Serotonin1A receptors in the dorsal hippocampus regulate working memory and long-term habituation in the hemiparkinsonian rats

doi:10.1016/j.bbr.2019.112207

Behavioural Brain Research

Volume 376, 30 December 2019, 112207

https://doi.org/10.1016/j.bbr.2019.112207 Get rights and content

Highlights

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dHPC injection of 5-HT_1A agonist impaired memories in sham and the lesioned rats.
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dHPC injection of 5-HT_1A antagonist improved memories in the lesioned rats.
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Activation or blockade dHPC 5-HT_1ARs changed monoamines levels in some brain regions.
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The lesion decreased 5-HT_1ARs and 5-HT_1ARs/ EAAC1 co-localization in the dHPC.

Abstract

Although the dorsal hippocampus (dHPC) and serotonin_1A (5-HT_1A) receptor are involved in cognition, their roles in cognitive impairments in Parkinson’ disease (PD) are still unclear. In the present study, the effects of the 5-HT_1A receptor agonist 8−OH-DPAT and antagonist WAY100635 administrated into the dHPC of rats were assessed in T-maze rewarded alternation test for working memory and in hole-board test for long-term habituation. Unilateral 6-hydroxydopamine (6−OHDA) lesions of the medial forebrain bundle in rats impaired working memory and long-term habituation, decreased dopamine (DA) levels in the medial prefrontal cortex (mPFC), dHPC and ventral hippocampus (vHPC), and decreased the mean density of 5-HT_1A receptors and co-localization of 5-HT_1A receptor and excitatory amino acid carrier 1-immunoreactive (EAAC1-ir) neurons in the dHPC compared to sham-operated rats. Activation of dHPC 5-HT_1A receptors by local infusion of 8−OH-DPAT impaired working memory and long-term habituation in both sham-operated and the 6−OHDA-lesioned rats. Furthermore, blockade of dHPC 5-HT_1A receptors by WAY100635 improved the memories in the 6−OHDA-lesioned rats, but had no effects in sham-operated rats. Additionally, dHPC injection of 8−OH-DPAT decreased noradrenaline (NA) levels, increased 5-HT levels in the mPFC, dHPC and vHPC in sham-operated and lesioned rats, while WAY100635 increased DA and NA levels only in lesioned rats. The results of the present study suggest that dHPC 5-HT_1A receptors regulate cognitive impairments in PD by changes of monoamines in the related brain regions.

Introduction

In Parkinson’s disease (PD), loss of nigral dopaminergic neurons and the resulting dopamine (DA) depletion in the striatum lead to altered neuronal activity. DA neurons originate from midbrain nuclei, including the retrorubral field, substantia nigra pars compacta (SNc), and ventral tegmental area (VTA) [1]. DA neurons densely innervate the dorsal and ventral striatum, and project to the hippocampus (HPC), prefrontal cortex cortical and other certain subregions. DA is a major catecholamine neurotransmitter in the mammalian brain and prominently involved in motor control, motivation, emotional, learning and memory [2].

Cognitive impairment is a common feature of PD, which can affect the patients’ quality of life. The most common symptoms in PD patients with mnemonic dysfunction is an impairment of executive functions including working memory [3]. Previous studies have shown cognitive impairments or unchanged cognitive behaviors in rats with 6-hydroxydopamine (6−OHDA) or 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions [[4], [5], [6]], recent evidence from our laboratory have shown that unilateral 6−OHDA lesions of the medial forebrain bundle (MFB) in rats induce impairment of working memory [7,8]. The typical pathology of PD is the degeneration of DA neurons of the substantia nigra. However, a wide body of evidence have suggested that degeneration of the nigrostriatal DA neurons causes abnormal serotonin (5-HT)-mediated neurotransmission within the brain in PD patients and animal models, including loss of 5-HT neurons, Lewy bodies within serotonergic raphe neurons and reduction of brain 5-HT level [9]. In addition, a recent study from our laboratory has found that activation and blockade of 5-HT₄ receptors in the lateral habenula improve working memory in unilateral 6−OHDA-lesioned parkinsonian rats [10]. From these findings, it is suggested that the brain 5-HT system is involved in the regulation of cognition in PD.

The 5-HT system consists of 14 receptor subtypes, which is involved in the regulation of cognition. The 5-HT_1A receptor is known to play an important role in learning and memory [11], and is a therapeutic target for memory deficits, such as cognitive dysfunction in schizophrenia, Alzheimer’s disease and epilepsy [[12], [13], [14]]. However, the effects of 5-HT_1A receptor on PD-related cognitive impairments are still unclear.

The HPC is a critical brain structure for learning, memory and cognition [15]. According to the gradients of gene expression, anatomical projections and functional characteristics, the HPC can be divided into separate zones along its rostral/caudal axis, including the dorsal HPC (dHPC), intermediate and ventral HPC (vHPC). Several lines of evidence have shown that the dHPC and vHPC have different functions, and the dHPC is more important in memory process [16]. The dHPC is innervated by 5-HT fibers from the midbrain dorsal and median raphe nuclei [17], and characterized by high concentration of 5-HT receptor binding sites, particularly the 5-HT_1A subtype. Although these findings strongly suggest that 5-HT_1A receptor and the dHPC may be involved in cognitive impairments in PD, the role and mechanism of dHPC 5-HT_1A receptors in cognitive impairments in parkinsonian rats are still unknown. Therefore, the aim of the present study was to observe (i) the effects of dHPC injection of 5-HT_1A receptor agonist 8−OH-DPAT and antagonist WAY100635 on working memory and long-term habituation measured by the T-maze rewarded alternation and hole-board tests in sham-operated rats and rats with complete unilateral 6−OHDA lesions of the MFB, (ii) the effects of dHPC 5-HT_1A receptors on monoamine levels including DA, noradrenaline (NA) and 5-HT in the related brain regions, and (iii) changes in the expression of 5-HT_1A receptors on glutamatergic neurons in the dHPC after lesioning of the MFB.

Section snippets

Animals and drugs

Male Sprague–Dawley rats (270–320 g) were used in the present study. All experiments were performed according to the National Institute of Health Guide for the Care and Use of Laboratory Animals, and approved by the Animal Care Committee of the University. All efforts were made to reduce experimental rat numbers and their suffering.

Desipramine hydrochloride, 6−OHDA hydrochloride, apomorphine hydrochloride, (2R)-(+)-8-Hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8−OH-DPAT; 5-HT_1A receptor

TH immunohistochemistry confirmed complete lesions in the SNc

In sham-operated rats, there was no significant loss of TH-positive neurons in the SNc and VTA in the ipsilateral side of saline injection compared to the contralateral side (P >  0.05, paired Student's t-test; Fig. 1B and D. In the 6−OHDA-lesioned rats, the SNc showed almost total loss of TH-ir neurons (99.6 ± 0.1%) on the 6−OHDA injected side compared to the contralateral side, and the number of TH-ir neurons in the VTA on lesioned side decreased significantly to 65.8 ± 0.9% of the

Discussion

PD is characterized by a massive degeneration of DA neurons in the midbrain. Rat models of PD have been widely used in which 6−OHDA was injected into either of SNc, MFB, or the caudate–putamen complex. Unilateral 6−OHDA lesions of MFB is one of the most widely used model of PD, which leads to degeneration of DA neurons in the SNc and VTA [28]. However, extensive bilateral MFB lesions cause severe motor symptomatology with akinesia, aphagia and adipsia in the rats, which has somewhat limited the

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by the Shaanxi International Scientific and Technological Cooperation and Exchange Program (2015KW-040), Shaanxi National Science Foundation (2019JM-439) and Xi’an Jiaotong University Innovation Fund for Undergraduate Research Training Practice (XJ201510698129 and SJ201610698097), China.

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In the present study, unilateral 6-OHDA lesions of the SNc in rats reduced the choice accuracy in the T-maze rewarded alteration test, indicating that depletion of DA induces working memory impairment. This finding is confirmed by our recent studies (Du et al., 2018; Guo et al., 2019; Liu et al., 2019), and supported by most previous reports showing that 6-OHDA or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesions of the nigrostriatal pathway in rats induce memory impairments as measured by different memory paradigms (Ciobica et al., 2012; Hsieh et al., 2012a, 2012b; Ramos-Moreno et al., 2012). However, a few studies have found that parkinsonian rats show unchanged cognitive behaviors (Branchi et al., 2008; Carvalho et al., 2013).
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Research reportSerotonin1A receptors in the dorsal hippocampus regulate working memory and long-term habituation in the hemiparkinsonian rats

Highlights

Abstract

Introduction

Section snippets

Animals and drugs

TH immunohistochemistry confirmed complete lesions in the SNc

Discussion

Declaration of Competing Interest

Acknowledgments

Trends Neurosci.

Exp. Neurol.

Neurobiol. Learn. Mem.

Neuropharmacology

Brain Res.

Neurosci. Biobehav. Rev.

Epilepsy Res.

Neuroscience

Exp. Neurol.

Neuropharmacology

Effects of the forced expression of BCL-X(L), Behav Brain Res

Neurosci. Biobehav. Rev.

Neurochem. Int.

Brain Res.

Exp. Neurol.

J. Neurosci. Methods

Neuropharmacology

Curr. Opin. Neurobiol.

Neuroscience

Neuropsychologia

Neuroscience

Prog. Neurobiol.

Neuroscience

Neuropsychopharmacology

Neuropharmacology

Brain Res.

Eur. J. Pharmacol.

Brain Res. Brain Res. Rev.

Neuropharmacology

Neuropharmacology

Eur. J. Pharmacol.

Neuropharmacology

Brain Res.

Eur. J. Pharmacol.

Research report
Serotonin_1A receptors in the dorsal hippocampus regulate working memory and long-term habituation in the hemiparkinsonian rats