directed, repetitive behaviors were exacerbated in lesioned mice. Remarkably, in mice with SCIN ablation, the normal pattern of social exploration was replayed continuously. The emerging pattern of social interactions is highly predictable and invariant across time. In vivo electrophysiological recordings indicate that SCIN ablation results in an increase of the functional connectivity between different cortical areas and the motor, but not associative, region of the striatum. Our results identify a role of SCIN in suppressing perseverative behaviors, including socially related ones. In sum, SCIN ablation in mice leads to exacerbated ritualistic-like behaviors that affect social performance, providing a link between SCIN dysfunction and the social impairments present in psychiatric disorders.SIGNIFICANCE STATEMENT We sought to uncover the impact of striatal cholinergic interneuron (SCIN) degeneration on perseverative behaviors related to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We found that extensive SCIN ablation results in exacerbated social interactions, in which normal social contacts were replayed continuously in a highly stereotyped, ritualistic pattern. SCIN ablation also leads to an increase in other spontaneously emitted repetitive behaviors without alteration of motor coordination, balance, or locomotion. Moreover, we identify an increase of functional connectivity between frontal cortical areas and the motor region of the striatum as a putative substrate for the observed behavioral alterations. Therefore, perseveration induced by SCIN ablation extends to social performance as occurs in neuropsychiatric conditions such as OCD and TS.
Assuntos
Potenciais de Ação , Neurônios Colinérgicos , Comportamento Compulsivo/fisiopatologia , Corpo Estriado/fisiopatologia , Interneurônios , Transtornos do Comportamento Social/fisiopatologia , Animais , Comportamento Compulsivo/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/fisiopatologia , Comportamento Social , Transtornos do Comportamento Social/complicaçõesRESUMO
UNLABELLED: The characteristic slowness of movement in Parkinson's disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 ± 7% dopaminergic neuron loss) and symptomatic (85 ± 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism. SIGNIFICANCE STATEMENT: Prevailing models of Parkinson's disease state that motor symptoms arise from an imbalance in the activity of medium spiny neurons (MSNs) from the direct (dMSNs) and indirect (iMSNs) pathways. Therefore, it is hypothesized that symptom severity and the magnitude of this imbalanced activity are correlated. Using a mouse model of Parkinson's disease, we found that behaviorally undetectable nigrostriatal lesions induced a significant disconnection of dMSNs from the motor cortex. In contrast, iMSNs show an increased connectivity with the motor cortex, but only after a severe dopaminergic lesion associated with an evident parkinsonian syndrome. Overall, our data suggest that the lack of symptoms after a partial dopaminergic lesion is not due to compensatory mechanisms maintaining the activity of both striatal pathways balanced.
Assuntos
Corpo Estriado/fisiopatologia , Homeostase , Córtex Motor/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Substância Negra/fisiopatologia , Animais , Doenças Assintomáticas , Mapeamento Encefálico , Neurônios Dopaminérgicos/metabolismo , Feminino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiopatologiaRESUMO
Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.
Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Hipocampo/patologia , Transtornos da Memória/patologia , Células Piramidais/metabolismo , Análise de Variância , Animais , Anisomicina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biofísica , Proteína de Ligação a CREB/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Fator de Iniciação 2 em Eucariotos/genética , Medo/psicologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Técnicas de Patch-Clamp , Fosforilação/genética , Proteínas Quinases/genética , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células Piramidais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estatísticas não Paramétricas , Estilbamidinas/metabolismo , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Fator de Transcrição 4RESUMO
Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.
Assuntos
Ondas Encefálicas/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Hipocampo/fisiopatologia , Interneurônios/fisiologia , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/deficiência , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Esquizofrenia/metabolismoRESUMO
Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-D-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave-ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced gamma-aminobutyric acid (GABA) levels, and the persistent 30-50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker alpha-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Morte Celular/fisiologia , Hipocampo/fisiologia , Ácido Caínico/farmacologia , Neurônios/fisiologia , Análise de Variância , Animais , Contagem de Células , Eletrofisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Fluoresceínas , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Orgânicos , Oscilometria , Periodicidade , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/fisiologia , Convulsões/induzido quimicamente , Processamento de Sinais Assistido por Computador , Coloração e Rotulagem , Ácido gama-Aminobutírico/metabolismoRESUMO
Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex (PFC) is a hallmark of schizophrenia pathophysiology. Although N-methyl-D-aspartate receptor (NMDAR) hypofunction is also implicated in schizophrenia, it remains unclear whether NMDAR hypofunction leads to dopamine release abnormalities. We previously demonstrated schizophrenia-like phenotypes in GABAergic neuron-specific NMDAR hypofunctional mutant mice, in which Ppp1r2-Cre dependent deletion of indispensable NMDAR channel subunit Grin1 is induced in corticolimbic GABAergic neurons including parvalbumin (PV)-positive neurons, in postnatal development, but not in adulthood. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: nucleus accumbens (NAc) dopamine release was enhanced by amphetamine in postnatal Ppp1r2-Cre/Grin1 knockout (KO) mice, whereas dopamine release was dramatically reduced in the medial PFC (mPFC) compared to controls. Basal tissue dopamine levels in both the NAc and mPFC were unaffected. Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area (VTA). These effects appear to be both developmentally and cell-type specifically modulated, since PV-specific Grin1 KO mice could induce the same effects as seen in postnatal-onset Ppp1r2-Cre/Grin1 KO mice, but no such abnormalities were observed in somatostatin-Cre/Grin1 KO mice or adult-onset Ppp1r2-Cre/Grin1 KO mice. These results suggest that PV GABAergic neuron-NMDAR hypofunction in postnatal development confers bidirectional NAc hyper- and mPFC hypo-sensitivity to amphetamine-induced dopamine release, similar to that classically observed in schizophrenia pathophysiology.
Assuntos
Comportamento Animal/fisiologia , Dopamina/metabolismo , Neurônios GABAérgicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Anfetamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Repetitive stimulation of cognitive forebrain circuits at frequencies capable of inducing corticostriatal long term plasticity is increasingly being used with therapeutic purposes in patients with neuropsychiatric disorders. However, corticostriatal plasticity is rarely studied in the intact brain. Our aim was to study the mechanisms of corticostriatal long term depression (LTD) induced by high frequency stimulation (HFS) of the medial prefrontal cortex in vivo. Our main finding is that the LTD induced in the dorsomedial striatum by medial prefrontal cortex HFS in vivo (prefrontostriatal LTD) is not affected by manipulations that block or reduce the LTD induced in the dorsolateral striatum by motor cortex HFS in brain slices, including pharmacological dopamine receptor and CB1 receptor blockade, chronic nigrostriatal dopamine depletion, CB1 receptor genetic deletion and selective striatal cholinergic interneuron (SCIN) ablation. Conversely, like in the hippocampus and other brain areas, prefrontostriatal LTD is NMDA receptor dependent. Thus, we describe a novel form of corticostriatal LTD that operates in brain circuits involved in reward and cognition and could be relevant for understanding the therapeutic effects of deep brain stimulation.
Assuntos
Corpo Estriado/citologia , Corpo Estriado/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Adrenérgicos/toxicidade , Animais , Animais Recém-Nascidos , Benzazepinas/farmacologia , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Corpo Estriado/lesões , Maleato de Dizocilpina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Findings showing that neonatal lesions of the forebrain dopaminergic system in rodents lead to juvenile locomotor hyperactivity and learning deficits have been taken as evidence of face validity for the attention deficit hyperactivity disorder. However, the core cognitive and physiological intermediate phenotypes underlying this rodent syndrome remain unknown. Here we show that early postnatal dopaminergic lesions cause long-lasting deficits in exploitation of shelter, social and nutritional resources, and an imbalanced exploratory behavior, where nondirected local exploration is exacerbated, whereas sophisticated search behaviors involving sequences of goal directed actions are degraded. Importantly, some behavioral deficits do not diminish after adolescence but instead worsen or mutate, particularly those related to the exploration of wide and spatially complex environments. The in vivo electrophysiological recordings and morphological reconstructions of striatal medium spiny neurons reveal corticostriatal alterations associated to the behavioral phenotype. More specifically, an attenuation of corticostriatal functional connectivity, affecting medial prefrontal inputs more markedly than cingulate and motor inputs, is accompanied by a contraction of the dendritic arbor of striatal projection neurons in this animal model. Thus, dopaminergic neurons are essential during postnatal development for the functional and structural maturation of corticostriatal connections. From a bottom-up viewpoint, our findings suggest that neuropsychiatric conditions presumably linked to developmental alterations of the dopaminergic system should be evaluated for deficits in foraging decision making, alterations in the recruitment of corticostriatal circuits during foraging tasks, and structural disorganization of the frontostriatal connections.
Assuntos
Córtex Cerebral/fisiopatologia , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/fisiopatologia , Dopamina/metabolismo , Comportamento Exploratório/fisiologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Corpo Estriado/patologia , Dendritos/patologia , Dendritos/fisiologia , Modelos Animais de Doenças , Eletrodos Implantados , Imuno-Histoquímica , Camundongos , Atividade Motora/fisiologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Oxidopamina , Fenótipo , Comportamento Social , Comportamento Espacial/fisiologiaRESUMO
The marked anatomical and functional changes taking place in the medial prefrontal cortex (PFC) during adolescence set grounds for the high incidence of neuropsychiatric disorders with adolescent onset. Although circuit refinement through synapse pruning may constitute the anatomical basis for the cognitive differences reported between adolescents and adults, a physiological correlate of circuit refinement at the level of neuronal ensembles has not been demonstrated. We have recorded neuronal activity together with local field potentials in the medial PFC of juvenile and adult mice under anesthesia, which allowed studying local functional connectivity without behavioral or sensorial interference. Entrainment of pyramidal neurons and interneurons to gamma oscillations, but not to theta or beta oscillations, was reduced after adolescence. Interneurons were synchronized to gamma oscillations across a wider area of the PFC than pyramidal neurons, and the span of interneuron synchronization was shorter in adults than juvenile mice. Thus, transition from childhood to adulthood is characterized by reduction of the strength and span of neuronal synchronization specific to gamma oscillations in the mPFC. The more restricted and weak ongoing synchronization in adults may allow a more dynamic rearrangement of neuronal ensembles during behavior and promote parallel processing of information.
Assuntos
Ondas Encefálicas , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Fatores Etários , Animais , Encéfalo/fisiologia , Eletroencefalografia , Interneurônios/fisiologia , Masculino , Camundongos , Células Piramidais/fisiologiaRESUMO
Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity's net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5-6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation.
Assuntos
Giro Denteado/fisiologia , Epilepsia/fisiopatologia , Hipocampo/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Animais , Giro Denteado/citologia , Toxina Diftérica , Comportamento Exploratório , Hipocampo/citologia , Camundongos , Camundongos Transgênicos , Degeneração Neural/induzido quimicamente , Neurônios/citologia , Neurônios/fisiologia , Ritmo Teta/fisiologiaRESUMO
Hypofunction of N-methyl-d-aspartic acid-type glutamate receptors (NMDAR) induced by the systemic administration of NMDAR antagonists is well known to cause schizophrenia-like symptoms in otherwise healthy subjects. However, the brain areas or cell-types responsible for the emergence of these symptoms following NMDAR hypofunction remain largely unknown. One possibility, the so-called "GABAergic origin hypothesis," is that NMDAR hypofunction at GABAergic interneurons, in particular, is sufficient for schizophrenia-like effects. In one attempt to address this issue, transgenic mice were generated in which NMDARs were selectively deleted from cortical and hippocampal GABAergic interneurons, a majority of which were parvalbumin (PV)-positive. This manipulation triggered a constellation of phenotypes--from molecular and physiological to behavioral--resembling characteristics of human schizophrenia. Based on these results, and in conjunction with previous literature, we argue that during development, NMDAR hypofunction at cortical, PV-positive, fast-spiking interneurons produces schizophrenia-like effects. This review summarizes the data demonstrating that in schizophrenia, GABAergic (particularly PV-positive) interneurons are disrupted. PV-positive interneurons, many of which display a fast-spiking firing pattern, are critical not only for tight temporal control of cortical inhibition but also for the generation of synchronous membrane-potential gamma-band oscillations. We therefore suggest that in schizophrenia the specific ability of fast-spiking interneurons to control and synchronize disparate cortical circuits is disrupted and that this disruption may underlie many of the schizophrenia symptoms. We further argue that the high vulnerability of corticolimbic fast-spiking interneurons to genetic predispositions and to early environmental insults--including excitotoxicity and oxidative stress--might help to explain their significant contribution to the development of schizophrenia.
Assuntos
Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Esquizofrenia/fisiopatologia , Animais , Humanos , Receptores de N-Metil-D-Aspartato/fisiologia , Esquizofrenia/etiologiaRESUMO
Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
Assuntos
Córtex Cerebral/patologia , Interneurônios/fisiologia , Sistema Límbico/patologia , Receptores de N-Metil-D-Aspartato/deficiência , Esquizofrenia , Potenciais de Ação/genética , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hipercinese/etiologia , Hipercinese/genética , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Vias Neurais/patologia , Parvalbuminas/genética , Parvalbuminas/metabolismo , Proteínas/genética , RNA Mensageiro/metabolismo , Reconhecimento Psicológico/fisiologia , Esquizofrenia/genética , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Isolamento Social/psicologia , Estatísticas não Paramétricas , Ácido gama-Aminobutírico/metabolismoRESUMO
We examined basal and reflex salivary flow rate and composition in 46 patients with Parkinson's disease (PD), both in off and on conditions, compared to 13 age-matched controls without underlying disease or treatment affecting autonomic function. Whole saliva was collected 12 hours after withdrawal of dopaminergic drugs and at the peak of levodopa-induced motor improvement. Twenty-three of the 46 PD patients had received domperidone a week before the study. Basal salivary flow rate was significantly lower in PD patients in the off state compared to controls (P<0.005). Levodopa increased salivary flow rate (P<0.05) both in the domperidone-pretreated and untreated groups. Citric acid stimulated salivary flow rate in both the off and on states in PD patients. This effect was higher in the domperidone-pretreated patients. Salivary concentration of sodium, chloride, and amylase was higher in PD patients than in controls and was not affected by levodopa or domperidone treatment. Levodopa stimulates both basal and reflex salivary flow rate in PD. The mechanism appears to be central, as the effect is not blocked by domperidone. Domperidone may have a peripheral effect that potentiates reflex salivary secretion. Salivary composition is abnormal in PD and is not affected by levodopa treatment.
Assuntos
Doença de Parkinson/fisiopatologia , Salivação/fisiologia , Taxa Secretória/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amilases/metabolismo , Análise de Variância , Antiparkinsonianos/sangue , Antiparkinsonianos/uso terapêutico , Estudos de Casos e Controles , Domperidona/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Feminino , Humanos , Levodopa/sangue , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Descanso/fisiologia , Taxa Secretória/efeitos dos fármacosRESUMO
The noxious evoked response in trigeminal sensory neurons was studied to address the role of striatum in the control of nociceptive inputs. In urethane-anesthetized rats, the jaw opening reflex (JOR) was produced by suprathreshold stimulation of the tooth pulp and measured as electromyographic response in the digastric muscle, with simultaneous recording of noxious responses in single unit neurons of the spinal trigeminal nucleus pars caudalis (Sp5c). The microinjection of glutamate (80 etamol/0.5 microl) into striatal JOR inhibitory sites significantly decreased the A delta and C fiber-mediated-evoked response (53 +/- 4.2 and 43.6 +/- 6.4% of control value, P < 0.0001) in 92% (31/34) of nociceptive Sp5c neurons. The microinjection of the solvent was ineffective, as was microinjection of glutamate in sites out of the JOR inhibitory ones. In another series of experiments, simultaneous single unit recordings were performed in the motor trigeminal nucleus (Mo5) and the Sp5c nucleus. Microinjection of glutamate decreased the noxious-evoked response in Sp5c and Mo5 neurons in parallel with the JOR, without modifying spontaneous neuronal activity of trigeminal motoneurons (n = 8 pairs). These results indicate that the striatum could be involved in the modulation of nociceptive inputs and confirm the role of the basal ganglia in the processing of nociceptive information.