Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 13, 2023

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools transgenic models for gaining long-term genetic access MOR+ neural types circuits involved in modulating pain, analgesia addiction across species are limited. To address this, we developed catalog MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression cells. MORp designed from regions upstream mouse Oprm1 gene (mMORp) were validated transduction efficiency selectivity endogenous neurons brain, spinal cord, periphery mice, with additional studies revealing robust rats, shrews, human induced pluripotent stem (iPSC)-derived nociceptors. The mMORp vivo fiber photometry, behavioral chemogenetics, intersectional strategies also demonstrated. Lastly, (hMORp) efficiently transduced macaque cortical OPRM1+ Together, our toolkit provides researchers type functionally mu-opioidergic range vertebrate translational addiction, neuropsychiatric disorders.

Язык: Английский

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Molecular diversity and functional dynamics in the central amygdala

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Фев. 14, 2024

The central amygdala (CeA) is crucial in integrating sensory and associative information to mediate adaptive responses emotional stimuli. Recent advances genetic techniques like optogenetics chemogenetics have deepened our understanding of distinct neuronal populations within the CeA, particularly those involved fear learning memory consolidation. However, challenges remain due overlapping markers complicating neuron identification. Furthermore, a comprehensive molecularly defined cell types their projection patterns, which are essential for elucidating functional roles, still developing. advancements transcriptomics starting bridge these gaps, offering new insights into dynamics CeA neurons. In this review, we provide an overview expanding research, encompassing recent developments current trends. We also discuss how novel transcriptomic approaches redefining setting stage studies.

Язык: Английский

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Development and function of the medial amygdala

Trends in Neurosciences, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

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The transcriptomic and spatial organization of telencephalic GABAergic neuronal types

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 18, 2024

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive integrative roles in a variety functions. There is wide array GABAergic neurons telencephalon; they multitude functions, dysfunction these has been implicated diverse disorders. In this study, we conducted systematic in-depth analysis transcriptomic spatial organization neuronal types all mouse their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from comprehensive high-resolution cell type atlas for adult whole have generated, supplemented with an additional RNA-sequencing dataset containing 99,438 high-quality collected pre- postnatal developing brain. We present hierarchically organized telencephalic taxonomy 7 classes, 52 subclasses, 284 supertypes, 1,051 clusters, as well corresponding 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among reflect both locations Transcriptomically developmentally related can often be found distant indicating long-distance migration dispersion common characteristic nearly classes neurons. Additionally, find various dimensions discrete continuous variations are correlated gene expression gradients. Lastly, cortical, striatal some pallidal undergo extensive diversification, whereas septal most emerge simultaneously during embryonic stage limited diversification. Overall, serve foundational reference molecular, structural functional studies circuits entire community.

Язык: Английский

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Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors

The Journal of Physiology, Год журнала: 2024, Номер unknown

Опубликована: Июль 2, 2024

Abstract The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression schizophrenia. However, the effect of histamine on neuronal activity centrolateral amygdala (CeL), an essential node for fear anxiety processing, remains unknown. Here, using immunostaining whole‐cell patch clamp recording combined with optogenetic manipulation terminals CeL slices prepared from histidine decarboxylase (HDC)‐Cre rats, we show that selectively suppresses excitatory synaptic transmissions, glutamatergic transmission basolateral amygdala, both PKC‐δ‐ SOM‐positive neurons. histamine‐induced is mediated by H3 receptors expressed VGLUT1‐/VGLUT2‐positive presynaptic CeL. Furthermore, optoactivation afferent hypothalamic tuberomammillary nucleus (TMN) also significantly transmissions via receptors. Histamine neither modulates inhibitory nor directly excites neurons postsynaptic H1, H2 or H4 These results suggest inputs heteroreceptors may hold critical position balancing selective modulation drive, which not only account pathophysiology disorders but provide potential psychotherapeutic targets. image Key points excitatory, rather than inhibitory, (CeL). VGLUT1‐ VGLUT2‐positive mediate suppression Optogenetic activation (TMN)–CeL projections inhibits

Язык: Английский

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Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans

American Journal of Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Окт. 30, 2024

Theories of amygdala function are central to our understanding psychiatric and neurodevelopmental disorders. However, limited knowledge the molecular cellular composition impedes translational research aimed at developing new treatments interventions. The aim this study was characterize compare cells help bridge gap between preclinical models human

Язык: Английский

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An Honest Reckoning With the Amygdala and Mental Illness

American Journal of Psychiatry, Год журнала: 2024, Номер 181(12), С. 1059 - 1075

Опубликована: Дек. 1, 2024

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments far from curative for many, underscoring the need to clarify underlying neural mechanisms. Although many brain regions contribute, amygdala has received most intense scientific attention. Over past several decades, this scrutiny yielded detailed understanding function, but it failed produce new clinical assays, biomarkers, or cures. Rising urgent public health challenge demands an honest reckoning with functional-neuroanatomical complexity shift theories anchored on "the amygdala" models centered specific nuclei cell types. This review begins by examining evidence studies rodents, monkeys, humans "canonical model," idea that plays central role in fear- anxiety-related states, traits, disorders. Next, authors selectively highlight work indicating canonical model, while true, is overly simplistic fails adequately capture actual state evidentiary record, breadth amygdala-associated functions illnesses, amygdala's functional architecture. The describe implications these facts basic neuroimaging research. concludes some general recommendations grappling accelerating efforts understand more effectively treat amygdala-related psychopathology.

Язык: Английский

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One‐hertz low‐frequency stimulation of anterior substantia nigra pars reticulata attenuates seizure via biased disinhibitory circuits

Epilepsia, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Abstract Objective Low‐frequency stimulation (LFS) targeting key seizure nodes holds promising potential for the treatment of epilepsy. The substantia nigra pars reticulata (SNr) plays an important role in control yet has structural heterogeneity. This study aims to explore therapeutic LFS across different subregions SNr. Methods Different types models, including kainic acid‐induced hippocampal and neocortical models a pentetrazol‐induced model, were used address Fiber photometry, specific cell ablation, viral tracing measure release neurotransmitters heterogeneous circuit organizations Results We found that 1‐Hz anterior SNr (a‐SNr), but not posterior (p‐SNr), generally alleviated severity all three mouse models. Notably, antiseizure effects frequency‐dependent, with 100‐Hz high‐frequency being less effective 20‐Hz having hardly any impact. Regarding mechanism discrepancy, fiber photometry showed 1‐Hz, rather than 20‐ or 100‐Hz, a‐SNr significantly increased γ‐aminobutyric acid from exogenous inputs compared p‐SNr, which was further supported by their biased brain‐wide disinhibitory inputs. Significance These results demonstrate may be significance various seizures, highlighting necessity precisely target at low frequency treatment.

Язык: Английский

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Inhibitory effects of dopamine agonists on pain-responsive neurons in the central nucleus of the amygdala

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

ABSTRACT The central nucleus of the amygdala (CeA) is a heterogenous region primarily GABAergic neurons that contributes to numerous behaviors, including fear learning, feeding, reward, and pain. Dopaminergic inputs CeA have been shown regulate many these but how dopamine exerts effects at cellular level has not well characterized. We used Targeted Recombination in Active Populations (TRAP) mouse line fluorescently label pain-responsive neurons, then targeted cells for patch-clamp recordings acute slices test agonists. D1 agonist SKF-38393 D2 quinpirole both had inhibitory effects, reducing input resistance evoked firing increasing rheobase labeled neurons. Both agents also inhibited NMDA component excitatory postsynaptic currents (EPSCs) by basolateral (BLA) stimulation, did affect AMPA component. activation, D2, appeared presynaptic effect, frequency spontaneous EPSCs. These results provide new insights into regulates activity within networks. NEW & NOTEWORTHY Dopamine known (CeA), an important pain processing. However, its examine synaptic Activation either or receptors induced suggesting signaling dampens pain-related could be target analgesics.

Язык: Английский

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Food and water intake are regulated by distinct central amygdala circuits revealed using intersectional genetics

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 29, 2025

Abstract The central amygdala (CeA) plays a crucial role in defensive and appetitive behaviours. It contains genetically defined GABAergic neuron subpopulations distributed over three anatomical subregions, capsular (CeC), lateral (CeL), medial (CeM). roles that these molecularly- anatomically-defined CeA neurons play behavior remain unclear. Using intersectional genetics mice, we found driving food or water consumption are confined to the CeM. Separate CeM exist for only versus consumption. In vivo calcium imaging revealed Htr2a promoting feeding responsive towards cues with little regard their physical attributes. Sst involved drinking sensitive properties of salient stimuli. Both subtypes receive inhibitory input from CeL send projections parabrachial nucleus promote behavior. These results suggest distinct microcircuits evaluate liquid solid stimuli drive appropriate behavioral responses.

Язык: Английский

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