Linking molecules to mood: new insight into the biology of depression

Abstract

Major depressive disorder is a heritable psychiatric syndrome that appears to be associated with subtle cellular and molecular alterations in a complex neural network. The affected brain regions display dynamic neuroplastic adaptations to endocrine and immunologic stimuli arising from within and outside the CNS. Depression's clinical and etiological heterogeneity adds a third level of complexity, implicating different pathophysiological mechanisms in different patients with the same DSM diagnosis. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are themselves incompletely understood. This review summarizes the current knowledge of the neurobiology of depression by combining insights from human clinical studies and molecular explanations from animal models. The authors provide recommendations for future research, with a focus on translating today's discoveries into improved diagnostic tests and treatments.

Figure 1. Two heuristic formulations of “depression circuits.”

a) An amygdala-centric circuit (8) largely inspired by structural brain imaging and postmortem studies. According to this model, the emotional symptoms of depression can be brought about by functional impairment (“lesion-like” effects) of the striatum or prefrontal and orbital prefrontal cortex (and/or their associated white matter tracts), resulting in disinhibition of the amygdala and downstream structures. Alternatively, they can arise from functional hypersensitivity of the amygdala (turquoise arrows) which gives rise to dysregulation of prefrontal cortical structures. b) Another circuit model (138) generated with a greater emphasis on functional imaging results. The main nodes consist of four clusters of brain regions with strong anatomical connections to each other; bidirectional arrows indicate strong inter-connections. This model compartmentalizes depressive endophenotypes into exteroceptive (cognitive), interoceptive (visceral-motor), mood-regulating and mood-monitoring functions, with numbers in parentheses reflecting formal Brodmann area assignments. Both formulations should be seen as offering a simplified heuristic framework for further research into depression’s diagnosis, pathophysiology and treatment. They do not convey the cellular and molecular heterogeneity of each node within the circuit (for example, the VTA is comprised of several types of dopaminergic and GABAergic neurons defined by differences in connectivity and receptor expression). Abbreviations: VTA (ventral tegmental area), LC (locus coeruleus), BNST (bed nucleus of the stria terminalis), PFC (prefrontal cortex), PAG (periaqueductal gray).

Figure 2. Common behavioral endpoints in rodent depression studies

This figure diagrams certain widely utilized quantitative and automatable behavioral endpoints used in experiments with rats or mice as measures of depression-related behavior. They can be employed following chronic stress paradigms such as social defeat, to phenotype genetic mutant mice, to validate antidepressant treatments or as tools to localize genomic mediators of complex behaviors in QTL analyses (quantitative trait locus). The most popular endpoint is immobility, which is interpreted as a measure of behavioral despair or freezing in response to an inescapable stressor like forced swimming or tail suspension. The closely related helplessness can be inferred through the learned helplessness paradigm, where animals receive a series of inescapable electrical shocks in one compartment, and on subsequent testing days display a deficit in their motivation to avoid these shocks when a clear escape route is provided. Anhedonia in mice and rats can be measured in several ways, ranging from simple measures of sucrose preference (measuring the relative preference for a dilute solution of sucrose versus water), to preference for a high fat diet, to ICSS (intracranial self stimulation) where one directly measures motivation (lever pressing) to receive highly rewarding electrical stimulation. Reductions in exploratory behavior are often interpreted as elevations in anxiety, and can be quantified by measuring amounts of time spent in aversive portions of a field of exploration such as the open arms of the elevated plus maze (top) or the brightly illuminated portion of the light-dark box. One can also measure deficits in sociability, which may reflect impairments in natural reward or social anxiety. These assays have been employed in stress paradigms, mutant mouse models as well as models of secondary depression such as that seen, for example, with obesity, breast cancer or chronic interferon treatment. A common practice is to generate behavioral profiles by employing a broad battery of these tests following stress, genetic, or pharmacological manipulations, which can also include changes in weight asnd appetite, as well as deficits in self-grooming (deteriorations in fur coat).

Figure 3. Effects of deep brain stimulation (DBS) on brain metabolic activity

a) In treatment-resistant depression, DBS applied to the nucleus accumbens and nearby regions produces significant clinical improvement as well as changes in metabolic activity across an array of neural substrates (as measured by fluorodeoxyglucose positron emission tomography before and 6 months after DBS implantation) (18, 19). Among responders, reduced glucose metabolism (blue shading) was observed in the orbitofrontal cortex, superior frontal gyrus and posterior and subgenual cingulate cortical areas. b) The subgenual (also known as subcallosal) cingulate cortex is itself another DBS target for depression (17, 18), and post-DBS PET studies reveal similar patterns of decreases in frontal cortical metabolism. In addition, DBS applied here normalizes heightened blood flow to this region that is associated with depressive episodes (not shown). These data, together with results from rodent DBS studies (98), suggest that continuous DBS in these areas may alleviate severe depressive symptoms by enhancing inhibition across a circuit of cortical and subcortical structures.

Figure 4. A genetic model to study gender differences in depression-related behavior

The neurobiology underlying the greater female vulnerability to depression (or the relative resilience in males) remains largely unknown. The vast majority of research in the field has focused on how gonadal hormones affect stress-related behavior (i.e., estrogens, progesterones, and testosterones). However, studies using the “four core genotypes” (FCG) model shown here have illustrated that important sexually dimorphic anatomic and behavioral traits are unrelated to gonadal output and are localized to the many genes contained on sex chromosomes. The FCG mouse model was developed following a spontaneous mutation resulting in the loss of SRY (sex determining region of Y) from the Y chromosome, resulting in gonadal females. A functional SRY transgene was inserted into an autosome rescuing these mice back to gonadal males (“XY⁻ Sry”). Mating these males with XX females results in the four core genotypes, comparisons between which have allowed for a dissociation of chromosomal and gonadal mediators of a variety of behavioral and physiological phenotypes (124). Studies utilizing the FCG mouse model generally employ gonadectomy to control for confounds related to menstrual cycling in gonadal females.

Figure 5. Mediators of energy homeostasis as targets for metabolic and affective illness

Leptin (synthesized by white adipose tissue) and ghrelin (synthesized in the stomach) are two canonical examples of how endocrine hormones that signal information about peripheral energy state can also exert effects on depression-related behaviors. Leptin and ghrelin receptors are expressed in the hypothalamic arcuate nucleus, which contains two main types of neurons defined by their neuropeptides. These two neuronal types differentially express neuropeptides which act on the same melanocortin receptor (MC4R) with opposing effects: AgRP (an endogenous antagonist) and α-MSH (an endogenous agonist). (α-MSH is a product of the pro-opiomelanocortin or POMC gene.) AgRP neurons also express NPY, while α-MSH neurons also express CART (cocaine- and amphetamine-regulated transcript, named for its original identification). NPY and AgRP are orexigenic, while α-MSH and CART are anorexigenic. Leptin reduces food intake and increases energy expenditure by inhibiting NPY/AgRP-releasing neurons and exciting α-MSH/CART neurons. Ghrelin acts by promoting the release of NPY and AgRP. MC4Rs are expressed widely in the brain, including in the paraventricular hypothalamic nucleus (PVN, influencing the release of numerous neuropeptides including corticotropin-releasing hormone and thyrotropin-releasing hormone), the lateral hypothalamus (containing MCH- and orexin-secreting neurons which regulate food intake and arousal) as well as extrahypothalamic sites such as the nucleus accumbens and amygdala (where they are thought to influence mood regulation) (50, 139). Synthetic antagonists of MC4R are antidepressant and anxiolytic (136), as are agonists of NPY (121). In the VTA, direct infusion of leptin or ghrelin exert opposing effects on food intake through their contrasting effects on dopaminergic neuronal firing. Their VTA actions are believed to control the motivational or hedonic aspects of food intake (135) and are likely altered in other reward-related disorders such as depression and substance dependence. In contrast to the VTA, leptin and ghrelin appear to have identical effects on hippocampal plasticity: they both positively modulate LTP (long-term potentiation, an electrophysiological assay for activity-dependent synapse strengthening) as well as enhance adult hippocampal neurogenesis through receptors expressed on hippocampal progenitor cells. Abbreviations: NPY (neuropeptide Y), AgRP (agouti-related peptide), α-MSH (α-melanocyte stimulating hormone), PVN (paraventricular [hypothalamic] nucleus), MCH (melanin concentrating hormone), SGZ (subgranular zone), GCL (granule cell layer), VTA (ventral tegmental area), DA (dopamine).