Chen, W;Mehlkop, O;Scharn, A;Nolte, H;Klemm, P;Henschke, S;Steuernagel, L;Sotelo-Hitschfeld, T;Kaya, E;Wunderlich, CM;Langer, T;Kononenko, NL;Giavalisco, P;Brüning, JC;
PMID: 37075752 | DOI: 10.1016/j.cmet.2023.03.019
Autophagy represents a key regulator of aging and metabolism in sensing energy deprivation. We find that fasting in mice activates autophagy in the liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators, and promotes ketogenesis. AgRP neuron-dependent induction of liver autophagy relies on NPY release in the paraventricular nucleus of the hypothalamus (PVH) via presynaptic inhibition of NPY1R-expressing neurons to activate PVHCRH neurons. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and rewiring of metabolism. AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of liver autophagy in control of metabolic adaptation during nutrient deprivation.
Shin, S;You, IJ;Jeong, M;Bae, Y;Wang, XY;Cawley, ML;Han, A;Lim, BK;
PMID: 36510113 | DOI: 10.1038/s41593-022-01208-0
Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LHLepr) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LHLepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LHLepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity.
Feng, C;Wang, Y;Zha, X;Cao, H;Huang, S;Cao, D;Zhang, K;Xie, T;Xu, X;Liang, Z;Zhang, Z;
PMID: 35675799 | DOI: 10.1016/j.cmet.2022.05.002
Homeostatic thermogenesis is an essential protective feature of endotherms. However, the specific neuronal types involved in cold-induced thermogenesis remain largely unknown. Using functional magnetic resonance imaging and in situ hybridization, we screened for cold-sensitive neurons and found preprodynorphin (PDYN)-expressing cells in the dorsal medial region of the ventromedial hypothalamus (dmVMH) to be a candidate. Subsequent in vivo calcium recording showed that cold temperature activates dmVMHPdyn neurons, whereas hot temperature suppresses them. In addition, optogenetic activation of dmVMHPdyn neurons increases the brown adipose tissue and core body temperature, heart rate, and blood pressure, whereas optogenetic inhibition shows opposite effects, supporting their role in homeostatic thermogenesis. Furthermore, we found that dmVMHPdyn neurons are linked to known thermoregulatory circuits. Importantly, dmVMHPdyn neurons also show activation during mouse social interaction, and optogenetic inhibition suppresses social interaction and associated hyperthermia. Together, our study describes dual functions of dmVMHPdyn neurons that allow coordinated regulation of body temperature and social behaviors.
Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing
Cleary, CM;Milla, BM;Kuo, FS;James, S;Flynn, WF;Robson, P;Mulkey, DK;
PMID: 34013884 | DOI: 10.7554/eLife.60317
Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.
Claypool, SM;Behdin, S;Applebey, SV;Orihuel, J;Ma, Z;Reiner, DJ;
PMID: 35768212 | DOI: 10.1523/ENEURO.0496-21.2022
The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence because of availability of alternative nondrug rewards. We used in situ hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/d), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine whether fentanyl relapse is associated with activity (indicated by Fos) in OFC and Pir cells expressing Cnr1 [which encodes cannabinoid 1 (CB1) receptors] or Drd1 and Drd2 (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a dopamine D1 receptor antagonist (1.0 or 3.0 µg SCH39166/hemisphere) into Pir to determine the effect on fentanyl relapse. Fentanyl relapse was associated with OFC cells co-expressing Fos and Cnr1 and Pir cells co-expressing Fos and Drd1 However, injections of the CB1 receptor antagonist AM251 or agonist WIN55,212-2 into OFC or the dopamine D1 receptor antagonist SCH39166 into Pir had no effect on fentanyl relapse. Fentanyl relapse is associated with activation of Cnr1-expressing OFC cells and Drd1-expressing Pir cells, but pharmacological manipulations do not support causal roles of OFC CB1 receptors or Pir dopamine D1 receptors in fentanyl relapse.
Spencer, C;
| DOI: 10.22215/etd/2022-15217
Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide that acts through its receptor (MCHR1) to promote positive energy balance by increasing food intake and decreasing energy expenditure. MCH has been shown to inhibit dopamine release from the mesocorticolimbic dopamine pathway originating in the ventral tegmental area (VTA), and a hyperdopaminergic state underlies hyperactivity observed in animals lacking MCH or MCHR1. However, it is not known if the inhibitory effect of MCH on dopaminergic tone could be due to direct regulation of dopaminergic VTA neurons. We used a combination of molecular, neuroanatomical, and electrophysiological techniques to assess MCHR1 expression and activation in the VTA. MCH neurons project to the VTA, which comprises nerve terminals that contain MCH and may represent MCH release sites. Consistent with this, we detected MCHR1 expression on major VTA cell types, including those that are dopaminergic, GABAergic, and glutamatergic. Functional MCHR1 activation may regulate dopamine release via two mechanisms, one by acutely and directly inhibiting dopaminergic VTA neurons, and the other by disinhibiting glutamatergic afferents to dopaminergic VTA neurons. While we have not measured dopamine release in this present thesis, we postulate that MCH may acutely suppress dopamine release, while concurrently engaging local glutamatergic signaling to restore dopamine levels. These results signify that the VTA is a novel target for MCH-mediated physiology, including for the maintenance of energy homeostasis
Weil, T;Daly, KM;Yarur Castillo, H;Thomsen, MB;Wang, H;Mercau, ME;Hattar, S;Tejeda, H;Fernandez, DC;
PMID: 35687680 | DOI: 10.1126/sciadv.abn3567
Exposure to irregular lighting schedules leads to deficits in affective behaviors. The retino-recipient perihabenular nucleus (PHb) of the dorsal thalamus has been shown to mediate these effects in mice. However, the mechanisms of how light information is processed within the PHb remains unknown. Here, we show that the PHb contains a distinct cluster of GABAergic neurons that receive direct retinal input. These neurons are part of a larger inhibitory network composed of the thalamic reticular nucleus and zona incerta, known to modulate thalamocortical communication. In addition, PHbGABA neurons locally modulate excitatory-relay neurons, which project to limbic centers. Chronic exposure to irregular light-dark cycles alters photo-responsiveness and synaptic output of PHbGABA neurons, disrupting daily oscillations of genes associated with inhibitory and excitatory PHb signaling. Consequently, selective and chronic PHbGABA manipulation results in mood alterations that mimic those caused by irregular light exposure. Together, light-mediated disruption of PHb inhibitory networks underlies mood deficits.
Faget L, Zell V, Souter E, McPherson A, Ressler R, Gutierrez-Reed N, Yoo JH, Dulcis D, Hnasko TS.
PMID: 29487284 | DOI: 10.1038/s41467-018-03125-y
The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing-with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease.
Macpherson T, Mizoguchi H, Yamanaka A, Hikida T.
PMID: 30797970 | DOI: 10.1016/j.neuint.2019.02.011
The ventral pallidum (VP) is a critical component of the basal ganglia neurocircuitry regulating learning and decision making; however, its precise role in controlling associative learning of environmental stimuli conditioned to appetitive or aversive outcomes is still unclear. Here, we investigated the expression of preproenkephalin, a polypeptide hormone previously shown to be expressed in nucleus accumbens neurons controlling aversive learning, within GABAergic and glutamatergic VP neurons. Next, we explored the behavioral consequences of chemicogenetic inhibition or excitation of preproenkephalin-expressing VP neurons on associative learning of reward- or aversion-paired stimuli in autoshaping and inhibitory avoidance tasks, respectively. We reveal for the first time that preproenkephalin is expressed predominantly in GABAergic rather than glutamatergic VP neurons, and that excitation of these preproenkephalin-expressing VP neurons was sufficient to impair inhibitory avoidance learning. These findings indicate the necessity for inhibition of preproenkephalin-expressing VP neurons for avoidance learning, and suggest these neurons as a potential therapeutic target for psychiatric disorders associated with maladaptive aversive learning.
Holly EN, Davatolhagh MF, Choi K, Alabi OO, Vargas Cifuentes L, Fuccillo MV.
PMID: 31097361 | DOI: 10.1016/j.neuron.2019.04.016
The dorsomedial striatum (DMS) is critically involved in motor control and reward processing, but the specific neural circuit mediators are poorly understood. Recent evidence highlights the extensive connectivity of low-threshold spiking interneurons (LTSIs) within local striatal circuitry; however, the in vivo function of LTSIs remains largely unexplored. We employed fiber photometry to assess LTSI calcium activity in a range of DMS-mediated behaviors, uncovering specific reward-related activity that is down-modulated during goal-directed learning. Using two mechanistically distinct manipulations, we demonstrated that this down-modulation of LTSI activity is critical for acquisition of novel contingencies, but not for their modification. In contrast, continued LTSI activation slowed instrumental learning. Similar manipulations of fast-spiking interneurons did not reproduce these effects, implying a specific function of LTSIs. Finally, we revealed a role for the γ-aminobutyric acid (GABA)ergic functions of LTSIs in learning. Together, our data provide new insights into this striatal interneuron subclass as important gatekeepers of goal-directed learning.
Wallace ML, Huang KW, Hochbaum D, Hyun M, Radeljic G, Sabatini BL
PMID: 32043968 | DOI: 10.7554/eLife.51271
The lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here, we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find five subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb, we describe four neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit
Teng, S;Zhen, F;Wang, L;Schalchli, JC;Simko, J;Chen, X;Jin, H;Makinson, CD;Peng, Y;
PMID: 35961989 | DOI: 10.1038/s41467-022-32461-3
Understanding the neural mechanisms underlying sleep state transitions is a fundamental goal of neurobiology and important for the development of new treatments for insomnia and other sleep disorders. Yet, brain circuits controlling this process remain poorly understood. Here we identify a population of sleep-active glutamatergic neurons in the ventrolateral medulla (VLM) that project to the preoptic area (POA), a prominent sleep-promoting region, in mice. Microendoscopic calcium imaging demonstrate that these VLM glutamatergic neurons display increased activity during the transitions from wakefulness to Non-Rapid Eye Movement (NREM) sleep. Chemogenetic silencing of POA-projecting VLM neurons suppresses NREM sleep, whereas chemogenetic activation of these neurons promotes NREM sleep. Moreover, we show that optogenetic activation of VLM glutamatergic neurons or their projections in the POA initiates NREM sleep in awake mice. Together, our findings uncover an excitatory brainstem-hypothalamic circuit that controls the wake-sleep transitions.
