Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Rodriguez, LA;Kim, SH;Page, SC;Nguyen, CV;Pattie, EA;Hallock, HL;Valerino, J;Maynard, KR;Jaffe, AE;Martinowich, K;
PMID: 36369482 | DOI: 10.1038/s41386-022-01487-y
The lateral septum (LS) is a basal forebrain GABAergic region that is implicated in social novelty. However, the neural circuits and cell signaling pathways that converge on the LS to mediate social behaviors aren't well understood. Multiple lines of evidence suggest that signaling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB plays important roles in social behavior. BDNF is not locally produced in LS, but we demonstrate that nearly all LS GABAergic neurons express TrkB. Local TrkB knock-down in LS neurons decreased social novelty recognition and reduced recruitment of neural activity in LS neurons in response to social novelty. Since BDNF is not synthesized in LS, we investigated which inputs to LS could serve as potential BDNF sources for controlling social novelty recognition. We demonstrate that selectively ablating inputs to LS from the basolateral amygdala (BLA), but not from ventral CA1 (vCA1), impairs social novelty recognition. Moreover, depleting BDNF selectively in BLA-LS projection neurons phenocopied the decrease in social novelty recognition caused by either local LS TrkB knockdown or ablation of BLA-LS inputs. These data support the hypothesis that BLA-LS projection neurons serve as a critical source of BDNF for activating TrkB signaling in LS neurons to control social novelty recognition.
Neuromodulatory effect of interleukin 1β in the dorsal raphe nucleus on individual differences in aggression
Takahashi, A;Aleyasin, H;Stavarache, MA;Li, L;Cathomas, F;Parise, LF;Lin, HY;Burnett, CJ;Aubry, A;Flanigan, ME;Brancato, A;Menard, C;Pfau, ML;Kana, V;Wang, J;Hodes, GE;Sasaki, T;Kaplitt, MG;Ogawa, S;McEwen, BS;Russo, SJ;
PMID: 33931727 | DOI: 10.1038/s41380-021-01110-4
Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1β (IL-1β) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1β in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1β signaling in the DRN controls expression of aggressive behavior.
Xue, T;Wang, X;Hu, Y;Cheng, Y;Li, H;Shi, Y;Wang, L;Yin, D;Cui, D;
PMID: 36291328 | DOI: 10.3390/brainsci12101395
The brain is susceptible to perturbations of redox balance, affecting neurogenesis and increasing the risks of psychiatric disorders. Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the thioredoxin antioxidant system. Its deletion or inhibition suggests protection for a brain with ischemic stroke or Alzheimer's disease. Combined with conditional knockout mice and schizophrenia samples, we aimed to investigate the function of TXNIP in healthy brain and psychiatric disorders, which are under-studied. We found TXNIP was remarkedly expressed in the prefrontal cortex (PFC) during healthy mice's prenatal and early postnatal periods, whereas it rapidly decreased throughout adulthood. During early life, TXNIP was primarily distributed in inhibitory and excitatory neurons. Contrary to the protective effect, the embryonic deletion of TXNIP in GABAergic (gamma-aminobutyric acid-ergic) neurons enhanced oxidative stress in PV+ interneurons of aging mice. The deleterious impact was brain region-specific. We also investigated the relationship between TXNIP and schizophrenia. TXNIP was significantly increased in the PFC of schizophrenia-like mice after MK801 administration, followed by oxidative stress. First episode and drug naïve schizophrenia patients with a higher level of plasma TXNIP displayed severer psychiatric symptoms than patients with a low level. We indicated a bidirectional function of TXNIP in the brain, whose high expression in the early stage is protective for development but might be harmful in a later period, associated with mental disorders.
Plexin-A1 expression in the inhibitory neurons of infralimbic cortex regulates the specificity of fear memory in male mice
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Cheng, X;Zhao, Y;Zheng, S;Zhao, P;Zou, JL;Lin, WJ;Wu, W;Ye, X;
PMID: 34508226 | DOI: 10.1038/s41386-021-01177-1
Maintaining appropriate levels of fear memory specificity is crucial for individual's survival and mental health, whereas overgeneralized fear commonly occurs in neuropsychiatric disorders, including posttraumatic stress disorder and generalized anxiety disorder. However, the molecular mechanisms regulating fear memory specificity remain poorly understood. The medial prefrontal cortex (mPFC) is considered as a key brain region in fear memory regulation. Previous transcriptomic studies have identified that plexin-A1, a transmembrane receptor critical for axon development, was downregulated in the mPFC after fear memory training. In this study, we identified that learning-induced downregulation of the mRNA and protein levels of plexin-A1 specifically occurred in the inhibitory but not excitatory neurons in the infralimbic cortex (IL) of mPFC. Further studies of plexin-A1 by virus-mediated over-expression of functional mutants selectively in the IL inhibitory neurons revealed the critical roles of plexin-A1 for regulating memory specificity and anxiety. Moreover, our findings revealed that plexin-A1 regulated the distribution of glutamic acid decarboxylase 67, a GABA synthetase, which in turn modulated the activity of IL and its downstream brain regions. Collectively, our findings elucidate the molecular modifier of IL inhibitory neurons in regulating memory specificity and anxiety, and provide candidates for developing therapeutic strategies for the prevention or treatment of a series of fear generalization-related neuropsychiatric disorders.
Wadsworth, HA;Anderson, EQ;Williams, BM;Ronström, JW;Moen, JK;Lee, AM;McIntosh, JM;Wu, J;Yorgason, JT;Steffensen, SC;
PMID: 36802012 | DOI: 10.1007/s12035-023-03263-5
The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1 Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.
Proc Natl Acad Sci U S A.
Shen H, Marino RAM, McDevitt RA, Bi GH, Chen K, Madeo G, Lee PT, Liang Y, De Biase LM, Su TP, Xi ZX, Bonci A.
PMID: 30442663 | DOI: 10.1073/pnas.1800886115
A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.
Nat Commun. 2015 Jun 1;6:7222.
Vullhorst D, Mitchell RM, Keating C, Roychowdhury S, Karavanova I, Tao-Cheng JH, Buonanno A.
PMID: 26047731 | DOI: 10.1016/j.neuroscience.2015.05.071.
The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders.
Zhang L, Hernández VS, Vázquez-Juárez E, Chay FK, Barrio RA.
PMID: 27065810 | DOI: 10.3389/fncir.2016.00013
Water-homeostasis is a fundamental physiological process for terrestrial life. In vertebrates, thirst drives water intake, but the neuronal circuits that connect the physiology of water regulation with emotional context are poorly understood. Vasopressin (VP) is a prominent messenger in this circuit, as well as L-glutamate. We have investigated the role of a VP circuit and interaction between thirst and motivational behaviors evoked by life-threatening stimuli in rats. We demonstrate a direct pathway from hypothalamic paraventricular VP-expressing, glutamatergic magnocellular neurons to the medial division of lateral habenula (LHbM), a region containing GABAergic neurons. In vivo recording and juxtacellular labeling revealed that GABAergic neurons in the LHbM had locally branching axons, and received VP-positive axon terminal contacts on their dendrites. Water deprivation significantly reduced freezing and immobility behaviors evoked by innate fear and behavioral despair, respectively, accompanied by decreased Fos expression in the lateral habenula. Our results reveal a novel VP-expressing hypothalamus to the LHbM circuit that is likely to evoke GABA-mediated inhibition in the LHbM, which promotes escape behavior during stress coping.
Li, L;Durand-de Cuttoli, R;Aubry, AV;Burnett, CJ;Cathomas, F;Parise, LF;Chan, KL;Morel, C;Yuan, C;Shimo, Y;Lin, HY;Wang, J;Russo, SJ;
PMID: 36450985 | DOI: 10.1038/s41586-022-05484-5
In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.
Fish KN, Rocco BR, Lewis DA.
PMID: 29503610 | DOI: 10.3389/fnana.2018.00009
In human prefrontal cortex (PFC), ~85% of γ-aminobutyric acid (GABA)-expressing neurons can be subdivided into non-overlapping groups by the presence of calbindin (CB), calretinin (CR) or parvalbumin (PV). Substantial research has focused on the differences in the laminar locations of the cells bodies of these neurons, with limited attention to the distribution of their axon terminals, their sites of action. We previously reported that in non-human primates subtypes of these cells are distinguishable by differences in terminal protein levels of the GABA synthesizing enzymes glutamic acid decarboxylase 65 (GAD65) and GAD67. Here we used multi-label fluorescence microscopy in human PFC to assess: (1) the laminar distributions of axon terminals containing CB, CR, or PV; and (2) the relative protein levels of GAD65, GAD67 and vesicular GABA transporter (vGAT) in CB, CR and PV terminals. The densities of the different CB, CR and PV terminal subpopulations differed across layers of the PFC. PV terminals comprised two subsets based on the presence of only GAD67 (GAD67+) or both GADs (GAD65/GAD67+), whereas CB and CR terminals comprised three subsets (GAD65+, GAD67+, or GAD65/GAD67+). The densities of the different CB, CR and PV GAD terminal subpopulations also differed across layers. Finally, within each of the three calcium-binding protein subpopulations intra-terminal protein levels of GAD and vGAT differed by GAD subpopulation. These findings are discussed in the context of the laminar distributions of CB, CR and PV cell bodies and the synaptic targets of their axons.
Jung, M;Dourado, M;Maksymetz, J;Jacobson, A;Laufer, BI;Baca, M;Foreman, O;Hackos, DH;Riol-Blanco, L;Kaminker, JS;
PMID: 36690629 | DOI: 10.1038/s41467-023-36014-0
Sensory neurons of the dorsal root ganglion (DRG) are critical for maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs by implementing a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations specifically in nociceptors that likely point to divergent function of nociceptors. Among these, we validated that TAFA4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.
Fgf15 neurons of the dorsomedial hypothalamus control glucagon secretion and hepatic gluconeogenesis
Picard, A;Metref, S;Tarussio, D;Dolci, W;Berney, X;Croizier, S;Labouebe, G;Thorens, B;
PMID: 33883213 | DOI: 10.2337/db20-1121
The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this gluco-regulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus, as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15CretdTomato mice and their use to further characterize these neurons. We showed that they were glutamatergic and comprised glucose inhibited and glucose excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the dorsomedial hypothalamus participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally-induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.
