Opposing Regulation of Cocaine Seeking by Glutamate and GABA Neurons in the Ventral Pallidum

Cell Rep

2020 Feb 11

Heinsbroek JA1, Bobadilla AC2, Dereschewitz E2, Assali A2, Chalhoub RM2, Cowan CW2, Kalivas PW3.
PMID: 32049028 | DOI: 10.1016/j.celrep.2020.01.023

Projections from the nucleus accumbens to the ventral pallidum (VP) regulate relapse in animal models of addiction. The VP contains GABAergic (VPGABA) and glutamatergic (VPGlu) neurons, and a subpopulation of GABAergic neurons co-express enkephalin (VPPenk). Rabies tracing reveals that VPGlu and VPPenk neurons receive preferential innervation from upstream D1- relative to D2-expressing accumbens neurons. Chemogenetic stimulation of VPGlu neurons inhibits, whereas stimulation of VPGABA and VPPenk neurons potentiates cocaine seeking in mice withdrawn from intravenous cocaine self-administration. Calcium imaging reveals cell type-specific activity patterns when animals learn to suppress drug seeking during extinction training versus engaging in cue-induced cocaine seeking. During cued seeking, VPGABA neurons increase their overall activity, and VPPenk neurons are selectively activated around nose pokes for cocaine. In contrast, VPGlu neurons increase their spike rate following extinction training. These data show that VP subpopulations differentially encode and regulate cocaine seeking, with VPPenk and VPGABA neurons facilitating and VPGlu neurons inhibiting cocaine seeking

IPAC integrates rewarding and environmental memory during the acquisition of morphine CPP

Science advances

2023 Jun 23

Liu, HM;Liao, ML;Liu, GX;Wang, LJ;Lian, D;Ren, J;Chi, XT;Lv, ZR;Liu, M;Wu, Y;Xu, T;Wei, JY;Feng, X;Jiang, B;Zhang, XQ;Xin, WJ;
PMID: 37352353 | DOI: 10.1126/sciadv.adg5849

The association between rewarding and drug-related memory is a leading factor for the formation of addiction, yet the neural circuits underlying the association remain unclear. Here, we showed that the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) integrated rewarding and environmental memory information by two different receiving projections from ventral tegmental area (VTA) and nucleus accumbens shell region (NAcSh) to mediate the acquisition of morphine conditioned place preference (CPP). A projection from the VTA GABAergic neurons (VTAGABA) to the IPAC lateral region GABAergic neurons (IPACLGABA) mediated the effect of morphine rewarding, whereas the pathway from NAcSh dopamine receptor 1-expressing neurons (NAcShD1) to the IPAC medial region GABAergic neurons (IPACMGABA) was involved in the acquisition of environmental memory. These findings demonstrated that the distinct IPAC circuits VTAGABA→IPACLGABA and NAcShD1R→IPACMGABA were attributable to the rewarding and environmental memory during the acquisition of morphine CPP, respectively, and provided the circuit-based potential targets for preventing and treating opioid addiction.

Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2023 Jun 03

Alvarez-Bagnarol, Y;García, R;Vendruscolo, LF;Morales, M;
PMID: 37270620 | DOI: 10.1038/s41386-023-01620-5

Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.

Excitatory somatostatin interneurons in the dentate gyrus drive a widespread seizure network in cortical dysplasia

Signal transduction and targeted therapy

2023 May 17

Zheng, Y;Xu, C;Sun, J;Ming, W;Dai, S;Shao, Y;Qiu, X;Li, M;Shen, C;Xu, J;Fei, F;Fang, J;Jiang, X;Zheng, G;Hu, W;Wang, Y;Wang, S;Ding, M;Chen, Z;
PMID: 37193687 | DOI: 10.1038/s41392-023-01404-9

Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery, likely due to the widespread seizure network. Previous studies have primarily focused on the disruption of dysplastic lesions, rather than remote regions such as the hippocampus. Here, we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia. We further investigated the cellular substrates leading to the epileptic hippocampus, using multiscale tools including calcium imaging, optogenetics, immunohistochemistry and electrophysiology. For the first time, we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures. Somatostatin-positive were recruited during cortical dysplasia-related seizures. Interestingly, optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization. By contrast, parvalbumin-positive interneurons retained an inhibitory role as in controls. Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus. Taken together, our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.

NMDAR-dependent synaptic potentiation via APPL1 signaling is required for the accessibility of a prefrontal neuronal assembly in retrieving fear extinction

Biological psychiatry

2023 Feb 24

Hua, SS;Ding, JJ;Sun, TC;Guo, C;Zhang, Y;Yu, ZH;Cao, YQ;Zhong, LH;Wu, Y;Guo, LY;Luo, JH;Cui, YH;Qiu, S;
PMID: 36842495 | DOI: 10.1016/j.biopsych.2023.02.013

The ventromedial prefrontal cortex (vmPFC) has been viewed as a locus to store and recall extinction memory. However, the synaptic and cellular mechanisms underlying this process remain elusive.We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the vmPFC for fear extinction retrieval.We found that both constitutive and conditional APPL1 knockout decreases NMDA receptor (NMDAR) function in the vmPFC and impairs fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduces NMDAR currents and disrupts extinction retrieval. We further identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolishes NMDAR-dependent synaptic potentiation and disrupts extinction retrieval, while simultaneously chemogenetic activation of this ensemble rescues the impaired behaviors.Therefore, our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons to retrieve extinction memory via controlling NMDAR-dependent potentiation.

Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2022 Dec 16

Xie, L;Wu, H;Chen, Q;Xu, F;Li, H;Xu, Q;Jiao, C;Sun, L;Ullah, R;Chen, X;
PMID: 36526697 | DOI: 10.1038/s41386-022-01520-0

The ventrolateral periaqueductal gray (vlPAG) collaborates with the dorsal raphe (DR) in pain regulation and emotional response. However, the roles of vlPAG and DR γ-aminobutyric acid (GABA)-ergic neurons in regulating nociception and anxiety are contradictory and poorly understood. Here, we observed that pharmacogenetic co-activation of vlPAG and DR GABAergic (vlPAG-DRGABA+) neurons enhanced sensitivity to mechanical stimulation and promoted anxiety-like behavior in naïve mice. Simultaneous inhibition of vlPAG-DRGABA+ neurons showed adaptive anti-nociception and anti-anxiety effects on mice with inflammatory pain. Notably, vlPAGGABA+ and DRGABA+ neurons exhibited opposing effects on the sensitivity to mechanical stimulation in both naïve state and inflammatory pain. In contrast to the role of vlPAGGABA+ neurons in pain processing, chemogenetic inhibition and chronic ablation of DRGABA+ neurons remarkably promoted nociception while selectively activating DRGABA+ neurons ameliorated inflammatory pain. Additionally, utilizing optogenetic technology, we observed that the pronociceptive effect arising from DRGABA+ neuronal inhibition was reversed by the systemic administration of morphine. Our results collectively provide new insights into the modulation of pain and anxiety by specific midbrain GABAergic subpopulations, which may provide a basis for cell type-targeted or subregion-targeted therapies for pain management.

Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development

Development (Cambridge, England)

2022 Nov 28

Kong, X;Shu, X;Wang, J;Liu, D;Ni, Y;Zhao, W;Wang, L;Gao, Z;Chen, J;Yang, B;Guo, X;Wang, Z;
PMID: 36440598 | DOI: 10.1242/dev.201286

Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders (NDDs). Here, we discover that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures, and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells (NPCs) and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitinates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of NPCs. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity.

A circuit from lateral septum neurotensin neurons to tuberal nucleus controls hedonic feeding

Molecular psychiatry

2022 Aug 26

Chen, Z;Chen, G;Zhong, J;Jiang, S;Lai, S;Xu, H;Deng, X;Li, F;Lu, S;Zhou, K;Li, C;Liu, Z;Zhang, X;Zhu, Y;
PMID: 36028570 | DOI: 10.1038/s41380-022-01742-0

Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding. LSNts neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LSNts→the supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LSNts neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LSNts or LSNts→TU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LSNts→TU is a key pathway in regulating hedonic feeding.

Orexin neurons inhibit sleep to promote arousal

Nature communications

2022 Jul 18

De Luca, R;Nardone, S;Grace, KP;Venner, A;Cristofolini, M;Bandaru, SS;Sohn, LT;Kong, D;Mochizuki, T;Viberti, B;Zhu, L;Zito, A;Scammell, TE;Saper, CB;Lowell, BB;Fuller, PM;Arrigoni, E;
PMID: 35851580 | DOI: 10.1038/s41467-022-31591-y

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.

Intersectional mapping of multi-transmitter neurons and other cell types in the brain

Cell reports

2022 Jul 05

Xu, J;Jo, A;DeVries, RP;Deniz, S;Cherian, S;Sunmola, I;Song, X;Marshall, JJ;Gruner, KA;Daigle, TL;Contractor, A;Lerner, TN;Zeng, H;Zhu, Y;
PMID: 35793636 | DOI: 10.1016/j.celrep.2022.111036

Recent developments in intersectional strategies have greatly advanced our ability to precisely target brain cell types based on unique co-expression patterns. To accelerate the application of intersectional genetics, we perform a brain-wide characterization of 13 Flp and tTA mouse driver lines and selected seven for further analysis based on expression of vesicular neurotransmitter transporters. Using selective Cre driver lines, we created more than 10 Cre/tTA combinational lines for cell type targeting and circuit analysis. We then used VGLUT-Cre/VGAT-Flp combinational lines to identify and map 30 brain regions containing neurons that co-express vesicular glutamate and gamma-aminobutyric acid (GABA) transporters, followed by tracing their projections with intersectional viral vectors. Focusing on the lateral habenula (LHb) as a target, we identified glutamatergic, GABAergic, or co-glutamatergic/GABAergic innervations from ∼40 brain regions. These data provide an important resource for the future application of intersectional strategies and expand our understanding of the neuronal subtypes in the brain.

The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep

Nature communications

2021 Aug 25

Zhang, Z;Beier, C;Weil, T;Hattar, S;
PMID: 34433830 | DOI: 10.1038/s41467-021-25378-w

Light regulates daily sleep rhythms by a neural circuit that connects intrinsically photosensitive retinal ganglion cells (ipRGCs) to the circadian pacemaker, the suprachiasmatic nucleus. Light, however, also acutely affects sleep in a circadian-independent manner. The neural circuits involving the acute effect of light on sleep remain unknown. Here we uncovered a neural circuit that drives this acute light response, independent of the suprachiasmatic nucleus, but still through ipRGCs. We show that ipRGCs substantially innervate the preoptic area (POA) to mediate the acute light effect on sleep in mice. Consistently, activation of either the POA projecting ipRGCs or the light-responsive POA neurons increased non-rapid eye movement (NREM) sleep without influencing REM sleep. In addition, inhibition of the light-responsive POA neurons blocked the acute light effects on NREM sleep. The predominant light-responsive POA neurons that receive ipRGC input belong to the corticotropin-releasing hormone subpopulation. Remarkably, the light-responsive POA neurons are inhibitory and project to well-known wakefulness-promoting brain regions, such as the tuberomammillary nucleus and the lateral hypothalamus. Therefore, activation of the ipRGC-POA circuit inhibits arousal brain regions to drive light-induced NREM sleep. Our findings reveal a functional retina-brain circuit that is both necessary and sufficient for the acute effect of light on sleep.

A neural circuit for excessive feeding driven by environmental context in mice

Nature neuroscience

2021 Jun 24

Mohammad, H;Senol, E;Graf, M;Lee, CY;Li, Q;Liu, Q;Yeo, XY;Wang, M;Laskaratos, A;Xu, F;Luo, SX;Jung, S;Augustine, GJ;Fu, Y;
PMID: 34168339 | DOI: 10.1038/s41593-021-00875-9

Despite notable genetic influences, obesity mainly results from the overconsumption of food, which arises from the interplay of physiological, cognitive and environmental factors. In patients with obesity, eating is determined more by external cues than by internal physiological needs. However, how environmental context drives non-homeostatic feeding is elusive. Here, we identify a population of somatostatin (TNSST) neurons in the mouse hypothalamic tuberal nucleus that are preferentially activated by palatable food. Activation of TNSST neurons enabled a context to drive non-homeostatic feeding in sated mice and required inputs from the subiculum. Pairing a context with palatable food greatly potentiated synaptic transmission between the subiculum and TNSST neurons and drove non-homeostatic feeding that could be selectively suppressed by inhibiting TNSST neurons or the subiculum but not other major orexigenic neurons. These results reveal how palatable food, through a specific hypothalamic circuit, empowers environmental context to drive non-homeostatic feeding.

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sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
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tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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