From stress to depression: development of extracellular matrix-dependent cognitive impairment following social stress

Abstract

Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. We profiled the development of an enduring depressive-like state by assessing affective behavior and hippocampal function during the 2 months following social-defeat stress. We measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during the sustained depressive-like state. Affective disturbance and cognitive impairments develop disparately after social stress, with gradual appearance of affective deficits. In contrast, spatial memory was impaired both early after stress and during the late-emerging chronic depressive-like state, while intact in-between. Similarly, we observed a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Together our data (1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, (2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and (3) support a role of the ECM in mediating long-lasting effects on memory. From a translational point of view, it is important to prioritize on temporal phenotypic aspects in animal models to elucidate the underlying mechanisms of depression.

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality

“…CWC22 is one of the protein-coding regions of the genome that is most often duplicated ( Pezer et al, 2015 ). CWC22 and the Rd2 segmental duplication have previously been implicated in brain microstructural changes in response to environmental factors such as social engagement ( Dause and Kirby, 2019 ), which has memory-inducing effects on the ECM ( Koskinen et al, 2019 ). Environmental enrichment (EE) describes exposure to situations that facilitate enhanced sensory, cognitive, and motor stimulation and is known to affect synaptic plasticity in humans ( Dause and Kirby, 2019 ).…”

Sleep and Memory Consolidation Dysfunction in Psychiatric Disorders: Evidence for the Involvement of Extracellular Matrix Molecules

“…Chronic social defeat stress in rats, commonly used to model depression, results in increased CSPG proteins and PNN numbers in the hippocampus, together with reduced frequency of inhibitory postsynaptic currents (Riga et al, 2017). These PNN changes emerge 4-8 weeks after social defeat stress, and coincide with the emergence of later stage spatial memory deficits (Koskinen et al, 2020). Chronic social defeat also results in changes in sleep, circadian rhythm, and clock gene measures in mice that persist afterward (Wells et al, 2017), suggesting that PNN alterations may be influenced by circadian rhythm disruption.…”

Interplay between perivascular and perineuronal extracellular matrix remodelling in neurological and psychiatric diseases

“…However, recent data suggest the importance of ECM remodelling in depression. Koskinen, van Mourik, Smit, Spijker, and Riga (2019) investigated the role of ECM changes in a rat model of depression induced by social defeat stress. Two days after stress induction, rats performed worse in an object F I G U R E 3 Schematic presentation of biphasic ECM regulation following vascular damage.…”