AbstractOrchestrating complex behaviors, such as approaching and consuming food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also controls appetite and satiety. However, specific neuronal subtypes of the NAc that are involved and how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood.

摘要协调复杂的行为，例如接近和食用食物，对于生存至关重要。除了下丘脑神经元回路外，伏隔核（NAc）还控制食欲和饱腹感。。

Here we decipher the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and define a dopamine receptor D1-expressing and Serpinb2-expressing subtype controlling food consumption in male mice. Chemogenetics and optogenetics-mediated regulation of Serpinb2+ neurons bidirectionally regulate food seeking and consumption specifically.

在这里，我们破译了NAc壳（NAcSh）神经元亚型的空间多样性，并定义了表达多巴胺受体D1和表达Serpinb2的亚型，控制雄性小鼠的食物消耗。化学遗传学和光遗传学介导的Serpinb2+神经元调节双向调节食物寻求和消费。

Circuitry stimulation reveals that the NAcShSerpinb2→LHLepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2+ neuron ablation reduces food intake and upregulates energy expenditure, resulting in reduced bodyweight gain. Our study reveals a neural circuit consisting of a molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, providing a potential therapeutic target for eating disorders..

电路刺激表明，NAcShSerpinb2→LHLepR投影控制再进食，并可以克服瘦素介导的进食抑制。此外，NAcSh Serpinb2+神经元消融减少食物摄入并上调能量消耗，导致体重增加减少。。。

MainFeeding is a complicated motivational and emotional behavior required for survival and is known for its extraordinary ability to adapt in response to environmental changes1,2. The obesity epidemic coupled with an increased population with eating disorders, such as binge eating and anorexia, underscores the urgent need for understanding the mechanisms controlling feeding behavior3,4.Maintaining the balance of energy homeostasis is important for health and survival.

主要喂养是生存所需的复杂动机和情绪行为，以其非凡的适应环境变化的能力而闻名1,2。肥胖的流行加上饮食失调（如暴饮暴食和厌食症）的人口增加，强调迫切需要了解控制喂养行为的机制3,4。维持能量稳态的平衡对健康和生存很重要。

The central nervous system has an important role in regulating this balance by coordinated activity of neuronal circuits of corticolimbic entities such as the brain executive5 and reward systems6,7, and the hypothalamus and brainstem autonomic circuits8,9,10, which control a wide range of physiological processes affecting energy intake and expenditure11.

中枢神经系统通过大脑执行器5和奖励系统6,7以及下丘脑和脑干自主神经回路8,9,10等皮质边缘实体的神经元回路的协调活动来调节这种平衡，这些回路控制着影响能量摄入和消耗的广泛生理过程11。

The systems and circuits that regulate food intake and energy expenditure are not only sensitive to endogenous homeostatic signals on the status of energy reserves but also to the organoleptic properties of food and emotional factors12.The hypothalamus, with a highly heterogeneous neuronal composition13, has a critical role in controlling feeding behavior14,15.

。

The core of the hypothalamic control system in the arcuate nucleus (Arc) comprises two neuronal populations: Agouti-related peptide neurons and Pro-opiomelanocortin neurons. These two types of neurons exert almost opposite functions in regulating feeding, with feeding-related hormones such as ghrelin and leptin coordinately mediating the sensations of appetite and satiety, leading to behavioral response16,17.

弓状核（Arc）中下丘脑控制系统的核心包括两个神经元群体：刺豚鼠相关肽神经元和前阿片黑皮素神经元。这两种类型的神经元在调节摄食方面发挥几乎相反的功能，摄食相关激素如生长素释放肽和瘦素协调介导食欲和饱腹感，导致行为反应16,17。

Leptin performs an anorexic function by acting on leptin receptors (LepR) in the hypothalamus18,19,20. In addition to the Arc, LepR is also highly expressed in the lateral hypothalamus (LH)21, .

瘦素通过作用于下丘脑中的瘦素受体（LepR）来执行厌食功能18,19,20。除Arc外，LepR还在下丘脑外侧（LH）21中高度表达。

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+ neurons are activated in the refeeding processThe NAc is a critical component of the basal ganglion circuitry, which receives and integrates information from cortical and limbic regions for actions. Previous studies have linked feeding behavior to the NAcSh22,23,26,29,30,38. D1-MSNs, but not D2-MSNs, provide the dominant source of accumbal inhibition to the LH and regulate complex feeding behaviors through LH GABA neurons22,30.

+神经元在再进食过程中被激活NAc是基底神经节回路的关键组成部分，它接收并整合来自皮层和边缘区域的信息以进行动作。。D1-MSNs而非D2-MSNs为LH提供了累积抑制的主要来源，并通过LH GABA神经元调节复杂的进食行为22,30。

Given the controversial findings of D1-MSNs in feeding22,30,31, studying the specific functions of neuronal subtypes in NAcSh is critical, as the discrepancies could have been caused by manipulation of different neuronal subtypes of NAcSh in the different studies.To identify the D1 neuronal subtypes located in the NAcSh, we integrated the single-cell and spatial transcriptomic data of NAc32 by analyzing 253 selected genes and the coronal sections between 1.94 mm and 0.74 mm from bregma to cover the entire NAcSh region.

鉴于D1-MSNs在喂养中的争议性发现22,30,31，研究NAcSh中神经元亚型的特定功能至关重要，因为差异可能是由不同研究中操纵NAcSh的不同神经元亚型引起的。为了鉴定位于NAcSh中的D1神经元亚型，我们通过分析253个选定基因和前囟1.94mm至0.74mm之间的冠状切片来整合NAc32的单细胞和空间转录组数据，以覆盖整个NAcSh区域。

Clustering analysis of the MERFISH data identified four major cell populations representing D1-MSNs, named D1_1 to D1_4 (Fig. 1a), which are marked by Stard5, Tac2, Spon1 and Serpinb2, respectively (Fig. 1b). Single-molecule FISH (smFISH) further confirmed that these neuronal subtypes are mainly located in the medial dorsal NAcSh and are predominantly dopamine receptor D1 (Drd1+) neurons (Fig.

MERFISH数据的聚类分析确定了代表D1 MSN的四个主要细胞群，命名为D1\U 1至D1\U 4（图1a），分别由Stard5，Tac2，Spon1和Serpinb2标记（图1b）。单分子FISH（smFISH）进一步证实，这些神经元亚型主要位于内侧背侧NAcSh，主要是多巴胺受体D1（Drd1+）神经元（图）。

1c,d and Extended Data Fig. 1a–c).Fig. 1: NAcSh Serpinb2+ neurons are activated in the refeeding process in vivo.a, Spatial patterns of D1-MSN subtypes in NAcSh. Dotted lines circle the anterior commissure olfactory limb (aco) and NAc core. The dorsal–ventral and medial–lateral axes are indicated. b, Spatial expression patterns of Stard5, Tac2, Spon1 and Serpinb2, determined by integrating single-cell RNA sequencing and MERFISH data using i.

1c，d和扩展数据图1a–c）。图1:NAcSh Serpinb2+神经元在体内再喂食过程中被激活。a，NAcSh中D1-MSN亚型的空间模式。虚线环绕前连合嗅肢（aco）和NAc核心。指示背腹轴和内侧-外侧轴。b、 通过使用i整合单细胞RNA测序和MERFISH数据来确定Stard5，Tac2，Spon1和Serpinb2的空间表达模式。

+ neurons respond to eating behaviorTo study the role of Serpinb2+ neurons in feeding, we generated a Serpinb2-Cre mouse line (Extended Data Fig. 2a,b). We validated this mouse model by crossing with the Ai9 mouse line, which expresses tdTomato (tdT) fluorescence following Cre-mediated recombination, and observed about 90% colocalization of the tdT signal with the endogenous Serpinb2 mRNA signal, which is consistent with endogenous Serpinb2 expression in the NAcSh as shown by the Allen Brain Atlas RNA in situ data (Extended Data Fig.

+神经元对进食行为的反应为了研究Serpinb2+神经元在进食中的作用，我们产生了Serpinb2-Cre小鼠系（扩展数据图2a，b）。我们通过与Ai9小鼠系杂交来验证该小鼠模型，该小鼠系在Cre介导的重组后表达tdTomato（tdT）荧光，并观察到tdT信号与内源性Serpinb2 mRNA信号的约90%共定位，这与内源性Serpinb2表达一致。如Allen Brain Atlas RNA原位数据所示（Extended data Fig.）。

2c). Thus, our Serpinb2-Cre mouse line is suitable for studying Serpinb2+ neurons.To determine whether Serpinb2+ neurons are indeed involved in regulating feeding behavior, we used fiber photometry to monitor Serpinb2+ neuronal activity of freely moving mice during food seeking and consumption. To this end, a Cre-dependent AAV vector expressing the calcium reporter GCaMP7s was delivered to the NAcSh of the Serpinb2-Cre mice by stereotaxic injection (Fig.

2c）。因此，我们的Serpinb2-Cre小鼠系适合研究Serpinb2+神经元。为了确定Serpinb2+神经元是否确实参与调节摄食行为，我们使用纤维光度法来监测自由活动小鼠在觅食和食用过程中的Serpinb2+神经元活动。为此，通过立体定向注射将表达钙报告基因GCaMP7s的Cre依赖性AAV载体递送至Serpinb2-Cre小鼠的NAcSh（图）。

2a) while AAV expressing eYFP was used as a negative control (Extended Data Fig. 3a), followed by the implantation of an optic cannula above the NAcSh (Fig. 2b). In parallel, we implanted cannula to the Tac2-Cre and Drd1-Cre mice to monitor the NAcSh Tac2+ neurons and the total NAcSh Drd1+ neuron activities during feeding (Extended Data Figs.

2a），而表达AAV的eYFP被用作阴性对照（扩展数据图3a），然后在NAcSh上方植入视神经套管（图2b）。同时，我们将套管植入Tac2-Cre和Drd1-Cre小鼠，以监测喂食期间NAcSh Tac2+神经元和总NAcSh Drd1+神经元活动（扩展数据图）。

3d and 2b). We performed fluorescence recordings during the feeding process in the home cage 3 weeks after the surgeries (Fig. 2c). We found that the Ca2+ signals of the Serpinb2+ neurons increased immediately when eating began and decreased when eating finished, whereas there was no obvious change in activity during interaction with a non-food object (Fig.

3d和2b）。手术后3周，我们在家笼的喂养过程中进行了荧光记录（图2c）。我们发现Serpinb2+神经元的Ca2+信号在进食开始时立即增加，进食结束时减少，而在与非食物物体相互作用期间活动没有明显变化（图）。

2d–f,h–j). To quantify the Serpinb2+ neuronal activity at different events, we averaged the calc.

2d–f，h–j）。为了量化不同事件下的Serpinb2+神经元活性，我们对计算值进行了平均。

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+ neurons bidirectionally regulate food intakeTo determine whether Serpinb2+ neuronal activity has a causal role in regulating feeding behavior, we examined whether feeding behavior can be influenced by selectively manipulating the Serpinb2+ neuronal activity. To this end, we injected the Cre-dependent chemogenetic activation vector AAV-DIO-hM3Dq-mCherry or the inhibitory vector AAV-DIO-hM4Di-mCherry into the NAcSh region, using the AAV-DIO-mCherry vector as a control (Fig.

+神经元双向调节食物摄入为了确定Serpinb2+神经元活动是否在调节摄食行为中起因果作用，我们检查了选择性操纵Serpinb2+神经元活动是否可以影响摄食行为。为此，我们使用AAV-DIO-mCherry载体作为对照，将Cre依赖性化学发生激活载体AAV-DIO-hM3Dq-mCherry或抑制性载体AAV-DIO-hM4Di-mCherry注射到NAcSh区域（图）。

3a). We also performed parallel experiments using Tac2-Cre and Drd1-Cre mice (Extended Data Fig. 4a).Fig. 3: Serpinb2+ neurons bidirectionally regulate food seeking and intake.a, Experimental scheme of the food approach and food consumption assays. b, Heat map encoding the spatial location of a fasted mouse using the free-access feeding paradigm.

3a）。我们还使用Tac2-Cre和Drd1-Cre小鼠进行了平行实验（扩展数据图4a）。。b、 使用自由进食范式编码禁食小鼠的空间位置的热图。

c, Percentage of time that mice spent in the food zone. Chemogenetic activation (hM3Dq) or inhibition (hM4Di) of Serpinb2+ neurons (left), Tac2+ neurons (middle) and Drd1+ neurons (right). n = 8 mice per group. One-way ANOVA, F2,21 = 15.05 (left), F2,21 = 1.970 (middle), F2,21 = 1.7 (right). d, Total food consumption during the 3 h test.

c、 小鼠在食物区停留的时间百分比。Serpinb2+神经元（左），Tac2+神经元（中）和Drd1+神经元（右）的化学发生激活（hM3Dq）或抑制（hM4Di）。每组n=8只小鼠。单因素方差分析，F2,21=15.05（左），F2,21=1.970（中），F2,21=1.7（右）。d、 3小时测试期间的总食物消耗量。

Chemogenetic activation (hM3Dq) or inhibition (hM4Di) of Serpinb2+, Tac2+ and Drd1+ neurons. n = 8 mice per group. Two-tailed, unpaired t-test, t14 = 0.5472 (Serpinb2-Cre, left), t14 = 3.552 (Serpinb2-Cre, right), t14 = 0.5472 (Tac2-Cre, left), t14 = 1.703 (Tac2-Cre, right), t14 = 0.278 (Drd1-Cre, left), t14 = 0.4571 (Drd1-Cre, right).

Serpinb2+、Tac2+和Drd1+神经元的化学激活（hM3Dq）或抑制（hM4Di）。每组8只小鼠。双尾非配对t检验，t14=0.5472（Serpinb2-Cre，左），t14=3.552（Serpinb2-Cre，右），t14%=0.5472，（Tac2-Cre，左）。

e, DO-EGFP/hM3Dq-EGFP virus expression in NAcSh and number of cFos+ neurons after CNO treatment. One technical replicate of three biological replicates. Two-tailed, unpaired t-test, t4 = 20.84. Scale bars, 100 μm. f, Percentage of time that mice spent in the food zone. n = 8 mice per group. On.

e、 。三个生物学重复的一个技术重复。双尾，不成对t检验，t4=20.84。比例尺，100μm。f、 小鼠在食物区停留的时间百分比。每组n=8只小鼠。打开。

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+ neurons mediate food consumption by LH projectionThus far, we have demonstrated the critical role of Serpinb2+ neurons in regulating feeding behaviors. Next, we attempted to reveal the circuit mechanism underlying the functions of Serpinb2+ neurons in regulating food consumption. Previous studies have indicated that NAcSh D1-MSNs project to multiple brain regions, including the VTA44, LH22 and ventral pallidum45.

+神经元通过LH投射介导食物消耗迄今为止，我们已经证明了Serpinb2+神经元在调节摄食行为中的关键作用。接下来，我们试图揭示Serpinb2+神经元在调节食物消耗中功能的电路机制。先前的研究表明，NAcSh D1 MSN投射到多个大脑区域，包括VTA44，LH22和腹侧苍白球45。

To determine the projection sites of Serpinb2+ neurons, we injected Cre-dependent AAVs expressing membrane-bound GFP (mGFP, for labeling axons) and synaptophysin-mRuby, for labeling putative presynaptic sites, into the NAcSh of the Serpinb2-Cre mice (Fig. 4a). We analyzed the brain sections 3 weeks after virus injection and observed colocalization of green neuronal terminals and red presynaptic puncta only in the LH (Fig.

为了确定Serpinb2+神经元的投射位点，我们将表达膜结合GFP（mGFP，用于标记轴突）和突触素mRuby（用于标记推定的突触前位点）的Cre依赖性AAV注射到Serpinb2-Cre小鼠的NAcSh中（图4a）。我们分析了病毒注射后3周的脑切片，观察到绿色神经元末端和红色突触前斑点仅在LH中共定位（图）。

4b,c) but not in the ventral pallidum, basolateral amygdala or VTA (Extended Data Fig. 6), indicating that the Serpinb2+ neurons only project to the LH. To further validate this projection, we injected the retrograde tracer Cholera toxin subunit B (CTB) conjugated with Alexa Fluor 555 (CTB-555)46 into the LH region (Fig.

4b，c），但不在腹侧苍白球，基底外侧杏仁核或VTA中（扩展数据图6），表明Serpinb2+神经元仅投射到LH。为了进一步验证这一预测，我们将与Alexa Fluor 555（CTB-555）46结合的逆行示踪剂霍乱毒素亚基B（CTB）注入LH区域（图）。

4d) and AAV-DIO-ChR2-eYFP into the NAcSh of Serpinb2-Cre mice. Immunostaining showed colocalization of CTB with eYFP in the NAcSh (Fig. 4e), supporting that the NAcSh Serpinb2+ neurons project to the LH.Fig. 4: Serpinb2+ neurons mediate food intake via LH projection.a,b, Diagram of injection of the NAc Serpinb2+ neurons with AAV-hSyn-FLEx-mGFP-2A-synaptophysin-mRuby (a) and the expression FLEx-mGFP in the NAcSh (b).

4d）和AAV-DIO-ChR2-eYFP进入Serpinb2-Cre小鼠的NAcSh。免疫染色显示CTB与eYFP在NAcSh中共定位（图4e），支持NAcSh Serpinb2+神经元投射到LH。图4:Serpinb2+神经元通过LH投射介导食物摄入。a，b，用AAV-hSyn-FLEx-mGFP-2A-突触素-mRuby（a）和表达FLEx-mGFP注射NAc Serpinb2+神经元的图NAcSh（b）。

Scale bar, 100 μm. One technical replicate of three biological replicates. c, Top, Serpinb2+ neuron projection to the LH. Scale bar, 500 μm. Bottom, enlarged image of the top square. Square in the right is an enl.

比例尺，100μm。三个生物学重复的一个技术重复。c、 顶部，Serpinb2+神经元投射到LH。比例尺，500μm。。右边的正方形是一个enl。

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+ neurons form a circuit with LH LepR+ GABA+ neurons and counterbalance the effects of leptinHaving demonstrated the functional importance of the NAcSh-to-LH projection, we next attempted to determine the neuron types in the LH that receive signals from the Serpinb2+ neurons. The LH is a highly heterogeneous brain region, controlling food intake, energy expenditure and many other physiological functions47.

+神经元与LH LepR+GABA+神经元形成回路并抵消瘦素的作用证明了NAcSh对LH投射的功能重要性，我们接下来试图确定LH中接收Serpinb2+神经元信号的神经元类型。LH是一个高度异质的大脑区域，控制食物摄入，能量消耗和许多其他生理功能47。

Given that the neuropeptides orexin/hypocretin and melanin-concentrating hormone (MCH) are associated with feeding48,49 and are mainly expressed in the LH, we first asked whether they are the downstream targets of the NAcSh Serpinb2+ neurons. To this end, we injected the AAV-hSyn-FLEx-mGFP-2A-synaptophysin-mRuby viruses to the NAcSh of the Serpinb2-Cre mice and performed immunostaining of candidate neuropeptides or transmitters on slices covering the LH (Fig.

鉴于神经肽食欲素/hypocretin和黑色素浓缩激素（MCH）与进食有关[48,49]，主要在LH中表达，我们首先询问它们是否是NAcSh Serpinb2+神经元的下游靶标。为此，我们将AAV-hSyn-FLEx-mGFP-2A-突触素-mRuby病毒注射到Serpinb2-Cre小鼠的NAcSh中，并在覆盖LH的切片上对候选神经肽或递质进行免疫染色（图）。

5a). We found that a small number of MCH-expressing or orexin-expressing neurons in the LH (Fig. 5b,c,f, indicated by arrows) overlapped with Serpinb2+ terminals (green). Given that GABAergic neurons are the most abundant subtype in the LH and are involved in feeding and leptin-regulated energy homeostasis13,50,51, we next checked whether LepR-positive GABAergic neurons21 receive projections from NAcSh Serpinb2+ neurons.

5a）。我们发现LH中少数表达MCH或表达食欲素的神经元（图5b，c，f，箭头所示）与Serpinb2+末端（绿色）重叠。鉴于GABA能神经元是LH中最丰富的亚型，参与摄食和瘦素调节的能量稳态[13,50,51]，我们接下来检查了LepR阳性GABA能神经元21是否接受来自NAcSh Serpinb2+神经元的投射。

After immunostaining with anti-GABA or anti-LepR antibodies, we found that the presynaptic puncta of Serpinb2+ neuron terminals were located around the LepR+ GABA+ somas (Fig. 5d–f, arrowheads). To confirm the connection of NAcSh Serpinb2+ neurons and LH LepR+ neurons, we performed monosynaptic rabies virus tracing by injecting Cre-dependent AAVs expressing mCherry-TVA and rabies G protein into the LH of LepR-Cre mice.

用抗GABA或抗LepR抗体进行免疫染色后，我们发现Serpinb2+神经元末端的突触前点位于LepR+GABA+体周围（图5d–f，箭头）。为了证实NAcSh Serpinb2+神经元和LH LepR+神经元的连接，我们通过将表达mCherry-TVA和狂犬病G蛋白的Cre依赖性AAV注射到LepR-Cre小鼠的LH中来进行单突触狂犬病病毒追踪。

After 2 weeks, Enva-ΔG rabies virus expressing GFP was injected into the same .

2周后，将表达GFP的Enva-ΔG狂犬病病毒注射到其中。

+ neurons promotes weight loss and increased metabolic levelTo assess whether the loss of function of the Serpinb2+ neurons can exert a long-term effect on energy homeostasis, we selectively ablated NAcSh Serpinb2+ neurons in Serpinb2-Cre mice by injecting a Cre-dependent AAV vector expressing caspase-3, which eliminates the neurons by inducing cell death (Fig.

+神经元促进体重减轻和代谢水平升高为了评估Serpinb2+神经元功能的丧失是否可以对能量稳态产生长期影响，我们通过注射Cre依赖性AAV载体选择性消融Serpinb2-Cre小鼠中的NAcSh Serpinb2+神经元表达半胱天冬酶-3，通过诱导细胞死亡消除神经元（图）。

6a). Ablation of the NAcSh Serpinb2+ neurons resulted in decreased food intake (Fig. 6b) as well as reduced bodyweight gain (~10% or 2 g over 7 weeks) despite food and water being freely available in the home cage (Fig. 6c). A reduction in bodyweight is normally caused by an imbalance between energy intake and expenditure.

。NAcSh Serpinb2+神经元的消融导致食物摄入减少（图6b）以及体重增加减少（7周内约10%或2克），尽管在家笼中可以免费获得食物和水（图6c）。体重减轻通常是由能量摄入和消耗之间的不平衡引起的。

To this end, we analyzed the effect of Serpinb2+ neuron ablation on metabolism by performing metabolism recording, which measures the volumes of oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER), energy expenditure, total movement, ambulatory movement and food intake (Fig.

为此，我们通过进行代谢记录来分析Serpinb2+神经元消融对代谢的影响，该记录测量了耗氧量（VO2），二氧化碳产生量（VCO2），呼吸交换率（RER），能量消耗，总运动，动态运动和食物摄入（图）。

6d–g and Extended Data Fig. 7a–c). We found that Serpinb2+ neuron ablation (the taCasp3 group) significantly increased VO2 consumption (Fig. 6d), VCO2 production (Fig. 6e), energy expenditure (Fig. 6f) as well as decreasing cumulative food intake (Fig. 6g). However, no significant change in RER or movement was observed (Extended Data Fig.

6d–g和扩展数据图7a–c）。我们发现Serpinb2+神经元消融（taCasp3组）显着增加VO2消耗（图6d），VCO2产生（图6e），能量消耗（图6f）以及减少累积食物摄入（图6g）。然而，没有观察到RER或运动的显着变化（扩展数据图）。

7a–c). Given that a previous study indicated that the NAcSh-to-LH pathway could modulate energy expenditure58, the metabolic changes observed could be the result of a lack of innervation from Serpinb2+ neurons. Collectively, these results demonstrate that ablation of Serpinb2+ neurons reduces long-term bodyweight gain, not only by reducing food intake but also by increasing energy expenditure.Fig.

7a–c）。鉴于先前的研究表明NAcSh-LH途径可以调节能量消耗58，观察到的代谢变化可能是Serpinb2+神经元缺乏神经支配的结果。总的来说，这些结果表明，Serpinb2+神经元的消融不仅通过减少食物摄入，而且通过增加能量消耗来减少长期体重增加。图。

6: Ablation of Serpinb2+ neurons decrease bodyweight.

6： Serpinb2+神经元的消融降低了体重。

+ neurons are functionally distinct from the pan D1-MSNs in NAcShPrevious studies have observed reduced activity of D1-MSNs during food consumption, and, consistently, suppressing D1-MSNs activity prolonged food intake22. Using Serpinb2-Cre, Tac2-Cre and Drd1-Cre mice, we compared the Serpinb2+, Tac2+ and Drd1+ MSNs in regulating feeding behaviors and found that manipulations of these neuron subtypes led to different outcomes (Figs.

+在NACSH中，神经元在功能上不同于泛D1-MSNs。之前的研究已经观察到D1-MSNs在食物消耗过程中的活性降低，并且一致地抑制D1-MSNs活性延长了食物摄入22。使用Serpinb2-Cre，Tac2-Cre和Drd1-Cre小鼠，我们比较了Serpinb2+，Tac2+和Drd1+MSNs在调节摄食行为中的作用，发现这些神经元亚型的操作导致了不同的结果（图）。

2 and 3). First, Serpinb2+ neurons are activated by food consumption but suppressed after the end of eating, whereas Drd1+ neurons are activated during the approach to food and after the end of eating. Second, Serpinb2+ neurons bidirectionally regulate food seeking and intake, whereas manipulating Drd1+ neurons does not significantly alter feeding behavior.

2和3）。首先，Serpinb2+神经元被食物消耗激活，但在进食结束后被抑制，而Drd1+神经元在接近食物和进食结束后被激活。其次，Serpinb2+神经元双向调节食物寻求和摄入，而操纵Drd1+神经元不会显着改变进食行为。

On the other hand, a previous study showed that inhibition of Drd1+ neurons promoted liquid fat food intake22. This discrepancy might be because of the different feeding assays used in the two studies. We used home cage free-access food intake in this study, whereas the previous study used head-fixed mice licking liquid fat food as the assay22.

另一方面，之前的一项研究表明，抑制Drd1+神经元可促进液体脂肪食物的摄入22。这种差异可能是由于两项研究中使用的喂养试验不同。在这项研究中，我们使用家笼自由获取食物摄入量，而之前的研究使用头部固定的小鼠舔液体脂肪食物作为测定22。

Third, ablation of the Serpinb2+ neurons significantly reduced food intake (Fig. 6), which is consistent with our finding that Serpinb2+ neuron activation positively regulates food intake (Fig. 3). However, a previous study indicated that lesions or inactivation of the NAc neurons do not significantly alter food consumption59.

第三，Serpinb2+神经元的消融显着减少了食物摄入（图6），这与我们发现Serpinb2+神经元激活正调节食物摄入的发现一致（图3）。然而，之前的一项研究表明，NAc神经元的损伤或失活不会显着改变食物消耗59。

We do not consider these results to be in conflict, as NAc is composed of many D1-MSN and D2-MSN neuron subtypes, of which many may not be involved in regulating food intake, while others can positively or negatively regulate food intake. Consequently, manipulating Serpinb2+ neurons versus the entire NAc neurons can have diff.

我们不认为这些结果存在冲突，因为NAc由许多D1-MSN和D2-MSN神经元亚型组成，其中许多可能不参与调节食物摄入，而其他人可以正向或负向调节食物摄入。因此，操纵Serpinb2+神经元与整个NAc神经元可能存在差异。

Data availability

数据可用性

The MERFISH data are available at the Brain Image Library (https://download.brainimagelibrary.org/fc/4c/fc4c2570c3711952/). Source data are provided with this paper.

MERFISH数据可在大脑图像库中获得(https://download.brainimagelibrary.org/fc/4c/fc4c2570c3711952/)。本文提供了源数据。

Code availability

代码可用性

No custom code was used in the study.

研究中没有使用自定义代码。

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Download referencesAcknowledgementsWe thank J. M. Friedman at Rockefeller University for discussions about the experiments, and A. Bhattachejee and V. Honnell for critical reading of the manuscript. We thank the Mouse Behavior Core of Harvard Medical School and its director, B. Caldarone, for her help.

下载参考文献致谢我们感谢洛克菲勒大学的J.M.Friedman对实验的讨论，以及A.Bhattachejee和V.Honnell对手稿的批判性阅读。我们感谢哈佛医学院小鼠行为核心及其主任B.Caldarone的帮助。

This project was partly supported by the National Institutes of Health (1R01DA050589), and the Howard Hughes Medical Institute (HHMI). Y.Z. is an investigator at the HHMI. This article is subject to HHMI’s Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI for their research articles.

该项目得到了美国国立卫生研究院（1R01DA050589）和霍华德·休斯医学研究所（HHMI）的部分支持。Y、 Z.是HHMI的调查员。本文受HHMI开放获取出版物政策的约束。HHMI实验室负责人之前已经向公众授予了非排他性CC BY 4.0许可证，并为HHMI的研究文章授予了可再许可证。

Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication.Author informationAuthors and AffiliationsHoward Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USAYiqiong Liu, Ying Wang, Zheng-dong Zhao, Guoguang Xie, Chao Zhang, Renchao Chen & Yi ZhangProgram in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USAYiqiong Liu, Ying Wang, Zheng-dong Zhao, Guoguang Xie, Chao Zhang, Renchao Chen & Yi ZhangDivision of Hematology/Oncology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USAYiqiong Liu, Ying Wang, Zheng-dong Zhao, Guoguang Xie, Chao Zhang, Renchao Chen & Yi ZhangDepartment of Genetics, Harvard Medical School, Boston, MA, USAYi ZhangHarvard Stem Cell Institute, Boston, MA, USAYi ZhangAuthorsYiqiong LiuView author publicationsYou can also search for this author in.

根据这些许可证，作者接受的本文手稿可以在发布后立即在CC BY 4.0许可证下免费提供。作者信息作者和附属机构马萨诸塞州波士顿儿童医院休斯医学研究所，USAiqiong Liu，Ying Wang，Zheng dong Zhao，Guoguang Xie，Chao Zhang，Renchao Chen＆Yi Zhang波士顿儿童医院细胞与分子医学项目，Boston，MA，USAiqiong Liu，Ying Wang，Zheng dong Zhao，Guoguang Xie，Chao Zhang，Renchao Chen＆Yi Zhang波士顿儿童医院儿科血液学/肿瘤学系，USAiqiong Liu，Ying Wang，Zheng dong Zhao，Guoguang Xie，Chao Zhang，Renchao Chen＆Yi Zhang哈佛医学院遗传学系美国马萨诸塞州波士顿市哈佛干细胞研究所（Harvard Stem Cell Institute，Boston，MA，USAYi Zhang AuthorsYiqiong LiuView Author Publications）您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsY.Z. conceived the project. Y.L. and Y.Z. designed the experiments; Y.L. performed most of the experiments. Y.W. and Z.-D.Z. helped with the fiber photometry and data analysis. G.X. helped with the catheter administration, retrograde tracing, CLAMS recording and staining.

PubMed谷歌学术贡献。Z、 。Y、 L.和Y.Z.设计了实验；Y、 L.进行了大部分实验。Y、 W.和Z.-D.Z.帮助进行了纤维光度测定和数据分析。G、 X.帮助导管管理，逆行追踪，CLAMS记录和染色。

C.Z. analyzed MERFISH data. R.C. initiated the Serpinb2-Cre mouse generation. Y.L., Y.W., Z.-D.Z., G.X. and Y.Z. interpreted the data; Y.L. and Y.Z. wrote the manuscript with input from Z.-D.Z. and R.C.Corresponding authorCorrespondence to.

C、 Z.分析了MERFISH数据。R、 C.启动了Serpinb2-Cre小鼠的产生。Y、 L.，Y.W.，Z.-D.Z.，G.X.和Y.Z.解释了数据；Y、 L.和Y.Z.在Z.-D.Z.和R.C.的输入下撰写了手稿。相应的作者回复。

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Competing interests

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The authors declare no competing interests.

作者声明没有利益冲突。

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Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

《自然新陈代谢》感谢匿名审稿人对这项工作的同行评审做出的贡献。主要处理编辑：Ashley Castellanos Jankiewicz，与《自然新陈代谢》团队合作。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 The markers of D1-MSN subtypes in NAcSh do not overlap with Drd2.a, ISH images showing the spatial distribution of Spon1, Stard5, Tac2 and Serpinb2 markers of certain D1-MSN subtypes, in mouse NAc.

Additional informationPublisher的注释Springer Nature在已发布地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1 NAcSh中D1-MSN亚型的标记不与Drd2重叠。a，ISH图像显示小鼠NAc中某些D1-MSN亚型的Spon1，Stard5，Tac2和Serpinb2标记的空间分布。

Boxed regions in left panels are enlarged and shown in the right panels. The data are from the Allen Mouse Brain Atlas. Scale bars, 500 µm. b, smFISH confirms the expression of D1-MSN subtype-specific markers in the NAcSh do not overlap with Drd2. Boxed regions in left panels are enlarged and shown in the right panels.

左侧面板中的方框区域被放大并显示在右侧面板中。数据来自艾伦老鼠大脑图谱。比例尺，500微米。b、 smFISH证实NAcSh中D1-MSN亚型特异性标记的表达不与Drd2重叠。左侧面板中的方框区域被放大并显示在右侧面板中。

Three independent experiments were performed with similar results. Scale bar, 50 µm. c, The percentage of NAcSpon1, NAcStard5, NAcTac2 and NAcSerpinb2 cells overlapping with Drd1+ or Drd2+ cells in the NAcSh. t4 = 52.36 (1st), t4 = 35.21 (2nd), t4 = 73.2761 (3rd), t4 = 85.70 (4th). For b,c, every fourth of 16-µm brain sections was counted.

。比例尺，50微米。c、 NAcSpon1，NAcStard5，NAcTac2和NAcSerpinb2细胞与NAcSh中的Drd1+或Drd2+细胞重叠的百分比。t4=52.36（第一），t4=35.21（第二），t4=73.2761（第三），t4=85.70（第四）。对于b，c，每四分之一的16µm脑切片被计数。

n = 3 mice for all groups. All statistical tests are two-tailed unpaired t-tests. Data are mean ± SEM.Source dataExtended Data Fig. 2 Generation and validation of a Serpinb2-Cre mouse line.a, Diagrams showing the gene targeting strategy. b, Genotyping by PCR. Homozygotes (Ho): 413 bp. Heterozygotes (Het): 413 bp/772 bp.

所有组n=3只小鼠。所有统计检验均为双尾不成对t检验。数据是平均值±SEM.Source数据扩展数据图2 Serpinb2-Cre小鼠系的产生和验证。a，显示基因靶向策略的图。b、 通过PCR进行基因分型。纯合子（Ho）：413 bp。杂合子（Het）：413 bp/772 bp。

c, Left, in situ hybridization (ISH) data of Serpinb2 from Allen Brain Atlas. Scale bar, 1000 μm. Middle, co-localization of endogenous Serpinb2 (green), tdTomato (red) and DAPI (blue). Scale bar, 100 μm. Right, quantification of tdTomato+ neurons among all Serpinb2+ neurons. n = 3 mice. Data are represented as mean ± SEM.Source dataExtended Data Fig.

c、 左，来自Allen Brain Atlas的Serpinb2的原位杂交（ISH）数据。比例尺，1000微米。中间，内源性Serpinb2（绿色），tdTomato（红色）和DAPI（蓝色）的共定位。比例尺，100微米。正确，所有Serpinb2+神经元中tdTomato+神经元的定量。n=3只小鼠。数据表示为平均值±SEM.Source dataExtended Data Fig。

3 Tac2+ neurons do not respond to feeding behavior.a–c, The injection si.

3个Tac2+神经元对摄食行为无反应。a–c，注射si。

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Reprints and permissionsAbout this articleCite this articleLiu, Y., Wang, Y., Zhao, Zd. et al. A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis.

。伏隔核中表达多巴胺受体的神经元的一个子集控制进食和能量稳态。

Nat Metab (2024). https://doi.org/10.1038/s42255-024-01100-0Download citationReceived: 24 April 2024Accepted: 09 July 2024Published: 15 August 2024DOI: https://doi.org/10.1038/s42255-024-01100-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Nat Metab（2024年）。https://doi.org/10.1038/s42255-024-01100-0Download引文接收日期：2024年4月24日接受日期：2024年7月9日发布日期：2024年8月15日OI：https://doi.org/10.1038/s42255-024-01100-0Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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