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Integrating neuroimmune systems in the neurobiology of depression

Key Points

  • The neurobiology of depression features dichotomous alterations in corticolimbic brain regions. For example, the prefrontal cortex and hippocampus exhibit neuronal atrophy and synaptic dysfunction, whereas the nucleus accumbens and amygdala exhibit neuronal hypertrophy and increased synaptic activity.

  • In subsets of depressed individuals, there is dysregulation of peripheral and central immune systems that are implicated in the neurobiology of depression. Rodents exposed to environmental and psychosocial stress recapitulate immune dysfunction observed in clinical populations.

  • Microglia, the brain-resident macrophages, integrate neuroimmune signals and mediate neuroplasticity in physiological and pathological conditions. Neurons provide soluble and contact-dependent signals that modulate the function and activation of microglia.

  • Typical antidepressant agents improve mood by regulating the levels of the monoamines serotonin and noradrenaline, but also partially through attenuation of immune dysregulation. Other antidepressant therapies that limit neuroimmune activation and promote anti-inflammatory pathways may provide alternative treatment options for subsets of depressed individuals.

  • Further studies of the dynamic role of microglia in the neurobiology of depression and synapse function may reveal novel molecular pathways that can be therapeutically targeted.

Abstract

Data from clinical and preclinical studies indicate that immune dysregulation, specifically of inflammatory processes, is associated with symptoms of major depressive disorder (MDD). In particular, increased levels of circulating pro-inflammatory cytokines and concomitant activation of brain-resident microglia can lead to depressive behavioural symptoms. Repeated exposure to psychological stress has a profound impact on peripheral immune responses and perturbs the function of brain microglia, which may contribute to neurobiological changes underlying MDD. Here, we review these findings and discuss ongoing studies examining neuroimmune mechanisms that influence neuronal activity as well as synaptic plasticity. Interventions targeting immune-related cellular and molecular pathways may benefit subsets of MDD patients with immune dysregulation.

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Figure 1: Neurobiology of depression.
Figure 2: Stress-associated changes in neuroimmune function.
Figure 3: Microglia–neuron interactions in the naive, homeostatic brain and in the stressed or depressed brain.
Figure 4: Neuroimmune mechanisms in the pathophysiology and treatment of depression.

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Acknowledgements

This work was supported by endowment funds from Yale University, New Haven, Connecticut, USA, and by the State of Connecticut, USA.

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Correspondence to Ronald S. Duman.

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Competing interests

R.S.D. has received consulting fees, speaking fees and/or grant support from Naurex, Taisho Pharmaceutical, Johnson & Johnson, Eli Lilly and Company, Lundbeck, Sunovion Pharmaceuticals, and Forest Laboratories. E.S.W., T.F. and M.I. declare no competing interests.

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Glossary

Endotoxin

A component of the bacterial cell wall that binds to pattern recognition receptors on host immune cells and elicits inflammatory responses without persistent infection.

Sickness behaviour

Reductions in locomotor activity, food intake and social interaction that are induced by inflammatory factors to facilitate pathogen clearance and recovery, and to prevent spread of infection.

Anhedonia

A core symptom of depression that manifests as an inability to experience pleasure during usually enjoyable activities.

Melancholic depression

A subtype of major depressive disorder that is characterized by anhedonia and diminished affect, leading to impaired mood in response to positive events.

Atypical depression

A subtype of major depressive disorder that is characterized by general fatigue, increased sleep and weight gain, as well as intense changes in mood based on extraneous circumstances and factors.

Neurovegetative

A cluster of depression symptoms, including but not limited to significant changes in weight and eating patterns, sleep patterns and sensitivity to interpersonal issues.

Social defeat

A standardized rodent model of psychosocial stress induced by losing a confrontation with a conspecific.

Minocycline

A brain-penetrating tetracycline antibiotic that exerts anti-inflammatory and neuroprotective effects by putatively directly inhibiting microglia.

Tricyclic antidepressant

An early chemical class of antidepressant drug that acts primarily by inhibiting serotonin and noradrenaline reuptake; however, therapeutic effects lag by several weeks, suggesting a role for adaptive changes.

Monoamine oxidase inhibitors

A class of antidepressant drugs that prevent enzymatic breakdown of monoamines, typically used when other drugs are ineffective.

β-hydroxybutyrate

A ketone metabolite recently reported to selectively block activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome, an effect that could underlie the anti-inflammatory effects of ketogenic diets.

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Wohleb, E., Franklin, T., Iwata, M. et al. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci 17, 497–511 (2016). https://doi.org/10.1038/nrn.2016.69

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