A Second Wave for the Neurokinin Tac2 Pathway in Brain Research

Abed, Alice Shaam Al; Reynolds, Nathan J; Dehorter, Nathalie

doi:10.1016/j.biopsych.2021.02.016

Cited by 7 publications

(5 citation statements)

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“…For example, we found strong upregulation of the Tac2 and Trh genes. Tac2 is upregulated in the brain after chronic social isolation stress [ 104 ], and its downstream pathways can affect dopaminergic release from the VTA [ 105 ]. Trh is involved in the regulation and release of thyroid-stimulating hormone (thyrotropin) and prolactin from the pituitary gland.…”

Section: Discussionmentioning

confidence: 99%

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

et al. 2022

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Early life stress (ELS) is known to modify trajectories of brain dopaminergic development, but the mechanisms underlying have not been determined. ELS perturbs immune system and microglia reactivity, and inflammation and microglia influence dopaminergic transmission and development. Whether microglia mediate the effects of ELS on dopamine (DA) system development is still unknown. We explored the effects of repeated early social stress on development of the dopaminergic system in male and female mice through histological, electrophysiological, and transcriptomic analyses. Furthermore, we tested whether these effects could be mediated by ELS-induced altered microglia/immune activity through a pharmacological approach. We found that social stress in early life altered DA neurons morphology, reduced dopamine transporter (DAT) and tyrosine hydroxylase expression, and lowered DAT-mediated currents in the ventral tegmental area but not substantia nigra of male mice only. Notably, stress-induced DA alterations were prevented by minocycline, an inhibitor of microglia activation. Transcriptome analysis in the developing male ventral tegmental area revealed that ELS caused downregulation of dopaminergic transmission and alteration in hormonal and peptide signaling pathways. Results from this study offer new insight into the mechanisms of stress response and altered brain dopaminergic maturation after ELS, providing evidence of neuroimmune interaction, sex differences, and regional specificity.

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Section: Discussionmentioning

confidence: 99%

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

et al. 2022

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“…Other members of the tachykinin neuropeptide family, including neurokinin A (NKA) and substance P (SP), are recognized by NK3R with a significantly reduced affinity (Steinhoff et al, 2014). Central NKB/NK3R signaling has been implicated in reproductive physiology and behavior in the hypothalamic arcuate and preoptic regions (Rance et al, 2010(Rance et al, , 2013, fear memory consolidation (Andero et al, 2014(Andero et al, , 2016Florido et al, 2021;Marvar et al, 2021;Shaam Al Abed et al, 2021), and appetitive behavior (Kim et al, 2017) in the central nucleus of the amygdala. Most recently, chronic social isolation stress in mice has been shown to induce a striking brainwide upregulation of Tac2 mRNA, along with enhanced aggressive and defensive behaviors (Zelikowsky et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Neurokinin B-Expressing Neurons of the Central Extended Amygdala Mediate Inhibitory Synaptic Input onto Melanin-Concentrating Hormone Neuron Subpopulations

et al. 2021

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The lateral hypothalamic area (LHA) is a highly conserved brain region critical for maintaining physiological homeostasis and goal-directed behavior. LHA neurons that express melanin-concentrating hormone (MCH) are key regulators of arousal, energy balance, and motivated behavior. However, cellular and functional diversity among LHAMCHneurons is not well understood. Previous anatomic and molecular data suggest that LHAMCHneurons may be parsed into at least two distinct subpopulations, one of which is enriched in neurokinin-3 receptor (NK3R), the receptor for neurokinin B (NKB), encoded by theTac2gene. This tachykininergic ligand-receptor system has been implicated in reproduction, fear memory, and stress in other brain regions, but NKB interactions with LHAMCHneurons are poorly understood. We first identified how LHAMCHsubpopulations may be distinguished anatomically and electrophysiologically. To dissect functional connectivity between NKB-expressing neurons and LHAMCHneurons, we used Cre-dependent retrograde and anterograde viral tracing in maleTac2-Cre mice and identifiedTac2/EYFP+ neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala, the central extended amygdala, as major sources of NKB input onto LHAMCHneurons. In addition to innervating the LHA, these limbic forebrain NKB neurons also project to midbrain and brainstem targets. Finally, using a dual-virus approach, we found that optogenetic activation of these inputs in slices evokes GABA release onto a subset of LHAMCHneurons but lacked specificity for the NK3R+ subpopulation. Overall, these data define parallel tachykininergic/GABAergic limbic forebrain projections that are positioned to modulate multiple nodes of homeostatic and behavioral control.SIGNIFICANCE STATEMENTThe LHA orchestrates fundamental behavioral states in the mammalian hypothalamus, including arousal, energy balance, memory, stress, and motivated behavior. The neuropeptide MCH defines one prominent population of LHA neurons, with multiple roles in the regulation of homeostatic behavior. Outstanding questions remain concerning the upstream inputs that control MCH neurons. We sought to define neurochemically distinct pathways in the mouse brain that may communicate with specific MCH neuron subpopulations using viral-based retrograde and anterograde neural pathway tracing and optogenetics in brain slices. Here, we identify a specific neuropeptide-defined forebrain circuit that makes functional synaptic connections with MCH neuron subpopulations. This work lays the foundation for further manipulating molecularly distinct neural circuits that modulate innate behavioral states.

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“…Taken together, these findings suggest that genetic variability in the neurokinin B receptor is one factor relevant to women's different experiences of hot flashes. Intriguingly, the neurokinin B signaling system has also been the focus of numerous investigations of psychiatric symptoms (Al Abed, Reynolds, & Dehorter, 2021; Zhang, Wang, & Chu, 2020).…”

Section: Discussionmentioning

confidence: 99%

Shared genetic influences on depression and menopause symptoms

et al. 2021

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Background Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. Methods The analysis included 232 993 women aged 39–71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. Results GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10−15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10−5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. Conclusions These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

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A Second Wave for the Neurokinin Tac2 Pathway in Brain Research

Cited by 7 publications

References 93 publications

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

Neurokinin B-Expressing Neurons of the Central Extended Amygdala Mediate Inhibitory Synaptic Input onto Melanin-Concentrating Hormone Neuron Subpopulations

Shared genetic influences on depression and menopause symptoms

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