Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

Zhang, Xiaoyang; Peng, Shi-Yu; Shen, Li-Ping; Zhuang, Qian-Xing; Li, Bin; Xie, Shutao; Li, Qian-Xiao; Shi, Ming-Run; Ma, Tian-Yu; Zhang, Qipeng; Wang, Jianjun; Zhu, Jing-Ning

doi:10.1073/pnas.2008456117

Cited by 44 publications

(29 citation statements)

References 54 publications

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“…In this context, it has been recently reported that stress‐evoked HA signalling recruits a presynaptic gain control mechanism at glutamatergic synapses in the NAc, an effect that is mediated by H3R (Manz et al., 2021). Moreover, it has been demonstrated that activation of the histaminergic afferent system, particularly the histamine H3R, inhibits glutamatergic synaptic transmission in the circuit from the prelimbic prefrontal cortex to the NAc and improves both anxiety‐ and obsessive‐compulsive‐like behaviours induced by restraint stress (Zhang et al., 2020). The H2R‐dependent enhancement of MSN excitability we observed in this study could conceivably represent another mechanism by which elevated extracellular histamine levels, following acute stress, may induce stress‐dependent decisional strategies.…”

Section: Discussionmentioning

confidence: 99%

Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens

Aceto

Nardella

Nanni

et al. 2022

The Journal of Physiology

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Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole‐cell patch‐clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half‐width. The increased excitability was protein kinase A‐dependent and associated with decreased A‐type K+ currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A‐type K+ currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R‐dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal‐induced behaviours. Key points Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole‐brain activity including the nucleus accumbens. Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A. Whole‐cell patch‐clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A‐dependent mechanisms. HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after‐hyperpolarization and increased the action potential half‐width. HR2 activation also reduced A‐type potassium current. Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation.

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Section: Discussionmentioning

confidence: 99%

Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens

Aceto

Nardella

Nanni

et al. 2022

The Journal of Physiology

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“…In the present study, a quinpirole (QNP)-induced OCD rat model was adopted, and the open field test (OFT) relevant to compulsive checking behavior and the elevated plus maze (EPM) were used for the behavioral assessment (Szechtman et al, 1998(Szechtman et al, , 2017Hoffman, 2011). Given that the core of the NAc mediates the control of goal-oriented behaviors and obsessive-compulsive-like behaviors (Di Chiara, 2002;Zhang et al, 2020), micro-electrodes were implanted into the NAc core for stimulation and recording. Then SPK signals were recorded to obtain information about neuronal firing patterns, including the firing rate and indicators of interspike interval (ISI), including the coefficient of variance (CV) and asymmetry index (AI) (Alam et al, 2012(Alam et al, , 2015.…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic mechanism of deep brain stimulation of the nucleus accumbens in obsessive-compulsive disorder

Shi

Wang

Xiao

et al. 2023

Front. Cell. Neurosci.

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Deep brain stimulation (DBS) of the nucleus accumbens (NAc) (NAc-DBS) is an effective solution to refractory obsessive-compulsive disorder (OCD). However, evidence for the neurobiological mechanisms of OCD and the effect of NAc-DBS is still lacking. One hypothesis is that the electrophysiological activities in the NAc are modulated by DBS, and another hypothesis is that the activities of neurotransmitters in the NAc are influenced by DBS. To investigate these potential alterations, rats with quinpirole (QNP)- induced OCD were treated with DBS of the core part of NAc. Then, extracellular spikes (SPK) and local field potentials (LFP) in the NAc were recorded, and the levels of relevant neurotransmitters and related proteins were measured. Analysis of SPK revealed that the firing rate was decreased and the firing pattern was changed after NAc-DBS, and analysis of LFP showed that overall power spectral density (PSD) levels were reduced after NAc-DBS. Additionally, we found that the relative powers of the theta band, alpha band and beta band were increased in OCD status, while the relative powers of the delta band and gamma band were decreased. This pathological pattern of power distribution was reformed by NAc-DBS. Furthermore, we found that the local levels of monoamines [dopamine (DA) and serotonin (5-HT)] and amino acids [glutamate (Glu) and gamma-aminobutyric acid (GABA)] in the NAc were increased in OCD status, and that the expression of the two types of DA receptors in the NAc exhibited an opposite change. These abnormalities could be reversed by NAc-DBS. These findings provide a more comprehensive understanding about the function of the NAc in the pathophysiology of OCD and provide more detailed evidence for the potential effect of NAc-DBS.

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“…This suggests that as parts of the brain reward system, the right and left NAcc function reflects how individuals respond to cues that signal a potential reward [1]. The right and left NAcc have also been implicated in obesity [2,6], food addiction [7], tobacco, alcohol, and drug-seeking behaviors [8][9][10], obsessive-compulsive disorder [11,12], depression [13], and anxiety [12].…”

Section: Introductionmentioning

confidence: 99%

Parental Education, Ethnicity, and Functional Connectivity between Nucleus Accumbens and Frontoparietal Network

Assari¹

2022

Parenting - Challenges of Child Rearing in a Changing Society

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While studies have indicated an association between socioeconomic status (SES) and neuroimaging measures, weaker SES effects are shown for Blacks than Whites. This is, in part, due to processes such as stratification, racism, minoritization, and othering of Black people in the United States. However, less is known about Latino youth. This study had two aims: First, to test the association between parental education and the right and left nucleus accumbens (NAcc) resting-state functional connectivity with the frontoparietal network (FPN) in children; and second, to investigate ethnic heterogeneity in this association. This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) study. We analyzed the resting-state functional connectivity data (rsFC) of 10,840 US preadolescents who were between 9 and 10 years old. The main outcomes were the NAcc resting-state functional connectivity with FPN separately calculated for right and left hemispheres. Parental education was our independent variable. Family structure, sex, and age were covariates. Furthermore, ethnicity (Latino vs. non-Latino) was regarded as the moderator. We used mixed-effects regression for data analysis with and without interaction terms between parental education and ethnicity. Most participants (n = 8690; 80.2%) were non-Latino and 2150 (19.8%) were Latino. Parental education was associated with higher right and left NAcc resting-state functional connectivity with FPN. Ethnicity showed statistically significant interactions with parental education, suggesting that the positive associations between parental education and right and left NAcc resting-state functional connectivity with FPN were different in non-Latino and Latino children. For right hemisphere, we found significantly stronger and for left hemisphere, we found significantly weaker association for Latino compared with non-Latino preadolescents. Preadolescents’ NAcc resting-state functional connectivity with FPN depends on the intersections of ethnicity, parental education, and laterality.

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Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors

Cited by 44 publications

References 54 publications

Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens

Activation of histamine type 2 receptors enhances intrinsic excitability of medium spiny neurons in the nucleus accumbens

Potential therapeutic mechanism of deep brain stimulation of the nucleus accumbens in obsessive-compulsive disorder

Parental Education, Ethnicity, and Functional Connectivity between Nucleus Accumbens and Frontoparietal Network

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