Social defeat models of schizophrenia

It’s nice to have a growing sense of friendship and social inclusion these days. Reflecting back, I can definitely relate to strong feelings of ‘social defeat’ and I know the negative consequences it carries. I’ve internalised a lot of things that my ‘voices’ still try to ‘socially defeat’ me with everyday, so it’s a constant struggle to keep positive and not let ‘them’ (or me…) emotionally defeat myself, or impact on the progress I’m making socially and with returning to study.

Epidemiological data suggest that the experience of being excluded from the majority group (or social defeat) may be the common denominator of social risks associated with schizophrenia [1].

Here are a few recent articles relating to social defeat that I found interesting [see an extensive review here]:

The dopaminergic system:

“Dopamine dysregulation involving striatal dopamine sensitization may represent a common mechanism, linking multiple environmental exposures to underlying biological mechanisms of psychosis (Yuii et al., 2007 and Collip et al., 2008). Additionally, previous research suggests a reciprocal relationship between prefrontal and striatal dopaminergic dysfunction in schizophrenia. A number of researchers have suggested that prefrontal dopaminergic dysfunction may partly be the result of dysregulated input from the midbrain dopamine system (Braver et al., 1999, Braver and Cohen, 2000 and Tanaka, 2006). On the other hand, according to the tonic-phasic dopamine theory introduced by Grace (1991), when the tonic activity is low, stressful stimuli are not optimally regulated by the PFC, resulting in increased phasic dopamine release in the striatum.”

The social defeat (SD) hypothesis of schizophrenia posits that repeated experiences of SD may lead to sensitisation of the mesolimbic dopaminergic system and to precipitation of psychosis. When exposed to social threat, defeated rats have elevated levels of extracellular dopamine in the nucleus accumbens and repeated experiences of SD lead to behavioral sensitisation and enhanced behavioral response to dopamine agonists [2]:

“…If the results of the animal studies can be extended to humans, chronic exposure to SD may lead to sensitization of the mesolimbic dopamine system and/or overactivity of this system, and thus foster the development of psychosis “

Schizophrenia: an integrated sociodevelopmental-cognitive model.

Schizophrenia remains a major burden on patients and society. The dopamine hypothesis attempts to explain the pathogenic mechanisms of the disorder, and the neurodevelopmental hypothesis the origins. In the past 10 years an alternative, the cognitive model, has gained popularity. However, the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of dopamine, neurodevelopment, or indeed the brain. In this Review we show that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated dopamine release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated dopamine dysregulation hardwires the psychotic beliefs. Finally, we consider the implications of this model for understanding and treatment of schizophrenia. [full text]

“Position in the social hierarchy affects the recovery of the dopamine
system after isolated animals are returned to the social group; dominant, but not subordinate, monkeys show reversal of the striatal dopamine changes”

“Stress also increases striatal dopamine release in human beings, although not in all studies. This inconsistency could be related to the severity of the stressor—findings from animal studies suggest that mild stressors do not always increase striatal dopamine concentrations. Furthermore, increased dopamine release is associated with greater cortisol response to a challenge.”

Adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction [3].

See more here.

The opioid system:

Research indicates that the mu opioid receptor is an important mediator of behavioural flexibility and responses to psychosocial stress [4]. Kappa-opioid receptors expressed in DAergic systems regulate the effects of acute, but not chronic, social stress in mice [5].

Neuroimmune effects:

Preexisting individual differences in the sensitivity of the peripheral immune system may predict and promote vulnerability to social stress [6]. Interleukin-1β was rapidly increased in key limbic structures (paraventricular nucleus of the hypothalamus, PVN; amygdala) in response to stress challenges that involve application of an aversive/noxious stimulus but not in response to social stress. On the contrary, social stressors appear to increase release of another pro-inflammatory cytokine, interleukin-6 (IL-6), in both plasma and brain [7]:

“Although IL-1, IL-6, and TNF-α are considered to be the classic proinflammatory cytokines – and all appear to be modulated in the CNS by stressor exposure – these are by no means the only neuroimmune factors impacted by stress. For example, monocyte chemoattractive protein-1 (MCP1/CCL2) is a chemokine expressed in the CNS in response to a number of stress challenges and likely plays a key role in recruitment of monocytes from the blood into the CNS (Blandino et al., 2009; Wohleb et al., 2013). Prostaglandins also appear to be highly active in cortical regions after stress (Garcia-Bueno et al., 2008). Thus, a multitude of distinct neuroimmune signaling pathways appear to be activated in response to stressful circumstances, and these effects often depend upon specific individual subject characteristics such as sex, age, strain and prior stress history.”

“In addition to stress-related increases in expression of cytokines and other inflammatory signaling molecules, stress exposure is often accompanied by other cellular manifestations of neuroimmune activation, such as dynamic changes in microglial activation state. Microglia play a prominent role in immune surveillance within the CNS, and are often viewed as the “first responders” in response to infection and/or damage. Prior studies have shown that microglia are highly responsive to stress, with evidence to date suggesting that microglia exhibit priming-like effects following stress exposure as evidenced by enhanced or accelerated activational responses to subsequent immune challenge either in vivo (Johnson et al., 2002) or ex vivo (Frank et al., 2010). An enhanced functional activation state of microglia is also associated with altered expression of cell surface markers that are known to modify or regulate microglia reactivity to antigens (Blandino et al., 2009; Frank et al., 2007). Other studies have shown that chronic stress enhanced microglial proliferation (Nair & Bonneau, 2006) and migration into the CNS (Wohleb et al., 2013). Although it is not clear whether these changes in microglia are the cause or consequence of cytokine expression, it is clear that microglial activation is associated with increased cytokine expression, and exogenous cytokine administration often enhances microglial activation. In this sense, it is notable that IL-1 in particular is often described in the neuroinjury literature as an immediate early gene indicative of microglial activation state. “

Microglia from mice exposed to repeated social defeat had higher mRNA expression of IL-6, TNF-α, and IL-1β, and these increases were reversed by imipramine treatment [8].

Infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression [9].

Lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress [10].

Central immune alterations in passive strategy following chronic defeat stress have been studied [11].

Social defeat causes long lasting anxiety behaviour :

Microglia and CD11b+/CD45 MCs contribute to social defeat-induced prolonged anxiety. The response to social defeat activates fear/threat appraisal circuitry in the brain. Activation of microglia in these areas results in the release proinflammatory cytokines including IL-1β and CCL2. In turn, these cytokine responses contribute to the development of a reactive endothelium in the regional neurovasculature. Social defeat also activates the HPA axis and SNS which stimulate the production of primed CD11+/CD45+MCs in the bone marrow. Release of MCs into circulation results in trafficking of these cells to the reactive neurovasculature which is followed by adhesion and diapedesis into the brain. The activation of microglia and the trafficking of primed MCs results in the development of prolonged anxiety-behavior.
Microglia and CD11b+/CD45 MCs contribute to social defeat-induced prolonged anxiety. The response to social defeat activates fear/threat appraisal circuitry in the brain. Activation of microglia in these areas results in the release proinflammatory cytokines including IL-1β and CCL2. In turn, these cytokine responses contribute to the development of a reactive endothelium in the regional neurovasculature. Social defeat also activates the HPA axis and SNS which stimulate the production of primed CD11+/CD45+MCs in the bone marrow. Release of MCs into circulation results in trafficking of these cells to the reactive neurovasculature which is followed by adhesion and diapedesis into the brain. The activation of microglia and the trafficking of primed MCs results in the development of prolonged anxiety-behavior. [source]
Directions for future therapeutics:

” …administration of specific pathway inhibitors such as IL-1 receptor antagonist (intra-cerebroventricular; i.c.v.) has been shown to block behavioral deficits indicative of learned-helplessness (Maier & Watkins, 1995), and the enhanced HPA axis response produced by inescapable tailshock (Johnson et al., 2002a). In our hands, IL-1 receptor antagonist reversed the suppression of social interaction produced by prior stressor exposure, and blocked the release of aversive odor cues emitted by stressed rats (Arakawa et al., 2009). Agents with more global anti-inflammatory properties, such as alpha-melanocyte stimulating hormone (α-MSH), have been shown to rescue stress-induced reductions in food intake and HPA axis aberrations (Milligan et al., 1998). IL-10, a potent anti-inflammatory cytokine, has also been shown to reverse sickness-like behavioral responses in a guinea pig model of maternal separation (Hennessy et al., 2011), and sensitization of febrile responses produced by this maternal separation experience was reversed with naproxen, a relatively selective inhibitor of cyclooxygenase-2 activity (i.e. the enzyme responsible for production of mature prostaglandin E2 synthesis) – a final common mediator of many inflammation-related effects (Hennessy et al., 2015). Although there is some recent evidence suggesting that antagonists to the P2X7 (purinergic) receptor can reverse some stress-related effects (presumably due to blocking IL-1 release), these effects are generally modest, perhaps because they are blocking only one cytokine within the context of many (Catanzaro et al., 2014; Lord et al., 2014). Thus, one very fruitful avenue of future studies will be the development of novel therapeutics targeting inflammatory signaling pathways that can be used to ameliorate adverse health consequences of stress. The key challenge for production of these therapeutics will be the formulation of agents that either (a) readily cross the blood-brain barrier (BBB) or (b) can be coupled to some form of vector (viruses, nanoparticles, etc.) in order to promote CNS penetration of the drugs.”

See more:

Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice.

Resilience to the effects of social stress: Evidence from clinical and preclinical studies on the role of coping strategies

Social Stress and Psychosis Risk: Common Neurochemical Substrates?

Inflammation in schizophrenia: A question of balance (2015)

Inflammation and microglia

Role of Inflammation in Psychiatric Disease (2015)

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