Abstract
Degeneration of the locus coeruleus (LC), the main source of cerebral noradrenaline (NA), has been reported in diverse neurodegenerative diseases, including Parkinson's diseases (PD). There is increasing evidence indicating the role of NA deficiency in the prefrontal cortex (PFC) and the development of early cognitive impairments in PD. Here, we evaluated whether a selective noradrenergic lesion of LC caused by 6-hydroxydopamine (6-OHDA) may induce memory deficits and neurochemical alterations in the PFC. Adult male Wistar rats received stereotaxic bilateral injections of 6-OHDA (5 μg/2 μl) into the LC, and two stainless-steel guide cannulas were implanted in the PFC. The SHAM group received just vehicle. To induce a selective noradrenergic lesion, animals received nomifensine (10 mg/kg), a dopamine transporter blocker, one hour before surgery. 6-OHDA-lesioned rats displayed impairments of the short- and long-term object recognition memory associated to reduced content of tyrosine hydroxylase in the LC. Neurochemical analysis revealed an altered mitochondrial membrane potential in LC. Regarding the PFC, an increased ROS production, cell membrane damage, and mitochondrial membrane potential disruption were observed. Remarkably, bilateral NA (1 μg/0.2 μl) infusion into the PFC restored the recognition memory deficits in LC-lesioned rats. These findings indicate that a selective noradrenergic LC lesion induced by 6-OHDA deregulates a noradrenergic network in the PFC, which could be involved in the early memory impairments observed in nondemented PD patients.
Highlights
Parkinson’s disease (PD) is the second more prevalent neurodegenerative disease in the world
Student’s t-test revealed lack of significant differences between the percentage of time spent by the animals exploring the familiar and the novel objects from the 6OHDA group during the test session evaluated 30 min or 24 h after the training session, indicating a mnemonic impairment caused by 6-OHDA-induced locus coeruleus (LC) lesion (Figures 1(b) and 1(c))
The present findings suggest the involvement of noradrenergic neurotransmission in the prefrontal cortex (PFC) on recognition memory impairments induced by LC lesion in rats. 6-OHDAinduced LC lesion caused short- and long-term recognition memory impairments addressed in the object recognition task (ORT) associated
Summary
Parkinson’s disease (PD) is the second more prevalent neurodegenerative disease in the world. PD is characterized by the appearance of cardinal motor symptoms, such as postural instability, bradykinesia, tremor, and rigidity that are related to dopaminergic damage in the nigrostriatal pathway [1, 2]. Despite these motor impairments, PD patients exhibited a constellation of nonmotor symptoms, which are still poorly understood and underdiagnosed [3]. Initial cognitive dysfunctions in PD involve frontal-executive deficits that impact attention and executive functions and decrease them. Mild cognitive impairment is found in carriers of nondemented PD since the early stages of disease [4, 7]
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