Fluoxetine and Ketamine Reverse the Depressive but Not Anxiety Behavior Induced by Lesion of Cholinergic Neurons in the Horizontal Limb of the Diagonal Band of Broca in Male Rat.

Linghong Chen,Hong Ma,Lei Gao,Huaqiang Zhu,Fuqiang Zhang,Yiying Zhou,Huifen Liu,Wenhua Zhou,Yuting Ke

doi:10.3389/fnbeh.2021.602708

Abstract

The basal forebrain cholinergic system is involved in cognitive processes, but the role of the basal forebrain cholinergic system in depression is unknown. We investigated whether a lesion of cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) produces depressive-like behavior and whether fluoxetine or ketamine inhibits such depressive-like behaviors. Here, in rats, we used 192 IgG-saporin to eliminate the cholinergic neurons of the HDB and evaluated depressive-like behaviors using a preference test for sucrose solution and the forced swimming test. Fourteen days after the injection of 192 IgG-saporin into the HDB, the rats exhibited a significantly fewer number of choline acetyltransferase positive cell density in HDB, accompanied with neuronal loss in the entire hippocampus. Meanwhile, these rats significantly reduced preference for sucrose solution, increased immobility time in the forced swimming test, reduced locomotor activity, decreased context dependent memory in fear conditioning and the time spent in the open arms of the plus-maze. A single dose of ketamine (10 mg/kg) increased the sucrose solution consumption, reduced the immobility time in the forced swim test (FST), and increased locomotor activity compared to vehicle-treated rats. Moreover, in rats that were continuously treated with fluoxetine (10 mg/kg/day for 11 days), the sucrose solution consumption increased, the immobility time in the FST decreased, and locomotor activity increased compared to vehicle-treated rats. The present results demonstrate that a lesion of HDB cholinergic neurons results in depressive-like and anxiety-like behaviors and that antidepressants such as fluoxetine or ketamine, can reverse these depressive-like behaviors but not anxiety-like behaviors, and suggest that a lesion of HDB cholinergic neurons and followed hippocampus damage may be involved in the pathogenesis of depression.

Highlights

The basal forebrain cholinergic complex, comprising the medial septum, the horizontal and vertical diagonal band of Broca (DB), and the nucleus basalis of Meynert, provides the major sources of cholinergic projection neurons to neocortex, hippocampus, and amygdala (Schliebs and Arendt, 2011; Ballinger et al, 2016)
The results showed that lesions of cholinergic neurons in the horizontal diagonal band of Broca (HDB) produced depressive-like and anxiety-like behaviors, such as anhedonia, increased immobility time in the forced swim test (FST), decreased locomotor activity, memory deficit in the contextual fear conditioning, and reduced time in open arms in the elevated plus maze (EPM)
These results clearly demonstrate that cholinergic neurons in the HDB play an important role in the production of depressive-like behaviors

Summary

Introduction

The basal forebrain cholinergic complex, comprising the medial septum, the horizontal and vertical diagonal band of Broca (DB), and the nucleus basalis of Meynert, provides the major sources of cholinergic projection neurons to neocortex, hippocampus, and amygdala (Schliebs and Arendt, 2011; Ballinger et al, 2016). The horizontal diagonal band of Broca (HDB), densely innervates the main olfactory bulb (MOB), the first processing station within the main olfactory system (Case et al, 2017). Brain imaging studies have revealed a reduction in the volume of limbic brain regions and other regions implicated in depression, such as the hippocampus and prefrontal cortex (Duman and Li, 2012). The hippocampus in mammals receives massive input from the cholinergic neurons in the horizontal and vertical diagonal band of Broca. We hypothesized that a lesion of the HDB may produce depressive-like behaviors in rat

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