RESUMEN
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.
Asunto(s)
Dopamina , Enfermedad de Parkinson , Masculino , Femenino , Ratones , Animales , Dopamina/metabolismo , Enfermedad de Parkinson/patología , Cuerpo Estriado/metabolismo , Ganglios Basales , Neuronas Dopaminérgicas/metabolismoRESUMEN
Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington's disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington's disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington's disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington's disease thus has a neurodevelopmental component and is not solely a degenerative disease.
Asunto(s)
Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Sistema Nervioso/embriología , Animales , Ciclo Celular , Endosomas/metabolismo , Feto , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ratones , Ratones Mutantes , Mitosis , Mutación , Células Neuroepiteliales/metabolismo , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Chronic exposure to stress is a major risk factor for neuropsychiatric disease, and elevated plasma corticosterone (CORT) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis. Precisely how these phenomena are linked, however, remains unclear. Using a cortico-hippocampal network-on-a-chip, we find that the glucocorticoid receptor agonist dexamethasone (DXM) stimulates the cyclin-dependent kinase 5 (CDK5) to phosphorylate huntingtin (HTT) at serines 1181 and 1201 (S1181/1201), which retards BDNF vesicular transport in cortical axons. Parallel studies in mice show that CORT induces phosphorylation of these same residues, reduces BDNF levels, and suppresses neurogenesis. The adverse effects of CORT are reduced in mice bearing an unphosphorylatable mutant HTT (HdhS1181A/S1201A). The protective effect of unphosphorylatable HTT, however, disappears if neurogenesis is blocked. The CDK5-HTT pathway, which regulates BDNF transport in the cortico-hippocampal network, thus provides a missing link between elevated CORT levels and suppressed neurogenesis.
Asunto(s)
Envejecimiento/metabolismo , Corticosterona/metabolismo , Hipocampo/metabolismo , Proteína Huntingtina/metabolismo , Neurogénesis , Animales , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Depresión/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Fosforilación , Transporte de ProteínasRESUMEN
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.
Asunto(s)
Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Adrenérgicos/toxicidad , Animales , Animales Recién Nacidos , Benzazepinas/farmacología , Colina O-Acetiltransferasa/genética , Colina O-Acetiltransferasa/metabolismo , Cuerpo Estriado/lesiones , Maleato de Dizocilpina/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Oxidopamina/toxicidad , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
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.
Asunto(s)
Potenciales de Acción , Neuronas Colinérgicas , Conducta Compulsiva/fisiopatología , Cuerpo Estriado/fisiopatología , Interneuronas , Trastorno de la Conducta Social/fisiopatología , Animales , Conducta Compulsiva/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/fisiopatología , Conducta Social , Trastorno de la Conducta Social/complicacionesRESUMEN
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.
Asunto(s)
Corteza Cerebral/fisiopatología , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Conducta Exploratoria/fisiología , Animales , Animales Recién Nacidos , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Cuerpo Estriado/patología , Dendritas/patología , Dendritas/fisiología , Modelos Animales de Enfermedad , Electrodos Implantados , Inmunohistoquímica , Ratones , Actividad Motora/fisiología , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Oxidopamina , Fenotipo , Conducta Social , Conducta Espacial/fisiologíaRESUMEN
Evoked striatal field potentials are seldom used to study corticostriatal communication in vivo because little is known about their origin and significance. Here we show that striatal field responses evoked by stimulating the prelimbic cortex in mice are reduced by more than 90% after infusing the AMPA receptor antagonist CNQX close to the recording electrode. Moreover, the amplitude of local field responses and dPSPs recorded in striatal medium spiny neurons increase in parallel with increasing stimulating current intensity. Finally, the evoked striatal fields show several of the basic known properties of corticostriatal transmission, including paired pulse facilitation and topographical organization. As a case study, we characterized the effect of local GABA(A) receptor blockade on striatal field and multiunitary action potential responses to prelimbic cortex stimulation. Striatal activity was recorded through a 24 channel silicon probe at about 600 µm from a microdialysis probe. Intrastriatal administration of the GABA(A) receptor antagonist bicuculline increased by 65±7% the duration of the evoked field responses. Moreover, the associated action potential responses were markedly enhanced during bicuculline infusion. Bicuculline enhancement took place at all the striatal sites that showed a response to cortical stimulation before drug infusion, but sites showing no field response before bicuculline remained unresponsive during GABA(A) receptor blockade. Thus, the data demonstrate that fast inhibitory connections exert a marked temporal regulation of input-output transformations within spatially delimited striatal networks responding to a cortical input. Overall, we propose that evoked striatal fields may be a useful tool to study corticostriatal synaptic connectivity in relation to behavior.