"Increased activity in the lateral habenula (induced e.g., by stress) can lead to an increase in the salience of aversive stimuli and a decrease in the saliency of appetitive stimuli, and as such offers a plausible neurobiological substrate for the negative information-processing bias seen in e.g., depressed patients (Disner et al., 2011; Willner et al., 2013). Dysfunctions of this limbic-striatal relay nucleus have been implicated in depression and schizophrenia (Hikosaka et al., 2008), and recently beneficial effects were reported in a treatment-resistant depressed patient receiving deep brain stimulation in this target (Sartorius et al., 2010). Overall, more studies are needed before we can make conclusive statements regarding the role of wanting, liking, and learning processes in anhedonia in psychiatric disorders. "
[Show abstract][Hide abstract] ABSTRACT: Anhedonia, the lack of pleasure, has been shown to be a critical feature of a range of psychiatric disorders. Yet, it is currently measured primarily through subjective self-reports and as such has been difficult to submit to rigorous scientific analysis. New insights from affective neuroscience hold considerable promise in improving our understanding of anhedonia and for providing useful objective behavioral measures to complement traditional self-report measures, potentially leading to better diagnoses and novel treatments. Here, we review the state-of-the-art of hedonia research and specifically the established mechanisms of wanting, liking, and learning. Based on this framework we propose to conceptualize anhedonia as impairments in some or all of these processes, thereby departing from the longstanding view of anhedonia as solely reduced subjective experience of pleasure. We discuss how deficits in each of the reward components can lead to different expressions, or subtypes, of anhedonia affording novel ways of measurement. Specifically, we review evidence suggesting that patients suffering from depression and schizophrenia show impairments in wanting and learning, while some aspects of conscious liking seem surprisingly intact. Furthermore, the evidence suggests that anhedonia is heterogeneous across psychiatric disorders, depending on which parts of the pleasure networks are most affected. This in turn has implications for diagnosis and treatment of anhedonia.
"Importantly, as the optic fiber in these experiments was targeted to ChR2+ somata in the mPFC, the exact projections that exerted the antidepressant-like effects remain to be determined by projectionspecific targeting. Warden et al. examined the role of mPFC efferents in depressive behavior, with a focus on projections to the dorsal raphe nucleus (DRN) and the lateral habenula (LHb; Warden et al., 2012), regions that are heavily implicated in MDD (Sartorius et al., 2010; Willner et al., 2013; Albert et al., 2014; Mahar et al., 2014). The mPFC-DRN projection is of particular interest, as the antidepressant effect of vmPFC DBS in rats is accompanied by structural and functional alterations in serotoninergic DRN neurons (Veerakumar et al., 2014) and it is completely abolished following serotoninergic depletion in the DRN (Hamani et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.
Frontiers in Systems Neuroscience 12/2014; 8:230. DOI:10.3389/fnsys.2014.00230
"There is precedent for such discoveries. For example, deep brain stimulation (DBS) of the lHb, using stimulation parameters that inhibit neural activity, has antidepressant-like effects in animal studies (Li et al., 2011; Winter et al., 2011), and a beneficial effect of DBS has been reported in one severely treatment-resistant depressed patient (Sartorius et al., 2010). Given that the lHb has strong interconnections with the suprachiasmatic nucleus and shows circadian rhythmicity, this might well turn out to be the site of action of the melatonin derivative agomelatine, which, since its introduction less than 10 years ago, has been shown to be among the most effective antidepressant drugs available, and has been approved for the treatment of depression in over 40 countries (Carney and Shelton, 2011). "
[Show abstract][Hide abstract] ABSTRACT: The first half of this paper briefly reviews the evidence that (i) stress precipitates depression by damaging the hippocampus, leading to changes in the activity of a distributed neural system involving, inter alia, the amygdala, the ventromedial and dorsolateral prefrontal cortex, the lateral habenula and ascending monoamine pathways, and (ii) antidepressants work by repairing the damaged hippocampus, thus restoring the normal balance of activity within that circuitry. In the second half of the paper we review the evidence that heightened vulnerability to depression, either because of a clinical history of depression or because of the presence of genetic, personality or developmental risk factors, also confers resistance to antidepressant drug treatment. Thus, although antidepressants provide an efficient means of reversing the neurotoxic effects of stress, they are much less effective in conditions where vulnerability to depression is elevated and the role of stress in precipitating depression is correspondingly lower. Consequently, the issue of vulnerability should feature much more prominently in antidepressant research. Most of the current animal models of depression are based on the induction of a depressive-like phenotype by stress, and pay scant attention to vulnerability. As antidepressants are relatively ineffective in vulnerable individuals, this in turn implies a need for the development of different clinical and preclinical methodologies, and a shift of focus away from the current preoccupation with the hippocampus as a target for antidepressant action in vulnerable patients.
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