Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens

J M Bessa,O F X Almeida,M Morais,N Sousa,L Pinto,F Marques,J A Palha

doi:10.1038/tp.2013.39

Abstract

There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression of plasticity-related molecules were examined in the NAc of rats displaying anhedonic behavior (measured in the sucrose-consumption test) in response to chronic mild stress. To demonstrate the relevance of our measurements to depression, we tested whether the observed changes were sensitive to reversal with antidepressants (imipramine and fluoxetine). Data show that animals displaying anhedonic behavior display an hypertrophy of medium spiny neurons in the NAc and, in parallel, have increased expression of the genes encoding for brain-derived neurotrophic factor, neural cell adhesion molecule and synaptic protein synapsin 1. Importantly, the reversal of stress-induced anhedonia by antidepressants is linked to a restoration of gene-expression patterns and dendritic morphology in the NAc. Using an animal model of depression, we show that stress induces anhedonic behavior that is associated with specific changes in the neuronal morphology and in the gene-expression profile of the NAc that are effectively reversed after treatment with antidepressants.

Highlights

One of the core symptoms of major depressive disorder is anhedonia.[1]
As previously shown,[24] the tricyclic antidepressant imipramine elicited an earlier onset of antidepressant action, reversing anhedonic behavior within the first week of treatment (Po0.001), whereas the response to the selective serotonin reuptake inhibitor fluoxetine was only evident after 2 weeks (Po0.001) (Figure 1a)
Antidepressant treatment proved to be a significant factor in recovery from learned helplessness (F2,52 1⁄4 27.962, Po0.001); when compared with stressed rats that did not receive drug treatments, immobility time was significantly reduced by fluoxetine (Po0.001) and imipramine (Po0.001) and the latency time to immobility was significantly increased by both drugs (Po0.001)

Summary

Introduction

One of the core symptoms of major depressive disorder is anhedonia (diminished interest or pleasure).[1] This suggests that dysfunction of brain reward pathways contributes to the pathophysiology of the disease. The NAc, a part of the ventral striatum, is involved in motivation, reward, learning, problem-solving and motor function, all of which are affected in clinical depression.[8] The NAc, a part of the ventral striatum, consists of two functionally distinct divisions: the core and the shell. The NAc is part of a complex network receiving glutamatergic, dopaminergic, serotonergic, noradrenergic and cholinergic afferents that originate in brain regions sensitive to stress-induced depression.[13,14,15] Previous studies have reported that stress-induced dendritic and synaptic plasticity in the NAc are modulated by brain-derived neurotrophic factor (BDNF)[16] and the neuropeptide melanocortin.[17]

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Conclusion