The effect of REM-sleep disruption on affective processing: A systematic review of human and animal experimental studies.

Evidence on the importance of rapid-eye-movement sleep (REMS) in processing emotions is accumulating. The focus of this systematic review is the outcomes of experimental REMS deprivation (REMSD), which is the most common method in animal models and human studies on REMSD. This review revealed that variations in the applied REMSD methods were substantial. Animal models used longer deprivation protocols compared with studies in humans, which mostly reported acute deprivation effects after one night. Studies on animal models showed that REMSD causes aggressive behavior, increased pain sensitivity, reduced sexual behavior, and compromised consolidation of fear memories. Animal models also revealed that REMSD during critical developmental periods elicits lasting consequences on affective-related behavior. The few human studies revealed increases in pain sensitivity and suggest stronger consolidation of emotional memories after REMSD. As pharmacological interventions (such as selective serotonin reuptake inhibitors [SSRIs]) may suppress REMS for long periods, there is a clear gap in knowledge regarding the effects and mechanisms of chronic REMS suppression in humans.

Node of Ranvier remodeling in chronic psychosocial stress and anxiety.

Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic social defeat stress on node morphology in the medial prefrontal cortex (mPFC) gray matter, including shortening of paranodes in C57BL/6NCrl stress-resilient and shortening of node gaps in DBA/2NCrl stress-susceptible mice compared to controls. Neuronal activity has been associated with changes in myelin thickness. To investigate whether neuronal activation is a mechanism influencing also node of Ranvier morphology, we used DREADDs to repeatedly activate the ventral hippocampus-to-mPFC pathway. We found reduced anxiety-like behavior and shortened paranodes specifically in stimulated, but not in the nearby non-stimulated axons. Altogether, our data demonstrate (1) nodal remodeling of the mPFC gray matter axons after chronic stress and (2) axon-specific regulation of paranodes in response to repeated neuronal activity in an anxiety-associated pathway. Nodal remodeling may thus contribute to aberrant circuit function associated with anxiety disorders.

Genetic insights into the neurobiology of anxiety.

Anxiety and fear are evolutionarily conserved emotions that increase the likelihood of an organism surviving threatening situations. Anxiety and vigilance states are regulated by neural networks involving multiple brain regions. In anxiety disorders, this intricate regulatory system is disturbed, leading to excessive or prolonged anxiety or fear. Anxiety disorders have both genetic and environmental risk factors. Genetic research has the potential to identify specific genetic variants causally associated with specific phenotypes. In recent decades, genome-wide association studies (GWASs) have revealed variants predisposing to neuropsychiatric disorders, suggesting novel neurobiological pathways in the etiology of these disorders. Here, we review recent human GWASs of anxiety disorders, and genetic studies of anxiety-like behavior in rodent models. These studies are paving the way for a better understanding of the neurobiological mechanisms underlying anxiety disorders.

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

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.

Incubation of depression: ECM assembly and parvalbumin interneurons after stress.

The extracellular space is occupied by a complex network of proteins creating a mesh-like assembly known as the extracellular matrix (ECM). ECM assembles into dense net-like structures, perineuronal nets (PNNs), that envelope cell somas and proximal neurites of predominantly parvalbumin+-(PV+) interneurons. ECM regulates cell-to-cell communication, thereby modulating neuronal network function. Accumulating evidence points to the importance of network dysfunction in the pathophysiology of psychiatric diseases, in which stress acts as a major predisposing factor. Here we review stress-induced changes in ECM/PNNs and PV+-interneurons in preclinical models of (or for) depression, with a special focus on social stress. We argue that the direction of these alterations largely depends on stress recency, as well as on stress timing and the brain region under investigation. A biphasic temporal regulation of ECM/PNNs and PV+-interneuron function is typically observed after stress. Understanding the complex mechanisms underlying ECM organization in relation to stress-induced molecular, cellular and network changes is crucial to further decipher the implications of ECM remodeling in the incubation of depressive symptoms.