Introduction
Major depressive disorder (MDD) is clinically characterised by motivational deficits.1 Motivational deficits are manifested in the symptoms of anhedonia and psychomotor retardation. Anhedonia refers to the reduced motivation or ability to experience pleasure, and psychomotor retardation is known as a slowing-down of thought and a reduction of physical movements.2 Evidence from clinical and preclinical studies has demonstrated that stress can trigger anhedonia and psychomotor deficits in vulnerable individuals.3 4 Chronic and acute stressors are among the strongest proximal risk factors for MDD.5 Consistent with this notion, chronic unpredictable mild stress (CUMS) and social defeat stress have been used to establish animal models of depression, resulting in anhedonia-like behaviours and increasing immobility time.6–8 However, few studies directly investigate the impact of stress on brain reward processing and explore the potential mechanisms in stress-induced motivational deficits. Some studies revealed that stress-induced motivational deficits may involve in the abnormal mesolimbic dopaminergic circuit,9 10 although the cause of such dysfunction remains elusive.
During the past decades, substantial evidence has demonstrated that exposure to stress can prime microglia and strengthen the neuroinflammatory response to the central nervous system (CNS) and peripheral inflammatory challenge.11 Accordingly, CNS and peripheral inflammation has been assumed to be associated with the psychopathology of MDD.12 Therefore, we review clinical and preclinical evidence to clarify the relationship between stress-induced motivational deficits in MDD and the potential signal pathway in the stress-inflammation-mesolimbic reward circuit.
The association between stress and neuroinflammation: the role of the danger-associated molecular pattern HMGB1
Psychological and physical stress can potentiate the proinflammatory response of microglia to subsequent immune stimulators through releasing endogenous danger molecules known as danger-associated molecular patterns (DAMPs).11 These DAMPs are recognised by pattern recognition receptors (PRRs) in the cellular surface, such as toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE). CNS and peripheral innate immune system become activated in response to the recognition of DAMPs-PRRs signalling.13 However, the proximate DAMPs mediators by which stress primes microglia still need to be elucidated. One previous review showed that several DAMPs, including S100 proteins, high mobility group box-1 (HMGB1), heat shock proteins, ATP and uric acid can result in depressive-like behaviours in stress-induced depression models.14 In particular, HMGB1 is considered as master regulator of innate immunity.15 Previous studies suggested that HMGB1 signalling is necessary and sufficient for stress-induced sensitisation of microglia, then amplifying the expression of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and proinflammatory cytokines.16 Moreover, HMGB1 has been involving in several neuroinflammatory conditions, such as Alzheimer’s disease17 and brain ischaemia injury.18 Therefore, the scope of our review focuses on the HMGB1 as a potential mediator of stress-induced neuroinflammation in MDD.
The association between neuroinflammation and motivational deficits mediated by brain structure and function
Experimental cytokine (eg, injection of typhoid vaccination or LPS) could quickly trigger fatigue, depressed mood, lack of interest and psychomotor retardation in healthy individuals, suggesting the underlying alterations of neural activity in specific regions. Previous studies suggest that stress is implicated with the aetiology of MDD through activating neuroinflammation processes and then involving structural and functional alterations of specific brain regions.19 Neuroinflammation exerts direct detrimental effects on brain structure and function by mediating neuronal damage/degeneration, glial activation, mitochondrial dysfunction, demyelination and endothelial damage.20 Moreover, these inflammation-induced behavioural changes have been assumed to be associated with the alterations of neurotransmitters metabolism (serotonin, dopamine (DA) and norepinephrine)21 22 and the activation of indoleamine 2,3-dioxygenase (IDO) in kynurenine pathway (KP),23 which are consistent with the psychopathology of MDD. Neuroimaging techniques have been advanced to confirm the link between inflammation and depression mediated by the alterations in neural regions associated with the regulations of motivation and reward, including prefrontal regions and ventral striatum,24 25 and the regulation of emotion, including amygdala, anterior cingulate cortex and prefrontal cortex.26 27
As mentioned above, evidence has showed that stress can cause depressive-like symptoms including anhedonia and psychomotor retardation, which are common in patients with MDD.28 Similar findings were observed in depressive-like animal models by reductions in saccharin preference and increased immobility time.29 However, little is known about the underlying mechanism of the relationship between motivational deficits and stress in depression. One candidate neurobiological mechanism, overactive inflammation, was supposed to be associated with motivational deficits in MDD.30 Therefore, we hypothesised that stress-induced neuroinflammation mediated by HMGB1 may be implicated with the alterations of corticostriatal reward neurocircuitry contributing to anhedonia and psychomotor retardation in MDD.