Elsevier

Neuropharmacology

Volume 58, Issues 4–5, March–April 2010, Pages 746-757
Neuropharmacology

Chronic stress enhances synaptic plasticity due to disinhibition in the anterior cingulate cortex and induces hyper-locomotion in mice

https://doi.org/10.1016/j.neuropharm.2009.12.011Get rights and content

Abstract

The anterior cingulate cortex (ACC) is involved in the pathophysiology of a variety of mental disorders, many of which are exacerbated by stress. There are few studies, however, of stress-induced modification of synaptic function in the ACC that is relevant to emotional behavior. We investigated the effects of chronic restraint stress (CRS) on behavior and synaptic function in layers II/III of the ACC in mice. The duration of field excitatory postsynaptic potentials (fEPSPs) was longer in CRS mice than in control mice. The frequency of miniature inhibitory postsynaptic currents (mIPSCs) recorded by whole-cell patch-clamping was reduced in CRS mice, while miniature excitatory postsynaptic currents (mEPSCs) remained unchanged. Paired-pulse ratios (PPRs) of the fEPSP and evoked EPSC were larger in CRS. There was no difference in NMDA component of evoked EPSCs between the groups. Both long-term potentiation (LTP) and long-term depression of fEPSP were larger in CRS mice than in control mice. The differences between the groups in fEPSP duration, PPRs and LTP level were not observed when the GABAA receptor was blocked by bicuculline. Compared to control mice, CRS mice exhibited hyper-locomotive activity in an open field test, while no difference was observed between the groups in anxiety-like behavior in a light/dark choice test. CRS mice displayed decreased freezing behavior in fear conditioning tests compared to control mice. These findings suggest that CRS facilitates synaptic plasticity in the ACC via increased excitability due to disinhibition of GABAA receptor signalling, which may underlie induction of behavioral hyper-locomotive activity after CRS.

Introduction

Dysfunction of the anterior cingulate cortex (ACC) is a feature of multiple mental disorders, such as depression (Yucel et al., 2008, Schlösser et al., 2008), post-traumatic stress disorder (PTSD) (Hamner et al., 1999, Woodward et al., 2006), and attention deficit hyperactivity disorder (ADHD) (Bush et al., 2005, Pliszka, 2007). The etiology of psychiatric disorders involves interactions between genetic background and life experience. Exposure to stress, both physical and psychological, is a critical factor underlying the severity of mental disorders. The impacts of stress have therefore been studied extensively in human mental illness, as well in animal models of psychiatric disorders. A number of studies have focused on the modification of synaptic function by stress in the limbic system (Moghaddam, 2002), specifically in the hippocampus and amygdala (McEwen, 1994, de Kloet et al., 1999, LeDoux, 2000, Diamond et al., 2007).

Relatively few studies have focused on the effects of stress on the medial prefrontal cortex (mPFC), which includes the ACC. Research in this area is mainly limited to morphological and neurochemical investigations. Glucocorticoid administration or chronic behavioral stress have been shown to lead to dendritic reorganization of pyramidal neurons in layer II/III of the mPFC, an area with high levels of GABAA receptors (Bowery et al., 1987, Wellman, 2001, Radley et al., 2004, Cerqueira et al., 2007). Exposure to stressors also increases the release of glutamate, acetylcholine and dopamine (DA) in the mPFC (Moghaddam, 1993, Jedema and Moghaddam, 1994, Feenstra et al., 1998). Post-weaning social isolation stress is associated with increased locomotor activity (Fone and Porkess, 2008) and decreased benzodiazepine-specific binding sites in the cerebral cortex of rats (Petkov and Yanev, 1982). In rats, following early maternal deprivation, the responsiveness of adult mPFC neurons to pharmacological manipulations of the GABAergic system is altered (Stevenson et al., 2008). These studies support stress-induced alteration of GABAergic function that modifies synaptic activities in the ACC, leading to behavioral changes. In the hypothalamus, restraint stress suppresses the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in the paraventricular nucleus of the rat (Verkuyl et al., 2005). Inhibitory postsynaptic potentials (IPSPs) in pyramidal neurons of the basolateral amygdala are also reduced in rats subjected to stress (Isoardi et al., 2007).

The mechanism underlying stress-induced changes in ACC function, including changes in plasticity, has yet to be investigated at the synaptic level. In the present study, therefore, we examined both physiological and behavioral changes after subjecting mice to chronic restraint stress (CRS). These experiments sought to examine stress-induced modifications of synaptic function in the ACC, with a focus on GABAergic function and synaptic plasticity.

Section snippets

Animals and CRS

Three-week-old male C57BL/6J mice were obtained from Japan SLC (Hamamatsu Japan). Mice were randomly assigned to two groups: control (no-stress) or CRS. Two to four mice were housed per cage with food and water ad libitum. After a 7-day habituation period, each mouse in the CRS group (CRS mice) was subjected to restraint stress. Specifically, each CRS mouse was immobilized (2 h/day, 7 consecutive days) in a perforated 50 ml plastic centrifuge tube that restrains movement but allows ventilation.

Effect of CRS on organ weights

CRS mice gained significantly less body weight over the 7 days of CRS exposure than the control mice (Table 1). The mean body weight of CRS mice was not significantly different from control mice on days 1 or 3, but was significantly less on days 5 and 7. In addition, the adrenal glands were significantly larger in the CRS mice, while the thymuses from CRS mice were significantly smaller (Table 1) than in controls.

Input–output relationship of fEPSPs

Extracellular field recordings were collected to examine synaptic function. There

Discussion

In the present study, mice exposed to chronic restraint stress gained significantly less body weight with a concurrent increase in adrenal gland weight and reduction in thymus weight compared to control mice. Such alterations are commonly associated with chronic stress (Moraska et al., 2000). CRS exposure also induced both physiological and behavioral changes in mice. Short-term and long-term synaptic plasticity were enhanced in the ascending pathway of the ACC in CRS mice, likely as a result

Acknowledgements

The authors thank Drs. Fumihito Saitow, Susumu Ito and Koichi Yoshioka for their invaluable comments on the manuscript, and Tomohiko Hata for his technical expertise. This work was funded in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan, to TM.

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