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Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.
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Dolor Crónico , Claustro , Cognición , Humanos , Dolor Crónico/fisiopatología , Masculino , Adulto , Cognición/fisiología , Femenino , Claustro/fisiología , Claustro/fisiopatología , Adulto Joven , Trastornos Migrañosos/fisiopatologíaRESUMEN
Generating animal models for individual patients within clinically-useful timeframes holds great potential toward enabling personalized medicine approaches for genetic epilepsies. The ability to rapidly incorporate patient-specific genomic variants into model animals recapitulating elements of the patient's clinical manifestations would enable applications ranging from validation and characterization of pathogenic variants to personalized models for tailoring pharmacotherapy to individual patients. Here, we demonstrate generation of an animal model of an individual epilepsy patient with an ultra-rare variant of the NMDA receptor subunit GRIN2A, without the need for germline transmission and breeding. Using in utero prime editing in the brain of wild-type mice, our approach yielded high in vivo editing precision and induced frequent, spontaneous seizures which mirrored specific elements of the patient's clinical presentation. Leveraging the speed and versatility of this approach, we introduce PegAssist, a generalizable workflow to generate bedside-to-bench animal models of individual patients within weeks. The capability to produce individualized animal models rapidly and cost-effectively will reduce barriers to access for precision medicine, and will accelerate drug development by offering versatile in vivo platforms to identify compounds with efficacy against rare neurological conditions.
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Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.
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Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained them in adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.
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Conducta Impulsiva , Corteza Prefrontal , Adolescente , Ratas , Masculino , Humanos , Animales , Conducta Impulsiva/fisiología , Corteza Prefrontal/fisiología , Recompensa , Núcleo Accumbens/fisiología , Conducta de Elección/fisiologíaRESUMEN
The dorsal striatum (DS) mediates the selection of actions for reward acquisition necessary for survival. Striatal pathology contributes to several neuropsychiatric conditions, including aberrant selection of actions for specific rewards in addiction. A major source of glutamate driving striatal activity is the rostral intralaminar nuclei (rILN) of the thalamus. Yet, the information that is relayed to the striatum to support action selection is unknown. Here, we discovered that rILN neurons projecting to the DS are innervated by a range of cortical and subcortical afferents and that rILNâDS neurons stably signaled at two time points in mice performing an action sequence task reinforced by sucrose reward: action initiation and reward acquisition. In vivo activation of this pathway increased the number of successful trials, whereas inhibition decreased the number of successful trials. These findings illuminate a role for the rostral intralaminar nuclear complex in reinforcing actions.
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Núcleos Talámicos Intralaminares , Tálamo , Ratones , Animales , Tálamo/fisiología , Cuerpo Estriado/fisiología , Neuronas/fisiología , Recompensa , NeostriadoRESUMEN
Parvalbumin-expressing dorsal striatal fast-spiking interneurons, comprising â¼1% of the total dorsal striatal neuronal population, are necessary for the expression of compulsive-like ethanol consumption mice. Fast-spiking interneurons are driven to fire by glutamatergic inputs derived primarily from the cortex. However, these neurons also receive substantial GABAergic input from two sources: the globus pallidus and the reticular nucleus of the thalamus. How ethanol modulates inhibitory input onto fast-spiking neurons is unclear and, more broadly, alcohol effects on GABAergic synaptic transmission onto GABAergic interneurons are understudied. Examining this, we found that acute bath application of ethanol (50 mM) potentiated GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto fast-spiking interneurons in mouse of both sexes. This ethanol-induced potentiation required postsynaptic calcium and was not accompanied by a sustained change in presynaptic GABA release probability. Examining whether this ethanol effect persisted following chronic intermittent ethanol exposure, we found attenuated acute-ethanol potentiation of GABAergic transmission from both the globus pallidus and the reticular nucleus of the thalamus onto striatal fast-spiking interneurons. These data underscore the impact of ethanol on GABAergic signaling in the dorsal striatum and support the notion that ethanol may disinhibit the dorsolateral striatum.
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Cuerpo Estriado , Etanol , Neuronas GABAérgicas , Interneuronas , Animales , Femenino , Masculino , Ratones , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Etanol/administración & dosificación , Etanol/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Globo Pálido/citología , Globo Pálido/efectos de los fármacos , Interneuronas/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Núcleos Talámicos/citología , Núcleos Talámicos/efectos de los fármacos , Núcleos Talámicos/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Calcio/metabolismoRESUMEN
Spatially distant areas of the cerebral cortex coordinate their activity into networks that are integral to cognitive processing. A common structural motif of cortical networks is co-activation of frontal and posterior cortical regions. The neural circuit mechanisms underlying such widespread inter-areal cortical coordination are unclear. Using a discovery based functional magnetic resonance imaging (fMRI) approach in mouse, we observe frontal and posterior cortical regions that demonstrate significant functional connectivity with the subcortical nucleus, the claustrum. Examining whether the claustrum synaptically supports such frontoposterior cortical network architecture, we observe cortico-claustro-cortical circuits reflecting the fMRI data: significant trans-claustral synaptic connectivity from frontal cortices to posteriorly lying sensory and sensory association cortices contralaterally. These data reveal discrete cortical pathways through the claustrum that are positioned to support cortical network motifs central to cognitive control functions and add to the canon of major extended cortico-subcortico-cortical systems in the mammalian brain.
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Claustro , Ratones , Animales , Ganglios Basales/fisiología , Corteza Cerebral , Lóbulo Frontal , Lóbulo Parietal/fisiología , Imagen por Resonancia Magnética , Vías Nerviosas/fisiología , MamíferosRESUMEN
Early hypotheses of claustrum function were fueled by neuroanatomical data and yielded suggestions that the claustrum is involved in processes ranging from salience detection to multisensory integration for perceptual binding. While these hypotheses spurred useful investigations, incompatibilities inherent in these views must be reconciled to further conceptualize claustrum function amid a wealth of new data. Here, we review the varied models of claustrum function and synthesize them with developments in the field to produce a novel functional model: network instantiation in cognitive control (NICC). This model proposes that frontal cortices direct the claustrum to flexibly instantiate cortical networks to subserve cognitive control. We present literature support for this model and provide testable predictions arising from this conceptual framework.
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Claustro , Humanos , Ganglios Basales , Vías Nerviosas , Lóbulo Frontal , CogniciónRESUMEN
Inhibitory fast-spiking interneurons in the dorsal striatum regulate actions and action strategies, including habits. Fast-spiking interneurons are widely believed to synchronize their firing due to the electrical synapses formed between these neurons. However, neuronal modelling data suggest convergent cortical input may also drive synchrony in fast-spiking interneuron networks. To better understand how fast-spiking interneuron synchrony arises, we performed dual whole-cell patch clamp electrophysiology experiments to inform a simple Bayesian network modelling cortico-fast-spiking interneuron circuitry. Dual whole-cell patch clamp electrophysiology revealed that while responsivity to corticostriatal input activation was high in fast-spiking interneurons, few of these neurons exhibited electrical coupling in adult mice. In simulations of a cortico-fast-spiking interneuron network informed by these data, the degree of glutamatergic cortical convergence onto fast-spiking interneurons significantly increased fast-spiking interneuron synchronization while manipulations of electrical coupling between these neurons exerted relatively little impact. These results suggest that the primary source of functional coordination of fast-spiking interneuron activity in adulthood arises from convergent corticostriatal input activation. KEY POINTS: Electrical synapses between striatal fast-spiking interneurons in adult mice occur in â¼8% of assayed pairs. Coincident, convergent cortical input onto fast-spiking interneurons significantly contributes to fast-spiking interneuron synchrony. Electrical synapses between fast-spiking interneurons provide only minor enhancement of fast-spiking interneuron synchrony. These results suggest a mechanism by which adult mouse fast-spiking interneurons of the striatum synchronize in the face of declining expression of the electrical synapse-forming connexin-36 protein.
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Cuerpo Estriado , Interneuronas , Potenciales de Acción/fisiología , Animales , Teorema de Bayes , Cuerpo Estriado/fisiología , Interneuronas/fisiología , Ratones , NeuronasRESUMEN
Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.
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Alucinógenos , Animales , Encéfalo , Corteza Cerebral , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Humanos , Dietilamida del Ácido Lisérgico/farmacología , Psilocibina/farmacologíaRESUMEN
Psychedelic substances produce unusual and compelling changes in conscious experience that have prompted some to propose that psychedelics may provide unique insights explaining the nature of consciousness. At present, psychedelics, like other current scientific tools and methods, seem unlikely to provide information relevant to the so-called "hard problem of consciousness," which involves explaining how first-person experience can emerge. However, psychedelics bear on multiple "easy problems of consciousness," which involve relations between subjectivity, brain function, and behavior. In this review, we discuss common meanings of the term "consciousness" when used with regard to psychedelics and consider some models of the effects of psychedelics on the brain that have also been associated with explanatory claims about consciousness. We conclude by calling for epistemic humility regarding the potential for psychedelic research to aid in explaining the hard problem of consciousness while pointing to ways in which psychedelics may advance the study of many specific aspects of consciousness.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Estado de Conciencia/efectos de los fármacos , Alucinógenos/farmacología , HumanosRESUMEN
The thalamic rostral intralaminar nuclei (rILN) are a contiguous band of neurons that include the central medial, paracentral, and central lateral nuclei. The rILN differ from both thalamic relay nuclei, such as the lateral geniculate nucleus, and caudal intralaminar nuclei, such as the parafascicular nucleus, in afferent and efferent connectivity as well as physiological and synaptic properties. rILN activity is associated with a range of neural functions and behaviors, including arousal, pain, executive function, and action control. Here, we review this evidence supporting a role for the rILN in integrating arousal, executive and motor feedback information. In light of rILN projections out to the striatum, amygdala, and sensory as well as executive cortices, we propose that such a function enables the rILN to modulate cognitive and motor resources to meet task-dependent behavioral engagement demands.
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In this issue of Neuron, Soria-Gomez et al. (2021) investigate whether activation of the type 1 cannabinoid receptor at specific subcellular locations within a single neural circuit produces multimodal behavior. Their results demonstrate that location matters: striatonigral mitochondrial CB1 drives catalepsy while striatonigral plasma membrane CB1 receptors enable antinociception.
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Cannabinoides , Animales , Conducta Animal , DronabinolRESUMEN
The chemical synapse is the principal form of contact between neurons of the central nervous system. These synapses are typically configured as presynaptic axon terminations onto postsynaptic dendrites or somata, giving rise to axo-dendritic and axo-somatic synapses, respectively. Beyond these common synapse configurations are less-studied, non-canonical synapse types that are prevalent throughout the brain and significantly contribute to neural circuit function. Among these are the axo-axonic synapses, which consist of an axon terminating on another axon or axon terminal. Here, we review evidence for axo-axonic synapse contributions to neural signaling in the mammalian nervous system and survey functional neural circuit motifs enabled by these synapses. We also detail how recent advances in microscopy, transgenics, and biological sensors may be used to identify and functionally assay axo-axonic synapses.
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Axones/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Animales , Axones/ultraestructura , Catecolaminas/metabolismo , Ácido Glutámico/metabolismo , Humanos , Red Nerviosa/ultraestructura , Neuronas/ultraestructura , Sinapsis/ultraestructuraRESUMEN
Compulsive alcohol consumption is a core, treatment-resistant feature of alcohol use disorder. The dorsomedial and dorsolateral striatum support goal-directed and habitual action strategies, respectively. How ethanol targets dorsolateral striatum to drive compulsive consumption is poorly understood. Parvalbumin-expressing striatal fast-spiking interneurons comprise ~1% of the total neuronal striatal population, are enriched dorsolaterally and are functionally modulated by ethanol. To test whether fast-spiking interneurons are necessary for the development of compulsive ethanol consumption, we selectively ablated these neurons in adult male and female C57BL/6 J mice undergoing a voluntary chronic intermittent ethanol consumption paradigm followed by a compulsive ethanol drinking assay. Fast-spiking interneuron ablation curtailed the development of organized ethanol lick sequence behavior, reduced ethanol consumption, and abrogated compulsive consumption of ethanol with the added bitterant quinine. In contrast, fast-spiking interneuron ablation did not affect any index of water or sucrose consumption. These data causally implicate the minority striatal fast-spiking interneuron population as a key component of compulsive ethanol consumption.
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Interneuronas , Parvalbúminas , Consumo de Bebidas Alcohólicas , Animales , Conducta Compulsiva , Cuerpo Estriado/metabolismo , Femenino , Interneuronas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Parvalbúminas/metabolismoRESUMEN
BACKGROUND: To achieve goals, organisms are often faced with complex tasks that require enhanced control of cognitive faculties for optimal performance. However, the neural circuit mechanisms underlying this ability are unclear. The claustrum is proposed to mediate a variety of functions ranging from sensory binding to cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking. METHODS: Here, we employed the Gnb4 (guanine nucleotide-binding subunit beta-4) cre driver line in mice to selectively monitor and manipulate claustrum projection neurons during 1-choice versus 5-choice serial reaction time task performance. RESULTS: Using fiber photometry, we found elevated claustrum activity prior to an expected cue during correct performance on the cognitively demanding 5-choice response assay relative to the less demanding 1-choice version of the task. Claustrum activity during reward acquisition was also enhanced when task demand was higher. Furthermore, optogenetically inhibiting the claustrum prior to the onset of the cue reduced choice accuracy on the 5-choice task but not on the 1-choice task. CONCLUSIONS: These results suggest that the claustrum supports a cognitive control function necessary for optimal behavioral performance under cognitively demanding conditions.
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Claustro , Animales , Ganglios Basales , Cognición , Interneuronas , Ratones , Vías NerviosasRESUMEN
Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 âmin after blinded oral administration of placebo and 10 mg/70 âkg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.
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Claustro/efectos de los fármacos , Alucinógenos/farmacología , Vías Nerviosas/efectos de los fármacos , Psilocibina/farmacología , Adulto , Anciano , Atención/efectos de los fármacos , Atención/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Persona de Mediana Edad , Percepción/efectos de los fármacos , Percepción/fisiologíaRESUMEN
Barbier and colleagues confirm a projection from the supramammillary nucleus to the claustrum using immunohistochemistry to validate the structural boundaries of the claustrum. This refines earlier conclusions made by Vertes and colleagues and highlights the importance of properly anatomically characterizing the claustrum for future structural and functional studies.
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Striatal fast-spiking interneurons (FSIs) potently inhibit the output neurons of the striatum and, as such, powerfully modulate action learning. Through electrical synaptic coupling, FSIs are theorized to temporally coordinate their activity. This has important implications for their ability to temporally summate inhibition on downstream striatal projection neurons. While some in vivo single-unit electrophysiological recordings of putative FSIs support coordinated firing, others do not. Moreover, it is unclear as to what aspect of action FSIs encode. To address this, we used in vivo calcium imaging of genetically identified FSIs in freely moving mice and applied machine learning analyses to decipher the relationship between FSI activity and movement. We report that FSIs exhibit ensemble activity that encodes the speed of action sub-components, including ambulation and head movements. These results suggest FSI population dynamics fit within a Hebbian model for ensemble inhibition of striatal output guiding action.
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Potenciales de Acción/fisiología , Cuerpo Estriado/fisiología , Interneuronas/fisiología , Neuronas/fisiología , Animales , Femenino , Masculino , Ratones Transgénicos , Neostriado/fisiologíaRESUMEN
Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5â¯mm isotropic voxels) using a 7T dataset (nâ¯=â¯20) and a separate 3T dataset for replication (nâ¯=â¯35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (nâ¯=â¯33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing.