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1.
Nat Protoc ; 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39075308

RESUMEN

Human neural organoids represent promising models for studying neural function; however, organoids grown in vitro lack certain microenvironments and sensory inputs that are thought to be essential for maturation. The transplantation of patient-derived neural organoids into animal hosts helps overcome some of these limitations and offers an approach for neural organoid maturation and circuit integration. Here, we describe a method for transplanting human stem cell-derived cortical organoids (hCOs) into the somatosensory cortex of newborn rats. The differentiation of human induced pluripotent stem cells into hCOs occurs over 30-60 days, and the transplantation procedure itself requires ~0.5-1 hours per animal. The use of neonatal hosts provides a developmentally appropriate stage for circuit integration and allows the generation and experimental manipulation of a unit of human neural tissue within the cortex of a living animal host. After transplantation, animals can be maintained for hundreds of days, and transplanted hCO growth can be monitored by using brain magnetic resonance imaging. We describe the assessment of human neural circuit function in vivo by monitoring genetically encoded calcium responses and extracellular activity. To demonstrate human neuron-host functional integration, we also describe a procedure for engaging host neural circuits and for modulating animal behavior by using an optogenetic behavioral training paradigm. The transplanted human neurons can then undergo ex vivo characterization across modalities including dendritic morphology reconstruction, single-nucleus transcriptomics, optogenetic manipulation and electrophysiology. This approach may enable the discovery of cellular phenotypes from patient-derived cells and uncover mechanisms that contribute to human brain evolution from previously inaccessible developmental stages.

2.
Nat Neurosci ; 26(9): 1566-1574, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37592039

RESUMEN

Animals must continually evaluate stimuli in their environment to decide which opportunities to pursue, and in many cases these decisions can be understood in fundamentally economic terms. Although several brain regions have been individually implicated in these processes, the brain-wide mechanisms relating these regions in decision-making are unclear. Using an economic decision-making task adapted for rats, we find that neural activity in both of two connected brain regions, the ventrolateral orbitofrontal cortex (OFC) and the dorsomedial striatum (DMS), was required for economic decision-making. Relevant neural activity in both brain regions was strikingly similar, dominated by the spatial features of the decision-making process. However, the neural encoding of choice direction in OFC preceded that of DMS, and this temporal relationship was strongly correlated with choice accuracy. Furthermore, activity specifically in the OFC projection to the DMS was required for appropriate economic decision-making. These results demonstrate that choice information in the OFC is relayed to the DMS to lead accurate economic decision-making.


Asunto(s)
Cuerpo Estriado , Neostriado , Animales , Ratas , Encéfalo , Corteza Prefrontal
3.
Nature ; 610(7931): 319-326, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36224417

RESUMEN

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.


Asunto(s)
Vías Nerviosas , Organoides , Animales , Animales Recién Nacidos , Trastorno Autístico , Humanos , Síndrome de QT Prolongado , Motivación , Neuronas/fisiología , Optogenética , Organoides/citología , Organoides/inervación , Organoides/trasplante , Ratas , Recompensa , Corteza Somatosensorial/citología , Corteza Somatosensorial/fisiología , Células Madre/citología , Sindactilia
5.
Comp Med ; 71(1): 86-98, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33500020

RESUMEN

Steroid-induced osteonecrosis of the femoral head (SONFH) is a condition documented in humans and animals exposed to chronic steroid administration. The rabbit has become a preferred animal model for investigating the pathogenesis and treatment of SONFH due to its shared femoral vascular anatomy with human patients, relative size of the femoral head, and general fecundity. However, morbidity and mortality are frequent during the steroid induction period, prior to surgical manipulation. These problems are poorly reported and inadequately described in the literature. In this study, we report the clinical, gross, and histopathologic findings of New Zealand white (NZW) rabbits undergoing the steroid induction phase of the SONFH model. Severe weight loss (>30%), lipemia, hypercholesterolemia, hyperglycemia, and elevations in ALT and AST were consistent findings across all rabbits, although these changes did not differentiate asymptomatic rabbits from those that became clinically symptomatic or died. Euthanized and spontaneously deceased rabbits exhibited hepatomegaly, hepatic lipidosis/glycogenosis, and hepatocellular necrosis, in addition to a lipid-rich and proteinaceous thoracic effusion. A subset of rabbits developed opportunistic pulmonary infections with Bordetella bronchiseptica and Escherichia coli and small intestine infections with Lawsonia intracellularis superimposed on hepatic and thoracic disease. Together, these findings allowed us to establish a clinical decision-making flowchart that reduced morbidities and mortalities in a subsequent cohort of SONFH rabbits. Recognition of these model-associated morbidities is critical for providing optimal clinical care during the disease induction phase of SONFH.


Asunto(s)
Necrosis de la Cabeza Femoral , Cabeza Femoral , Animales , Modelos Animales de Enfermedad , Necrosis de la Cabeza Femoral/inducido químicamente , Humanos , Morbilidad , Conejos , Esteroides
6.
Nat Biotechnol ; 39(2): 161-164, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33020604

RESUMEN

Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.


Asunto(s)
Encéfalo/cirugía , Optogenética , Animales , Encéfalo/efectos de la radiación , Luz , Masculino , Ratones Endogámicos C57BL , Neuronas/fisiología , Neuronas/efectos de la radiación , Ratas , Área Tegmental Ventral/fisiología , Área Tegmental Ventral/efectos de la radiación
7.
Nature ; 586(7827): 87-94, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32939091

RESUMEN

Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1-12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.


Asunto(s)
Ondas Encefálicas/fisiología , Corteza Cerebral/fisiología , Trastornos Disociativos/fisiopatología , Potenciales de Acción/efectos de los fármacos , Animales , Conducta/efectos de los fármacos , Ondas Encefálicas/efectos de los fármacos , Corteza Cerebral/citología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/efectos de los fármacos , Trastornos Disociativos/diagnóstico por imagen , Electrofisiología , Femenino , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Ketamina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Optogenética , Autoinforme , Tálamo/citología , Tálamo/diagnóstico por imagen , Tálamo/efectos de los fármacos , Tálamo/fisiología
8.
Neuron ; 106(6): 1026-1043.e9, 2020 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-32294466

RESUMEN

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.


Asunto(s)
Conducta Apetitiva/fisiología , Reacción de Prevención/fisiología , Núcleo Amigdalino Central/fisiología , Neuronas Dopaminérgicas/fisiología , Neuronas GABAérgicas/fisiología , Sustancia Negra/fisiología , Animales , Condicionamiento Clásico/fisiología , Emociones , Ratones , Vías Nerviosas , Refuerzo en Psicología , Recompensa , Sustancia Negra/citología
9.
IEEE Trans Biomed Circuits Syst ; 12(2): 257-270, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29578414

RESUMEN

A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm3, 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 µA amplitude, ∼14 to 470 µs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm2 optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves.


Asunto(s)
Terapia por Estimulación Eléctrica/instrumentación , Electrodos Implantados , Nervios Periféricos/fisiología , Diseño de Equipo , Humanos , Modelos Teóricos
10.
Curr Opin Neurobiol ; 49: 175-183, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29525574

RESUMEN

All organisms must solve the same fundamental problem: they must acquire rewards and avoid danger in order to survive. A key challenge for the nervous system is therefore to connect motivationally salient sensory stimuli to neural circuits that engage appropriate valence-specific behavioral responses. Anatomical, behavioral, and electrophysiological data have long suggested that the amygdala plays a central role in this process. Here we review experimental efforts leveraging recent technological advances to provide previously unattainable insights into the functional, anatomical, and genetic identity of neural populations within the amygdala that connect sensory stimuli to valence-specific behavioral responses.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Red Nerviosa/fisiología , Refuerzo en Psicología , Animales , Complejo Nuclear Basolateral/citología , Humanos
11.
Philos Trans R Soc Lond B Biol Sci ; 370(1677): 20140216, 2015 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-26240431

RESUMEN

Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour.


Asunto(s)
Neuronas/fisiología , Animales , Conducta/fisiología , Encéfalo/citología , Encéfalo/fisiología , Condicionamiento Psicológico/fisiología , Fenómenos Electrofisiológicos , Miedo/fisiología , Miedo/psicología , Técnicas Genéticas , Humanos , Aprendizaje/fisiología , Memoria/fisiología , Neuronas/clasificación , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicología
12.
Cell ; 162(1): 134-45, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26140594

RESUMEN

Stimuli that possess inherently rewarding or aversive qualities elicit emotional responses and also induce learning by imparting valence upon neutral sensory cues. Evidence has accumulated implicating the amygdala as a critical structure in mediating these processes. We have developed a genetic strategy to identify the representations of rewarding and aversive unconditioned stimuli (USs) in the basolateral amygdala (BLA) and have examined their role in innate and learned responses. Activation of an ensemble of US-responsive cells in the BLA elicits innate physiological and behavioral responses of different valence. Activation of this US ensemble can also reinforce appetitive and aversive learning when paired with differing neutral stimuli. Moreover, we establish that the activation of US-responsive cells in the BLA is necessary for the expression of a conditioned response. Neural representations of conditioned and unconditioned stimuli therefore ultimately connect to US-responsive cells in the BLA to elicit both innate and learned responses.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Condicionamiento Clásico , Aprendizaje , Animales , Conducta Apetitiva , Conducta Animal , Masculino , Ratones , Ratones Endogámicos C57BL , Recompensa
13.
Psychopharmacology (Berl) ; 219(3): 751-61, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21766171

RESUMEN

RATIONALE: Reconsolidation is the process by which memories require restabilisation following destabilisation at retrieval. Since even old, well-established memories become susceptible to disruption following reactivation, treatments based upon disrupting reconsolidation could provide a novel form of therapy for neuropsychiatric disorders based upon maladaptive memories, such as drug addiction. Pavlovian cues are potent precipitators of relapse to drug-seeking behaviour and influence instrumental drug seeking through at least three psychologically and neurobiologically distinct processes: conditioned reinforcement, conditioned approach (autoshaping) and conditioned motivation (pavlovian-instrumental transfer or PIT). We have previously demonstrated that the reconsolidation of memories underlying the conditioned reinforcing properties of drug cues depends upon NMDA receptor (NMDAR)- and ß-adrenergic receptor (ßAR)-mediated signalling. However, it is unknown whether the drug cue memory representations underlying conditioned approach and PIT depend upon the same mechanisms. OBJECTIVES: Using orally self-administered ethanol as a reinforcer in two separate experiments, we investigated whether the reconsolidation of the memories underlying conditioned approach and PIT requires ßAR- and NMDAR-dependent neurotransmission. RESULTS: For ethanol self-administering but non-dependent rats, the memories underlying conditioned approach and PIT for a pavlovian drug cue were disrupted by the administration of the NMDAR antagonist MK-801, but not the administration of the ßAR antagonist propranolol, when given in conjunction with memory reactivation. CONCLUSIONS: As for natural reinforcers, NMDARs are required for the reconsolidation of all aspects of pavlovian drug memories, but ßARs are only required for the memory representation underlying conditioned reinforcement. These results indicate the potential utility of treatments based upon disrupting cue-drug memory reconsolidation in preventing relapse.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Condicionamiento Operante/efectos de los fármacos , Etanol/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores Adrenérgicos beta , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Maleato de Dizocilpina/farmacología , Masculino , Ratas , Receptores Adrenérgicos beta/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Autoadministración
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