Whole-brain mapping of histaminergic projections in mouse brain

Abstract

Histamine is a conserved neuromodulator in mammalian brains and critically involved in many physiological functions. Understanding the precise structure of the histaminergic network is the cornerstone in elucidating its function. Herein, using histidine decarboxylase (HDC)-CreERT2 mice and genetic labeling strategies, we reconstructed a whole-brain three dimensional (3D) structure of histaminergic neurons and their outputs at 0.32 × 0.32 × 2 μm 3 pixel resolution with a cutting-edge fluorescence microoptical sectioning tomography system. We quantified the fluorescence density of all brain areas and found that histaminergic fiber density varied significantly among brain regions. The density of histaminergic fiber was positively correlated with the amount of histamine release induced by optogenetic stimulation or physiological aversive stimulation. Lastly, we reconstructed a fine morphological structure of 60 histaminergic neurons via sparse labeling and uncovered the largely heterogeneous projection pattern of individual histaminergic neurons. Collectively, this study reveals an unprecedented whole-brain quantitative analysis of histaminergic projections at the mesoscopic level, providing a foundation for future functional histaminergic study.

Histamine originating from the BNST modulates corticostriatal synaptic transmission during early postnatal development

“…It is puzzling that striatal innervation by histaminergic afferents is sparse or undetectable in the first postnatal weeks (Vanhala et al, 1994;Han et al, 2020) and even in adulthood is not very dense, as compared to other neuromodulators such as dopamine (Ellender et al, 2011;Awasthi et al, 2021;Lin et al, 2023). Close examination of sagittal sections stained for histamine revealed a region in close proximity and medio-caudal with respect to striatum that is heavily innervated by histaminecontaining axons which both anatomical analysis as well as further immunohistochemistry (e.g.…”

“…Even in adulthood this does not reach the axonal density exhibited by other neuromodulators, such as dopamine or serotonin (Ellender et al, 2011;Awasthi et al, 2021;Lin et al, 2023). The sparsity of innervation seems incongruous with the many observations demonstrating high expression of histamine receptors as well as histaminergic modulation of striatal neurons and synapses from the first postnatal weeks onwards (Pillot et al, 2002;Ellender et al, 2011;Rapanelli et al, 2017b;Han et al, 2020).…”

“…The fact that exogenously applied histamine modulates young striatal neurons and synapses raises the question what the physiological sources for striatal histamine might be. Puzzlingly, numerous observations would suggest that histamine-containing axons are sparse to undetectable in many brain regions, including the striatum, during both early development as well as in adulthood (Ellender et al, 2011;Yu et al, 2015;Han et al, 2020;Lin et al, 2023). To explore in detail the rostro-caudal distribution of histamine-containing axons in the developing brain fixed sagittal brain sections from P9-10 mice were immunolabeled for histamine (Figure 3A -C).…”

“…The neuromodulator histamine is synthesized by neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus which send wide-spread axonal projections and release histamine throughout the central nervous system (Haas & Panula, 2003;Haas et al, 2008;Lin et al, 2023). Although classically assumed to mainly regulate the sleep-wake cycle, the histaminergic system is now thought to have many more diverse physiological roles in a multitude of brain regions and stages of life (Schwartz et al, 1991;Takahashi et al, 2006;Panula et al, 2014;Han et al, 2020;Lucaci et al, 2023), and has been shown to be dysfunctional in various neurological and neurodevelopmental disorders (Ercan-Sencicek, 2010; Shan et al, 2015;Carthy & Ellender, 2021;Xu et al, 2022;Ma et al, 2023).…”

“…The early onset of these disorders has led to an increased interest in understanding the physiological and pathological roles for histamine during early prenatal and postnatal stages (Panula et al, 2014;Rapanelli et al, 2017a;Han et al, 2020;Valle-Bautista et al, 2021) as well as its potential as a target for treatment Zhang et al, 2020;Carthy & Ellender, 2021). It is puzzling that although histamineexpressing neurons can be readily detected in the hypothalamic tuberomammillary nucleus (TMN) from the first postnatal week onwards in rodents (Reiner, 1988;Panula et al, 2014) many brain regions, including the striatum, do not contain detectable histamine-containing axons until much later in life and even then are rather sparse (Vanhala et al, 1994;Ellender et al, 2011;Han et al, 2020;Lin et al, 2023). For example, in striatum these start to only be seen in the second postnatal week and even then are infrequent and in many striatal regions seemingly absent (Han et al, 2020).…”