Review
Is subcortical–cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach

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Abstract

Major depressive disorder has recently been characterized by abnormal resting state hyperactivity in anterior midline regions. The neurochemical mechanisms underlying resting state hyperactivity remain unclear. Since animal studies provide an opportunity to investigate subcortical regions and neurochemical mechanisms in more detail, we used a cross-species translational approach comparing a meta-analysis of human data to animal data on the functional anatomy and neurochemical modulation of resting state activity in depression. Animal and human data converged in showing resting state hyperactivity in various ventral midline regions. These were also characterized by abnormal concentrations of glutamate and γ-aminobutyric acid (GABA) as well as by NMDA receptor up-regulation and AMPA and GABA receptor down-regulation. This cross-species translational investigation suggests that resting state hyperactivity in depression occurs in subcortical and cortical midline regions and is mediated by glutamate and GABA metabolism. This provides insight into the biochemical underpinnings of resting state activity in both depressed and healthy subjects.

Introduction

Major depressive disorder (MDD) is a psychiatric disorder characterized by depressive symptoms like anhedonia, poor motivation, psychomotor retardation, and ruminations including an increased self-focus (see Thase, 2005, Northoff, 2007). Recent imaging studies demonstrated consistently elevated resting state activity in various cortical and subcortical midline regions like the sub- and perigenual anterior cingulate cortex (PACC), medial prefrontal cortex (PFC), the ventral striatum (VS), and the thalamus (Th) (see reviews and meta-analyses in Fitzgerald et al., 2006, Fitzgerald et al., 2007, Greicius et al., 2007, Grimm et al., 2009a, Grimm et al., 2009b, Mayberg, 2002, Mayberg, 2003, Phillips et al., 2003). Unfortunately, the exact role of subcortical regions remains unclear due to the limited resolution in human imaging. Moreover, the exact neurochemical mechanisms mediating abnormal resting state activity also remain unclear.

Animal models of depression provide an excellent opportunity to investigate subcortical regions related to primary process emotions and their neurochemical mechanisms in greater anatomical detail compared to human imaging studies (Panksepp, 1998, Panksepp, 2005). Recent animal studies focus on various subcortical regions like the ventral tegmental area (VTA), locus coeruleus (LC), periaqueductal grey (PAG), hypothalamus (Hyp), habenula (Hab), various nuclei of the amygdala (Amyg), bed nucleus of stria terminalis (BNST), dorsal raphe nuclei (DR), nucleus of the solitary tract (NST), basal ganglia, especially the nucleus accumbens (NACC) and caudate-putamen (CP), septum, and thalamic nuclei like the pulvinar and the mediodorsal thalamus (MDT) (see Krishnan and Nestler, 2008, Ressler and Mayberg, 2007, Shumake and Gonzalez-Lima, 2003 for recent reviews). Interestingly, many of these regions show abnormal resting state activity in animal models of depression which may be convergent with human imaging findings. Though one must be cautious when comparing structural and functional neuroanatomy across species, nonetheless there is evidence for many subcortical and cortical homologies across mammals (Cenci et al., 2002, Dalley et al., 2004, Robbins, 1998). A potential relationship of abnormal resting state activity between humans and animals, however, remains to be demonstrated in systematic translational analyses.

Moreover, animal models provide some evidence of GABA and glutamate abnormalities in the very same brain regions showing resting state hyperactivity (see below for details). This raises the question of whether resting state hyperactivity in depression may be due to glutamatergic and GABAergic abnormalities. Though recent animal models have clarified genetic contributions to depression (Cryan and Slattery, 2007, Krishnan and Nestler, 2008, McArthur and Borsini, 2006), neurochemical data in animals may need to be complemented by human data in order to bridge the gap to human clinical issues. This makes it necessary to translate the animal resting state and neurochemical findings into the context of human imaging findings. More specifically, there is a need to merge the observations of abnormal resting state activity in both animals and humans into a common neurochemical model (see Stone et al., 2008, Krishnan and Nestler, 2008 for reviews).

The general aim of this investigation was to develop a cross-species translational pathophysiological model of abnormal resting state activity in MDD. More specifically, our first aim was to directly compare human and animal data on resting state activity in order to yield a common subcortical–cortical network. With this common anatomical model in place, we then aimed to characterize this abnormal subcortical–cortical resting state network in neurochemical terms drawing again on both animal and human data. We hypothesized that increased resting state activity in a ventral anterior subcortical–cortical network, including many limbic regions, may be related to abnormal activity in both glutamatergic and GABAergic metabolism.

To pursue this hypothesis, we performed a two-step investigation. In the first step, we used a systematic meta-analysis of human positron emission tomography (PET) imaging studies in the resting state. The regions identified were then compared with those observed to be abnormal in resting state data of human fMRI studies and animal models; the overall aim was to identify anatomical similarities in the direction of resting state activity showing either hypo- or hyper-activity. The second step consisted of searching for neurochemical abnormalities in those subcortical–cortical regions. Since glutamatergic and GABAergic substances can be investigated in both animals and humans, and have recently been shown to be therapeutically effective in human MDD (see Northoff et al., 1997, Zarate et al., 2006), we then focused on those neurotransmitters. This analysis sheds light on one important aspect of the pathophysiology of depression (i.e. resting state hyperactivity), and thereby may increase our understanding of the biochemical modulation of resting state activity in the default-mode network (Buckner et al., 2008, Raichle et al., 2001, Vincent et al., 2007) in both humans and animals.

Section snippets

Literature search

To form a dataset of coordinates, we conducted multiple PubMed (http://www.pubmed.gov) searches to initially identify all imaging studies – positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) – including patients with depressive disorders published from May 1998 to February 2008. The search included the keywords “depression”, “MDD”, “PET”, “positron emission tomography”, “fMRI”, and “functional magnetic resonance imaging”. In addition, we used the brainmap.org

Humans

Our meta-analysis revealed that MDD patients showed significantly higher resting state activity in the following regions when compared to healthy subjects: PACC, ventromedial prefrontal cortex (VMPFC), thalamic regions including the pulvinar and the dorsomedial thalamus (MDT), pallidum/putamen, and midbrain regions including VTA/SN and PAG/tectum (see Fig. 1 and Table 1a).

Animals

The findings of the various studies are specified in Table 1b; these are organized by dependent measure (i.e. indices of

Discussion

This study investigated the functional anatomy and neurochemical modulation of resting state activity using a cross-species translational approach. A direct comparison was made between the human data (using a meta-analysis of studies involving patients with MDD), and the animal data (investigating anatomical, biochemical, and pharmacological changes and manipulations in models of depression). The main results of our translational analysis are as follows. First, we observed resting state

Acknowledgements

We wish to acknowledge the generous support of Audrey Gruss and the Hope of Depression Research Foundation (HDRF) to G.N. and J.P. and the German Research Foundation (SFB77686). G.N. holds a Canada Research Chair for Mind, Brain imaging and Neuroethics as well as an EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health. Jaak Panksepp is Bailey Endowed Professor of Animal Well-Being Science at WSU.

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