Chronic cerebral hypoperfusion-induced memory impairment and hippocampal long-term potentiation deficits are improved by cholinergic stimulation in rats

Highlights

• PBOCCA is a model of vascular dementia in rats.

• PBOCCA in rats leads to learning and memory dysfunctions.

• Cholinergic stimulation attenuated PBOCCA induced cognitive deficits.

• Cholinergic activation reversed LTP impairment induced by PBOCCA.

Abstract

Background

Chronic cerebral hypoperfusion (CCH) can induce the accumulation of reactive oxygen species, which leads to oxidative damage, neuronal injury, and central cholinergic dysfunction in vulnerable regions of the brain, such as the hippocampus and cerebral cortex. These effects can lead to significant cognitive impairments in clinical populations of vascular dementia (VaD). The present studies aimed to investigate the role of the cholinergic system in memory functions and hippocampal long-term potentiation (LTP) impairments induced by CCH in rats.

Methods

Male Sprague Dawley rats were subjected to permanent bilateral occlusion of common carotid arteries (PBOCCA) or sham surgery. Then, PBOCCA rats received ip injections with, either vehicle (control group), the muscarinic receptor agonist oxotremorine (0.1 mg/kg), or the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg). Cognitive functions were evaluated using a passive avoidance task and the Morris water maze test. In addition, hippocampal LTP was recorded in vivo under anaesthesia.

Results

The PBOCCA rats exhibited significant deficits in passive avoidance retention and spatial learning and memory tests. They also showed a suppression of LTP formation in the hippocampus. Oxotremorine and physostigmine significantly improved the learning and memory deficits as well as the suppression of LTP in PBOCCA rats.

Conclusions

The present data suggest that the cholinergic system plays an important role in CCH-induced cognitive deficits and could be an effective therapeutic target for the treatment of VaD.

Introduction

Dementia is a syndrome related to a general decline in cognition and memory functions. Alzheimer’s disease (AD), the most common form of dementia, manifests by the accumulation of amyloid plaques and neurofibrillary tangles in the brain [1]. Vascular demencia (VaD), the second most prevalent type of dementia after AD, results from various types of vascular-related diseases. The incidence rate of VaD has been reported to be 6–12 cases per 1000 people over 70 years of age annually [2,3]. Risk factors, such as advanced age, hypertension, high blood cholesterol, and arteriosclerosis, cause moderate cerebral hypoperfusion and ischemic brain injuries, which lead to progressive decline in cognitive and memory functions, as observed in VaD and AD [4,5].

Chronic cerebral hypoperfusion (CCH) is a condition of reduced cerebral blood flow in the brain, which can induce the accumulation of reactive oxygen species (ROS) and the deprivation of glucose and oxygen, which are vital for normal cellular functioning and the survival of brain tissue. A sustained reduction of cerebral blood flow may initiate a cascade of neuropathological events, such as microglial activation, neurodegeneration, and cholinergic dysfunction that are thought to contribute to the cognitive impairment observed in AD and VaD [6,7]. In our previous studies, we employed a PBOCCA rat model to study the time course of behavioural functions after CCH. Our data have shown that PBOCCA effectively impaired cognitive functions without affecting basic motor function over the course of 4 weeks period. Thus, this model provides a valuable approach to discover the potential neuroprotective strategies against CCH-induced learning and memory impairments [8].

Numerous pharmacological studies have supported a crucial role of acetylcholine (ACh) in cognition by demonstrating that drugs known to interfere with cholinergic transmission impair cognitive performance [[9], [10], [11]], while cholinergic agonists such as physostigmine, an acetylcholinesterase (AChE) inhibitor, or oxotremorine, a muscarinic receptor agonist, can improve cognitive functions or reverse cognitive deficits in humans and non-human species [[12], [13], [14], [15]]. ACh is easily metabolized into choline and acetate by the enzyme AChE and other non-specific esterases. Hence, inhibition of these enzymes will provide a potential way of increasing the amount of ACh in the synapse and helping to restore cholinergic function in AD patients. Physostigmine, an AChE inhibitor is known to augment the amount of ACh available in the synaptic cleft. Another approach to cholinergic therapy is the targeting of cholinergic receptors. Direct receptor activation may improve cognitive performance. In addition, degeneration of basal forebrain cholinergic neurons (BFCN), which widely innervate the hippocampus and neocortex, has been linked to cognitive impairments occurring in VaD and AD [16,17].

LTP is a long-lasting enhancement of synaptic strength induced by repetitive high frequency stimulation of the pre-synaptic terminal. Thereby, the Schaffer collateral of the CA3 area of the hippocampus is stimulated and extracellular field potentials can be recorded from the pyramidal cell layer of CA1. In contrast, long term depression (LTD) describes the long-lasting decrease in synaptic strength following repetitive low frequency stimulation [18,19]. LTP is the leading candidate for activity-dependent synaptic mechanisms which underlie learning and memory functions. Moreover, cholinergic transmission has been suggested to play an important role in the modulation of synaptic plasticity [20,21]. Even though LTP is found in several other regions of the brain which are associated with certain forms of memory, LTP in the hippocampus is the most studied form of synaptic plasticity in the mammalian brain [18,22].

To date, a potentially causal relationship between CCH, cholinergic system dysfunction, and neurobehavioural- and LTP abnormalities has not been established. In the present study, we evaluated CCH-induced memory impairments, hippocampal LTP suppression, and assessed the role of the cholinergic system in these impairments.