Courtney NA, Briguglio JS, Bradberry MM, Greer C, Chapman ER.
PMID: - | DOI: 10.1016/j.neuron.2018.04.022
Spontaneous neurotransmitter release (mini) is an important form of Ca2+-dependent synaptic transmission that occurs in the absence of action potentials. A molecular understanding of this process requires an identification of the underlying Ca2+ sensors. Here, we address the roles of the relatively low- and high-affinity Ca2+ sensors, synapotagmin-1 (syt1) and Doc2α/β, respectively. We found that both syt1 and Doc2 regulate minis, but, surprisingly, their relative contributions depend on whether release was from excitatory or inhibitory neurons. Doc2α promoted glutamatergic minis, while Doc2β and syt1 both regulated GABAergic minis. We identified Ca2+ ligand mutations in Doc2 that either disrupted or constitutively activated the regulation of minis. Finally, Ca2+ entry via voltage-gated Ca2+ channels triggered miniature GABA release by activating syt1, but had no effect on Doc2-driven minis. This work reveals an unexpected divergence in the regulation of spontaneous excitatory and inhibitory transmission in terms of both Ca2+ sensors and sources.
Ahrlund-Richter S, Xuan Y, van Lunteren JA, Kim H, Ortiz C, Pollak Dorocic I, Meletis K and Carlen M
PMID: 30886408 | DOI: 10.1038/s41593-019-0354-y
The local and long-range connectivity of cortical neurons are considered instrumental to the functional repertoire of the cortical region in which they reside. In cortical networks, distinct cell types build local circuit structures enabling computational operations. Computations in the medial prefrontal cortex (mPFC) are thought to be central to cognitive operation, including decision-making and memory. We used a retrograde trans-synaptic rabies virus system to generate brain-wide maps of the input to excitatory neurons as well as three inhibitory interneuron subtypes in the mPFC. On the global scale the input patterns were found to be mainly cell type independent, with quantitative differences in key brain regions, including the basal forebrain. Mapping of the local mPFC network revealed high connectivity between the different subtypes of interneurons. The connectivity mapping gives insight into the information that the mPFC processes and the structural architecture underlying the mPFC's unique functions.
Rizzi G, Tan KR.
PMID: 31091455 | DOI: 10.1016/j.celrep.2019.04.068
Locomotion relies on the activity of basal ganglia networks, where, as the output, the substantia nigra pars reticulata (SNr) integrates incoming signals and relays them to downstream areas. The cellular and circuit substrates of such a complex function remain unclear. We hypothesized that the SNr controls different aspects of locomotion through coordinated cell-type-specific sub-circuits. Using anatomical mapping, single-cell qPCR, and electrophysiological techniques, we identified two SNr sub-populations: the centromedial-thalamo projectors (CMps) and the SN compacta projectors (SNcps), which are genetically targeted based on vesicular transporter for gamma-aminobutyric acid (VGAT) or parvalbumin (PV) expression, respectively. Optogenetic manipulation of these two sub-types across a series of motor tests provided evidence that they govern different aspects of motor behavior. While CMp activity supports the continuity of motor patterns, SNcp modulates the immediate motor drive behind them. Collectively, our data suggest that at least two different sub-circuits arise from the SNr, engage different behavioral motor components, and collaborate to produce correct locomotion.
Rizzi G, Coban M, Tan KR.
PMID: 31113944 | DOI: 10.1038/s41467-019-10223-y
The red nucleus (RN) is required for limb control, specifically fine motor coordination. There is some evidence for a role of the RN in reaching and grasping, mainly from lesion studies, but results so far have been inconsistent. In addition, the role of RN neurons in such learned motor functions at the level of synaptic transmission has been largely neglected. Here, we show that Vglut2-expressing RN neurons undergo plastic events and encode the optimization of fine movements. RN light-ablation severely impairs reaching and grasping functions while sparing general locomotion. We identify a neuronal population co-expressing Vglut2, PV and C1QL2, which specifically undergoes training-dependent plasticity. Selective chemo-genetic inhibition of these neurons perturbs reaching and grasping skills. Our study highlights the role of the Vglut2-positive rubral population in complex fine motor tasks, with its related plasticity representing an important starting point for the investigation of mechanistic substrates of fine motor coordination training.
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
Lu L, Ren Y, Yu T, Liu Z, Wang S, Tan L, Zeng J, Feng Q, Lin R, Liu Y, Guo Q, Luo M
PMID: 31937768 | DOI: 10.1038/s41467-019-14116-y
Navigation requires not only the execution of locomotor programs but also high arousal and real-time retrieval of spatial memory that is often associated with hippocampal theta oscillations. However, the neural circuits for coordinately controlling these important processes remain to be fully dissected. Here we show that the activity of the neuromedin B (NMB) neurons in the nucleus incertus (NI) is tightly correlated with mouse locomotor speed, arousal level, and hippocampal theta power. These processes are reversibly suppressed by optogenetic inhibition and rapidly promoted by optogenetic stimulation of NI NMB neurons. These neurons form reciprocal connections with several subcortical areas associated with arousal, theta oscillation, and premotor processing. Their projections to multiple downstream stations regulate locomotion and hippocampal theta, with the projection to the medial septum being particularly important for promoting arousal. Therefore, NI NMB neurons functionally impact the neural circuit for navigation control according to particular brains states
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.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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.
Signal transduction and targeted therapy
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.
Frontiers in neuroendocrinology
Beekly, BG;Rupp, A;Burgess, CR;Elias, CF;
PMID: 37149229 | DOI: 10.1016/j.yfrne.2023.101069
Hypothalamic melanin-concentrating hormone (MCH) neurons participate in many fundamental neuroendocrine processes. While some of their effects can be attributed to MCH itself, others appear to depend on co-released neurotransmitters. Historically, the subject of fast neurotransmitter co-release from MCH neurons has been contentious, with data to support MCH neurons releasing GABA, glutamate, both, and neither. Rather than assuming a position in that debate, this review considers the evidence for all sides and presents an alternative explanation: neurochemical identity, including classical neurotransmitter content, is subject to change. With an emphasis on the variability of experimental details, we posit that MCH neurons may release GABA and/or glutamate at different points according to environmental and contextual factors. Through the lens of the MCH system, we offer evidence that the field of neuroendocrinology would benefit from a more nuanced and dynamic interpretation of neurotransmitter identity.
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.
Science translational medicine
Tang, YL;Liu, AL;Lv, SS;Zhou, ZR;Cao, H;Weng, SJ;Zhang, YQ;
PMID: 36475906 | DOI: 10.1126/scitranslmed.abq6474
Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light-mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino-ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)-positive neurons in the vLGN (vLGNPenk). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGNPenk neurons. In addition, activation of the projections from vLGNPenk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGNPenk-DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.
