RESUMO
Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-ß family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-ß2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-ß and/or Smads.
Assuntos
Corpo Estriado , Dopamina , Animais , Camundongos , Mesencéfalo , Motivação , Movimento , SinapsesRESUMO
Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.
Assuntos
Terapia Genética , Doença de Parkinson , Animais , Humanos , Camundongos , Corpo Estriado/metabolismo , Levodopa/uso terapêutico , Levodopa/genética , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/terapia , Primatas , Receptores de Dopamina D1/metabolismo , Modelos Animais de DoençasRESUMO
Significant evidence supports the view that dopamine shapes learning by encoding reward prediction errors. However, it is unknown whether striatal targets receive tailored dopamine dynamics based on regional functional specialization. Here, we report wave-like spatiotemporal activity patterns in dopamine axons and release across the dorsal striatum. These waves switch between activational motifs and organize dopamine transients into localized clusters within functionally related striatal subregions. Notably, wave trajectories were tailored to task demands, propagating from dorsomedial to dorsolateral striatum when rewards are contingent on animal behavior and in the opponent direction when rewards are independent of behavioral responses. We propose a computational architecture in which striatal dopamine waves are sculpted by inference about agency and provide a mechanism to direct credit assignment to specialized striatal subregions. Supporting model predictions, dorsomedial dopamine activity during reward-pursuit signaled the extent of instrumental control and interacted with reward waves to predict future behavioral adjustments.
Assuntos
Axônios/metabolismo , Comportamento Animal , Corpo Estriado/metabolismo , Dopamina/metabolismo , Recompensa , Animais , Feminino , Masculino , Camundongos , Camundongos MutantesRESUMO
Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition. Striosomal function during discrimination learning was disturbed with aging and severely so in a mouse model of Huntington's disease. Anatomical and functional connectivity of parvalbumin-positive, putative fast-spiking interneurons (FSIs) to striatal projection neurons was enhanced in striosomes compared with matrix in mice that learned. Computational modeling of these findings suggests that FSIs can modulate the striosomal signal-to-noise ratio, crucial for discrimination and learning.
Assuntos
Envelhecimento/patologia , Corpo Estriado/patologia , Doença de Huntington/patologia , Aprendizagem , Potenciais de Ação , Animais , Comportamento Animal , Biomarcadores/metabolismo , Corpo Estriado/fisiopatologia , Aprendizagem por Discriminação , Modelos Animais de Doenças , Doença de Huntington/fisiopatologia , Interneurônios/patologia , Camundongos Transgênicos , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Parvalbuminas/metabolismo , Fotometria , Recompensa , Análise e Desempenho de TarefasRESUMO
The ability to record transient cellular events in the DNA or RNA of cells would enable precise, large-scale analysis, selection, and reprogramming of heterogeneous cell populations. Here, we report a molecular technology for stable genetic tagging of cells that exhibit activity-related increases in intracellular calcium concentration (FLiCRE). We used FLiCRE to transcriptionally label activated neural ensembles in the nucleus accumbens of the mouse brain during brief stimulation of aversive inputs. Using single-cell RNA sequencing, we detected FLiCRE transcripts among the endogenous transcriptome, providing simultaneous readout of both cell-type and calcium activation history. We identified a cell type in the nucleus accumbens activated downstream of long-range excitatory projections. Taking advantage of FLiCRE's modular design, we expressed an optogenetic channel selectively in this cell type and showed that direct recruitment of this otherwise genetically inaccessible population elicits behavioral aversion. The specificity and minute resolution of FLiCRE enables molecularly informed characterization, manipulation, and reprogramming of activated cellular ensembles.
Assuntos
Comportamento Animal , Cálcio/metabolismo , Corpo Estriado/metabolismo , Animais , Feminino , Células HEK293 , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética , Ratos , Análise de Célula Única , Transcriptoma/genéticaRESUMO
The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.
Assuntos
Aprendizagem da Esquiva/fisiologia , Corpo Estriado/fisiologia , Proteínas de Homeodomínio/genética , Proteínas Repressoras/genética , Animais , Gânglios da Base , Feminino , Proteínas de Homeodomínio/metabolismo , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Motivação , Neurônios/fisiologia , Punição , Reforço Psicológico , Proteínas Repressoras/metabolismoRESUMO
Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.
Assuntos
Comportamento Animal , Corpo Estriado/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Corpo Estriado/efeitos dos fármacos , Eletrodos Implantados , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fotometria , Receptores de Dopamina D1/deficiência , Receptores de Dopamina D1/genéticaRESUMO
Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.
Assuntos
Proteína Huntingtina/genética , Doença de Huntington/patologia , Animais , Peso Corporal , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas/genética , Córtex Cerebral/patologia , Córtex Cerebral/ultraestrutura , Corpo Estriado/patologia , Corpo Estriado/ultraestrutura , Modelos Animais de Doenças , Proteína Huntingtina/metabolismo , Doença de Huntington/mortalidade , Imageamento por Ressonância Magnética , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Transferência Nuclear , Taxa de Sobrevida , Suínos , Repetições de TrinucleotídeosRESUMO
Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in â¼30% of dopamine varicosities. Conditional RIM knockout disrupted this scaffold and, unexpectedly, abolished dopamine release, while ELKS knockout had no effect. Optogenetic experiments revealed that dopamine release was fast and had a high release probability, indicating the presence of protein scaffolds for coupling Ca2+ influx to vesicle fusion. Hence, dopamine secretion is mediated by sparse, mechanistically specialized active zone-like release sites. This architecture supports spatially and temporally precise coding for dopamine and provides molecular machinery for regulation.
Assuntos
Axônios/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Transmissão Sináptica/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Corpo Estriado/citologia , Dopamina/genética , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas rab de Ligação ao GTPRESUMO
How does stress promote risky decision-making? Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome.
Assuntos
Tomada de Decisões , Síndrome de Tourette , Animais , Gânglios da Base , Corpo Estriado , Córtex Pré-FrontalRESUMO
Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up of modules called matrisomes. Striosome-matrix architecture is multiplexed with the canonical direct-indirect organization of the striatum. Striosomal functions remain to be fully clarified, but key information is emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, with a following rebound excitation. Second, striosomes receive limbic and cognition-related corticostriatal afferents and are dynamically modulated in relation to value-based actions. Third, striosomes are spatially interspersed among matrisomes and interneurons and are influenced by local and global neuromodulatory and oscillatory activities. Fourth, striosomes tune engagement and the motivation to perform reinforcement learning, to manifest stereotypical behaviors, and to navigate valence conflicts and valence discriminations. We suggest that, at an algorithmic level, striosomes could serve as distributed scaffolds to provide formats of the striatal computations generated through development and refined through learning. We propose that striosomes affect subjective states. By transforming corticothalamic and other inputs to the functional formats of the striatum, they could implement state transitions in nigro-striato-nigral circuits to affect bodily and cognitive actions according to internal motives whose functions are compromised in neuropsychiatric conditions.
Assuntos
Gânglios da Base , Volição , Gânglios da Base/fisiologia , Corpo Estriado/fisiologia , Interneurônios , Reforço PsicológicoRESUMO
The performance of an action relies on the initiation and execution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution of learned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. The inhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution.
Assuntos
Corpo Estriado/fisiologia , Vias Neurais/fisiologia , Desempenho Psicomotor/fisiologia , Animais , Gânglios da Base/fisiologia , Corpo Estriado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Movimento , Neurônios/fisiologia , OptogenéticaRESUMO
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.
Assuntos
Anedonia/fisiologia , Corpo Estriado/imunologia , Depressão/imunologia , Microglia/imunologia , Neurônios/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Animal , Células Cultivadas , Modelos Animais de Doenças , Humanos , Inflamação , Interleucina-6/metabolismo , Ativação de Macrófagos , Camundongos , Inflamação Neurogênica , Prostaglandinas/metabolismoRESUMO
Astrocytes are heterogeneous glial cells of the central nervous system1-3. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses µ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders4-7. In adult mice, reducing the levels of µ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics8, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders9-12. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.
Assuntos
Astrócitos , Corpo Estriado , Ruminação Cognitiva , Cristalinas mu , Animais , Humanos , Camundongos , Astrócitos/metabolismo , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Edição de Genes , Técnicas de Inativação de Genes , Cristalinas mu/deficiência , Cristalinas mu/genética , Cristalinas mu/metabolismo , Ruminação Cognitiva/fisiologia , Transmissão Sináptica , Sistemas CRISPR-Cas , Neurônios Espinhosos Médios/metabolismo , Sinapses/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Terminações Pré-Sinápticas/metabolismo , Inibição NeuralRESUMO
Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences1,2. However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour.
Assuntos
Comportamento Animal , Reforço Psicológico , Recompensa , Animais , Camundongos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Sinais (Psicologia) , Optogenética , FotometriaRESUMO
External rewards such as food and money are potent modifiers of behaviour1,2. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA in the striatum3,4 at the same time that striatal cholinergic interneurons (CINs) produce a characteristic pause in firing5,6. These phasic responses are thought to create unique, temporally limited conditions that motivate action and promote learning7-11. However, the dynamics of DA and ACh outside explicitly rewarded situations remain poorly understood. Here we show that extracellular DA and ACh levels fluctuate spontaneously and periodically at a frequency of approximately 2 Hz in the dorsal striatum of mice and maintain the same temporal relationship relative to one another as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within the striatum. Instead, we provide evidence that periodic fluctuations in striatal DA are inherited from midbrain DANs, while striatal ACh transients are driven by glutamatergic inputs, which act to locally synchronize the spiking of CINs. Together, our findings show that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents. The dominance of intrinsic rhythms in DA and ACh offers new insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.
Assuntos
Acetilcolina , Corpo Estriado , Dopamina , Animais , Camundongos , Acetilcolina/metabolismo , Potenciais de Ação , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Glutamina/metabolismo , Interneurônios/metabolismo , Motivação , Neostriado/citologia , Neostriado/metabolismo , Recompensa , Vias AferentesRESUMO
Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making1. In vitro studies have revealed an intrastriatal circuit in which acetylcholine, released by cholinergic interneurons (CINs), drives the release of dopamine, and dopamine, in turn, inhibits the activity of CINs through dopamine D2 receptors (D2Rs). Whether and how this circuit contributes to striatal function in vivo is largely unknown. Here, to define the role of this circuit in a living system, we monitored acetylcholine and dopamine signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that dopamine and acetylcholine exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. Dopamine dynamics and reward encoding do not require the release of acetylcholine by CINs. However, dopamine inhibits acetylcholine transients in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other striatal inputs shape acetylcholine signals, we assessed the contribution of cortical and thalamic projections, and found that glutamate release from both sources is required for acetylcholine release. Altogether, we uncover a dynamic relationship between dopamine and acetylcholine during decision-making, and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behaviour.
Assuntos
Acetilcolina , Corpo Estriado , Tomada de Decisões , Dopamina , Ácido Glutâmico , Animais , Camundongos , Acetilcolina/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Neostriado/citologia , Neostriado/metabolismo , Tomada de Decisões/fisiologia , Recompensa , Receptores de Dopamina D2/metabolismo , Neurônios Colinérgicos/metabolismo , Vias NeuraisRESUMO
The direct and indirect pathways of the basal ganglia are classically thought to promote and suppress action, respectively1. However, the observed co-activation of striatal direct and indirect medium spiny neurons2 (dMSNs and iMSNs, respectively) has challenged this view. Here we study these circuits in mice performing an interval categorization task that requires a series of self-initiated and cued actions and, critically, a sustained period of dynamic action suppression. Although movement produced the co-activation of iMSNs and dMSNs in the sensorimotor, dorsolateral striatum (DLS), fibre photometry and photo-identified electrophysiological recordings revealed signatures of functional opponency between the two pathways during action suppression. Notably, optogenetic inhibition showed that DLS circuits were largely engaged to suppress-and not promote-action. Specifically, iMSNs on a given hemisphere were dynamically engaged to suppress tempting contralateral action. To understand how such regionally specific circuit function arose, we constructed a computational reinforcement learning model that reproduced key features of behaviour, neural activity and optogenetic inhibition. The model predicted that parallel striatal circuits outside the DLS learned the action-promoting functions, generating the temptation to act. Consistent with this, optogenetic inhibition experiments revealed that dMSNs in the associative, dorsomedial striatum, in contrast to those in the DLS, promote contralateral actions. These data highlight how opponent interactions between multiple circuit- and region-specific basal ganglia processes can lead to behavioural control, and establish a critical role for the sensorimotor indirect pathway in the proactive suppression of tempting actions.
Assuntos
Corpo Estriado , Modelos Neurológicos , Inibição Neural , Vias Neurais , Neurônios , Animais , Simulação por Computador , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Camundongos , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , OptogenéticaRESUMO
The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinase A (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine1-7. However, the precise dynamics of PKA in dorsolateral SPNs during locomotion remain to be determined. It is also unclear whether other neuromodulators are involved. Here we show that PKA activity in both types of SPNs is essential for normal locomotion. Using two-photon fluorescence lifetime imaging8-10 of a PKA sensor10 through gradient index lenses, we measured PKA activity within individual SPNs of the mouse dorsolateral striatum during locomotion. Consistent with the canonical view, dopamine activated PKA activity in direct pathway SPNs during locomotion through the dopamine D1 receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A2A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor11 revealed an acute increase in extracellular adenosine during locomotion. Functionally, antagonism of dopamine or adenosine receptors resulted in distinct changes in SPN PKA activity, neuronal activity and locomotion. Together, our results suggest that acute adenosine accumulation interplays with dopamine release to orchestrate PKA activity in SPNs and proper striatal function during animal locomotion.
Assuntos
Adenosina , Corpo Estriado , Proteínas Quinases Dependentes de AMP Cíclico , Dopamina , Locomoção , Neurônios , Animais , Camundongos , Adenosina/metabolismo , Corpo Estriado/citologia , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dopamina/metabolismo , Locomoção/fisiologia , Neurônios/enzimologia , Neurônios/metabolismo , Receptores de Dopamina D1/metabolismo , Receptor A2A de Adenosina/metabolismoRESUMO
Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs)1, and recent studies have identified primate-specific neuronal populations at the molecular level2. However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution.