RESUMO
Can we one day prevent mental disorders? Mukherjee et al. (2019) use a genetic mouse model of schizophrenia-risk with established abnormalities in adult hippocampal-prefrontal circuit function and cognitive behaviors to identify circuit-specific treatments during adolescence that prevent the onset of the adult deficits.
Assuntos
Disfunção Cognitiva , Esquizofrenia , Adolescente , Adulto , Animais , Modelos Animais de Doenças , Hipocampo , Humanos , Camundongos , Córtex Pré-FrontalRESUMO
The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders1. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC)2 and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. Here we show that novelty resets the neural circuits that link the ventral hippocampus (vHPC) and the mPFC, facilitating the ability to overcome an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4-12 Hz) oscillations and weakening existing vHPC-mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC-mPFC connectivity was strengthened, and mPFC neurons updated to encode the new rules. Without novelty, however, mice adhered to their established strategy. Blocking dopamine D1 receptors (D1Rs) or inhibiting novelty-tagged cells that express D1Rs in the vHPC prevented these behavioural and physiological effects of novelty. Furthermore, activation of D1Rs mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling subsequent learning-associated circuit plasticity.
Assuntos
Hipocampo/fisiologia , Aprendizagem em Labirinto/fisiologia , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Feminino , Hipocampo/citologia , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/citologiaRESUMO
It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.
Assuntos
Motivação , Esquizofrenia , Animais , Corpo Estriado/metabolismo , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismoRESUMO
Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice-physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing, yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).
Assuntos
Dopamina , Receptores de Dopamina D2 , Acetilcolina , Colinérgicos , Corpo Estriado , Interneurônios/fisiologia , Núcleo AccumbensRESUMO
Anorexia nervosa (AN) is an eating disorder observed predominantly in women and girls that is characterized by a low body-mass index, hypophagia, and hyperactivity. Activity-based anorexia (ABA), which refers to the weight loss, hypophagia, and hyperactivity exhibited by rodents exposed to both running wheels and scheduled fasting, provides a model for aspects of AN. Increased dopamine D2/D3 receptor binding in the anteroventral striatum has been reported in AN patients. We virally overexpressed D2Rs on nucleus accumbens core (D2R-OENAc) neurons that endogenously express D2Rs, and tested mice of both sexes in the open field test, ABA paradigm, and intraperitoneal glucose tolerance test (IGTT). D2R-OENAc did not alter baseline body weight, but increased locomotor activity in the open field across both sexes. During constant access to food and running wheels, D2R-OENAc mice of both sexes increased food intake and ran more than controls. However, when food was available only 7 h a day, only female D2R-OENAc mice rapidly lost 25% of their initial body weight, reduced food intake, and substantially increased wheel running. Surprisingly, female D2R-OENAc mice also rapidly lost 25% of their initial body weight during scheduled fasting without wheel access and showed no changes in food intake. In contrast, male D2R-OENAc mice maintained body weight during scheduled fasting. D2R-OENAc mice of both sexes also showed glucose intolerance in the IGTT. In conclusion, D2R-OENAc alters glucose metabolism in both sexes but drives robust weight loss only in females during scheduled fasting, implicating metabolic mechanisms in this sexually dimorphic effect.
Assuntos
Atividade Motora , Núcleo Accumbens , Receptores de Dopamina D2 , Redução de Peso , Animais , Jejum , Feminino , Masculino , Camundongos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMO
The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson's disease. However, the development of improved therapeutic strategies has been hampered by our incomplete understanding of this receptor's downstream signaling processes in vivo and how these relate to the desired and undesired effects of drugs. D2R is a G protein-coupled receptor (GPCR) that activates G protein-dependent as well as non-canonical arrestin-dependent signaling pathways. Whether these effector pathways act alone or in concert to facilitate specific D2R-dependent behaviors is unclear. Here, we report on the development of a D2R mutant that recruits arrestin but is devoid of G protein activity. When expressed virally in "indirect pathway" medium spiny neurons (iMSNs) in the ventral striatum of D2R knockout mice, this mutant restored basal locomotor activity and cocaine-induced locomotor activity in a manner indistinguishable from wild-type D2R, indicating that arrestin recruitment can drive locomotion in the absence of D2R-mediated G protein signaling. In contrast, incentive motivation was enhanced only by wild-type D2R, signifying a dissociation in the mechanisms that underlie distinct D2R-dependent behaviors, and opening the door to more targeted therapeutics.
Assuntos
Arrestina , Locomoção , Motivação , Receptores de Dopamina D2 , Animais , Cocaína , Corpo Estriado/metabolismo , Camundongos , Camundongos Knockout , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMO
Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic ß-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D2-like receptors including D2 (D2R) and D3 (D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic ß-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursor L-DOPA in ß-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA's inhibition of GSIS. Our results show that the uptake of L-DOPA is essential for establishing intracellular DA stores in ß-cells. Glucose stimulation significantly enhances L-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which ß-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D2-like receptors modify DA release to modulate GSIS. Lastly, ß-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.
Assuntos
Dopamina , Células Secretoras de Insulina , Animais , Dopamina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismoRESUMO
Dopaminergic signaling in the striatum, particularly at dopamine 2 receptors (D2R), has been a topic of active investigation in obesity research in the past decades. However, it still remains unclear whether variations in striatal D2Rs modulate the risk for obesity and if so in which direction. Human studies have yielded contradictory findings that likely reflect a complex nonlinear relationship, possibly involving a combination of causal effects and compensatory changes. Animal work indicates that although chronic obesogenic diets reduce striatal D2R function, striatal D2R down-regulation does not lead to obesity. In this study, we evaluated the consequences of striatal D2R up-regulation on body-weight gain susceptibility and energy balance in mice. We used a mouse model of D2R overexpression (D2R-OE) in which D2Rs were selectively up-regulated in striatal medium spiny neurons. We uncover a pathological mechanism by which striatal D2R-OE leads to reduced brown adipose tissue thermogenesis, reduced energy expenditure, and accelerated obesity despite reduced eating. We also show that D2R-OE restricted to development is sufficient to promote obesity and to induce energy-balance deficits. Together, our findings indicate that striatal D2R-OE during development persistently increases the propensity for obesity by reducing energy output in mice. This suggests that early alterations in the striatal dopamine system could represent a key predisposition factor toward obesity.
Assuntos
Corpo Estriado/metabolismo , Dieta/efeitos adversos , Metabolismo Energético , Neostriado/metabolismo , Obesidade/etiologia , Receptores de Dopamina D2/fisiologia , Animais , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/patologia , Aumento de PesoRESUMO
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
Assuntos
Gânglios da Base/fisiologia , Transportador 3 de Aminoácido Excitatório/genética , Atividade Motora/genética , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Anfetaminas/farmacologia , Animais , Linhagem Celular , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Asseio Animal/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Receptores de Dopamina D1/metabolismo , Reflexo de Sobressalto/fisiologiaRESUMO
UNLABELLED: Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OEdev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the Gαi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OEdev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization. SIGNIFICANCE STATEMENT: Motivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease.
Assuntos
Corpo Estriado/fisiologia , Globo Pálido/fisiologia , Objetivos , Motivação/fisiologia , Vias Neurais/fisiologia , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Condicionamento Clássico , Condicionamento Operante , Corpo Estriado/citologia , Comportamento Exploratório/fisiologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Globo Pálido/citologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Receptores de Dopamina D2/genética , Reforço PsicológicoRESUMO
Current therapies for treating movement disorders such as Parkinson's disease are effective but limited by undesirable and intractable side effects. Developing more effective therapies will require better understanding of what causes basal ganglia dysregulation and why medication-induced side effects develop. Although basal ganglia have been extensively studied in the last decades, its circuit anatomy is very complex, and significant controversy exists as to how the interplay of different basal ganglia nuclei process motor information and output. We have recently identified the importance of an underappreciated collateral projection that bridges the striatal output direct pathway with the indirect pathway. These bridging collaterals are extremely plastic in the adult brain and are involved in the regulation of motor balance. Our findings add a new angle to the classical model of basal ganglia circuitry that could be exploited for the development of new therapies against movement disorders. In this Scientific Perspective, we describe the function of bridging collaterals and other recent discoveries that challenge the simplicity of the classical basal ganglia circuit model. We then discuss the potential implication of bridging collaterals in the pathophysiology of Parkinson's disease and schizophrenia. Because dopamine D2 receptors and striatal neuron excitability have been found to regulate the density of bridging collaterals, we propose that targeting these projections downstream of D2 receptors could be a possible strategy for the treatment of basal ganglia disorders. © 2015 International Parkinson and Movement Disorder Society.
Assuntos
Doenças dos Gânglios da Base/fisiopatologia , Gânglios da Base/fisiopatologia , Rede Nervosa/fisiopatologia , Receptores de Dopamina D2/fisiologia , Animais , Gânglios da Base/fisiologia , Doenças dos Gânglios da Base/terapia , Humanos , Rede Nervosa/fisiologiaRESUMO
A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val(158) allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val(158) allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val(158) allele, stimulus-response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans.
Assuntos
Catecol O-Metiltransferase/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Deficiências da Aprendizagem/metabolismo , Aprendizagem/fisiologia , Animais , Catecol O-Metiltransferase/genética , Cognição/fisiologia , Comportamento Compulsivo/genética , Comportamento Compulsivo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Impulsivo , Deficiências da Aprendizagem/genética , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Atividade Motora/genética , Atividade Motora/fisiologia , Testes Neuropsicológicos , Polimorfismo Genético , Prosencéfalo/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Two distinct defects are thought to be important for the pathophysiology of schizophrenia. One is an increase of D2 receptors (D2Rs) in the striatum and another is a decrease in the GABAergic function in the prefrontal cortex (PFC). Whether these two defects are functionally linked is not known. We previously reported that selective overexpression of D2Rs in the striatum of the mouse causes behavioral abnormality associated with PFC functions. Using patch-clamp recording, we find that overexpression of D2Rs in the striatum affects inhibitory transmission in the PFC and dopamine (DA) sensitivity. The overexpression of D2Rs in the striatum caused an increase in frequency of spontaneous excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons, whereas their neuronal excitability was unaffected. In contrast, both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) were significantly decreased in these mice, indicating a reduced inhibitory transmission. Furthermore, in D2R transgenic mice the dopaminergic modulation of evoked IPSCs was shifted, with reduced sensitivity. The change in dopamine sensitivity in the PFC of D2R transgenic mice appears specific for D2Rs because in D2R transgenic mice the effects of D2 agonist but not D1 agonist, on both evoked IPSCs and EPSCs, were reduced. Together, these results indicate that overexpression of D2Rs in the striatum leads to a functional deficit in the GABAergic system. These results provide a functional link between D2R overexpression and GABAergic inhibition in the PFC and suggest that the postulated deficit in GABAergic function in schizophrenia could be secondary to alterations in the striatal dopamine system.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D2/metabolismo , Esquizofrenia/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Genótipo , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Reação em Cadeia da Polimerase , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/genética , Esquizofrenia/metabolismoRESUMO
Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuit connectivity during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in the mouse from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target twenty-four hours later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III nucleus accumbens (NAc) and layer V/VI medio-dorsal thalamus projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosally-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).
RESUMO
Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long-lasting deficits in prefrontal-cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal-cortex maturation, it is unclear how inhibition of these projections affect prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in male/female mice from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (MD, NAc or callosal mPFC) twenty-four hours later using slice physiology. We chose mPFC and MD-projecting cells as they are largely distinguished by cortical layer (II/III versus V/VI, respectively) and NAc-projecting cells as they span both layers and therefore provide a within-layer comparison for the other two populations. We found a decrease in the frequency of excitatory and inhibitory currents in layer-II/III-nucleus-accumbens (NAc) and layer-V/VI-mediodorsal-thalamus-projecting neurons while layer-V/VI-NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal-cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).Significance Statement Connectivity between two brain regions, the thalamus and the prefrontal cortex, has been found to be reduced in patients with schizophrenia. Neuronal activity in thalamo-cortical projections is important for the proper development of sensory cortices. How thalamo-cortical activity regulates prefrontal cortex development is less well understood. Here, we show that decreasing activity in thalamo-prefrontal projections in mice during early adolescence alters synaptic connectivity to distinct neuronal projections within the prefrontal cortex that are already evident in adolescence. While some of these changes can be explained by reduced thalamo-cortical projections, other adaptations are intrinsic to the prefrontal cortex. These findings implicate adolescence as a critical period of cortical development and demonstrate this period as a potential target for therapeutic intervention.
RESUMO
Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a remarkable degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with downregulation of inward rectifier potassium channels (Kir2.1/2.3). Downregulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally mediated expression of a dominant-negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.
Assuntos
Corpo Estriado/metabolismo , Dendritos/metabolismo , Neurônios/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Dendritos/fisiologia , Regulação para Baixo/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/fisiologia , Neurônios/classificação , Neurônios/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Receptores de Dopamina D2/metabolismoRESUMO
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.
Assuntos
Encéfalo/fisiologia , Degeneração Neural/etiologia , Proteínas Repressoras , Fatores de Transcrição/fisiologia , Animais , Apoptose , Corpo Estriado/patologia , Modulador de Elemento de Resposta do AMP Cíclico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Feminino , Humanos , Doença de Huntington/etiologia , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/patologia , Peptídeos/genética , Fenótipo , Transdução de Sinais , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
After repeatedly failing to get out of a stressful, uncontrollable environment, mice switch from escape behavior to inactivity. In this issue of Neuron, Li et al. identify a circuit involving noradrenergic projections from the locus coeruleus to GABAergic projection neurons in the orbitofrontal cortex that participate in this adaptive behavior.
Assuntos
Encéfalo , Locus Cerúleo , Animais , Camundongos , Humanos , Adaptação Psicológica , Etnicidade , Neurônios GABAérgicosRESUMO
Learning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs. In vivo electrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task.
RESUMO
In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess "bridging" collaterals within the globus pallidus (GPe), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches to dissect the roles of bridging collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of pallidostriatal Npas1 neurons. We propose a model by which dSPN GPe collaterals ("striatopallidal Go pathway") act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 signals going back to the striatum.