Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Mar 15;89(6):588-599.
doi: 10.1016/j.biopsych.2020.07.023. Epub 2020 Aug 6.

Histamine H3 Receptor Function Biases Excitatory Gain in the Nucleus Accumbens

Kevin M Manz  1 , Jennifer C Becker  2 , Carrie A Grueter  3 , Brad A Grueter  4
Affiliations

Histamine H3 Receptor Function Biases Excitatory Gain in the Nucleus Accumbens

Kevin M Manz et al. Biol Psychiatry. .

Abstract

Background: Histamine (HA), a wake-promoting monoamine implicated in stress-related arousal states, is synthesized in histidine decarboxylase-expressing hypothalamic neurons of the tuberomammillary nucleus. Histidine decarboxylase-containing varicosities diffusely innervate striatal and mesolimbic networks, including the nucleus accumbens (NAc). The NAc integrates diverse monoaminergic inputs to coordinate motivated behavior. While the NAc expresses various HA receptor subtypes, mechanisms by which HA modulates NAc circuit dynamics are undefined.

Methods: Using male D1tdTomato transgenic reporter mice, whole-cell patch-clamp electrophysiology, and input-specific optogenetics, we employed a targeted pharmacological approach to interrogate synaptic mechanisms recruited by HA signaling at glutamatergic synapses in the NAc. We incorporated an immobilization stress protocol to assess whether acute stress engages these mechanisms at glutamatergic synapses onto D1 receptor-expressing [D1(+)] medium spiny neurons (MSNs) in the NAc core.

Results: HA negatively regulates excitatory gain onto D1(+)-MSNs via presynaptic H3 receptor-dependent long-term depression that requires Gβγ-directed Akt-GSK3β signaling. Furthermore, HA asymmetrically regulates glutamatergic transmission from the prefrontal cortex and mediodorsal thalamus, with inputs from the prefrontal cortex undergoing robust HA-induced long-term depression. Finally, we report that acute immobilization stress attenuates this long-term depression by recruiting endogenous H3 receptor signaling in the NAc at glutamatergic synapses onto D1(+)-MSNs.

Conclusions: Stress-evoked HA signaling in the NAc recruits H3 heteroreceptor signaling to shift thalamocortical input onto D1(+)-MSNs in the NAc. Our findings provide novel insight into an understudied neuromodulatory system within the NAc and implicate HA in stress-associated physiological states.

Keywords: Glutamatergic transmission; Histamine; Histamine H3 receptor; Nucleus accumbens; Stress; Synaptic plasticity.

PubMed Disclaimer

Conflict of interest statement

Financial Disclosures

All authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.. HA recruits a gain control mechanism that differentially modulates glutamatergic transmission onto D1(+) and D1(−) MSNs in the NAc core.
(A) Schematic of sagittal mouse brain slice depicting electrophysiological recording location in the dorsomedial NAc core. (B) Representative experiment and traces (above) of EPSCs obtained at baseline and in the presence of HA (10 μM) from tdTomato-expressing [D1(+)] MSNs. (C) Representative experiment and traces (above) of EPSCs obtained at baseline and in the presence of HA (10 μM) from tdTomato-negative [D1(−), putative D2] MSNs. Scale bars: 100 pA/50-ms. (D) Time-course summary of normalized EPSCs in D1(+) MSNs depicting the HA-induced depression in EPSC amplitude that persists post-drug wash out [64.55±4.03%, n=10, p<0.0001]. (E) Time-course summary of normalized EPSCs in D1(−) MSNs depicting a modest HA-induced depression in EPSC amplitude that returns to baseline [92.94±4.47%, n=7, p=0.126]. (F) Average EPSC amplitude in D1(+) (blue circles) and D1(−) MSNs (open circles) obtained at t(gray)= 45–50-min [2-way RM-ANOVA, effect of MSN subtype, F(3,27)=35.95, Sidak’s post-hoc analysis, p<0.0001]. (G) Representative traces from D1(+) MSNs showing EPSPs and APs obtained following 1, 5, 10, 20 and 30 Hz stimulation of glutamatergic synapses in ACSF and HA-superfused slices Scale bars: 20 mV/20-ms. (H) Input-output gain curve with AP probability (y-axis) plotted as a function of input frequency (x-axis) in ACSF and HA. (I) Average AP probability obtained at 30 Hz in ACSF (open bar) and HA (closed green bar). (J) Gain of EPSCs in ACSF (open bar) and HA (closed green bar) [PAP 30 Hz ACSF: 0.921±0.039, n=16; PAP 30 Hz HA: 0.453±0.055, n=16, p<0.001; Gain ACSF: 0.029±0.001, n=16; Gain HA: 0.017±0.002, n=16, p<0.001]. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 2.
Figure 2.. HA decreases glutamatergic synaptic efficacy onto D1(+) MSNs via a presynaptic locus of action.
(A) Representation traces of 50-ms ISI paired-pulse EPSCs obtained in D1(+) (blue circles) and D1(−) MSNs (open circles) at baseline and following HA (10 μM) bath-application with light-blue shaded region indicating ΔPPR. Scale bars [D1(+)]: 50-pA, 100-pA/50-ms. Scale bars [D1(−)]: 50-pA/50-ms. (B) Average PPR obtained at baseline and post-HA at t(gray)= 45–50-min in D1(+) and D1(−) MSNs [D1(+) PPR baseline: 1.12±0.05, D1(+) PPR HA: 1.33±0.07, n=11, p=0.007; D1(−) PPR baseline: 1.24±0.06, D1(−) PPR HA: 1.31±0.06, n=8, p=0.187]. (C) Average coefficient of variance (CV) of EPSCs obtained during 10-min baseline and post-HA at t(gray)= 45–50-min in D1(+) and D1(−) MSNs [D1(+) CV baseline: 0.11±0.01, n=5, D1(+) CV HA: 0.17±0.02, n=5, p=0.012;; D1(−) CV baseline: 0.15±0.007, CV HA: 0.146±0.006, n=5, p=0.483]. (D) Representative traces of sEPSCs in D1(+) (blue traces) and D1(−) MSNs (black traces) in ACSF alone and in HA-containing ACSF. Scale bars: 20 pA/1-s. (E) Average sEPSC frequency (Hz) and amplitude (pA) in D1(+) (blue bars) and D1(−) (open bars) in ACSF alone and in the presence of HA [sEPSC frequency = D1(+) baseline: 1.97±0.304 Hz, n=13 D1(+) HA: 0.80±0.09 Hz, n=10, p<0.001; D1(−) baseline: 1.54±0.316 Hz, n=11, D1(−) HA: 1.29±0.15 Hz, n=8, p=0.483; sEPSC amplitude = D1(+) baseline: −18.8±1.09 pA, n=13, D1(+) HA: −19.49±1.48 pA, n=10, p=0.3524; D1(−) baseline: −18.99±1.04 pA, n=11, D1(−) HA: −20.34±1.99 pA, n=8, p=0.2483. (F) Representative traces of optically-evoked RuBi-Glu EPSCs (RuBi-Glu oEPSCs) in D1(+) and D1(−) MSNs at baseline and in the presence of HA. Superimposed traces show that AMPAR-antagonist, NBQX, abolishes RuBi-Glu oEPSCs in both MSNs. Scale bars: 20-pA/50-ms. (G) Time-course summary of RuBi-Glu oEPSCs in D1(+) (blue circles) and D1(−) MSNs (open circles) showing that HA has no effect on RuBi-Glu oEPSC amplitude. (H) Average RuBi-Glu oEPSC amplitude obtained at t(gray) = 15–20-min in D1(+) and D1(−) MSNs [D1(+): 101.26±1.96, n=4, p=0.5113; D1(−) 99.65±2.99%, n=4, p=0.899]. (I) Representative traces of eEPSCs obtained from D1(+) MSNs postsynaptically-loaded with GDPβS at baseline and in the presence of HA. Scale bars: 100-pA/50-ms (J) Time-course summary of EPSCs in D1(+) MSNs showing the inhibitory actions of HA remain intact in GDPβS-loaded cells. (K) Quantification of average EPSC amplitude pre- and post-HA in GDPβS-loaded cells at t(gray) = 45–50-min [HA GDPβS: 75.39±13.04%, n=6, p<0.001]. (L) Average PPR pre- and post-HA in GDPβS-loaded cells [PPR = pre-HA: 1.20±.043, post-HA: 1.38±0.08, n=8, p=0.0163]. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 3.
Figure 3.. HA acts via H3 heteroreceptors to elicit long-term depression of glutamatergic transmission onto D1(+) MSNs.
(A) Representative traces (left) and normalized time-course summary of EPSCs obtained in D1(+) MSNs (blue circles) showing the effects of HA in the presence of H1R antagonist, cetirizine (CTZ) [D1(+) HA: 58.12±2.60%, n=6, p=0.247]. (B) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of H2R antagonist, ranitidine [D1(+) HA: 67.11±3.76%, n=6, p=0.656]. (C) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing that imidazole or non-imidazole H3R antagonists, thioperamide (black) and JNJ 5207852 (green), respectively, completely block the effects of HA [D1(+) HA in thioperamide: 100.98±2.24%, n=5, p=0.005; HA in JNJ: 104.46±3.02%, n=4, p<0.001]. (D) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of selective H3R agonist, R-(−)-α-methylhistamine (RAMH) [D1(+) RAMH: 71.06±2.16%, n=9, p<0.001]. (E) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA chased with H3R antagonist, thioperamide [: D1(+) HA: 66±3.70, D1(+) thioperamide chase: 79.68±4.86%, n=9, p=0.002]. (F) Average EPSC amplitude in D1(+) MSNs obtained at baseline, t(grey) = 25–30-min, and t(blue) = 45–50-min. (G) Summary table of average EPSC amplitude at D1(+) MSNs following each pharmacological treatment. Scale bars: 100 pA/20-ms. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 4.
Figure 4.. H3R activity tonically regulates glutamatergic synapses onto D1(−) MSNs but not D1(+) MSNs.
(A) Representative traces (left) and experiments of EPSCs in D1(+) MSNs depicting the effects of H3R antagonist, JNJ 5207852. (B) Time-course summary of EPSCs during bath-application of imidazole or non-imidazole H3R antagonists, thioperamide (black) and JNJ 5207852 (green), respectively [D1(+) JNJ: 100.02±3.33%, n=8, p=0.497; D1(+) in thioperamide: 95.69±1.49%, n= 4, p=0.065]. (C) Quantification of average EPSC amplitude in D1(+) MSNs at baseline in the presence of thioperamide or JNJ 5207852 at t(grey) = 45–50-min. (D) PPR in D1(+) MSNs at baseline and in the presence of thioperamide (black) or JNJ 5207852 (green) [D1(+) PPR baseline: 1.92±0.07, D1(+) PPR H3R antagonist: 1.22±0.05, n=11, p=0.309]. (E) Representative traces (left) and experiments of EPSCs in D1(−) MSNs depicting the effects of H3R antagonist, JNJ 5207852. (F) Time-course summary of EPSCs during bath-application of H3R antagonists, thioperamide (black) and JNJ 5207852 (open) in D1(−) MSNs [D1(−) JNJ: 134.72±4.06%, n=7, p<0.001; D1(−) in thioperamide: 128.10±6.57%, n=7, p=0.005]. (G) Quantification of average EPSC amplitude in D1(−) MSNs at baseline in the presence of thioperamide or JNJ 5207852 at t(grey) = 45–50-min. (H) PPR in D1(+) MSNs at baseline and in the presence of thioperamide (black) or JNJ 5207852 (open) [D1(−) PPR baseline: 1.42±0.05, D1(−) PPR H3R antagonist: 1.24±0.06, n=15, p<0.001]. Scale bars: 50-pA/20-ms. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 5.
Figure 5.. Gβγ-dependent recruitment of the Akt-GSK3β axis mediates HA-LTD at glutamatergic synapses onto D1(+) MSNs.
(A) Representative traces (left) and normalized time-course summary of EPSCs obtained in D1(+) MSNs (green circles) showing the effects of HA in slices incubated in Ca2+ chelator, BAPTA-AM [HA in BAPTA-AM: 60.02±3.74%, n=7, 1-way ANOVA, F(7,44)=13.78, Sidak’s post-hoc analysis, ACSF vs. BAPTA-AM, p=0.935)]. (B) Representative traces (left) and normalized time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of AC activator, forskolin [D1(+) HA in forskolin: 65.80±4.81%, n=7, 1-way ANOVA, ACSF vs. FSK, p=0.999]. (C) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of PKA inhibitor, H89 [: D1(+) HA in H89: 67.12±3.76%, n=6, 1-way ANOVA, ACSF vs. H89, p=0.997]. (D) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of Gβγ inhibitor, gallein [D1(+) HA in gallein: 94.38±4.51%, 1-way ANOVA, ACSF vs. gallein, n=6, p<0.001]. (E) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of Akt-1/2 inhibitor, Akti1/2 [D1(+) HA in Akti1/2 : 91.38±3.01%, 1-way ANOVA, ACSF vs. Akti1/2, n=4, p<0.001]. (F) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of MAPK (MEK1/2) inhibitor, U0126 [D1(+) HA in U0126: 87.02±5.99%, 1-way ANOVA, ACSF vs. U0126, n=6, p=0.002]. (G) Representative traces (left) and time-course summary of EPSCs obtained in D1(+) MSNs showing the effects of HA in the presence of GSK-3 inhibitor, CHIR 99021 [: D1(+) HA in CHIR 99021: 92.45±3.45%, 1-way ANOVA, ACSF vs. CHIR, n=6, p<0.001]. (H) Quantification of average HA-induced depression during each pharmacological manipulation at t(grey) = 45–50-min. Scale bars: 100-pA/20-ms. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 6.
Figure 6.. Thalamocortical drive onto D1(+) MSNs in the NAc is differentially regulated by HA signaling.
(A) Schematic of (1) stereotaxic delivery of ChR2-eYP-harboring viral vectors into the medial PFC of D1tdTomato mice; (2) patch-clamp recordings in NAc core D1(+) MSNs of mice expressing ChR2 in the PFC (purple). (B) Representative traces (above) and time-course summary of optically-evoked EPSCs (oEPSCs) from the PFC at baseline and in the presence of HA (closed circles) and HA in thioperamide (open circles) in D1(+) MSNs [PFC-to-D1(+) HA: 60.66±4.79%, n=10, p<0.001]. Scale bars (PFC): 50-pA/20-ms. (C) Representative traces and time-course summary of oEPSCs from the PFC at baseline and in the presence of BAC (3 μM). Scale bars: 50-pA/20-ms (D) Schematic of (1) stereotaxic delivery of ChR2-eYP-harboring viral vectors into the MDT of D1tdTomato mice; (2) patch-clamp recordings in NAc core D1(+) MSNs of mice expressing ChR2 in the MDT (red). (E) Representative traces (above) and time-course summary of optically-evoked EPSCs (oEPSCs) from the MDT at baseline and in the presence of HA (closed red circles) and HA+ thioperamide (open circles) in D1(+) MSNs [MDT-to-D1(+) HA: 80.25±5.15%, n=6, p<0.001; 1-way RM-ANOVA, input effect: F3,28 = 39.4, p=0.0017, Sidak’s post-hoc analysis]. (F) Representative traces (above) and time-course summary MDT oEPSCs obtained in D1(+) MSNs showing the effects of BAC on oEPSC amplitude. Scale bars (MDT): 100-pA/20-ms. (G) Average oEPSC amplitude at PFC- and MDT-to-NAc D1(+) MSN synapses obtained at t(grey) = 45–50-min post-HA and post-HA + thioperamide. (H) Average BAC-induced oEPSC amplitude at PFC- and MDT-to-NAc D1(+) MSN synapses obtained at t(grey) = 25–30-min [PFC-to-D1(+) BAC: 27.49±4.6%, n=6, p<0.001; MDT-to-D1(+) BAC: 30.10±5.28%, n=7, p<0.001; 1-way ANOVA, input effect: F3,22 = 158, p=0.994]. Error bars indicate SEM with (*) signifying p < 0.05.
Figure 7.
Figure 7.. Acute immobilization stress recruits endogenous H3R signaling at glutamatergic synapses onto D1(+) MSNs in the NAc core.
(A) Schematic depicting 30-min acute immobilization stress (AIS) paradigm and recording strategy in D1(+) MSNs of control (open circles) and AIS-exposed D1tdTomato mice (green circles), (B) Time-course summary of electrically-evoked EPSCs in control homecage mice and AIS-exposed mice depicting the effects of HA at synapses onto D1(+) MSNs in the NAcC [D1(+) HA control: 61.48±3.64%, n=5, N(animals)=4; D1(+) HA AIS: 87.88±4.13%, n=7, N(animals)=5, p<0.001]. (C) Time-course summary of EPSCs in control mice (left) and AIS-exposed mice (right) depicting the effects of H3R agonist, RAMH, at synapses onto D1(+) MSNs [D1(+) RAMH control: 66.78±3.61%, n=7, N (animals)=4; D1(+) RAMH AIS: 93.08±7.13%, n=7, N(animals)=5, p=0.004]. (D) Average HA and RAMH-induced EPSC amplitude obtained at t(gray) = 45–50 min in control and AIS-exposed mice. (E) Schematic depicting prophylactic treatment with water-soluble non-imidazole H3R antagonist, JNJ 5207852, or vehicle (saline) prior to AIS exposure. (F) Time-course summary of EPSCs in D1(+) MSNs of vehicle-treated (open squares) AIS-exposed mice. (G) Time-course summary of EPSCs in D1(+) MSNs of JNJ 5207852-treated (green squares) AIS-exposed mice [D1(+) HA-VEH: 85.61±4.82%, n=10, N(animals)=5; D1(+) HA-JNJ: 66.85±5.38%, n=7, N(animals)=6, p=0.008]. (H) Average HA-induced EPSC amplitude obtained at t(gray) = 45–50 min in vehicle vs. JNJ 5207852-treated AIS-exposed mice. (I) Schematic depicting intra-NAc microinfusion of 3.86 μg/μL JNJ 5207852 or vehicle prior to AIS exposure. (J) Time-course summary of EPSCs in D1(+) MSNs of intra-NAc vehicle-infused (open squares) AIS-exposed mice. (K) Time-course summary of EPSCs in D1(+) MSNs of JNJ 5207852-infused (green squares) AIS-exposed mice [Fig. 8j-l: HA-VEH: 95.35±5.62%, n=4, N(animals)=2; HA-JNJ: 73.65±6.14%, n=8, N(animals)=4, p=0.0481]. (L) Average HA-induced EPSC amplitude obtained at t(gray) = 35–40 min in intra-NAc vehicle vs. JNJ 5207852-infused AIS-exposed mice. Error bars indicate SEM with (*) signifying p < 0.05.
See this image and copyright information in PMC

References

    1. Bunney BS, Aghajanian GK (1975): Evidence for drug actions on both pre- and postsynaptic catecholamine receptors in the CNS. Psychopharmacol Bull 11: 8–10. - PubMed
    1. Passani MB, Blandina P (2011): Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol Sci 32: 242–249. - PubMed
    1. Yu X, Ye Z, Houston CM, Zecharia AY, Ma Y, Zhang Z, et al. (2015): Wakefulness Is Governed by GABA and Histamine Cotransmission. Neuron 87: 164–178. - PMC - PubMed
    1. Takagi H, Morishima Y, Matsuyama T, Hayashi H, Watanabe T, Wada H (1986): Histaminergic axons in the neostriatum and cerebral cortex of the rat: a correlated light and electron microscopic immunocytochemical study using histidine decarboxylase as a marker. Brain Res 364: 114–123. - PubMed
    1. Shoblock J, O’Donnell P (2000): Histamine Modulation of Nucleus Accumbens Neurons. Annals of the New York Academy of Sciences 909: 270–2. - PubMed

Publication types

LinkOut - more resources