Descending projections from the basal forebrain to the orexin neurons in mice

Agostinelli, Lindsay J; Ferrari, Loris; Mahoney, Carrie E.; Mochizuki, Takatoshi; Lowell, Bradford B.; Arrigoni, Elda; Scammell, Thomas E.

doi:10.1002/cne.24158

Cited by 29 publications

(28 citation statements)

References 101 publications

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“…In vitro studies in mice suggested excitatory intra-BF connections to PV and somatostatin-containing GABAergic neurons as well as to cholinergic neurons (Xu et al, 2015). Both retrograde (Hur and Zaborszky, 2005) and anterograde studies Do et al, 2016;Agostinelli et al, 2017Agostinelli et al, , 2019 in the rodent suggested that subsets of BF vGluT2+ neurons are projection neurons which target the frontal cortex, lateral hypothalamus and other brain areas. Our anterograde tracing experiments demonstrated projections to brain areas involved in the control of arousal and (negative) reward processing.…”

Section: Introductionmentioning

confidence: 99%

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Mckenna

Yang

Bellio

et al. 2020

Preprint

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The basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF subtypes is still being uncovered. Glutamatergic neurons are the least wellunderstood of the three major BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of the major group of BF glutamate neurons expressing the vesicular glutamate transporter subtype 2 (vGluT2) and tested the functional effect of activating them. Mice expressing Cre recombinase under control of the vGluT2 promoter were crossed with a reporter strain expressing the red fluorescent protein, tdTomato, to generate vGluT2-cre-tdTomato mice. Immunohistochemical staining for choline acetyltransferase and a cross with mice expressing green fluorescent protein selectively in GABAergic neurons confirmed cholinergic, GABAergic and vGluT2+ neurons represent separate BF subpopulations. Subsets of BF vGluT2+ neurons expressed the calcium binding proteins calbindin or calretinin, suggesting that multiple subtypes of BF vGluT2+ neurons exist.Anterograde tracing using adeno-associated viral vectors expressing channelrhodopsin2enhanced yellow fluorescent fusion proteins revealed major projections of BF vGluT2+ neurons to neighboring BF cholinergic and parvalbumin neurons, as well as to extra-BF areas involved in the control of arousal and regions responding to aversive or rewarding stimuli such as the lateral habenula and ventral tegmental area. Optogenetic activation of BF vGluT2 neurons in a place preference paradigm elicited a striking avoidance of the area where stimulation was given.Together with previous optogenetic findings suggesting an arousal-promoting role, our findings suggest BF vGluT2 neurons play a dual role in promoting wakefulness and avoidance behavior.

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Section: Introductionmentioning

confidence: 99%

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Mckenna

Yang

Bellio

et al. 2020

Preprint

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“…The antisense vGAT riboprobe corresponds to nucleotide 875-1,416 of mouse Slc32a1 mRNA (Vgat; NM_009508.2) (Agostinelli et al, 2017). Using a plasmid linearized with SacI (New England Biolabs, Beverly, MA), it was transcribed with T7 polymerase (Promega, Madison, WI) in the presence of digoxigenin (DIG)-conjugated UTP (Roche Diagnostics, Mannheim, Germany).…”

Section: 42: Fish and Ihc Proceduresmentioning

confidence: 99%

Distributions of hypothalamic neuron populations co-expressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse

Negishi

Payant

Schumacker

et al. 2019

Preprint

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The hypothalamus, which includes the zona incerta, contains a discrete population of catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers may coexist in each neuron, we determined if hypothalamic THimmunoreactive (ir) neurons may also express glutamate or GABA. We used Cre/loxP recombination to express enhanced GFP fluorescence in neurons that express the vesicular glutamate (vGLUT2) or GABA transporter (vGAT) and determined TH immunoreactivity in glutamatergic or GABAergic neurons, respectively. EGFP-labeled vGLUT2 neurons were not TH-ir. However, there were discrete TH-ir signals that colocalized with EGFP-positive vGAT neurons, which we validated by in situ hybridization for Vgat mRNA. In order to contextualize the observed pattern of TH+EGFP colocalization in vGAT neurons, we first performed Nissl-based parcellation and plane-of-section analysis, and then mapped the distribution of TH-ir vGAT neurons onto atlas templates from the Allen Reference Atlas of the mouse brain. TH-ir vGAT neurons were distributed throughout the rostrocaudal extent of the hypothalamus and were localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a very strong presence of EGFP fluorescence in TH-ir neurons across all brain regions where it was observed, but the most striking colocalization was found in the zona incerta (ZI), where every TH-ir neuron was EGFP-positive. Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine β-hydroxylase. In aggregate, these findings indicate the existence of a novel hypothalamic population that may signal through the release of GABA and/or dopamine.

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“…Subsets of all three of these groups project to the neocortex (Freund and Meskenaite, 1992; Gritti et al, 2003; Henny and Jones, 2008; Kim et al, 2015; Zaborszky et al, 2015; Do et al, 2016) and have been implicated in promoting wakefulness and fast cortical rhythms (Anaclet et al, 2015; Kim et al, 2015; Xu et al, 2015; Zant et al, 2016). Other subsets project caudally to areas involved in reward processing and sleep-wake control such as the lateral hypothalamus and lateral habenula and/or locally within the BF (Zaborszky et al, 2012; McKenna et al, 2015a; Xu et al, 2015; Agostinelli et al, 2016; Brown et al, 2016; Do et al, 2016; Golden et al, 2016). …”

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confidence: 99%

“…The discovery of vesicular glutamate transporters (vGluT) allowed the first definitive identification of glutamate neurons throughout the brain (Fremeau et al, 2004), including BF. In the BF, vGluT2 is the predominant isoform (Hur and Zaborszky, 2005), including in BF glutamatergic neurons which project outside the BF to the cortex, lateral habenula, hypothalamus and other subcortical regions (Hur and Zaborszky, 2005; Henny and Jones, 2006, 2008; McKenna et al, 2015a; Agostinelli et al, 2016; Do et al, 2016). Strong optogenetic excitation of BF vGluT2+ neurons increased wakefulness (Xu et al, 2015), whereas weaker chemogenetic activation reduced cortical delta activity (Anaclet et al, 2015) suggesting that BF vGluT2+ neurons promote arousal.…”

mentioning

confidence: 99%

“…Strong optogenetic excitation of BF vGluT2+ neurons increased wakefulness (Xu et al, 2015), whereas weaker chemogenetic activation reduced cortical delta activity (Anaclet et al, 2015) suggesting that BF vGluT2+ neurons promote arousal. Furthermore, the caudal projections of BF vGluT2+ neurons to the lateral habenula and lateral hypothalamus are suggestive of a role in reward processing (Henny and Jones, 2006; McKenna et al, 2015a; Agostinelli et al, 2016; Brown et al, 2016; Do et al, 2016; Golden et al, 2016). However, the ionic and neurotransmitter mechanisms which regulate their activity remain to be elucidated.…”

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confidence: 99%

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Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro

2017

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The basal forebrain (BF) controls sleep-wake cycles, attention and reward processing. Compared to cholinergic and GABAergic neurons, BF glutamatergic neurons are less well understood, due to difficulties in identification. Here, we use vesicular glutamate transporter 2 (vGluT2)-tdTomato mice, expressing a red fluorescent protein (tdTomato) in the major group of BF glutamatergic neurons (vGluT2+) to characterize their intrinsic electrical properties and cholinergic modulation. Whole-cell, patch-clamp recordings were made from vGluT2+ neurons in coronal BF slices. Most BF vGluT2+ neurons were small/medium sized (<20 μm), exhibited moderately sized H-currents and had a maximal firing frequency of ∼50 Hz. However, vGluT2+ neurons in dorsal BF (ventral pallidum) had larger H-currents and a higher maximal firing rate (83 Hz). A subset of BF vGluT2+ neurons exhibited burst/cluster firing. Most vGluT2+ neurons had low-threshold calcium spikes/currents. vGluT2+ neurons located in ventromedial regions of BF (in or adjacent to the horizontal limb of the diagonal band) were strongly hyperpolarized by the cholinergic agonist, carbachol, a finding apparently in conflict with their increased discharge during wakefulness/REM sleep and hypothesized role in wake-promotion. In contrast, most vGluT2+ neurons located in lateral BF (magnocellular preoptic area) or dorsal BF did not respond to carbachol. Our results suggest that BF glutamatergic neurons are heterogeneous and have morphological, electrical and pharmacological properties which distinguish them from BF cholinergic and GABAergic neurons. A subset of vGluT2+ neurons, possibly those neurons which project to reward-related areas such as the habenula, are hyperpolarized by cholinergic inputs, which may cause phasic inhibition during reward-related events.

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Descending projections from the basal forebrain to the orexin neurons in mice

Cited by 29 publications

References 101 publications

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Distributions of hypothalamic neuron populations co-expressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse

Intrinsic membrane properties and cholinergic modulation of mouse basal forebrain glutamatergic neurons in vitro

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