Major depressive disorder (MDD) is among the most prevalent psychiatric disorders, with an immense socioeconomic burden, yet with unknown etiology. Although the cause(s) of MDD remain unknown, psychosocial stress is a major predisposing factor for MDD. While MDD is well-known for its mood-related symptoms, cognitive dysfunction is a common symptom of MDD. Yet, deficits of the cognitive domain in MDD remain less studied and the underlying mechanisms are largely unexplored. In my PhD thesis, I aimed to unravel the lasting effects of psychosocial stress, with an emphasis on its effects on cognition. Furthermore, I aimed to characterize the neurobiological mechanisms that underlie these long-lasting stress-induced cognitive deficits. To gain access to the molecular and cellular mechanisms driving chronic stress effects, I used social defeat, an animal model of psychosocial stress, both in rats and mice. In chapter 2, our unbiased proteomic study identified extracellular matrix (ECM) proteins to be regulated in SDPS (social-defeat induced persistent stress)-exposed rats during a depressive-like state. This was accompanied with an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin expressing (PV)-interneurons at the hippocampal CA1 subfield. Moreover, maintenance of LTP (long-term potentiation), together with reduced inhibitory neurotransmission was present during the depressive-like state. Importantly, enzyme-mediated normalization of hippocampal ECM levels reversed the SDPS-induced physiological and cognitive deficits. Taken together, these findings identified hippocampal ECM as a novel substrate for hippocampal dysfunction during the sustained depressive-like state. In chapter 3, I characterized how the depressive-like state develops by assessing behavioral and ECM changes over the weeks and months after social defeat stress. Temporal profiling of behavioral disturbances revealed major differences between early stress effects and the late-emerging depressive-like state. Cognitive function was disturbed immediately after stress, but this deficit subsided in the weeks after stress, and re-emerged long after stress. Conversely, affective deficit took weeks to develop. Temporal profiling of hippocampal ECM remodeling revealed a co-occurrence with cognitive dysfunction. These findings underscore a dichotomy in the effects of stress on the affective and cognitive domains and highlights time-dependence of stress effects. Yet, the mechanisms driving these dynamic stress-induced changes on hippocampal ECM remain unknown. Therefore, in chapter 4 I investigated the upstream mechanisms that could propel stress-induced ECM remodeling. Specifically, I assessed the potential role of metalloproteinase mediated (MMP) regulation of ECM in driving the initial effects of stress. I showed that systemic administration of IPR-179, a gelatinase inhibitor, before each daily defeat prevented the early, defeat-induced memory impairment, suggesting that MMP-mediated mechanisms play a role in stress-induced cognitive deficits. In chapter 5, I aimed to set up a social defeat-based model for depression in mice. For this, I developed a novel stress paradigm, in which physical social defeat is combined with vicarious defeat. Behavioral profiling of the effects of PVDPS (physical and vicarious defeat-induced persistent stress) demonstrated a temporal discrepancy in the development of cognitive and affective dysfunction. Moreover, increased build-up of the ECM, together with aberrant inhibitory transmission at the CA1, coincided with late hippocampal memory deficit. Together, these findings emphasize a temporal discrepancy in stress-induced cognitive and affective disturbances in mice. Furthermore, this study further supports the important role of the hippocampal ECM in mediating persistent stress-induced memory deficits. Together, my studies highlight the cross-species SDPS model as valuable tool to study depression-related pathology, as it recapitulates individual subdomains of depression. Importantly, temporal characterization of stress effects demonstrates stress recency as a crucial factor in determining the final stress-triggered outcome, both at the molecular and behavioral levels. Furthermore, my data suggest an important role for hippocampal ECM in mediating stress-induced memory impairments. Thus, ECM-targeted interventions offer promising therapeutic strategies against MDD.
|Award date||5 Oct 2021|
|Publication status||Published - 5 Oct 2021|